linagliptin and Diabetes-Mellitus--Type-2

Treatment of diabetes mellitus includes more than one drug of different groups, which may lead to a high pill burden and non-adherence to drugs. We have aimed to systematically analyze the clinical efficacy, safety, and pharmacoeconomic cost-effectiveness of the fixed-dose combination of empagliflozin plus a linagliptin in Type-2 Diabetes mellitus (T2DM) patients.. A literature search of PubMed/MEDLINE, SCOPUS, Google Scholar, and EMBASE was performed using the MeSH terms and/or keywords"((Single-pill combination) OR ((Fixeddose combination) OR (Combination therapy)) AND (Empagliflozin add on-to Linagliptin) OR (Empagliflozin combined with Linagliptin) OR ((Combination of Empagliflozin and Linagliptin)" from the inception to February 2021.. Search results were found in a total of 13 clinical studies. After removing duplicates and studies not according to inclusion criteria, a total of eight clinical studies (Randomized controlled trials: 7; Observational cohort studies: 1) were included (n=7491). A significant reduction in the primary endpoint, the mean changes in baseline HbA1c at the end of 24 weeks and/or 52 weeks was found in the empagliflozin plus a linagliptin combination group in all included studies. In addition, significant efficacy was seen in decreasing the secondary endpoints such as the mean change in the fasting plasma glucose, systolic and diastolic blood pressure (DBP), and body weight with fewer adverse events than the adverse effects with either drug alone.. After reviewing findings from the available clinical studies of the combination of empagliflozin plus linagliptin, we conclude that the combination is effective, safe, tolerable, and rationale cost effective compared to placebo and either drug alone for the management of T2DM in patients with inadequate glycemic control with metformin alone, patients with intolerance to metformin, increased baseline HbA1c, patients with overweight or obesity and diabetic hypertensive, CHF, atherosclerotic cardiovascular disease, and renal dysfunction patients. Future randomized controlled trials in a larger number of T2DM patients with or without CHF and renal failure patients are recommended.

Topics: Benzhydryl Compounds; Blood Glucose; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Glucosides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Linagliptin; Metformin; Observational Studies as Topic; Randomized Controlled Trials as Topic; Treatment Outcome

Safety and tolerability of glucose-lowering drugs is a key consideration for use in type 2 diabetes (T2D). We evaluated the safety and tolerability of the dipeptidyl peptidase-4 inhibitor linagliptin in Asian patients with T2D.. This was a post-hoc, descriptive pooled analysis of 21 randomized, double-blind, placebo-controlled clinical trials of linagliptin in T2D patients lasting ≤52 weeks. We evaluated adverse events (AEs) and laboratory parameters in Asian participants living in Asia, both overall and in the East Asian subgroup.. This analysis included 4457 Asian patients overall (2712 receiving linagliptin; 1745 receiving placebo) and 3057 (68.6%) East Asians. AEs were reported in 1510 (55.7%) Asian patients receiving linagliptin and 1032 (59.1%) receiving placebo but were considered drug-related in only 13.0% of each group. Serious AEs occurred in 109 (4.0%) linagliptin patients and 90 (5.2%) placebo patients. The most common AEs were nasopharyngitis (6.4% linagliptin, 7.3% placebo), upper respiratory tract infection (5.7% linagliptin, 6.5% placebo), and hypoglycemia (7.3% linagliptin, 6.3% placebo). One linagliptin patient had pancreatitis; none had bullous pemphigoid. No clinically relevant mean changes in laboratory parameters occurred. These findings were consistent in East Asians.. Linagliptin is well tolerated in Asian T2D patients, including East Asians, with low risk for AEs.

Topics: Asian People; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Linagliptin; Randomized Controlled Trials as Topic; Treatment Outcome

Type 2 diabetes is more common in adults, but is becoming the major concern in children and adolescent recently. This study aimed to provide additional pharmaceutical management for children and adolescents with type 2 diabetes by assessing the efficacy and safety of several glucose-lowering drugs.. Searches were performed in PubMed, Medline, Ovid, Cochrane Controlled Register of Trials (CENTRAL), and ClinicalTrials.gov that reported the efficacy and safety of drugs for children and adolescents with type 2 diabetes. Pooled effects were calculated by frequentist fixed effects network meta-analyses and additive network meta-analyses.. A total of 12 trials assessing eight glucose-lowering drugs were included, which compose of seven trials with monotherapy and five trials with combination therapies. Network meta-analysis results showed compared to placebo, saxagliptin+metformin (mean difference (MD) -1.91% [-2.85%, -0.97%]), liraglutide+metformin (MD -1.45% [-1.65%, -1.26%]), and liraglutide (MD -0.90% [-1.35%, -0.45%]) were the top 3 drugs that significantly reduced hemoglobin A1c (HbA1c). Sitagliptin+metformin, dapagliflozin, exenatide-2mcg, linagliptin-5mg, metformin, exenatide-5/10mcg, glimepiride, and sitagliptin also showed significant reduction in HbA1c. There were no significant differences between treatments in the incidence of adverse events, except that liraglutide+metformin had significant adverse effect such as abdominal pain. In addition, dapagliflozin, sitagliptin+metformin, and saxagliptin+metformin showed better efficacy compared with FDA-approved drugs.. The top 10 treatments of type 2 diabetes in children and adolescents aged 10-17 years were saxagliptin+metformin, liraglutide+metformin, liraglutide, dapagliflozin, exenatide-2 mcg, sitagliptin+metformin, linagliptin-5 mg, linagliptin-1 mg, metformin, and exenatide-5/10 mcg.. https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=284897, identifier CRD42021284897.

Topics: Adolescent; Adult; Child; Diabetes Mellitus, Type 2; Exenatide; Glucose; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Linagliptin; Liraglutide; Metformin; Network Meta-Analysis; Sitagliptin Phosphate

The dipeptidyl peptidase-4 inhibitor (DPP-4i) drugs, such as evogliptin, as the second-line drugs for type 2 diabetes mellitus (T2DM) treatment have been reported to facilitate insulin secretion by reducing glucagon and inhibiting glucagon like peptides. With a vague consensus, the advantageous and non-inferior effects of evogliptin relative to other DPP-4i drugs were recently demonstrated on hemoglobin A1c (HbA1c) levels and overall adverse events in T2DM patients. Thus, the aim was to evaluate the overall influence of evogliptin on HbA1c levels and the adverse events in T2DM patients compared to sitagliptin and linagliptin.. Complying with PRISMA guidelines, we conducted a systematic literature search in databases and a meta-analysis. Data about HbA1c levels and the adverse events of T2DM patients were collected and analyzed.. From 1,397 studies, we found five matched studies involving 845 subjects (mean age: 54.7 ± 3 years). The meta-analysis revealed that evogliptin was non-inferior to sitagliptin/linagliptin with a mean difference of 0.062 (95% CI: -0.092 to 0.215. I. The study provides preliminary evidence regarding the similarity in the efficacy of evogliptin compared to other DPP-4i drugs, including sitagliptin and linagliptin, for managing HbA1c levels and adverse events.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Linagliptin; Middle Aged; Piperazines; Sitagliptin Phosphate

The present meta-analysis evaluated the efficacy and safety of empagliflozin + linagliptin combination compared with either monotherapy [n=6 randomized controlled trials; 2857 adults with type 2 diabetes (T2DM) on diet + exercise ± metformin; 39.7% women; mean age: 54.6-59.9 years]. The combination of empagliflozin 10 mg + linagliptin 5 mg led to significantly greater reductions in glycated haemoglobin (HbA1c) compared with either drug alone over 24 weeks: weighted mean difference [WMD; -0.72%, 95% confidence interval (CI): -1.04, -0.40], and fasting plasma glucose (-1.60 mmol/L 95% CI: -2.21, -1.00). Similar results were observed when empagliflozin 25 mg + linagliptin 5 mg was compared with linagliptin 5 mg monotherapy or with empagliflozin 10 or 25 mg monotherapy. Patients with T2DM treated with the drug combination had more than three times higher likelihood of achieving HbA1c <7% than those on either monotherapy. Weight reduction was significantly greater in the combination group only when compared with linagliptin monotherapy. Safety profile was similar between combination treatment and monotherapies. Overall, the empagliflozin + linagliptin combination had superior efficacy and similar safety in achieving euglycaemia compared with either monotherapy. This combination, administered once daily, has the potential to reduce regimen complexity, enhance adherence and improve outcomes in clinical practice.

Topics: Adult; Benzhydryl Compounds; Blood Glucose; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glucosides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Linagliptin; Male; Metformin; Middle Aged; Treatment Outcome

The fixed-dose combination of empagliflozin and linagliptin, two glucose-lowering drugs prescribed for type 2 diabetes mellitus, has demonstrated good tolerability in phase III clinical trials. To further evaluate the safety profile of this combination, the data from these trials were pooled and analyzed.. This was a post-hoc pooled analysis of five randomized, double-blind, clinical trials of the empagliflozin/linagliptin fixed-dose combination. Data for adverse events and laboratory parameters were evaluated.. The analysis included 2895 patients: 1410, 1015, and 470 receiving the empagliflozin/linagliptin combination, empagliflozin monotherapy, and linagliptin monotherapy, respectively. Overall, the incidence of adverse events with the empagliflozin/linagliptin combination was similar to that with empagliflozin or linagliptin alone. Fewer than 2% of patients experienced hypoglycemia, and its incidence was similar across treatment groups. Genital infections occurred in more patients receiving empagliflozin/linagliptin (3.0%) or empagliflozin monotherapy (5.1%) than in those receiving linagliptin monotherapy (1.9%). No cases of Fournier's gangrene, diabetic ketoacidosis, or pemphigoid occurred, and no clinically relevant mean changes in laboratory parameters were noted.. The safety profile of the fixed-dose combination of empagliflozin and linagliptin was similar to the individual monotherapies. No new safety signals were identified.

Topics: Benzhydryl Compounds; Diabetes Mellitus, Type 2; Drug Combinations; Glucosides; Humans; Hypoglycemia; Hypoglycemic Agents; Linagliptin; Randomized Controlled Trials as Topic; Sodium-Glucose Transporter 2 Inhibitors

There have been a number of case reports and small clinical series reporting the potential association between dipeptidyl peptidase-4 inhibitors (DPPIs) for diabetes and the onset of bullous pemphigoid (BP). The aim of this study was to assess the association between DPPI use and BP, and whether this varied according to DPPI type.. We performed a systematic review and meta-analysis according to PRISMA guidelines. We identified five studies with cases and controls. We performed unadjusted and adjusted meta-analyses to assess the potential association.. Limitations were that studies reviewed were retrospective by design which are susceptible to bias and lack of randomisation. Our adjusted analysis supports a significant association between DPPI use and onset of bullous pemphigoid. Vildagliptin had the highest odds of BP. These findings have clinical implications for dermatologists and the management of patients with diabetes and being treated with DPPI agents.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Linagliptin; Pemphigoid, Bullous; Sitagliptin Phosphate; Vildagliptin

The continuously increasing incidence of diabetes worldwide has attracted the attention of the scientific community and driven the development of a novel class of antidiabetic drugs that can be safely and effectively used in diabetic patients. Of particular interest in this context are complications associated with diabetes, such as renal impairment, which is the main cause of high cardiovascular morbidity and mortality in diabetic patients. Intensive control of glucose levels and other risk factors associated with diabetes and metabolic syndrome provides the foundations for both preventing and treating diabetic nephropathy. Dipeptidyl peptidase-4 (DPP-4) inhibitors represent a highly promising novel class of oral agents used in the treatment of type 2 diabetes mellitus that may be successfully combined with currently available antidiabetic therapeutics in order to achieve blood glucose goals. Beyond glycemic control, emerging evidence suggests that DPP-4 inhibitors may have desirable off-target effects, including renoprotection. All type 2 diabetes mellitus patients with impaired renal function require dose adjustment of any DPP-4 inhibitor administered except for linagliptin, for which renal excretion is a minor elimination pathway. Thus, linagliptin is the drug most frequently chosen to treat type 2 diabetes mellitus patients with renal failure.

Topics: Blood Glucose; Diabetes Complications; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Incretins; Linagliptin; Renal Insufficiency

Dipeptidyl peptidase-4 inhibitors are a relatively new class of oral anti-hyperglycaemic drugs to treat type 2 diabetes through prevention of degradation of incretins by the dipeptidyl peptidase-4 enzyme. The large trials evaluating the dipeptidyl peptidase-4 inhibitors sitagliptin, alogliptin and saxagliptin demonstrated safety for cardiovascular disease. Post hoc analyses on renal endpoints yielded similar findings. Linagliptin is the latest dipeptidyl peptidase-4 inhibitor evaluated in the CARMELINA trial. CARMELINA included individuals with type 2 diabetes and high cardiovascular and renal risk. Even in this setting, linagliptin displayed cardiovascular safety. CARMELINA also removed initial concerns for heart failure as a class-specific side-effect of dipeptidyl peptidase-4 inhibitors, as no signal for heart failure was found. Although numerically low, CARMELINA did confirm increased rates of pancreatitis in the linagliptin group, suggesting that pancreatitis is a class-specific side-effect of dipeptidyl peptidase-4 inhibitors. Linagliptin reduced progression of albuminuria, but had no effect on other hard renal endpoints. Overall, dipeptidyl peptidase-4 inhibitors are safe but do not confer significant reductions in complications observed for some of the other new glucose-lowering drugs. However, linagliptin is a safe alternative in renal impairment, without dose adjustment. Furthermore, dipeptidyl peptidase-4 inhibitors may hold value as alternatives to sulfonyl-urea derivatives or as an add-on therapy to delay insulin prescription given their favourable safety profile.

Topics: Animals; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Health Status; Humans; Kidney Diseases; Linagliptin; Patient Selection; Risk Factors; Treatment Outcome

Diabetes is a fast growing chronic metabolic disorder around the world. Dipeptidyl peptidase-4 (DPP-4) is a new promising target during type 2 diabetes glycemic control. Thus, a number of potent DPP-4 inhibitors were developed and play a rapidly evolving role in the management of type 2 diabetes in recent years. This article reviews the development of synthetic and natural DPP-4 inhibitors from 2012 to 2017 and provides their physico-chemical properties, biological activities against DPP-4 and selectivity over dipeptidyl peptidase-8/9. Moreover, the glucose-lowering mechanisms and the active site of DPP-4 are also discussed. We also discuss strategies and structure-activity relationships for identifying potent DPP-4 inhibitors, which will provide useful information for developing potent DPP-4 drugs as type 2 diabtes treatments.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Molecular Docking Simulation; Structure-Activity Relationship

Type 2 diabetes mellitus has become a growing epidemic and therefore efficient treatment strategies that target its management are needed. The treatment of diabetic patients often requires the combination of antidiabetic drug classes. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) block glucose reabsorption in the proximal renal tubules. Dipeptidyl peptidase-4 inhibitors (DPP-4i) improve glucose metabolism by blocking the enzyme that degrades incretins leading to increased insulin secretion. Areas covered: The aim of the review is to present the available data on pharmacokinetic properties/pharmacodynamics, metabolic and cardiovascular effects of empagliflozin plus linagliptin combination. Expert opinion: Both empagliflozin and linagliptin have established safety and efficacy in the treatment of diabetes. Available data demonstrate the absence of pharmacological interactions when the two drugs are given together. The complementary mechanisms of action would be expected to provide additive benefits on carbohydrate metabolism variables, but the results from clinical trials have shown that the empagliflozin/linagliptin combination provides only mild improvements of glycated hemoglobin compared with either monotherapy. However, the single-tablet formulation of empagliflozin/linagliptin is expected to provide better compliance and thus improved glycaemic control coupled with a favourable safety profile. Thus, the fixed-dose combination of empagliflozin/linagliptin has the capacity to both effectively and safely manage diabetic patients.

Topics: Benzhydryl Compounds; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Combinations; Glucosides; Humans; Hypoglycemic Agents; Linagliptin; Medication Adherence; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Tablets

Emerging evidence suggests that dipeptidyl peptidase-4 (DPP-4) inhibitors used to treat type 2 diabetes may have nephroprotective effects beyond the reduced renal risk conferred by glycemic control. DPP-4 is a ubiquitous protein with exopeptidase activity that exists in cell membrane-bound and soluble forms. The kidneys contain the highest levels of DPP-4, which is increased in diabetic nephropathy. DPP-4 inhibitors are a chemically heterogeneous class of drugs with important pharmacological differences. Of the globally marketed DPP-4 inhibitors, linagliptin is of particular interest for diabetic nephropathy as it is the only compound that is not predominantly excreted in the urine. Linagliptin is also the most potent DPP-4 inhibitor, has the highest affinity for this protein, and has the largest volume of distribution; these properties allow linagliptin to penetrate kidney tissue and tightly bind resident DPP-4. In animal models of kidney disease, linagliptin elicited multiple renoprotective effects, including reducing albuminuria, glomerulosclerosis, and tubulointerstitial fibrosis, independent of changes in glucagon-like peptide-1 (GLP-1) and glucose levels. At the molecular level, linagliptin prevented the pro-fibrotic endothelial-to-mesenchymal transition by disrupting the interaction between membrane-bound DPP-4 and integrin β1 that enhances signaling by transforming growth factor-β1 and vascular endothelial growth factor receptor-1. Linagliptin also increased stromal cell derived factor-1 levels, ameliorated endothelial dysfunction, and displayed unique antioxidant effects. Although the nephroprotective effects of linagliptin are yet to be translated to the clinical setting, the ongoing Cardiovascular and Renal Microvascular Outcome Study with Linagliptin in Patients with Type 2 Diabetes Mellitus (CARMELINA®) study will definitively assess the renal effects of this DPP-4 inhibitor. CARMELINA® is the only clinical trial of a DPP-4 inhibitor powered to evaluate kidney outcomes.

Topics: Animals; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Linagliptin

Multiple population based analyses have demonstrated a high incidence of cardiovascular disease (CVD) and cardiovascular (CV) mortality in subjects with T2DM that reduces life expectancy by as much as 15 years. Importantly, the CV system is particularly sensitive to the metabolic and immune derangements present in obese pre-diabetic and diabetic individuals; consequently, CV dysfunction is often the initial CV derangement to occur and promotes the progression to end organ/tissue damage in T2DM. Specifically, diabetic CVD can manifest as microvascular complications, such as nephropathy, retinopathy, and neuropathy, as well as, macrovascular impairments, including ischemic heart disease, peripheral vascular disease, and cerebrovascular disease. Despite some progress in prevention and treatment of CVD, mainly via blood pressure and dyslipidemia control strategies, the impact of metabolic disease on CV outcomes is still a major challenge and persists in proportion to the epidemics of obesity and diabetes. There is abundant pre-clinical and clinical evidence implicating the DPP-4-incretin axis in CVD. In this regard, linagliptin is a unique DPP-4 inhibitor with both CV and renal safety profiles. Moreover, it exerts beneficial CV effects beyond glycemic control and beyond class effects. Linagliptin is protective for both macrovascular and microvascular complications of diabetes in preclinical models, as well as clinical models. Given the role of endothelial-immune cell interactions as one of the key events in the initiation and progression of CVD, linagliptin modulates these cell-cell interactions by affecting two important pathways involving stimulation of NO signaling and potent inhibition of a key immunoregulatory molecule.

Topics: Animals; Cardiovascular Diseases; Comorbidity; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Humans; Linagliptin; Risk Factors; Signal Transduction; Time Factors; Treatment Outcome

Bullous pemphigoid (BP) is a common autoimmune blistering disease in which autoantibodies mainly target the hemidesmosomal component BP180 (also known as type XVII collagen) in basal keratinocytes. Various triggering factors are known to induce BP onset, including radiotherapy, burns, ultraviolet exposure, surgery, and the use of dipeptidyl peptidase-IV inhibitors (DPP4i), which are widely used antihyperglycemic drugs. Here, we present a case of BP triggered by a thermal burn under medication with DPP4i. A 60-year-old man with type II diabetes had been treated with the DPP4i linagliptin for 1 year. After the right forearm experienced a thermal burn, blisters developed around the burned area and gradually spread over the whole body with the production of autoantibodies targeting the non-NC16A domain of BP180. The diagnosis of BP was confirmed by immunohistopathological examination. Upon withdrawal of linagliptin and treatment with topical steroid and minocycline, complete remission was achieved after 4 months. Previously, 13 cases of BP that developed after thermal burns have been reported, and our case shared some of the clinical features of these thermal burn-induced BP cases. Interestingly, the present case also showed the typical clinical, histopathological, and immunological features of the non-inflammatory type of DPP4i-associated BP (DPP4i-BP). Although the pathogenesis of BP remains uncertain, the present case suggests that DPP4i may trigger the onset of BP similarly to a thermal burn. In addition, the clinical and histopathological features of DPP4i-BP may be distinct from other types of BP.

Topics: Burns; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Humans; Linagliptin; Male; Middle Aged; Pemphigoid, Bullous

To describe the safety profile of linagliptin.. Systematic review using PubMed/MEDLINE, BVS and Web of Science. The search strategy "Linagliptin" AND "safety" was used. The inclusion criteria were clinical trials with a control group composed of conventional DM2 pharmacotherapy.. We identified 16 studies, and the most frequent adverse events (AEs) were nasopharyngitis with linagliptin at 5 and 10mg in monotherapy (31.6% and 29.6%, respectively) and gastrointestinal events (>10.0%) with linagliptin in combination. Of the AEs, 14.9 (±3.1)% were associated with the use of linagliptin in monotherapy, and 17.6 (±6.0)% in combination. The linagliptin AEs have a varied occurrence and frequency, ranging from mild to moderate intensity.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Linagliptin; Male; Middle Aged; Patient Safety; Risk Factors; Treatment Outcome; Young Adult

To investigate the risk of hypoglycaemia in people aged ≥65 years with type 2 diabetes mellitus (T2DM) treated with linagliptin, in the largest pooled analysis performed to date.. One thousand four hundred and eighty-nine patients aged ≥65 years with T2DM were pooled from 11 randomised, double-blind, parallel group, placebo-controlled trials evaluating linagliptin 5 mg alone, or in addition to various background therapies. The primary safety endpoint was the incidence of investigator-defined hypoglycaemia.. There was no significant difference in the risk of hypoglycaemia between linagliptin and placebo in the all-patient population at 24 weeks (hazard ratio [HR] 1.07; 95% confidence interval [CI]: 0.84, 1.36; P = 0.5943)-despite significant (P < 0.0001) improvements in glycaemic control-and 1 year (HR 1.02; 95% CI: 0.81, 1.27; P = 0.8803). Similar findings were observed for linagliptin vs placebo in subgroup analyses by background medication (eg, sulphonylureas (SUs) and/or insulin vs no such drugs), age, baseline glycated haemoglobin (HbA1c), ethnicity, and baseline estimated glomerular filtration rate. Patients with a baseline HbA1c ≥7.5% had significantly higher odds of achieving HbA1c <7.5% without hypoglycaemia in the linagliptin group compared with placebo at 24 weeks (34.1% vs 13.7%; 95% CI: 2.04, 4.12; P < 0.0001).. This pooled analysis indicates that linagliptin was effective in treating older people with T2DM towards their HbA1c targets with a favourable safety and tolerability profile and low risk of hypoglycaemia. The safety profile was maintained even on background therapies with known risk of hypoglycaemia, such as insulin and SU.

Topics: Aged; Aged, 80 and over; Blood Glucose; Diabetes Mellitus, Type 2; Glomerular Filtration Rate; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Incidence; Insulin; Linagliptin; Randomized Controlled Trials as Topic; Risk Factors; Sulfonylurea Compounds

Type 2 diabetes mellitus is a progressive disease with multiple underlying pathophysiologic defects. Monotherapy alone cannot maintain glycemic control and leads to treatment failure. Ideally, a combination of glucose-lowering agents should have complementary mechanisms of action that address multiple pathophysiologic pathways, can be used at all stages of the disease, and be generally well tolerated with no increased risk of hypoglycemia, cardiovascular events, or weight gain. The combination should also provide conveniences for patients, such as oral dosing, single-pill formulations, and once-daily administration, potentially translating to improved adherence. Two classes of glucose-lowering agents that meet these criteria are the sodium glucose cotransporter-2 (SGLT2) inhibitors and dipeptidyl peptidase-4 (DPP-4) inhibitors. This article reviews the rationale for combination therapy with these agents, and evidence from clinical trials with empagliflozin and linagliptin or dapagliflozin and saxagliptin in the management of type 2 diabetes mellitus. Both combinations have been approved as single-pill formulations.

Topics: Adamantane; Benzhydryl Compounds; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Drug Combinations; Glucosides; Humans; Hypoglycemic Agents; Linagliptin; Sodium-Glucose Transporter 2 Inhibitors

This article reviews evidence supporting sodium glucose cotransporter 2 (SGLT2) inhibitor and dipeptidyl peptidase-4 (DPP-4) inhibitor combination therapy for management of type 2 diabetes mellitus (T2DM).. We conducted a nonsystematic review of the literature focusing on single-pill or fixed-dose combinations of SGLT2 inhibitors and DPP-4 inhibitors available in the United States.. SGLT2 inhibitors and DPP-4 inhibitors have complementary mechanisms of action that address several of the underlying pathophysiologic abnormalities present in T2DM without overlapping toxicities. The combination of these 2 agents has several advantages including a low risk of hypoglycemia, the potential for weight loss, the ability to coformulate into a pill with once-daily administration, and the possibility to use with other classes of glucose-lowering agents. Cardiovascular outcomes trials reported to date support the safety of the DPP-4 class and suggest possible cardioprotective effects for SGLT2 inhibitors - at least based on the first reported study that used empagliflozin. Recent clinical evidence shows that SGLT2 inhibitor/DPP-4 inhibitor therapy is an effective combination for T2DM treatment, providing glycated hemoglobin (HbA1c) reductions of 1.1 to 1.5%, and weight reductions of approximately 2 kg when added to metformin, which is its primary place in therapy.. The combination of an SGLT2 inhibitor/DPP-4 inhibitor is a safe and effective treatment choice for patients with T2DM who are unable to obtain adequate glycemic control with metformin therapy, cannot use metformin, or have a higher baseline HbA1c.. BP = blood pressure; CI = confidence interval; CVOT = cardiovascular outcomes; DKA = diabetic ketoacidosis; DPP-4 = dipeptidyl peptidase-4; EXAMINE = EXamination of cArdiovascular outcoMes with alogliptiN versus standard of carE in patients with type 2 diabetes mellitus and acute coronary syndrome; FDA = Food and Drug Administration; HbA1c = glycated hemoglobin; HR = hazard ratio; MACE = major adverse cardiovascular events; SAVOR-TIMI 53 = Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Type 2 Diabetes Mellitus; SBP = systolic blood pressure; SGLT2 = sodium glucose cotransporter 2; TECOS = Trial to Evaluate Cardiovascular Outcomes after Treatment with Sitagliptin; T2DM = type 2 diabetes mellitus; XR = extended release.

Topics: Adamantane; Benzhydryl Compounds; Blood Glucose; Canagliflozin; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Glucosides; Humans; Hypoglycemia; Hypoglycemic Agents; Linagliptin; Metformin; Piperidines; Sitagliptin Phosphate; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome; Uracil

Dipeptidyl-peptidase-IV inhibitors (DPP-4i) and sodium-glucose-transporter-2 inhibitors (SGLT-2i) are oral antidiabetic drugs that improve glycemic parameters and possess a very low intrinsic hypoglycemia risk and favorable cardiovascular data. Areas covered: An overview on the clinical studies investigating the combination therapy with the DPP-4i linagliptin and the SGLT-2i empagliflozin is given. The clinical evidence for the efficacy and safety of free combinations as well as for their fixed dose combinations is presented. Empagliflozin has recently proved to reduce cardiovascular risk in type 2 diabetes and cardiovascular high risk situations. A fixed dose combination (FDC) of empagliflozin and linagliptin as add on therapy to metformin or as initial treatment lowered the HbA1c by approximately 1.1% and reduced the body weight by 2.0-3.0 kg. The hypoglycemia risk was not significantly increased. The relevant studies were identified by a search in Medline and in clinicaltrials.gov. Expert opinion/commentary: A DPP-4i/SGLT-2i FDC may be especially useful to simplify treatment, to reduce the tablet burden and to increase medication adherence. This FDC may be particularly beneficial for patients where the reduction of body weight, blood pressure and cardiovascular risk are important and in whom hypoglycemia should be avoided.

Topics: Benzhydryl Compounds; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Combinations; Drug Therapy, Combination; Glucosides; Humans; Hypoglycemic Agents; Linagliptin; Medication Adherence; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors

Diabetes is one of the most common chronic and costly diseases worldwide and type 2 diabetes is the most common type which accounts for about 90% of cases with diabetes. New medication-therapy regimens such as those containing linagliptin alone or in combination with other medications (within the category of DDP-4 inhibitors) must be evaluated in terms of efficacy and compared with other currently used drugs and then enter the medication list of the country. Hence, this study aimed to compare the clinical efficacy of the two drugs, i.e. linagliptin and sitagliptin, in patients with type 2 diabetes.. A systematic review was conducted to identify all clinical trials published by 2015 which compared the two drugs in patients with type 2 diabetes. Using keywords such as "linagliptin", "type 2 diabetes mellitus", "sitagliptin" and related combinations, we searched databases including Scopus, PubMed, and Web of Science. The quality of the selected studies was evaluated using the Jadad score. Considering primary and secondary outcomes extracted from the reviewed studies, a network meta-analysis was used to conduct a systematic comparison between the two studied drugs.. This network meta-analysis included 32 studies (Linagliptin vs PLB: n = 8, Sitagliptin vs PLB: n = 13, Linagliptin + MET vs PLB + MET: n = 4, and Sitagliptin + MET vs PLB + MET: n = 7) and a total of 13,747 patients. The results showed no significant difference between linagliptin and sitagliptin in terms of key efficacy and safety outcomes such as HbA1c changes from baseline, body weight change from baseline, percentage of patients achieving HbA1c <7, and percentage of patients experiencing hypoglycemic events (p > 0.05). The results showed that the efficacy of the two drug regimens was the same.. Based on the results, there was no significant difference between the two drugs, i.e. linagliptin and sitagliptin, in terms of efficacy; in other words, the efficacy of the two drugs was the same. Therefore, the use of these two drugs depends on their availability and cost. Graphical abstract of the network meta-analysis performed to evaluate the alternatives under the study.

Topics: Aged; Aged, 80 and over; Body Weight; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Linagliptin; Male; Middle Aged; Network Meta-Analysis; Sitagliptin Phosphate; Treatment Outcome

Our aims were to summarize the clinical pharmacokinetics and pharmacodynamics of the dipeptidyl-peptidase-4 inhibitor, linagliptin, and to consider how these characteristics influence its clinical utility. Differences between linagliptin and other dipeptidyl-peptidase-4 inhibitors were also considered, in addition to the influence of Asian race on the pharmacology of linagliptin. Linagliptin has a xanthine-based structure, a difference that might account for some of the pharmacological differences observed with linagliptin versus other dipeptidyl-peptidase-4 inhibitors. The long terminal half-life of linagliptin results from its strong binding to dipeptidyl-peptidase-4. Despite this, linagliptin shows a short accumulation half-life, as a result of saturable, high-affinity binding to dipeptidyl-peptidase-4. The pharmacokinetic characteristics of linagliptin make it suitable for once-daily dosing in a broad range of patients with type 2 diabetes mellitus. Unlike most other dipeptidyl-peptidase-4 inhibitors, linagliptin has a largely non-renal excretion route, and dose adjustment is not required in patients with renal impairment. Furthermore, linagliptin exposure is not substantially altered in patients with hepatic impairment, and dose adjustment is not necessary for these patients. The 5-mg dose is also suitable for patients of Asian ethnicity. Linagliptin shows unique pharmacological features within the dipeptidyl-peptidase-4 inhibitor class. Although most clinical trials of linagliptin have involved largely Caucasian populations, data on the pharmacokinetic/pharmacodynamic properties of linagliptin show that these features are not substantially altered in Asian populations. The 5-mg dose of linagliptin is suitable for patients with type 2 diabetes mellitus irrespective of their ethnicity or the presence of renal or hepatic impairment.

Topics: Administration, Oral; Asian People; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Linagliptin

Type 2 diabetes (T2D) generally requires a combination of several pharmacological approaches to control hyperglycaemia. Combining a sodium-glucose cotransporter type 2 inhibitor (SGLT2I, also known as gliflozin) and a dipeptidyl peptidase-4 inhibitor (DPP-4I, also known as gliptin) appears to be an attractive strategy because of complementary modes of action. This narrative review analyzes the pharmacokinetics and clinical efficacy of different combined therapies with an SGLT2I (canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, tofogliflozin) and DPP-4I (linagliptin, saxagliptin, sitagliptin, teneligliptin). Drug-drug pharmacokinetic interaction studies do not show any significant changes in peak concentrations (C

Topics: Adamantane; Benzhydryl Compounds; Canagliflozin; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Glucosides; Humans; Linagliptin; Sitagliptin Phosphate; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

Cardiovascular disease (CVD) is the greatest burden of type 2 diabetes mellitus (T2DM) in terms of morbility, mortality and costs for individuals and societies. Therefore, its prevention is a major goal in diabetes care. Optimal treatment of hyperglycemia is certainly instrumental to CVD prevention. Optimal treatment means both establishing the most appropriate glycemic target for the given individual and selecting the medication(s) with the most favourable benefit/safety ratio. CVD safety, if not a clear CVD benefit, is certainly required for all antidiabetic agents. Dipeptidyl-peptidase-4 (DPP-4) inhibitors are among the classes of antidiabetic agents most recently made available for diabetes care. A major question to be addressed is the effect of these compounds on CVD. Expectations were high for their mechanism of action, which targets also post-prandial glucose and minimize hypoglycemia risk, thereby providing a sort of global glucose control, and for some potentially beneficial extra-glycemic effects. This article reviews the existing literature on this issue.. Data published so far document that DPP-4 inhibitors have a wide spectrum of glycemic and extra-glycemic effects potentially reducing the risk of CVD as well as favourable effects on intermediate or surrogate CVD endpoints. These data heralded a better CVD outcome. Accordingly, pooling CVD safety data from phase 3 and 4 studies conducted with DPP-4 inhibitors suggested that their use might translate into a better CVD outcome. Data from three CVD outcome RCTs with alogliptin, saxagliptin and sitagliptin documented no harm but did not show any benefit on major CVD events. A modest but significant increased risk of hospitalization for heart failure was observed with saxagliptin and with alogliptin (only in subjects with no history of heart failure before randomization) but not with sitagliptin. A study currently in progress with linagliptin will provide further insights in the issue of CVD safety and benefit.. It should be considered that most alternative oral antidiabetic agents generally do not possess a better CVD risk profile than DPP-4 inhibitors and that some of them, indeed, should be used with caution because of potentially adverse effects on heart and vasculature. Overall, the selection of antidiabetic agent(s) with the most favourable CVD profile is mandatory but still challenging in diabetes care.

Topics: Cardiovascular Diseases; Clinical Trials, Phase III as Topic; Clinical Trials, Phase IV as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Endpoint Determination; Humans; Hypoglycemic Agents; Linagliptin; Meta-Analysis as Topic; Observational Studies as Topic; Piperidines; Randomized Controlled Trials as Topic; Risk Factors; Sitagliptin Phosphate; Uracil

To evaluate the efficacy and safety of the dipeptidyl peptidase (DPP)-4 inhibitor linagliptin in Asian patients with type 2 diabetes mellitus (T2DM), a rapidly increasing population.. Data were pooled for Asian patients receiving linagliptin orally once daily, as monotherapy or added to existing oral antidiabetes therapies, in multinational randomized placebo-controlled clinical trials. Efficacy data were taken from four pivotal trials with 24-week durations to allow for robust efficacy assessment. Safety data were pooled from a wider group of 10 trials with varying durations to capture the largest possible incidence of adverse events (AEs). The primary efficacy endpoint was change from baseline to week 24 in HbA1c. AEs were analyzed descriptively.. Mean baseline HbA1c (±SD) in this population was 8.2 ± 0.9%. Placebo-corrected mean change in HbA1c after 24 weeks was -0.79% (95% confidence interval [CI]: -0.92 to -0.67; p < 0.0001). Placebo-corrected mean change in fasting plasma glucose was -17.8 ± 2.4 mg/dL (95% CI: -22.6, -13.0; p < 0.0001). In a small subgroup, mean post-prandial glucose was reduced by a placebo-corrected -56.9 ± 14.0 mg/dL (95% CI: -85.2, -28.5). AEs occurred in 58.0% of linagliptin patients (serious AEs in 2.4%) and 58.2% of placebo patients (serious AEs in 3.0%).. This study was limited by the post hoc nature of the analysis, and because the pooling did not differentiate between geographically distant Asian regions. Nonetheless, this analysis provides evidence that linagliptin was efficacious and well tolerated as monotherapy or added to other oral antidiabetes therapies in Asian patients with T2DM.

Topics: Adult; Aged; Asian People; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Linagliptin; Male; Middle Aged; Purines; Quinazolines; Treatment Outcome

Established treatments for type 2 diabetes mellitus (T2DM) have side effects that limit their use in specific populations. New therapies with improved safety profiles are needed, especially because of the chronic and progressive nature of T2DM.. This review describes the overall safety and tolerability of linagliptin--a dipeptidyl peptidase-4 inhibitor that improves glycemic control without increasing risk for hypoglycemia and without weight gain. Specifically, the safety of linagliptin is evaluated in difficult-to-treat patients with T2DM, in relation to risk of cardiovascular (CV) events and acute pancreatitis, and in comparison with other antihyperglycemic drugs.. Linagliptin is generally well tolerated in a broad range of patient populations. It can be used in patients with renal impairment without dose titration and may be a rational alternative treatment in this vulnerable population. Ongoing long-term trials are fully evaluating the CV and renal safety profile of linagliptin.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Linagliptin; Purines; Quinazolines

Treatment of type 2 diabetes mellitus invariably requires the use of multiple daily medications which can impact negatively on patient adherence. As a result, there is growing interest in the use of single-pill combinations that can reduce the pill burden. Many such formulations incorporate metformin, although this agent is not suitable for all patients. The single-pill combination of the dipeptidyl peptidase-4 inhibitor linagliptin with the sodium glucose co-transporter 2 inhibitor empagliflozin offers a new and attractive option, given their complementary mechanisms of action.. Publications with titles containing the keywords 'linagliptin' or 'empagliflozin' were identified from a non-systematic search of PubMed without date restrictions, together with abstracts presented at the annual meetings of the American Diabetes Association and the European Association for the Study of Diabetes 2012-2014. ClinicalTrials.gov was searched for entries containing these two keywords. Additional references known to the author were included.. The efficacy and safety of linagliptin and empagliflozin as monotherapy or in combination with other oral antidiabetic drugs has been established through extensive clinical trial programs. Studies specifically evaluating the efficacy/safety of a dipeptidyl peptidase-4 inhibitor/sodium glucose co-transporter 2 inhibitor in combination are limited, but do include two studies of linagliptin/empagliflozin of up to 52 weeks in duration. These studies show that the single-pill combination of linagliptin and empagliflozin produced clinical improvements in glycemic control that were generally superior to the improvements seen with linagliptin and empagliflozin alone, but with a safety profile comparable to that of the individual constituents.. The single-pill combination of linagliptin and empagliflozin, with their complementary mechanisms of action, is a promising treatment option for patients with type 2 diabetes mellitus. It would reduce the daily pill burden in this population, potentially improving adherence to, and optimizing the benefits of, treatment of diabetes mellitus.

Topics: Benzhydryl Compounds; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Combinations; Glucosides; Humans; Hypoglycemic Agents; Linagliptin; Purines; Quinazolines

The prevalence of type 2 diabetes in black/African Americans from North and South America is high; yet data evaluating antidiabetic agents in this population is scarce. To address this gap, we pooled data from the clinical development program for linagliptin.. A retrospective pooled analysis of eight completed randomized, placebo-controlled Phase III trials of linagliptin identified 336 patients with type 2 diabetes who self-identified their ethnicity as black or African American. Participants received linagliptin (n = 173, 5 mg/day) or placebo (n = 163) as monotherapy, or as add-on to other antidiabetic agents, including insulin. The primary end point was the change in glycated hemoglobin (HbA1c) from baseline to week 18 or 24.. The placebo-adjusted mean change (95% confidence interval [CI]) in HbA1c from baseline was -0.69% (-0.92 to -0.46; p < 0.0001) at week 18 (eight trials), and -0.64% (-0.90 to -0.39; p < 0.0001) at week 24 (six trials). The placebo-adjusted mean change (95% CI) in fasting plasma glucose from baseline was -11.7 mg/dL (-23.1 to -0.3; p = 0.0446) at week 18 and -14.7 mg/dL (-25.7 to -3.8; p = 0.0087) at week 24. Incidence of investigator-defined hypoglycemia was similar between the two groups (linagliptin, 12.1%; placebo, 11.7%). Overall, the safety profile of linagliptin in this patient group was comparable to that of placebo, with comparable incidence of adverse events; linagliptin was weight-neutral in this patient population.. Linagliptin provided clinically significant improvements in glycemic control without increased risk of hypoglycemia and without weight gain, representing a useful type 2 diabetes therapy option for the black/African American population.

Topics: Argentina; Black People; Brazil; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Fasting; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Linagliptin; Male; Mexico; Purines; Quinazolines; Randomized Controlled Trials as Topic; Retrospective Studies; Treatment Outcome; United States

Topics: Animals; Benzhydryl Compounds; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Combinations; Glucosides; Humans; Hypoglycemic Agents; Linagliptin; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors

Although assessment of cardiovascular safety is mandated by regulatory agencies for the development of new drugs to treat type 2 diabetes, evaluation of their renal safety has been relatively neglected.. Individual patient-level data pooled analysis of 13 phase 2 or 3 randomized, double-blind, placebo-controlled, clinical trials of the dipeptidyl peptidase 4 inhibitor linagliptin.. Participants who participated in any of 13 randomized clinical trials and fulfilled predefined inclusion/exclusion criteria, such as being drug-naive (hemoglobin A1c, 7.0%-11.0% [53-97 mmol/mol]) or being on background glucose-lowering therapy (hemoglobin A1c, 6.5%-10.5% [48-91 mmol/mol]).. Of 5,466 consenting individuals with inadequately controlled type 2 diabetes, 3,505 received linagliptin, 5mg/d, and 1,961 received placebo.. The primary kidney disease outcome was defined as first occurrence during the study of 6 predefined safety end points: new onset of moderate elevation of albuminuria (urinary albumin-creatinine ratio [ACR] >30 mg/g with baseline values ≤ 30 mg/g), new onset of severe elevation of albuminuria (ACR > 300 mg/g with baseline values ≤ 300 mg/g), reduction in kidney function (serum creatinine increase to ≥250 μmol/L from a baseline value <250 μmol/L), halving of estimated glomerular filtration rate (loss of baseline eGFR >50%), acute renal failure (ascertained from diagnostic codes), or death from any cause.. Albuminuria was assessed using ACR. GFR was estimated using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation.. Cumulative exposure (person-years) was 1,751 for linagliptin and 1,055 for placebo. The primary composite outcome occurred in 448 (12.8%) and 306 (15.6%) participants in the linagliptin and placebo groups, respectively. Linagliptin treatment significantly reduced the hazard of kidney disease events by 16% compared with placebo (HR, 0.84; 95% CI, 0.72-0.97; P=0.02).. Retrospective and hypothesis-generating study involving short- to midterm clinical trials.. Linagliptin was not associated with increased kidney disease risk in patients with type 2 diabetes. The potential of this drug to improve kidney disease outcomes warrants further investigation.

Topics: Aged; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Hypoglycemic Agents; Linagliptin; Male; Middle Aged; Purines; Quinazolines; Randomized Controlled Trials as Topic; Treatment Outcome

To assess the efficacy, hypoglycaemia risk and other safety markers of linagliptin as an additional therapy in older patients (aged ≥70 years) inadequately controlled with basal insulin.. A prespecified safety analysis from the linagliptin trials programme was carried out to explore the hypoglycaemia risk when linagliptin was added to background basal insulin therapy in elderly patients (≥70 years). To do this, two eligible, randomized, placebo-controlled, clinical trials (NCT00954447 and NCT01084005) of 24 and ≥52 weeks, respectively, were analysed.. A total of 247 elderly individuals [mean ± standard deviation (s.d.) age 74 ± 4 years, glycated haemoglobin (HbA1c) 8.2 ± 0.8%] on basal insulin (mean ± s.d. baseline dose 36 ± 25 IU/day) were identified. Alongside placebo-adjusted change in HbA1c with linagliptin of -0.77% [95% confidence interval (CI) -0.95 to 0.59; p < 0.0001] after 24 weeks, the hazard ratios (HRs) of both overall and confirmed hypoglycaemia [blood glucose ≤3.9 mmol/l (70 mg/dl)], were significantly lower with linagliptin than with placebo: HR 0.61 (95% CI 0.39-0.97) versus 0.59 (95% CI 0.37-0.94), respectively (both p < 0.05). Moreover, significantly less confirmed hypoglycaemia was present in linagliptin-treated patients with renal impairment [HR 0.45 (95% CI 0.27-0.76)], moderate hyperglycaemia [HbA1c 7.5 to <9.0%; HR 0.51 (95% CI 0.27-0.99)], lower fasting plasma glucose levels [<152 mg/dl; HR 0.49 (95% CI 0.28-0.86)] and those treated with higher insulin doses [insulin ≥35.6 IU/day; HR 0.46 (95% CI 0.23-0.91); p < 0.05 for all]. Severe hypoglycaemia was rare and the incidence was lower with linagliptin (0.8%) versus placebo (2.5%): HR 0.21 (95% CI 0.02-2.30).. Despite improvements in hyperglycaemia and no relevant on-trial insulin dose reductions, adding linagliptin to basal insulin appears to decrease hypoglycaemia risk. The biological basis of this phenomenon warrants further research but may involve counter-regulatory effects of incretin hormones.

Topics: Aged; Aged, 80 and over; Blood Glucose; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Fasting; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Incidence; Insulin, Long-Acting; Linagliptin; Male; Randomized Controlled Trials as Topic; Treatment Outcome

The cardiovascular (CV) safety of linagliptin was evaluated in subjects with type 2 diabetes (T2DM).. Pre-specified patient-level pooled analysis of all available double-blind, randomized, controlled trials, ≥ 12 weeks' duration (19 trials, 9459 subjects) of linagliptin versus placebo/active treatment. Primary end point: composite of prospectively adjudicated CV death, non-fatal myocardial infarction, non-fatal stroke, and hospitalization for unstable angina (4P-MACE). Hospitalization for congestive heart failure (CHF) was also evaluated; adjudication of CHF was introduced during the phase 3 program (8 trials; 3314 subjects). 4P-MACE was assessed in placebo-controlled trials (subgroup of 18 trials; 7746 subjects). Investigator-reported events suggestive of CHF from 24 placebo-controlled trials (including trials <12 weeks' duration, 8778 subjects) were also analyzed.. 5847 patients received linagliptin (5 mg: 5687, 10 mg: 160) and 3612 comparator (glimepiride: 775, voglibose: 162, placebo: 2675); cumulative exposure, 4421.3 and 3254.7 patient-years, respectively. 4P-MACE incidence rates: 13.4 per 1000 patient-years, linagliptin (60 events), 18.9, total comparators (62 events); overall hazard ratio (HR), 0.78 (95% confidence interval [CI], 0.55-1.12). HR for adjudicated hospitalization for CHF (n = 21): 1.04 (0.43-2.47). For placebo-controlled trials, 4P-MACE incidence rates: 14.9 per 1000 patient-years, linagliptin (43 events), 16.4, total comparators (29 events); overall HR, 1.09 (95% CI, 0.68-1.75). Occurrence of investigator-reported events suggestive of CHF was low for linagliptin- (26 events, 0.5%; serious: 16 events, 0.3%) and placebo-treated (8 events, 0.2%; serious: 6 events, 0.2%) patients.. Linagliptin is not associated with increased CV risk versus pooled active comparators or placebo in patients with T2DM.

Topics: Aged; Angina, Unstable; Cardiovascular Diseases; Cohort Studies; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Heart Failure; Hospitalization; Humans; Incidence; Linagliptin; Male; Middle Aged; Myocardial Infarction; Proportional Hazards Models; Prospective Studies; Randomized Controlled Trials as Topic; Risk Factors; Stroke

The availability of a dual sodium glucose co-transporter 2/dipeptidyl peptidase-4 inhibitor combination in a single-tablet combination (STC) represents a new therapeutic option for patients with type 2 diabetes. Empagliflozin/linagliptin STC has been recently approved by the US Food and Drug Administration for the treatment of type 2 diabetes mellitus (T2DM).. The aim of this study was to describe the latest clinical evidence on the efficacy and safety profiles of empagliflozin/linagliptin STCs in comparison with the individual components. Juxtaposition of the STC with dapagliflozin/saxagliptin combination was also presented.. Empagliflozin/linagliptin STC given as initial therapy or on metformin background lowered mean glycated haemoglobin (HbA1c) by approximately 1.1% (mean baseline HbA1c, 8.0%). Furthermore, the STC reduced mean body weight by 2.0-3.0 kg from baseline. With the STC treatment, no confirmed incidents of hypoglycaemia were reported in drug-naïve patients; in patients taking metformin hypoglycaemia occurred at low rates which were comparable with monotherapy. Use of STCs in the treatment of T2DM can simplify drug dosing regimen, reduce pill burden and increase treatment adherence. Empagliflozin/linagliptin STC is a combination that offers potential additional benefits such as body weight loss and moderate reductions in blood pressure, without increasing risk of hypoglycaemia.. Empagliflozin/linagliptin STC appears to be a rational choice for a wide range of patients in need of multiple agents for controlling hyperglycaemia. The STC should be particularly useful in patients in whom hypoglycaemia, weight gain and treatment adherence are of concern.

Topics: Benzhydryl Compounds; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Combinations; Glucosides; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Linagliptin; Randomized Controlled Trials as Topic

Empagliflozin/linagliptin (Glyxambi(®)) is a once-daily sodium glucose co-transporter type 2 (SGLT2) inhibitor and dipeptidyl peptidase (DPP)-4 inhibitor fixed-dose combination product that is approved in the USA as an adjunct to diet and exercise in adults with type 2 diabetes (T2D) when treatment with both empagliflozin and linagliptin is appropriate. This article reviews the clinical efficacy and tolerability of oral empagliflozin/linagliptin in patients with T2D and summarizes the pharmacological properties of the agents. Results of two randomized controlled trials of 52 weeks' duration in adults with T2D demonstrated that empagliflozin/linagliptin improved glycaemic control significantly more than linagliptin when administered as initial therapy (whereas results vs. empagliflozin were mixed in this setting) and significantly more than linagliptin or empagliflozin when administered as an add-on therapy to metformin. In addition to glycaemic control, empagliflozin/linagliptin provided significant weight loss compared with linagliptin in both trials. Empagliflozin/linagliptin was generally well tolerated in patients with T2D, with a low risk of hypoglycaemia and no reports of exacerbations of, or hospitalizations for, heart failure during the trials. As the first SGLT2 inhibitor/DPP-4 inhibitor fixed-dose combination available, empagliflozin/linagliptin is a useful new option for patients with T2D.

Topics: Adult; Benzhydryl Compounds; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Combinations; Glucosides; Humans; Hypoglycemia; Hypoglycemic Agents; Linagliptin; Randomized Controlled Trials as Topic; Sodium-Glucose Transporter 2 Inhibitors

Many patients with type 2 diabetes mellitus (T2DM) fail to achieve the desired A1c goal because the antidiabetic medications used do not correct the underlying pathophysiologic abnormalities and monotherapy is not sufficiently potent to reduce the A1c to the 6.5 - 7.0% range. Insulin resistance and islet (beta and alpha) cell dysfunction are major pathophysiologic abnormalities in T2DM. We examine combination therapy with linagliptin plus empagliflozin as a therapeutic approach for the treatment of inadequately controlled T2DM patients.. A literature search of all human diabetes, metabolism and general medicine journals from year 2000 to the present was conducted. Glucagon like peptide-1 (GLP-1) deficiency/resistance contributes to islet cell dysfunction by impairing insulin secretion and increasing glucagon secretion. DPP-4 inhibitors (DPP4i) improve pancreatic islet function by augmenting glucose-dependent insulin secretion and decreasing elevated plasma glucagon levels. Linagliptin, a DPP-4 inhibitor, reduces HbA1c, is weight neutral, has an excellent safety profile and a low risk of hypoglycemia. The expression of sodium-glucose cotransporter-2 (SGLT2) in the proximal renal tubule is upregulated in T2DM, causing excess reabsorption of filtered glucose. The SGLT2 inhibitor (SGLT2i), empagliflozin, improves HbA1c by causing glucosuria and ameliorating glucotoxicity. It also decreases weight and blood pressure, and has a low risk of hypoglycemia.. The once daily oral combination of linagliptin plus empagliflozin does not increase the risk of hypoglycemia and tolerability and discontinuation rates are similar to those with each as monotherapy. At HbA1c values below 8.5% linagliptin/empagliflozin treatment produces an additive effect, whereas above 8.5%, there is a less than additive reduction with combination therapy compared with the effect of each agent alone. Linagliptin/empagliflozin addition is a logical combination in patients with T2DM, especially those with an HbA1c < 8.5%.

Topics: Benzhydryl Compounds; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Glucagon-Like Peptide 1; Glucose; Glucosides; Humans; Hypoglycemic Agents; Linagliptin; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors

The proline-specific dipeptidyl aminopeptidase IV (DPP IV, DPP-4, CD26), widely expressed in mammalians, releases X-Pro/Ala dipeptides from the N-terminus of peptides. DPP IV is responsible of the degradation of the incretin peptide hormones regulating blood glucose levels. Several families of DPP IV inhibitors have been synthesized and evaluated. Their positive effects on the degradation of the incretins and the control of blood glucose levels have been demonstrated in biological models and in clinical trials. Presently, several DPP IV inhibitors, the "gliptins", are approved for type 2 diabetes or are under clinical evaluation. However, the gliptins may also be of therapeutic interest for other diseases beyond the inhibition of incretin degradation. In this Perspective, the biological functions and potential substrates of DPP IV enzymes are reviewed and the characteristics of the DPP IV inhibitors are discussed in view of type 2 diabetes and further therapeutic interest.

Topics: Animals; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Humans; Structure-Activity Relationship

Unlike other dipeptidyl peptidase 4 (DPP-4) inhibitors, the excretion of linagliptin is mainly through a biliary route. Despite this fact, liver injury with linagliptin has thus far not been reported in the literature. However, this report describes the first case of probable linagliptin-induced liver toxicity.. The clinical history, diagnosis, investigations and drug treatment of the patient are reviewed here.. A 58-year-old Japanese woman presented with fatigue, nausea, jaundice and marked elevations of hepatic enzymes 4weeks after starting linagliptin 5mg/day as monotherapy. No other medications were taken, and imaging studies revealed no other obvious causes of hepatic injury. Tests for viral serology and antinuclear antigen were negative. Symptoms disappeared and the levels of hepatic parameters (serum aminotransferases and biliary enzymes) slowly recovered after discontinuation of linagliptin. The slow recovery process may have been due to the very long half-life of the drug. The patient's Naranjo scale score was 6 and RUCAM score was 7.. Although linagliptin currently carries no liver warnings, it may be necessary to monitor hepatic function in some patients upon administration of this drug until further evidence is obtained.

Topics: Chemical and Drug Induced Liver Injury; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Fatigue; Female; Half-Life; Humans; Jaundice; Linagliptin; Metabolic Clearance Rate; Middle Aged; Nausea; Purines; Quinazolines

Effective, evidence-based management of type 2 diabetes (T2D) requires the integration of the best available evidence with clinical experience and patient preferences.. Studies published from 2000 to 2012 evaluating glucagon-like peptide-1 receptor agonists (GLP-1RAs) or dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors) were identified using PubMed. The author contextualized the study findings with his clinical experience.. Incretin-based therapy targets multiple dysfunctional organs in T2D. Injectable GLP-1RAs provide substantial glycemic control and weight reduction; while oral DPP-4 inhibitors provide moderate glycemic control and weight neutrality. Both classes are effective, well tolerated, and associated with a low incidence of hypoglycemia when used alone or in combination with other antidiabetes agents. GLP-1RAs are associated with transient nausea and, like DPP-4 inhibitors, rare pancreatitis.. Data indicate and clinical experience confirms that incretins are well tolerated in appropriate patients and provide sustained glycemic control and weight loss or weight neutrality throughout T2D progression.

Topics: Adamantane; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Linagliptin; Liraglutide; Peptides; Piperidines; Purines; Pyrazines; Quinazolines; Receptors, Glucagon; Sitagliptin Phosphate; Treatment Outcome; Triazoles; Uracil; Venoms; Weight Loss

Renal disease is a frequent comorbidity of type 2 diabetes mellitus (T2DM) and an important factor complicating the choice of glucose-lowering drugs. The aim of this analysis was to evaluate the efficacy and safety of the dipeptidyl peptidase (DPP)-4 inhibitor linagliptin (5 mg/day) in mono, dual or triple oral glucose-lowering regimens in subjects with T2DM and mild or moderate renal impairment (RI).. In this pooled analysis of three 24-week, placebo-controlled, phase 3 trials, subjects with mild (estimated glomerular filtration rate (eGFR) 60-<90 ml/min/1.73 m(2) , n = 838) or moderate RI (30-<60 ml/min/1.73 m(2), n = 93) were compared with subjects with normal renal function (≥90 ml/min/1.73 m(2), n = 1212).. Subjects with RI were older, had longer duration of diabetes, and increased prevalence of diabetes-related comorbidities. After 24 weeks, linagliptin achieved consistent placebo-corrected mean glycated haemoglobin (HbA1c) changes across the three renal function categories: normal (-0.63%; p < 0.0001), mild RI (-0.67%; p < 0.0001) and moderate RI (-0.53%; p < 0.01), with no inter-group difference (p = 0.74). Renal function with linagliptin remained stable across all categories. In linagliptin-treated subjects, overall adverse event (AE) rates and serious AE rates were similar to placebo. The incidence of hypoglycaemia with linagliptin and placebo was 11.1 versus 6.9%, 11.9 versus 9.0% and 15.9 versus 12.0% in the normal, mild RI and moderate RI categories, respectively.. This pooled analysis provides evidence that linagliptin is an effective, well-tolerated and convenient treatment in subjects with T2DM and mild or moderate RI.

Topics: Adult; Aged; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Female; Humans; Hypoglycemia; Hypoglycemic Agents; Linagliptin; Male; Middle Aged; Placebos; Purines; Quinazolines; Randomized Controlled Trials as Topic; Severity of Illness Index

Dipeptidyl-peptidase-4 (DPP-4) inhibitors are a class of anti-hyperglycemic agents with proven efficacy in patients with type 2 diabetes mellitus (T2DM).. This review considers the pharmacokinetic profile, adverse effects and drug interactions of DPP-4 inhibitors. DPP-4 inhibitors have certain differences in their structure, metabolism, route of elimination and selectivity for DPP-4 over structurally related enzymes, such as DPP-8/DPP-9. They have a low potential for drug interactions, with the exception of saxagliptin that is largely metabolized by cytochrome CYP3A4/A5. Reports of pancreatitis and pancreatic cancer have raised concerns regarding the safety of DPP-4 inhibitors and are under investigation. Post-marketing surveillance has revealed less common adverse effects, especially a number of skin- and immune-related adverse effects. These issues are covered in the present review.. DPP-4 inhibitors are useful and efficient drugs. DPP-4 inhibitors have similar mechanism of action and similar efficacy. However, DPP-4 inhibitors have certain differences in their pharmacokinetic properties that may be associated with different clinical effects and adverse event profiles. Although clinical trials indicated a favorable safety profile, post-marketing reports revealed certain safety aspects that need further investigation. Certainly, more research is needed to clarify if the differences among DPP-4 inhibitors could lead to a different clinical and safety profile.

Topics: Adamantane; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Drug Interactions; Humans; Linagliptin; Nitriles; Piperidines; Piperidones; Purines; Pyrazines; Pyrazoles; Pyrimidines; Pyrrolidines; Quinazolines; Sitagliptin Phosphate; Thiazolidines; Triazoles; Uracil; Vildagliptin

Progressive deterioration of pancreatic β-cell function in patients with type 2 diabetes mellitus (T2DM) contributes to worsening of hyperglycaemia. To investigate the effects of the dipeptidyl peptidase-4 inhibitor linagliptin on β-cell function parameters, a pooled analysis of six randomized, 24-week, placebo-controlled, phase 3 trials of 5 mg of linagliptin daily was performed in 2701 patients with T2DM (linagliptin, n = 1905; placebo, n = 796). At week 24, observed improvements in HbA1c, fasting plasma glucose, and 2-h postprandial glucose were significantly greater for linagliptin than placebo (all p < 0.0001). Homeostasis model assessment (HOMA)-%β, as a surrogate marker of fasting β-cell function, was significantly improved with linagliptin, and did not change with placebo (placebo-adjusted mean ± s.e. change for linagliptin: 16.5 ± 4.6 (mU/l)/(mmol/l); p = 0.0003). Further study is required to determine if the significant improvement in HOMA-%β with linagliptin will translate into long-term improvements in β-cell function.

Topics: Diabetes Mellitus, Type 2; Glucose; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin-Secreting Cells; Linagliptin; Postprandial Period; Purines; Quinazolines; Randomized Controlled Trials as Topic; Treatment Outcome

The nature of biomedical research affords a broad range of investigational topics at the preclinical stage, not all of which may be explored in subsequent clinical studies. To provide a comprehensive perspective on the physiologic effects of the dipeptidyl peptidase-4 inhibitor linagliptin, this review will discuss the results of both preclinical and clinical research, summarizing data describing outcomes associated with its use.. Clinical studies demonstrate an overall favorable safety profile, low risk for hypoglycemia, weight neutrality, primarily nonrenal clearance, and efficacy for glycosylated hemoglobin reduction, typically ranging from 0.6% to 0.8% depending on baseline levels. In addition to these characteristics, preclinical research on linagliptin has yielded several interesting findings such as improved wound healing, reduced hepatic fat content, decreased infarct size following myocardial infarction or intracranial stroke, and improved vascular function with decreased oxidative stress. In accordance with its preclinical profile, linagliptin is unique among available dipeptidyl peptidase-4 compounds because it does not require dose adjustment when used in patients with renal dysfunction. Reduction of albuminuria with linagliptin on top of inhibitors of the renin-angiotensin-aldosterone system in both preclinical and post hoc clinical analysis serves as the foundation for ongoing clinical trials.. In addition to its efficacy for glycemic control, current literature points to other potential opportunities associated with linagliptin therapy. These results warrant further investigation and underscore the importance of translational study based on findings from preclinical research. Moving forward, we can expect that future research on linagliptin and other incretin-based therapies will continue to expand their applications beyond the maintenance of glycemic control in patients with type 2 diabetes.

Topics: Animals; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Linagliptin; Purines; Quinazolines; Wound Healing

Older people have the highest prevalence of type 2 diabetes mellitus (T2DM) of any age group and are thus frequent users of glucose-lowering agents. Because individuals 65 years or older are underrepresented in clinical studies, there is a lack of information regarding the efficacy and safety of available treatments in this population. Additionally, a high prevalence of comorbidities, polypharmacy, and frailty can make treatment of T2DM in this population challenging. Safety is an important consideration when choosing a treatment for older individuals. Renal impairment is quite common in older patients with T2DM and can contribute to hypoglycemia. Hypoglycemia can lead to serious consequences, such as falls and fractures, and cognitive changes. As such, hemoglobin A₁c treatment targets, typically <7% in the general population, are less stringent in older people, with the goal being an individualized target that balances efficacy and safety. Many glucose-lowering agents can cause adverse events detrimental to older individuals, such as hypoglycemia (insulin, sulfonylureas), weight gain (sulfonylureas, thiazolidinediones), gastrointestinal events (metformin), and fractures (thiazolidinediones), and are contraindicated or require dose adjustments in those with renal impairment (most oral/injectable agents). Orally administered dipeptidyl peptidase (DPP)-4 inhibitors have a low risk of hypoglycemia and are generally well tolerated. Linagliptin is the only DPP-4 inhibitor excreted through nonrenal pathways and therefore does not require any dose adjustment in older patients with kidney disease. This paper reviews the findings of a recent study by Barnett et al assessing the efficacy and safety of the DPP-4 inhibitor linagliptin in patients with T2DM aged 70 years or older, which concluded that linagliptin may be a useful glucose-lowering option for older patients with T2DM.

Topics: Aged; Aging; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Linagliptin; Purines; Quinazolines

Linagliptin (Trajenta(®), Tradjenta(®)) is a dipeptidyl peptidase (DPP)-4 inhibitor approved for the treatment of adults with type 2 diabetes mellitus in several countries. A fixed-dose combination of linagliptin/metformin (Jentadueto(®)) is also available. This article reviews the pharmacology, therapeutic efficacy and tolerability of linagliptin in the management of type 2 diabetes, with the aim of updating its place in therapy based on recently published data. In randomized, controlled trials, oral linagliptin 5 mg once daily (or 2.5 mg twice daily when combined with metformin) improved glycaemic control when used alone or in combination with other antidiabetic agents, including metformin, a sulfonylurea, thiazolidinedione or insulin. Improvements in glycaemic control were also shown in patients with renal impairment, including severe impairment, and the elderly (aged ≥70 years). Linagliptin is the first DPP-4 inhibitor to be eliminated primarily via a nonrenal route, enabling its use without dosage adjustment in patients with any degree of renal impairment. Linagliptin is generally well tolerated and, as with other DPP-4 inhibitors, it is associated with a low risk of hypoglycaemia and has no effect on bodyweight. Some data indicate that linagliptin may have beneficial effects on cardiovascular and renal safety profiles in patients with type 2 diabetes, but more data are needed. Meanwhile, the low risk of hypoglycaemia and the nonrenal route of elimination may provide important advantages for some patient groups, including elderly or renally impaired patients.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Humans; Linagliptin; Purines; Quinazolines

Metformin is the first-choice drug in the management of type 2 diabetes. However, most patients require a combined therapy to reach and/or maintain targets of glucose control. Dipeptidyl peptidase-4 (DPP-4) inhibitors offer new options for combined therapy with metformin. Linagliptin shares a similar pharmacodynamic (PD) profile with other gliptins, but has a unique pharmacokinetic (PK) profile characterized by negligible renal excretion.. An extensive literature search was performed to analyze the potential PK/PD interactions between linagliptin and metformin. They are not prone to PK drug-drug interactions. The two compounds may be administered together, either separately or using a fixed-dose combination (FDC) as shown by bioequivalence studies. The addition of linagliptin in patients not well controlled with metformin alone has proven its efficacy in improving glucose levels with a good safety profile. Initial co-administration of linagliptin plus metformin improves glucose control more potently than either compound separately, without hypoglycemia, weight gain or increased metformin-related gastrointestinal side effects.. The linagliptin plus metformin combination may offer some advantages over the classical sulfonylurea-metformin combination. Even if linagliptin is safe in patients with renal impairment, the use of metformin (and thus of the linagliptin plus metformin FDC) is still controversial in this population.

Topics: Animals; Diabetes Mellitus, Type 2; Drug Combinations; Humans; Hypoglycemic Agents; Linagliptin; Metformin; Purines; Quinazolines; Randomized Controlled Trials as Topic; Treatment Outcome

Topics: Biomarkers; Diabetes Complications; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Hypersensitivity; Drug Interactions; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Immune System; Linagliptin; Pancreatitis; Patient Selection; Purines; Quinazolines; Risk Assessment; Risk Factors; Treatment Outcome

In patients with type 2 diabetes mellitus (T2DM), hypertension and microalbuminuria are predictive markers for increased renal and cardiovascular risk. This post hoc analysis of data from a global development program aimed to evaluate the efficacy and safety of linagliptin in a population with joint prevalence of these two vascular risk factors.. Data for patients with baseline microalbuminuria (urine albumin-to-creatinine ratio 30-300 mg/g) and hypertension (systolic blood pressure ≥ 140 mm Hg and/or diastolic blood pressure ≥ 90 mm Hg and/or a history of hypertension; and/or an antihypertensive treatment at baseline) who participated in any of six randomized, placebo-controlled, phase III trials were analyzed. Participants received linagliptin 5 mg daily (alone or in combination with other oral antidiabetic drugs) or placebo for 18 to 24 weeks.. Of 3,119 patients, 512 had both microalbuminuria and hypertension (linagliptin, 366; placebo, 146). Baseline mean (SD) HbA1c was 8.3 (0.9)% and 8.4 (0.9)%; median (range) urine albumin-to-creatinine ratio was 60 (30-292) mg/g and 64 (30-298) mg/g; mean (SD) systolic blood pressure was 138 (15) mm Hg and 135 (16) mm Hg; and mean (SD) diastolic blood pressure was 81 (10) mm Hg and 81 (10) mm Hg, for linagliptin and placebo, respectively. Placebo-corrected mean change in HbA1c from baseline to week 18 and week 24 was -0.57% (95% CI: -0.75, -0.39; P < 0.0001) and -0.59% (95% CI: -0.80, -0.39; P < 0.0001), respectively. Placebo-corrected mean change in FPG from baseline to week 24 was -21.3 mg/dl (95% CI: -31.0, -11.6; P < 0.0001). The incidence of drug-related adverse events was similar for linagliptin and placebo (10.4% and 8.2%, respectively). Changes in systolic and diastolic blood pressure, cholesterol and triglyceride levels were similar between linagliptin and placebo.. In T2DM patients with the two common vascular risk factors of hypertension and microalbuminuria, linagliptin achieved significant improvements in glycemic control. In this vulnerable patient population at high risk for micro- and macrovascular complications, linagliptin was well tolerated.

Topics: Cardiovascular Diseases; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Kidney Diseases; Linagliptin; Purines; Quinazolines; Randomized Controlled Trials as Topic; Risk Factors; Treatment Outcome

Topics: Contraindications; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Interactions; Humans; Hypoglycemic Agents; Linagliptin; Purines; Quinazolines

As type 2 diabetes mellitus (T2DM) progresses, most patients will require insulin replacement therapy. Whether oral antidiabetic drug (OAD) therapy should be retained when initiating insulin is still debated. While the rationale to keep metformin with insulin is strong (mostly as an insulin-sparing agent to limit weight gain), the evidence is less clear for other OADs. In particular, the question now comes up what the expected benefit could be of combining the newer agents, such as the dipeptidyl peptidase-4 (DPP-4) inhibitors with insulin. Additionally, when metformin is no longer a treatment option, as in the case of patients with severe renal impairment, insulin is often used as monotherapy, with little evidence of benefit in maintaining other OADs. In this specific situation, it is also of interest to evaluate the potential benefit of combined treatment with a DPP-4 inhibitor and insulin. Among the classic limitations of insulin therapy in patients with T2DM, hypoglycemia remains a major barrier to glycemic control, along with weight gain exacerbation. The oral DPP-4 inhibitors improve glycemic control by increasing the sensitivity of the islet cells to glucose, and thus are not associated with an increased risk for hypoglycemia and are weight neutral. In addition to the expected benefits associated with limiting insulin dose and regimen complexity, the specific advantages the DPP-4 inhibitor drug class on hypoglycemia and weight gain could justify combining DPP-4 inhibitors with insulin; additionally, a DPP-4 inhibitor may be of special value to decrease glycemic excursions that are not properly addressed by basal insulin therapy and metformin use, even after optimizing titration of the basal insulin. However, given the common original perception that treatment with DPP-4 inhibitors may be less beneficial with increasing disease progression because of the loss of β-cell function, the potential relevance of these agents in the setting of advanced T2DM treated with insulin was not necessarily anticipated. Promising data from studies on the use of these new agents in insulin-treated patients with T2DM have started to emerge. Our article provides a comprehensive overview of the currently available evidence from controlled randomized clinical trials and we discuss the potential role of DPP-4 inhibitors in the this setting. Further clinical experience will allow to fully assess the positioning of these agents in insulin-treated T2DM populations.

Topics: Adamantane; Body Weight; Diabetes Complications; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Disease Progression; Drug Therapy, Combination; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Linagliptin; Nitriles; Piperidines; Purines; Pyrazines; Pyrrolidines; Quinazolines; Renal Insufficiency, Chronic; Sitagliptin Phosphate; Triazoles; Uracil; Vildagliptin

Dipeptidyl peptidase-4 (DPP-4) inhibitors have emerged as new options in the management of type 2 diabetes mellitus, demonstrating meaningful antihyperglycemic effects and good tolerability profiles. Glycemic control is improved by preventing the DPP-4-mediated degradation of incretin hormones, with a resulting increase in insulin secretion and inhibition of glucagon secretion.. This article provides a discussion of the clinical utility of linagliptin.. Linagliptin is a xanthine-based, oral DPP-4 inhibitor that has been approved in the United States and Europe. It has been evaluated extensively in clinical trials, and results in improved glycemic control when used as monotherapy, initial combination therapy with metformin or pioglitazone, add-on therapy to metformin and/or a sulfonylurea, or add-on therapy to basal insulin (with or without oral antidiabetic drugs). Consistent with other members of its class, the benefits of linagliptin also include a low risk of hypoglycemia and weight gain. However, linagliptin is the first DPP-4 inhibitor to be approved as a once-daily, 5-mg dose and, due to its primarily non-renal route of excretion, no dosage adjustment is required for patients with renal or hepatic impairment. The pharmacokinetics and pharmacodynamics of linagliptin are not affected to a clinically meaningful degree by race or ethnicity and linagliptin has very low potential for drug-drug interactions.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hyperglycemia; Hypoglycemic Agents; Linagliptin; Purines; Quinazolines

In case of failure of metformin monotherapy, several pharmacological strategies may be considered for the treatment of type 2 diabetes. Among these, the addition of an inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme, a medication commonly named as gliptin, is increasingly used because of two main advantages over sulfonylureas, i.e. the absence of both hypoglycaemia and weight gain. The combination of a gliptin and metformin further improves glycaemic control compared to either monotherapy, due to complementary mechanisms of action. Most patients with type 2 diabetes are treated every day with numerous drugs because of the presence of comorbidities so that poor drug compliance is a major concern in such a population. The use of fixed-dose combinations (FDCs) may improve compliance and, therefore, several gliptin-metformin FDCs are now available. The most recent one is Jentadueto, which combines linagliptin, a selective DPP-4 inhibitor without renal excretion, and metformin, the first-line antidiabetic compound. This FDC is commercialized with two dosages of metformin, i.e. 2.5 mg linagliptin/850 mg metformin and 2.5 mg linagliptin/1.000 mg metformin, and should be administered twice daily with meal.While linagliptin may be prescribed whatever the renal function, the use of FDC should take into account classical restrictions imposed by the presence of metformin.

Topics: Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Combinations; Drug Interactions; Humans; Hypoglycemic Agents; Linagliptin; Metformin; Purines; Quinazolines

Type 2 diabetes mellitus (T2DM) is a highly prevalent, progressive disease that often is poorly controlled. The combination of an incretin-based therapy and insulin is a promising approach to optimize the management of glycemic control without hypoglycemia and weight gain. Linagliptin, a recently approved oral dipeptidyl peptidase-4 inhibitor, has a unique pharmacological profile. The convenient, once-daily dosing does not need adjustment in patients with hepatic and/or renal impairment. In clinical studies linagliptin shows an important reduction of blood glucose with an overall safety profile similar to that of placebo. So far, the combination of linagliptin and insulin has been tested in three major clinical studies in different populations. It has been shown that linagliptin is an effective and safe add-on therapy to insulin in patients with T2DM. The efficacy and safety of this combination was also shown in vulnerable, elderly T2DM patients and in patients with T2DM and renal impairment. Favorable effects regarding the counteraction of hypoglycemia make linagliptin especially interesting as an add-on therapy to insulin. This review aims to present the existing clinical studies on the efficacy and safety of linagliptin as add-on therapy to insulin in patients with T2DM in the context of current literature. Additionally, the possible advantages of linagliptin as an add-on therapy to insulin in relation to cardiovascular safety, patient-centered therapy and the prevention of hypoglycemia, are discussed.

Topics: Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Insulin; Linagliptin; Patient Selection; Purines; Quinazolines; Risk Factors; Treatment Outcome

The first-choice drug therapy in the management of type 2 diabetes is metformin . However, most patients require a combined therapy to reach and/or maintain targets of glucose control. Dipeptidyl peptidase-4 (DPP-4) inhibitors, commonly referred to as gliptins, offer new options for combined therapy with metformin. Linagliptin is the most recently launched gliptin, with a unique pharmacokinetic (PK) profile characterized by negligible renal excretion and is now also available as a fixed-dose combination (FDC) with metformin.. An extensive literature search was performed to analyze the potential PK and pharmacodynamic interactions between linagliptin and metformin. Linagliptin and metformin may be administered together, either separately or as FDC supported by bioequivalence studies. Linagliptin and metformin are not prone to PK drug-drug interactions. Their coadministration improves blood glucose control more potently than either compound separately, without hypoglycemia and without increasing metformin-related gastrointestinal side effects.. The combination linaglitpin plus metformin, if not contraindicated (renal failure), may be used as first-line or second-line therapy in the management of type 2 diabetes. That being said, the durability of the glucose-lowering effect of this combination needs to be further explored in long-term controlled trials.

Topics: Blood Glucose; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Drug Evaluation; Drug Interactions; Humans; Hypoglycemic Agents; Linagliptin; Metformin; Purines; Quinazolines; Randomized Controlled Trials as Topic

Increasing population age, obesity and physical inactivity mean that type 2 diabetes mellitus (T2DM) is increasingly common. Current treatments may be limited by adverse events, drug-drug interactions or contraindication/need for dose adjustment in patients with renal impairment.. This paper reviews studies that evaluate the pharmacokinetics, pharmacodynamics and clinical efficacy and safety of linagliptin , a dipeptidyl peptidase-4 (DPP-4) inhibitor, recently approved in the US, Japan and Europe for the treatment of T2DM.. Oral linagliptin, 5 mg once daily, is an effective, well-tolerated DPP-4 inhibitor, suitable for use in a wide range of patients with T2DM. It is weight-neutral, without increasing the risk of hypoglycemia, and can be administered either alone or in combination with other diabetes treatments. It has a unique pharmacological profile within its class and, unlike other DPP-4 inhibitors, linagliptin does not require dose adjustment in patients with renal impairment.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Linagliptin; Purines; Quinazolines

Dipeptidyl peptidase-4 (DPP-4) inhibitors offer new options for the management of type 2 diabetes. Direct comparisons with active glucose-lowering comparators in drug-naive patients have demonstrated that DPP-4 inhibitors exert slightly less pronounced HbA(1c) reduction than metformin (with the advantage of better gastrointestinal tolerability) and similar glucose-lowering effects as with a thiazolidinedione (TZD; with the advantage of no weight gain). In metformin-treated patients, gliptins were associated with similar HbA(1c) reductions compared with a sulphonylurea (SU; with the advantage of no weight gain, considerably fewer hypoglycaemic episodes and no need for titration) and a TZD (with the advantage of no weight gain and better overall tolerability). DPP-4 inhibitors also exert clinically relevant glucose-lowering effects compared with a placebo in patients treated with SU or TZD (of potential interest when metformin is either not tolerated or contraindicated), and as oral triple therapy with a good tolerability profile when added to a metformin-SU or pioglitazone-SU combination. Several clinical trials also showed a consistent reduction in HbA(1c) when DPP-4 inhibitors were added to basal insulin therapy, with no increased risk of hypoglycaemia. Because of the complex pathophysiology of type 2 diabetes and the complementary actions of glucose-lowering agents, initial combination of a DPP-4 inhibitor with either metformin or a glitazone may be applied in drug-naive patients, resulting in greater efficacy and similar safety compared with either drug as monotherapy. However, DPP-4 inhibitors were less effective than GLP-1 receptor agonists for reducing HbA(1c) and body weight, but offer the advantage of being easier to use (oral instead of injected administration) and lower in cost. Only one head-to-head trial demonstrated the non-inferiority of saxagliptin vs sitagliptin. Clearly, more trials of direct comparisons between different incretin-based therapies are needed. Because of their pharmacokinetic characteristics, pharmacodynamic properties (glucose-dependent glucose-lowering effect) and good overall tolerability profile, DPP-4 inhibitors may have a key role to play in patients with renal impairment and in the elderly. The role of DPP-4 inhibitors in the therapeutic armamentarium of type 2 diabetes is rapidly evolving as their potential strengths and weaknesses become better defined mainly through controlled clinical trials.

Topics: Adamantane; Clinical Trials as Topic; Cost-Benefit Analysis; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Linagliptin; Male; Metformin; Nitriles; Piperidines; Purines; Pyrazines; Pyrrolidines; Quinazolines; Sitagliptin Phosphate; Triazoles; Uracil; Vildagliptin; Weight Gain

This study investigated the cardiovascular (CV) safety profile of the dipeptidyl peptidase (DPP)-4 inhibitor linagliptin versus comparator treatments.. This was a pre-specified meta-analysis of CV events in linagliptin or comparator-treated patients with type 2 diabetes mellitus (T2DM) from eight Phase 3 studies. All suspected CV events were prospectively adjudicated by a blinded independent expert committee. The primary endpoint was a composite of CV death, stroke, myocardial infarction, and hospitalization for unstable angina. Three secondary composite endpoints derived from the adjudicated CV events were also pre-specified. Risk estimates were calculated using several statistical methods including Cox regression analysis.. Of 5239 treated patients (mean ± SD HbA1c 65 ± 10 mmol/mol [8.0 ± 0.9%], age 58 ± 10 years, BMI 29 ± 5 kg/m2), 3319 received linagliptin once daily (5 mg, 3159; 10 mg, 160) and 1920 received comparators (placebo, 977; glimepiride 1-4 mg, 781; voglibose 0.6 mg, 162). Cumulative exposure (patient-years) was 2060 for linagliptin and 1372 for comparators. Primary CV events occurred in 11 (0.3%) patients receiving linagliptin and 23 (1.2%) receiving comparators. The hazard ratio (HR) for the primary endpoint showed significantly lower risk with linagliptin than comparators (HR 0.34 [95% confidence interval (CI) 0.16-0.70]) as did estimates for all secondary endpoints (HR ranging from 0.34 to 0.55 [all upper 95% CIs < 1.0]).. These results from a large Phase 3 programme support the hypothesis that linagliptin may have CV benefits in patients with T2DM.

Topics: Aged; Angina, Unstable; Biomarkers; Blood Glucose; Cardiovascular Diseases; Clinical Trials, Phase III as Topic; Diabetes Complications; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Evidence-Based Medicine; Female; Glycated Hemoglobin; Hospitalization; Humans; Linagliptin; Male; Middle Aged; Myocardial Infarction; Patient Safety; Proportional Hazards Models; Prospective Studies; Purines; Quinazolines; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Stroke; Treatment Outcome

To assess the safety and tolerability of the dipeptidyl peptidase-4 inhibitor linagliptin in patients with type 2 diabetes.. Data were pooled from eight randomized, double-blind, placebo-controlled Phase III clinical trials lasting ≤24 weeks. Incidences were calculated with descriptive statistics for the overall population and for subgroups of elderly and renally impaired patients.. A total of 2523 patients received linagliptin 5 mg once daily and 1049 patients received placebo. The overall incidence of adverse events (AEs) or serious AEs with linagliptin was similar to placebo (AEs 55.8% vs. 55.0%; serious AEs 2.8% vs. 2.7%). Overall aggregated infection incidence was 19.5% for linagliptin and 21.4% for placebo. Similar or reduced incidence of AEs versus placebo were seen with linagliptin for upper respiratory tract infection (3.3% vs. 4.9%), headache (2.9% vs. 3.1%), urinary tract infection (2.2% vs. 2.7%), blood and lymphatic disorders (1.0% vs. 1.2%), hypersensitivity (0.1% vs. 0.1%), hepatic enzyme increase (0.1% and 0.1%) and serum creatinine increase (0.0% and 0.1%). There was a slight increased frequency of nasopharyngitis (5.9% vs. 5.1%) and cough (1.7% vs. 1.0%) with linagliptin. Hypoglycaemia incidence was 8.2% for linagliptin and 5.1% for placebo; incidence was higher in patients with a background of sulphonylurea therapy (20.7% and 13.3%, respectively). In patients not receiving concomitant sulphonylurea, the hypoglycaemic incidence with linagliptin was very low in both the total population (<1%), and elderly and renally impaired patients (both <1%).. This pooled analysis shows that linagliptin is well tolerated, with a low risk of hypoglycaemia.

Topics: Blood Glucose; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Female; Humans; Hypoglycemic Agents; Linagliptin; Male; Middle Aged; Purines; Quinazolines; Randomized Controlled Trials as Topic; Sulfonylurea Compounds

To review the pharmacology, pharmacokinetics, and clinical efficacy and safety of linagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor recently approved in the US for use as a treatment for type 2 diabetes mellitus.. English-language articles in the PubMed database to October 2011 (selected using the search terms linagliptin, alogliptin, sitagliptin, saxagliptin, vildagliptin, and pharmacokinetics, pharmacodynamics, or diabetes) were identified for review. Reference lists from identified articles were reviewed for additional references of interest. Abstracts published at relevant meetings were also evaluated, and information was obtained from the manufacturer.. Publications reporting the pharmacology, pharmacokinetics, and clinical efficacy and safety of linagliptin were reviewed.. Linagliptin therapy results in clinically meaningful reductions in hemoglobin A(1c), as well as fasting and postprandial plasma glucose levels in patients with type 2 diabetes mellitus. It contrasts with other agents in its class by not requiring dosage adjustment in patients with renal or hepatic impairment. Oral doses of linagliptin 5 mg once daily have been shown to be clinically effective, well tolerated, and weight-neutral. An increased rate of hypoglycemia when linagliptin was used in combination with an insulin secretagogue compared to placebo was noted in clinical trials.. Linagliptin provides an additional therapeutic option for type 2 diabetes mellitus and, in contrast to other agents in the DPP-4 class, can be used without dose adjustment in patients with any degree of declining renal function.

Topics: Animals; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Interactions; Humans; Linagliptin; Purines; Quinazolines

According to the latest American Diabetes Association guidelines, lowering glycated hemoglobin (HbA(1c)) to below or around 7% has been shown to reduce microvascular and neuropathic complications of diabetes and, if implemented soon after the diagnosis of diabetes, is associated with long-term reduction in macrovascular disease. Recently a new class of antidiabetes drugs has been developed, dipeptidyl peptidase-4 (DPP-4) inhibitors, which act by inhibiting DPP-4, the enzyme that inactivates glucagon-like peptide-1 (GLP-1). Through the inhibition of DPP-4, DPP-4 inhibitors enhance the effects of GLP-1 and glucose-dependent insulinotropic peptide, increasing glucose-mediated insulin secretion and suppressing glucagon secretion. We conducted a review analyzing clinical efficacy and safety of DPP-4 inhibitors, both alone and in combination with other antidiabetes drugs, including randomized controlled trials about sitagliptin, vildagliptin, saxagliptin, and linagliptin conducted in the latest 15 years. We concluded that, once metformin fails to maintain glycemic control, addition of DPP-4 inhibitors should be the logical choice: they seems to lower HbA(1c) levels by 0.6-0.9 percentage points and to have a comparable effect on HbA(1c) versus the addition of a sulfonylurea or glitazone. They also have positive effects on β-cell function, and they have neutral effects on body weight. Furthermore, DPP-4 inhibitors prevent the risk of hypoglycemia posed by sulfonylureas.

Topics: Adamantane; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Linagliptin; Male; Metformin; Nitriles; Purines; Pyrrolidines; Quinazolines; Randomized Controlled Trials as Topic; Vildagliptin

Linagliptin is a new dipeptidyl peptidase-4 inhibitor recently approved for use in the USA. The objective of this systematic review and meta-analysis was to assess effect of linagliptin on glycaemic control, biomarkers and incidence of adverse events (AEs) in patients with type 2 diabetes mellitus.. Five published and four unpublished randomized, clinical trials were identified from multiple databases. Qualitative assessments and quantitative analyses were performed.. Nine studies included 4246 participants with 53% men, 59.4% Caucasians, 38.7% Asians, and age range 45-69 years. Linagliptin was given as monotherapy (vs. placebo) or combined with metformin (vs. metformin + placebo), sulphonylurea (vs. sulphonylurea + placebo) or pioglitazone (vs. pioglitazone + placebo). Linagliptin 5 mg/day for 12-24 weeks, significantly reduced haemoglobin A1c (HbA1c) (-0.63%, p < 0.00001), fasting plasma glucose (FPG) (-1.01 mmol/l, p < 0.00001) and improved disposition index (DI, product of insulin sensitivity and acute insulin secretion) (p = 0.0001). Linagliptin monotherapy was not more effective than metformin at reducing HbA1c or FPG. Similar proportion of patients in linagliptin and placebo groups reported AEs including upper respiratory tract infections, headaches, nausea, hypertension and back pain.. Linagliptin was associated with modest but significant reduction in HbA1c and FPG and improved DI after 12-24 weeks. Patients who would probably benefit most are those with HbA1c <9%, already on an active agent, compliant with weight reduction strategies, and can recognize and manage hypoglycaemia, fluid retention and upper respiratory tract infections. Long-term studies are needed to determine durability of response, incidence of microvascular and macrovacular complications, cost-effectiveness and safety.

Topics: Aged; Biomarkers; Blood Glucose; Cost-Benefit Analysis; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Linagliptin; Male; Metformin; Middle Aged; Pioglitazone; Purines; Quinazolines; Randomized Controlled Trials as Topic; Thiazolidinediones; Treatment Outcome; United States

Chemically, methylxanthine nucleus based Linagliptin (BI-1356, BI-1356-BS) is a dipeptidyl peptidase-IV inhibitor, which has been developed by Boehringer Ingelheim in association with Lilly for the treatment of Type-II Diabetes. Linagliptin was marketed by Lilly under the trade name Tradjenta and Trajenta. Linagliptin was approved as the once-daily dose by USFDA on 2 May 2011, for the treatment of Type-II Diabetes. Linagliptin 5mg once daily dose was approved based on a clinical trial program, which was conducted on approximately 4,000 adults with Type-II Diabetes. Linagliptin demonstrated statistically significant mean difference in HbA1c from placebo of up to 0.72 percent, when it was used monotherapically. In patients, who were not adequately controlled on metformin or metformin plus sulphonylurea, the addition of Linagliptin resulted in a statistically significant mean difference in HbA1c from placebo of -0.6 percent. Linagliptin was observed to produce significant reduction in fasting plasma glucose (FPG) compared to placebo, when used as a monotherapy in combination with metformin, sulfonylurea and/or pioglitazone. Linagliptin demonstrated significant reduction post-prandial glucose (PPG) levels in two hours as compared with placebo in monotherapy as well as in combination with metformin. In vitro assays also anticipated that Linagliptin is a potent DPPIV inhibitor as well as it exhibits good selectivity for DPP-IV as compared with other DPPs. The in-vivo studies also demonstrated same anticipation with respect to Linagliptin. Consequently, increasing the GLP-1 levels so far improved glucose tolerance in both healthy animals. X-ray crystallography anticipates that Linagliptin complexes with human DPPIV enzyme, e.g. butynyl substituent occupies the S1 hydrophobic pocket of the enzyme; the aminopiperidine substituent in the xanthine scaffold occupies the S2 subsite and its primary amine interacts with the key amino acid residues, which involves in the recognition of peptide substrates. In the present review, we have tried to cover comparative study of DPPIV inhibitors, chemistry, physical properties, commercial synthesis, patent portfolio, crystalline polymorphic forms of Linagliptin and its receptor interaction, Pharmacophore rational, mechanism, clinical studies, preclinical, adverse effect, available formulations, dose regimen, co-therapy of Linagliptin, giving emphasis on the medicinal chemistry aspects.

Topics: Animals; Crystallography, X-Ray; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Linagliptin; Purines; Quinazolines; Structure-Activity Relationship

Dipeptidyl peptidase -4 inhibitors represent a novel way to augment the incretin system and one of the newest class of medications in the treatment of type 2 diabetes mellitus. Their mechanism of action is to decrease the inactivation of glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide, both of which are involved in maintaining euglycemia subsequent to carbohydrate intake. Currently investigated agents include sitagliptin, vildagliptin, saxagliptin, linagliptin, and alogliptin. Each agent has been shown to provide significant improvements in glycemic control compared to placebo. They are effective when added to other oral diabetes agents and in the cases of sitagliptin, vildagliptin, and alogliptin in addition to insulin. These agents may not provide as significant improvement in glucose concentrations as some other medications including metformin, thiazolidinediones, or glucagon-like peptide 1 agonists. The lack of head to head clinical data comparing the various dipeptidyl peptidase 4 inhibitors does not allow for specific recommendations if one agent is more effective or safer than another within the class. Their side effect profile suggests they are very well tolerated and have few drug interactions. For patients with mildly elevated glucose concentrations, they are therapeutic options in both drug-naive patients as well as those not optimally controlled on other diabetes medications.

Topics: Adamantane; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Drug Interactions; Female; Glucagon-Like Peptide 1; Humans; Linagliptin; Male; Nitriles; Piperidines; Purines; Pyrazines; Pyrrolidines; Quinazolines; Sitagliptin Phosphate; Treatment Outcome; Triazoles; Uracil; Vildagliptin

Linagliptin is a dipeptidyl peptidase-4 inhibitor that was approved in 2011 by the US Food and Drug Administration as a treatment adjunctive to diet and exercise for the improvement of glycemic control in adults with type 2 diabetes mellitus (T2DM).. The purpose of this article is to review the pharmacology, pharmacokinetic properties, efficacy, tolerability including drug-drug interactions, contraindications/precautions, and dosage and administration of linagliptin, and the potential role of linagliptin in the management of glycemia in adults with T2DM.. MEDLINE (1966-January 12, 2012), PubMed (1950-January 12, 2012), Science Direct (1994-January 12, 2012), Web of Science (1980-January 12, 2012), and the American Diabetes Association Scientific Abstracts (2008-2011) were searched using the term linagliptin. Articles and abstracts published in English, both original research and review articles, were identified for review. Reference lists from identified articles were also searched for additional references of interest. Manufacturers' prescribing information was additionally examined.. Data from clinical trials of linagliptin suggest clinical efficacy in terms of reductions in hemoglobin A(1c) (A(1c)), fasting plasma glucose, and postprandial glucose when linagliptin was administered as monotherapy or in combination with other oral antidiabetic agents, with placebo-subtracted A(1c) changes ranging from -0.47% to -0.69% in placebo-controlled trials. Adverse events that occurred in ≥2% of patients treated with linagliptin and at a prevalence of ≥2-fold greater compared with placebo were nasopharyngitis, hyperlipidemia, cough, hypertriglyceridemia, and weight increase (when used in combination with a thiazolidinedione [TZD]). Although linagliptin administered as monotherapy or in combination with metformin or a TZD may convey a low risk for hypoglycemia (0%-1.2%), caution is warranted when linagliptin is administered in combination with insulin secretagogues due to an increased risk for hypoglycemic events. Dosage adjustments based on renal or hepatic function are not required. Additionally, according to the currently approved prescribing information, the efficacy of linagliptin may be limited in patients receiving concurrent inducers of the cytochrome P450 3A4 isozyme or P-glycoprotein (eg, rifampin).. Based on the findings from the present review, patients and clinicians should be aware of the risk for hypoglycemia when linagliptin is prescribed as a treatment adjunctive to a regimen of an insulin secretagogue. An initial dose decrease in the secretagogue should be considered to prevent hypoglycemic events. Dosage adjustment of linagliptin is not required in patients with renal impairment.

Topics: Adult; Animals; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Interactions; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Linagliptin; Purines; Quinazolines

Topics: Animals; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Linagliptin; Purines; Quinazolines; Renal Insufficiency

Linagliptin is an orally active small-molecule inhibitor of dipeptidyl peptidase (DPP)-4, which was first licensed in the US, Europe, Japan and other territories in 2011 to improve glycaemic control in adults with type 2 diabetes mellitus. Linagliptin is the first and thus far the only DPP-4 inhibitor, and oral antihyperglycaemic drug in general, to be approved as a single-strength once-daily dose (5 mg). Compared with other available DPP-4 inhibitors, linagliptin has a unique pharmacokinetic/pharmacodynamic profile that is characterized by target-mediated nonlinear pharmacokinetics, concentration-dependent protein binding, minimal renal clearance and no requirements for dose adjustment for any intrinsic or extrinsic factor. After single or multiple oral doses of 1-10 mg, linagliptin displays less than dose-proportional increases in maximum plasma concentration (C(max)) and area under the plasma concentration-time curve (AUC). Linagliptin is rapidly absorbed after oral administration, with C(max) occurring after approximately 90 minutes, and reaches steady-state concentrations within 4 days. With the therapeutic dose, steady-state C(max) (11-12 nmol/L) and AUC (∼150 nmol · h/L) are approximately 1.3-fold greater than after a single dose, indicating little drug accumulation with repeat dosing. Linagliptin exhibits concentration-dependent protein binding in human plasma in vitro (99% at 1 nmol/L to 75-89% at >30 nmol/L) and has a large apparent volume of distribution, demonstrating extensive distribution into tissues. The nonlinear pharmacokinetics of linagliptin are best described by a two-compartmental model that incorporates target-mediated drug disposition resulting from high-affinity, saturable binding to DPP-4. The oral bioavailability of linagliptin estimated with this model is approximately 30%. Linagliptin has a long terminal half-life (>100 hours); however, its accumulation half-life is much shorter (approximately 10 hours), accounting for the rapid attainment of steady state. The majority of linagliptin is eliminated as parent compound, demonstrating that metabolism plays a minor role in the overall pharmacokinetics in humans. The main, pharmacologically inactive S-3-hydroxypiperidinyl metabolite accounted for approximately 17% of the total drug-related compounds in plasma. Linagliptin is eliminated primarily in faeces, with only around 5% of the oral therapeutic dose excreted in the urine at steady state. Linagliptin potently inhibits DPP-4 (inh

Topics: Animals; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Interactions; Humans; Linagliptin; Purines; Quinazolines

Linagliptin (Trajenta®, Tradjenta™, Trazenta™, Trayenta™) is an oral, highly selective inhibitor of dipeptidyl peptidase-4 and is the first agent of its class to be eliminated predominantly via a nonrenal route. Linagliptin is indicated for once-daily use for the treatment of adults with type 2 diabetes mellitus, and a twice-daily fixed-dose combination of linagliptin/metformin (Jentadueto®) is also available. In this article, the pharmacological, clinical efficacy and tolerability data relevant to the use of linagliptin in patients with type 2 diabetes are reviewed. The efficacy of oral linagliptin in the treatment of adults with type 2 diabetes has been investigated in several double-blind, multicentre trials. Following 12-24 weeks of treatment, improvements in glycaemic control parameters, including glycosylated haemoglobin (HbA(1c); primary endpoint in all trials), were seen with linagliptin relative to placebo when used as monotherapy, initial combination therapy (with metformin or pioglitazone) or add-on therapy to other oral antihyperglycaemia agents (metformin and/or a sulfonylurea) or basal insulin (with or without metformin and/or pioglitazone). In terms of lowering HbA(1c), linagliptin was more effective than voglibose in a 26-week monotherapy trial and noninferior to glimepiride when used as add-on therapy to metformin in a 104-week study. Additional trials and subgroup analyses of pooled data suggest that linagliptin improves glycaemic control regardless of factors such as age, duration of type 2 diabetes, ethnicity and renal function, and as linagliptin is eliminated primarily via a nonrenal route, it can be used without dosage adjustment in patients with renal impairment of any degree. Oral linagliptin was generally well tolerated and was associated with a low likelihood of hypoglycaemia (except when used in combination with a sulfonylurea) and had little effect on bodyweight. Further long-term and comparative efficacy and tolerability data are required to help position linagliptin more definitively with respect to other antihyperglycaemia agents. However, clinical data currently available indicate that linagliptin is an effective and generally well tolerated treatment option for use in patients with type 2 diabetes, including those with renal impairment for whom other antihyperglycaemia agents require dosage adjustment or are not suitable.

Topics: Administration, Oral; Blood Glucose; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Drug Therapy, Combination; Humans; Insulin; Insulin Secretion; Insulin-Secreting Cells; Linagliptin; Metformin; Purines; Quinazolines; Treatment Outcome

The pathogenesis of type 2 diabetes (T2D) can result in decreased levels of glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which under normal circumstances increase insulin secretion and suppress glucagon release. A new form of drug therapy known as dipeptidyl peptidase 4 (DPP IV) inhibitors has focused on increasing the circulating levels of these "incretin" hormones in order to improve glycemic control in patients with T2D. The DPP IV inhibitors saxagliptin, vildagliptin, linagliptin, alogliptin and sitagliptin function by inhibiting the enzyme DPP IV, which breaks down GLP-1 and GIP, and have had significant success. However, with most DPP IV inhibitors being extensively excreted renally, this is a significant issue, as a large proportion of diabetic patients suffer from renal complications. Linagliptin is a novel DPP IV inhibitor that is excreted primarily by the hepatic route, with little need for dose adjustment in patients with renal impairment. It therefore represents a major advancement in the pharmacotherapy of patients with T2D.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Interactions; Humans; Linagliptin; Purines; Quinazolines

Most patients with type 2 diabetes mellitus (T2DM) are prescribed multiple medications - typically more than one for glycemic control alone, and others for the management of lipids and hypertension. Within a few years following diagnosis, many patients progress beyond an initial starting regimen of metformin and/or sulfonylurea in order to maintain glycemic control. With the broad selection of antidiabetes medications available today, the choice of which agents to add when progressing from monotherapy to combination therapy has led to much discussion on how to best tailor a treatment regimen to the individual patient's needs.. The aim of this paper is to review the literature describing the use of linagliptin as a component of combination therapy for the treatment of T2DM. Literature searches were conducted to retrieve articles reporting on linagliptin clinical trial data. For comparison of safety and efficacy, studies of linagliptin as monotherapy were included.. Dipeptidyl peptidase-4 inhibitors are used across all stages of treatment, from monotherapy to dual or triple therapy regimens for glycemic control. Linagliptin has been studied in combination with the most commonly used classes of antihyperglycemic medications, with demonstrated efficacy and a safety profile comparable to placebo.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Evidence-Based Medicine; Humans; Hypoglycemic Agents; Linagliptin; Purines; Quinazolines

Combination therapies are a widely accepted approach to type 2 diabetes treatment, considering that monotherapies fail to provide adequate glycemic control in the majority of cases. The combination of oral antidiabetic agents into a single tablet would significantly simplify the therapeutic regimen and maximize patients' adherence to treatment. Recently, a fixed-dose, single-tablet, combined formulation of linagliptin (a dipeptidyl peptidase-4 inhibitor) and metformin has been approved for use in type 2 diabetic patients, and is indicated as an adjunct to diet and exercise for those patients who remain inadequately controlled despite maximal tolerated doses of metformin, metformin and sulfonylurea, or linagliptin and metformin monotherapies. The combination tablet is administered twice daily and can be used either alone or combined with sulfonylureas. Clinical trials suggest that this fixed-dose combination provides significantly superior glycemic control compared to linagliptin and metformin monotherapy, in terms of improving key parameters of glucose homeostasis such as glycosylated hemoglobin, fasting and postprandial glucose levels. It also exhibits an excellent tolerability profile, without promoting weight gain and hypoglycemic episodes. The compounds of this formulation do not display clinically relevant pharmacokinetic interactions with each other, and exert synergistic (complementary) pharmacodynamic effects, including an enhanced incretin effect, suppressed hepatic glucose production, and improved peripheral insulin sensitivity. As a result, a linagliptin/metformin fixed-dose combination offers the potential to address multiple defects of type 2 diabetes pathophysiology (pancreatic islet dysfunction, insulin resistance, increased hepatic glucose output), and most importantly, in the context of a safe, efficacious, flexible, and convenient therapeutic regimen.

Topics: Adult; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Humans; Hypoglycemic Agents; Linagliptin; Male; Metformin; Purines; Quinazolines

Making appropriate treatment decisions for patients newly diagnosed with type 2 diabetes mellitus (T2DM) and severe hyperglycemia (glycated hemoglobin [HbA1c]>10% or fasting plasma glucose≥250 mg/dL) presents a formidable challenge to primary care physicians. Extreme defects in insulin secretion make it unlikely that these patients will achieve glycemic targets with metformin monotherapy. Additionally, uncontrolled hyperglycemia is associated with an increased risk of short-term acute complications, such as hyperosmolar coma, and long-term complications affecting the micro- and macrovasculature. Thus, severely hyperglycemic patients require prompt, intensive treatment to re-establish glycemic control. Current guidelines indicate that either initial insulin therapy or initial combination therapy with metformin plus non-insulin drug(s) are the treatments of choice for these challenging-to-treat patients. This mini-review examines the clinical evidence supporting these two treatment options, with particular reference to the findings of a phase 3 study of treatment with an initial combination of metformin plus the dipeptidyl peptidase-4 inhibitor, linagliptin. Intensive insulin therapy can induce sustained euglycemia and improve beta-cell function in newly diagnosed patients. However, insulin use is associated with an increased risk of adverse events, such as hypoglycemia and weight gain. These potentially serious side effects cause concern among patients and physicians, and are a major barrier to initiating and maintaining adherence to insulin treatment. In the phase 3 study, open-label treatment of severely hyperglycemic patients (HbA1c≥11.0%) with linagliptin plus metformin resulted in a mean change in HbA1c of -3.7%±1.7%. This combination therapy was generally well tolerated with most adverse events being of mild or moderate intensity; asymptomatic hypoglycemia was reported by just 1 of 66 (1.5%) patients. These findings provide evidence in support of linagliptin plus metformin as a well-tolerated and effective treatment alternative to insulin for new-onset patients with T2DM and severe hyperglycemia.

Topics: Adult; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Humans; Hyperglycemia; Hypoglycemic Agents; Linagliptin; Male; Metformin; Practice Guidelines as Topic; Purines; Quinazolines

Aging is characterized by a progressive increase in the prevalence of type 2 diabetes mellitus (T2DM), which approaches 20% by age 70 years. Older patients with T2DM are a very heterogeneous group with multiple comorbidities, an increased risk of hypoglycemia, and a greater susceptibility to adverse effects of antihyperglycemic drugs, making treatment of T2DM in this population challenging. The risk of severe hypoglycemia likely represents the greatest barrier to T2DM care in the elderly. Although recent guidelines recommend more flexibility in treating this population with individualized targets, inadequate glycemic control is still closely linked to poor outcome in elderly patients. Incretins (glucose-dependent insulinotropic polypeptide [GIP] and glucagon-like peptide-1 [GLP-1]) are hormones released post-meal from intestinal endocrine cells that stimulate insulin secretion and suppress postprandial glucagon secretion in a glucose-dependent manner. "Incretin therapies," comprising the injectable GLP-1 analogs and oral dipeptidyl peptidase-4 (DPP-4) inhibitors, are promising new therapies for use in older patients because of their consistent efficacy and low risk of hypoglycemia. However, data with these new agents are still scarce in this population, which has not been particularly well represented in clinical trials, highlighting the need for additional specific studies. The objective of this article is to provide an overview of the available data and potential role of these novel incretin therapies in managing T2DM in the elderly. With the exception of the DPP-4 inhibitor vildagliptin, there is no published trial to date dedicated to this population, although a few studies are currently ongoing. Therefore, available data from elderly subgroups of individual studies were also reviewed when available, as well as pooled analyses by age subgroups across clinical programs conducted with incretin therapies.

Topics: Adamantane; Age Factors; Aged; Aging; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Linagliptin; Liraglutide; Male; Middle Aged; Nitriles; Peptides; Piperidines; Purines; Pyrazines; Pyrrolidines; Quinazolines; Sitagliptin Phosphate; Treatment Outcome; Triazoles; Uracil; Venoms; Vildagliptin

Linagliptin, a novel dipeptidyl peptidase-4 (DPP-4) inhibitor, has a favourable pharmacokinetic profile in terms of its predominantly non-renal elimination. It shows highly selective, potent, dose-dependent inhibition of DPP-4, with ≥ 80% inhibition of DPP-4 throughout the 24-hour dosing interval. In two double-blind, multicentre trials (n >350 evaluable patients/trial) in adult patients with inadequately controlled type 2 diabetes mellitus, oral linagliptin monotherapy (5 or 10 mg once daily) was significantly more effective than placebo in improving glycaemic control and several parameters of pancreatic function, with placebo-corrected adjusted mean changes in glycosylated haemoglobin (HbA(1c)) levels of -0.69% to -0.88% after 12 or 24 weeks. Linagliptin 5 or 10 mg once daily was also significantly more efficacious than voglibose 0.2 mg three times daily in terms of improving glycaemic control in a 26-week, double-blind, multicentre trial (n >450 evaluable patients). In several similarly designed trials (n >250 evaluable patients/trial) of 12-24 weeks' duration in adult patients with inadequately controlled type 2 diabetes, oral linagliptin (5 mg once daily) as add-on therapy to metformin, a sulfonylurea drug or metformin plus a sulfonylurea drug, or in combination with pioglitazone, improved glycaemic control significantly more than placebo plus the respective oral antihyperglycaemic therapy, with improvements in adjusted mean HbA(1c) levels considered clinically relevant. Linagliptin, as monotherapy or in combination with other oral antihyperglycaemic drugs, was generally well tolerated in clinical trials, having neutral or minimal effects on bodyweight and generally being associated with a very low incidence of hypoglycaemia.

Topics: Adult; Animals; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Humans; Hypoglycemic Agents; Linagliptin; Purines; Quinazolines

A recent treatment advance for type 2 diabetes is the oral therapy with DPP IV inhibitors. New substances of this class are in development in order to increase alternatives for treating this important metabolic disease. The reader will gain detailed pharmacological and clinical information on alogliptin, dutogliptin and linagliptin and will learn how these DPP IV inhibitors may widen the whole drug class. Possible special indications for the various DPP IV inhibitors are discussed.. The DPP IV inhibitors and their current role in type 2 diabetes are highlighted. Preclinical and clinical studies of the novel DPP IV inhibitors alogliptin, dutogliptin and linagliptin, including published data since 2007, are presented and a comparison of these compounds is made.. The efficacy and safety profile of DPP IV inhibitors are promising and advantageous so far. In contrast to sulfonylureas, DPP IV inhibitors do not have an intrinsic risk for causing hypoglycemia and they are body weight neutral. Their tolerability profile is good and no specific adverse reactions have been reported. Experience so far suggests that there are no safety issues associated with inhibition of DPP IV activity by itself. Novel DPP IV inhibitors with distinct properties may offer alternative choices within this drug class.

Topics: Administration, Oral; Animals; Boronic Acids; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Design; Humans; Hypoglycemic Agents; Linagliptin; Piperidines; Purines; Quinazolines; Uracil

The dipeptidyl peptidase 4 (DPP-4) inhibitors comprise a promising new class of agent for the management of type 2 diabetes. They possess a range of physiological effects associated with improved glycemic control including stimulation of glucose-dependent insulin secretion and suppression of glucagon secretion, and lower blood glucose levels through different, but potentially complementary, mechanisms to standard oral therapies. Linagliptin is the latest DPP-4 inhibitor to complete pivotal phase 3 trials. The data show that linagliptin provides significant, clinically meaningful and sustained improvements in glycemic control, with an incidence of adverse events similar to placebo and an excellent tolerability profile. In addition, linagliptin has been shown to be weight neutral and, importantly, there was no increased risk of hypoglycemia attributed to linagliptin use in monotherapy or combination therapy with metformin or pioglitazone. A unique characteristic of linagliptin that differentiates it from other members of the class is its primarily nonrenal route of excretion. The linagliptin phase 3 program included several hundred patients with type 2 diabetes and different stages of renal disease and the data suggest that the drug would not need dose adjustment, regardless of the degree of renal impairment. There is a particular need for safe and effective therapeutic agents that can be used when renal function declines. Linagliptin has recently been approved by the US Food and Drug Administration and may find a place in therapy as a treatment option for the significant number of patients in whom metformin and the other DPP-4 inhibitors are either contraindicated or require dose adjustment because of moderate to severe renal impairment.

Topics: Blood Glucose; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Linagliptin; Purines; Quinazolines

Incretin-based therapies constitute a relatively new pharmacological approach to the treatment of type 2 diabetes mellitus. As reflected in the rapidly growing body of literature and the number of glucagon-like peptide-1 and dipeptidyl peptidase-4 inhibitor (DPP-4) compounds that are either approved or in development, there is considerable interest in treatments that target the incretin axis. Linagliptin is a recently approved DPP-4 inhibitor with unique pharmacological properties, including very high affinity for the DPP-4 enzyme, postdose DPP-4 inhibition>80% after 24 hours, and a primarily fecal route of elimination. Phase 3 clinical trials on >4000 patients have demonstrated the efficacy of linagliptin as monotherapy or in combination with other antidiabetic agents. Treatment with linagliptin reduced glycated hemoglobin by 0.6% to 0.8%, with a safety profile comparable with placebo. This article provides a review of linagliptin clinical data for primary care physicians treating patients with type 2 diabetes mellitus.

Topics: Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Linagliptin; Purines; Quinazolines

Topics: Animals; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Linagliptin; Purines; Quinazolines

As knowledge of pathophysiologic mechanisms of diabetes mellitus has increased, clinical attention has shifted to the incretin system. Incretin hormones, including glucagon-like peptide-1, or GLP-1, and glucose-dependent insulinotropic polypeptide, are vital to the control of glucose homeostasis and pancreatic β-cell preservation. Novel strategies for the treatment of patients with type 2 diabetes mellitus (T2DM) engage the incretin system. Glucagon-like peptide-1 receptor agonists provide robust glycemic control as well as beneficial reductions in body weight. Dipeptidyl peptidase-4, or DPP-4, inhibitors exhibit beneficial glycemic effects and are weight-neutral. Incretin-based medications are becoming increasingly recognized in guidelines as early treatment options because of their efficacy and well-tolerated profiles. The author reviews the safety and efficacy of currently approved incretin-based agents, as well as the role of these medications in treatment paradigms for patients with T2DM. He also discusses investigational incretin-based agents.

Topics: Adult; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Glucagon-Like Peptide 1; Humans; Incretins; Linagliptin; Male; Middle Aged; Purines; Quinazolines; Randomized Controlled Trials as Topic; Severity of Illness Index; Treatment Outcome

Nearly 90% of the diabetic patients are suffering of type 2 diabetes while approximately 60-65% of patients with type 2 diabetes are treated with oral antidiabetic drugs. In the last couple of years a new treatment option, namely incretin-based therapy, became available. The dipeptidyl-peptidase-4-inhibitors (gliptins) are designated as incretin enhancers. Using gliptins, sustained glycemic control can be achieved without gaining weight and increasing the risk of hypoglycemia. All gliptins (sitagliptin, vildagliptin, saxagliptin, linagliptin) can be used as tablets without a need for dose titration. For treating patients with type 2 diabetes, gliptins can primarily be used in combination with metformin.

Topics: Adamantane; Animals; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Drug Administration Schedule; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Incretins; Linagliptin; Metformin; Nitriles; Purines; Pyrazines; Pyrrolidines; Quinazolines; Sitagliptin Phosphate; Tablets; Treatment Outcome; Triazoles; Vildagliptin

Type 2 diabetes mellitus causes significant morbidity and mortality on account of its progressive nature and results in considerable burden on healthcare resources. Current treatment strategies have only limited long-term efficacy and tolerability given the progressive nature of the disease leading to inadequate glycemic control and are also associated with undesirable side effects such as weight gain, hypoglycemia and gastrointestinal distress. In the light of these existing limitations, exploring new treatment targets and new therapies have become the need of the hour at present. The incretin pathway, in particular, glucagon-like peptide (GLP-1), plays an important pathological role in the development of type 2 diabetes mellitus, and treatments targeting the incretin system have recently generated surmount interest. These can mainly be categorized into two broad classes; GLP-1 agonists/analogs (exenatide, liraglutide), and dipeptidyl peptidase- 4 inhibitors (sitagliptin, vildagliptin). The gliptins act by prolonging the action of incretins, the gut hormones which can boost insulin levels. Linagliptin is the latest dipeptidyl peptidase-4 inhibitor to complete pivotal phase III trials, which have demonstrated its superiority to its competitors based on its low therapeutic dose, long-lasting inhibition of DPP-4 activity and a good safety/tolerability profile. One of the unique characteristics of linagliptin is its primarily non-renal route of excretion. The drug has recently been approved by the US Food and Drug Administration and has been portrayed as a promising treatment option for patients in whom metformin and the other DPP-4 inhibitors are either contraindicated or require dose adjustment because of moderate to severe renal impairment.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptides; Humans; Hypoglycemic Agents; Linagliptin; Purines; Quinazolines; Treatment Outcome

Dipeptidyl peptidase-4 (DPP-4) inhibitors offer new options for the management of type 2 diabetes (T2DM). The novel compound linagliptin has important different pharmacokinetic (PK) properties, when compared with previously commercialized DPP-4 inhibitors, which may offer some advantages in clinical practice. Linagliptin has a unique PK/pharmacodynamic (PD) profile and is the first DPP-4 inhibitor with a nonrenal elimination route. Therefore, it can be administered in patients with renal impairment without dose adjustment or monitoring of renal function. The drug has a low potential for drug-drug interactions (DDIs) and no clinically relevant ones were reported so far.. An extensive literature search was performed to analyse primarily PK and secondarily PD characteristics of linagliptin in both healthy volunteers and patients with T2DM (treated with linagliptin as monotherapy or combined therapy). Updated information about linagliptin PK either after single administration (large dose range) or after chronic administration (steady state) were also included. A special focus has been put on DDIs and on PK/PD of linagliptin in patients with renal impairment.. Head-to-head comparative studies and/or increased clinical experience with DPP-4 inhibitors will determine the clinical advantage, if any, of one agent over another.

Topics: Area Under Curve; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Drug Combinations; Drug Interactions; Glyburide; Humans; Hypoglycemic Agents; Linagliptin; Metformin; Pioglitazone; Purines; Quinazolines; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Thiazolidinediones

In the last couple of years, a new class of antidiabetic drugs became available for the clinical practice. Due to the intensive research, several new drugs reached the market. Among the incretinmimetics both the GLP-1 (glucagon like peptide-1)-receptor agonist exenatide and the GLP-1-analogue liraglutide can be used for treatment. As for incretin enhancers (dipeptidyl-peptidase-4 [DPP-4]-inhibitors), sitagliptin, vildagliptin and saxagliptin are available in Hungary, linagliptin will be introduced to the market in the near future. In clinical practice, any incretin-based new drugs can be used for treating patients with type 2 diabetes, preferably in combination with metformin. The clinical experiences with these new drugs are reviewed focusing on both the benefits and the potential side-effects of the particular compounds.

Topics: Adamantane; Body Mass Index; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Drug Approval; Drug Therapy, Combination; Exenatide; Gliclazide; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Humans; Hungary; Hypoglycemic Agents; Incretins; Linagliptin; Liraglutide; Metformin; Nitriles; Peptides; Pioglitazone; Purines; Pyrazines; Pyrrolidines; Quinazolines; Receptors, Glucagon; Sitagliptin Phosphate; Sulfonylurea Compounds; Thiazolidinediones; Triazoles; Venoms; Vildagliptin

Type 2 diabetes is a progressive disease for which current treatments are often unsatisfactory with respect to achieving therapeutic goals and unwanted side effects.. Preclinical and clinical studies of linagliptin, a new oral antidiabetic agent, including data presented at Scientific Meetings and peer-reviewed studies published since 2007.. This article reviews pharmacokinetic and pharmacodynamic characteristics of linagliptin. Linagliptin belongs to a new chemical class of dipeptidyl pepidase-4 (DPP-4) inhibitors, which comprise xanthine-based compounds. It is a potent, long-acting inhibitor with high selectivity for DPP-4 versus the related enzymes DPP-8 and DPP-9. The drug has modest oral availability in humans, but is absorbed rapidly to inhibit plasma DPP-4 activity by > 80% over 24 h. It is not metabolized appreciably in vivo, but binds extensively to plasma proteins, with elimination occurring primarily in the liver. Linagliptin reduces degradation of the incretin hormone glucagon-like peptide-1 and is associated with reduced fasting and postprandial glucose in preclinical and clinical studies. Limited data from longer duration clinical trials show it improves glycemic control in patients with type 2 diabetes.. Linagliptin is a new oral antidiabetic agent associated with minimal risk of hypoglycemia, which holds promise for treatment of type 2 diabetes.

Topics: Animals; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Evaluation, Preclinical; Humans; Hypoglycemic Agents; Linagliptin; Molecular Structure; Purines; Quinazolines; Xanthine

Patients with type 2 diabetes mellitus (T2DM) are generally treated with many pharmacological compounds and are exposed to a high risk of drug-drug interactions. Indeed, blood glucose control usually requires a combination of various glucose-lowering agents, and the recommended global approach to reduce overall cardiovascular risk generally implies administration of several protective compounds, including HMG-CoA reductase inhibitors (statins), antihypertensive compounds and antiplatelet agents. New compounds have been developed to improve glucose-induced beta-cell secretion and glucose control, without inducing hypoglycaemia or weight gain, in patients with T2DM. Dipeptidylpeptidase-4 (DPP-4) inhibitors are novel oral glucose-lowering agents, which may be used as monotherapy or in combination with other antidiabetic compounds, metformin, thiazolidinediones or even sulfonylureas. Sitagliptin, vildagliptin and saxagliptin are already on the market, either as single agents or in fixed-dose combined formulations with metformin. Other compounds, such as alogliptin and linagliptin, are in a late phase of development. This review summarizes the available data on drug-drug interactions reported in the literature for these five DDP-4 inhibitors: sitagliptin, vildagliptin, saxagliptin, alogliptin and linagliptin. Possible pharmacokinetic interferences have been investigated between each of these compounds and various pharmacological agents, which were selected because there are other glucose-lowering agents (metformin, glibenclamide [glyburide], pioglitazone/rosiglitazone) that may be prescribed in combination with DPP-4 inhibitors, other drugs that are currently used in patients with T2DM (statins, antihypertensive agents), compounds that are known to interfere with the cytochrome P450 (CYP) system (ketoconazole, diltiazem, rifampicin [rifampin]) or with P-glycoprotein transport (ciclosporin), or agents with a narrow therapeutic safety window (warfarin, digoxin). Generally speaking, almost no drug-drug interactions or only minor drug-drug interactions have been reported between DPP-4 inhibitors and any of these drugs. The gliptins do not significantly modify the pharmacokinetic profile and exposure of the other tested drugs, and the other drugs do not significantly alter the pharmacokinetic profile of the gliptins or exposure to these. The only exception concerns saxagliptin, which is metabolized to an active metabolite by CYP3A4/5. Therefore, exposure to saxagli

Topics: Adamantane; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Drug Interactions; Humans; Linagliptin; Nitriles; Piperidines; Purines; Pyrazines; Pyrrolidines; Quinazolines; Sitagliptin Phosphate; Triazoles; Uracil; Vildagliptin

Attenuation of the prandial incretin effect, mediated by glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), contributes to hyperglycemia in type 2 diabetes mellitus (T2DM). Since the launch of sitagliptin in 2006, a compelling body of evidence has accumulated showing that dipeptidyl peptidase-4 (DPP-4) inhibitors, which augment endogenous GLP-1 and GIP levels, represent an important advance in the management of T2DM. Currently, three DPP-4 inhibitors - sitagliptin, vildagliptin and saxagliptin - have been approved in various countries worldwide. Several other DPP-4 inhibitors, including linagliptin and alogliptin, are currently in clinical development. As understanding of, and experience with, the growing number of DPP-4 inhibitors broadens, increasing evidence suggests that the class may offer advantages over other antidiabetic drugs in particular patient populations. The expanding evidence base also suggests that certain differences between DPP-4 inhibitors may prove to be clinically significant. This therapeutic diversity should help clinicians tailor treatment to the individual patient, thereby increasing the proportion that safely attain target HbA(1c) levels, and reducing morbidity and mortality. This review offers an overview of DPP-4 inhibitors in T2DM and suggests some characteristics that may provide clinically relevant differentiators within this class.

Topics: Adamantane; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Energy Intake; Gastric Emptying; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Incretins; Intestinal Mucosa; Linagliptin; Neurons; Nitriles; Piperidines; Purines; Pyrazines; Pyrrolidines; Quinazolines; Sitagliptin Phosphate; Triazoles; Uracil; Vildagliptin

BI 1356, a xanthine-based DPP-4 inhibitor, has reached Phase III trials. The compound efficiently inhibits dipeptidyl peptidase 4 (DPP-4) in vitro and in vivo. In vivo GLP-1 levels increase to levels at or above the levels of other DPP-4 inhibitors. Preclinical trials suggest a once-daily administration of 5 mg to be efficient, long-lasting and without known side effects.

Topics: Animals; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Drugs, Investigational; Glucagon-Like Peptide 1; Humans; Insulin-Secreting Cells; Linagliptin; Molecular Structure; Purines; Quinazolines

Boehringer Ingelheim Corp is developing the novel, xanthine-based dipeptidyl peptidase (DPP)-4 inhibitor linagliptin for the potential treatment of type 2 diabetes mellitus. In vitro assays suggested that linagliptin was a potent DPP-4 inhibitor, with good selectivity for DPP-4 compared with other DPPs and proteases. The inhibition of DPP-4 by linagliptin was also demonstrated in vivo, resulting in increased glucagon-like peptide 1 levels and improved glucose tolerance in both healthy animals and models of disease. Furthermore, linagliptin exhibited prolonged pharmacodynamic activity, with long-lasting DPP-4 inhibition across different species. The prolonged DPP-4 inhibition observed in preclinical models has translated to humans; linagliptin demonstrated approximately 80% inhibition of DPP-4 activity at daily doses as low as 5 mg in phase II clinical trials. The effects were sustained, and no signs or symptoms of hypoglycemia were observed, even at high doses of up to 600 mg. The low therapeutic dose of linagliptin, the long-lasting inhibition of DPP-4 activity and the good safety/tolerability profile exhibited thus far suggest that linagliptin may be superior to competitors. The results from ongoing phase III clinical trials will provide further information on such aspects; however, from the available data, linagliptin appears to have promise for market success.

Topics: Animals; Controlled Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Drug Evaluation, Preclinical; Humans; Hypoglycemic Agents; Linagliptin; Purines; Quinazolines; Species Specificity

Renin-angiotensin system (RAS) inhibitors decrease the urinary albumin to creatinine ratio (UACR) but are ineffective in up to 40% of patients. We hypothesized that rotation through different drug classes overcomes RAS inhibitor resistance and tested this in a randomized crossover trial.. We assigned 26 adults with type 1 diabetes and 37 with type 2 diabetes and UACR between 30 and 500 mg/g and estimated glomerular filtration rate >45 mL/min/1.73 m2 to 4-week treatment periods with telmisartan 80 mg, empagliflozin 10 mg, linagliptin 5 mg, and baricitinib 2 mg in random order, separated by 4-week washout periods. Each participant was then re-exposed for 4 weeks to the drug that induced that individual's largest UACR reduction. Primary outcome was the difference in UACR response to the best-performing drug during the confirmation period versus UACR response to the other three drugs.. There was substantial variation in the best-performing drug. Telmisartan was best performing for 33 participants (52%), empagliflozin and linagliptin in 11 (17%), and baricitinib in 8 participants (13%). The individuals' best-performing drug changed UACR from baseline during the first and confirmatory exposures by a mean of -39.6% (95% CI -44.8, -33.8; P < 0.001) and -22.4% (95% CI -29.7, -12.5; P < 0.001), respectively. The Pearson correlation for first versus confirmatory exposure was 0.39 (P = 0.017). The mean change in UACR with the other three drugs was +1.6% (95% CI -4.3%, 8.0%; P = 0.593 versus baseline; difference versus individuals' best-performing drug at confirmation, 30.9% [95% CI 18.0, 45.3]; P < 0.001).. We demonstrated a large and reproducible variation in participants' responses to different UACR-lowering drug classes. These data support systematic rotation through different drug classes to overcome therapy resistance to RAS inhibition.

Topics: Adult; Albuminuria; Creatinine; Cross-Over Studies; Diabetes Mellitus, Type 2; Enzyme Inhibitors; Glomerular Filtration Rate; Humans; Linagliptin; Rotation; Telmisartan

The CAROLINA trial established non-inferiority of linagliptin versus glimepiride for major adverse cardiovascular events in patients with relatively early type 2 diabetes at increased cardiovascular risk. In pre-specified and post-hoc analyses, we investigated treatment effects on total hypoglycaemic burden in CAROLINA.. Patients were randomized and treated with 5 mg linagliptin (n = 3014) or 1-4 mg glimepiride (n = 3000) once daily added to standard care. Hypoglycaemia captured from investigator-reported adverse events was analysed with Poisson and negative binomial regressions for the first and total (first plus recurrent) events, respectively. The influence of insulin initiation and glycated haemoglobin (HbA1c) change on the treatment effect for hypoglycaemia was also explored.. Over 6.3 years median follow-up, average HbA1c over time did not differ between linagliptin versus glimepiride (weighted mean difference [95% confidence interval]: 0.00%, [-0.05, 0.05]), nor did insulin initiation (18.6% vs. 19.2% of patients, respectively), whereas body weight was lower with linagliptin (-1.54 kg, [-1.80, -1.28]). Hypoglycaemia frequency was lower with linagliptin across all hypoglycaemia categories, including severe episodes. Rate ratios (95% confidence interval) for first and total events for investigator-reported hypoglycaemia were 0.21 (0.19-0.24) and 0.12 (0.10-0.14), respectively, with 8.7 first and 60.8 total estimated events prevented/100 patient-years with linagliptin versus glimepiride. These differences occurred during night-time and daytime, and in subgroup analyses of total events. Treatment differences in hypoglycaemia were neither impacted by HbA1c changes nor insulin initiation.. Across the severity spectrum, linagliptin substantially reduced the hypoglycaemic burden versus glimepiride in patients with relatively early type 2 diabetes at increased cardiovascular risk.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulins; Linagliptin; Treatment Outcome

To evaluate the effect of four different drug classes on soluble urokinase plasminogen activator receptor (suPAR), a biomarker active in multiple inflammatory processes and a risk factor for complications, in people with type 1 and type 2 diabetes.. We conducted post hoc analyses of a randomized, open-label, crossover trial including 26 adults with type 1 and 40 with type 2 diabetes with urinary albumin-creatinine ratio ≥30 and ≤500 mg/g assigned to 4-week treatments with telmisartan 80 mg, empagliflozin 10 mg, linagliptin 5 mg and baricitinib 2 mg, separated by 4-week washouts. Plasma suPAR was measured before and after each treatment. SuPAR change after each treatment was calculated and, for each individual, the best suPAR-reducing drug was identified. Subsequently, the effect of the best individual drug was compared against the mean of the other three drugs. Repeated-measures linear mixed-effects models were employed.. The baseline median (interquartile range) plasma suPAR was 3.5 (2.9, 4.3) ng/mL. No overall effect on suPAR levels was observed for any one drug. The individual best-performing drug varied, with baricitinib being selected for 20 participants (30%), followed by empagliflozin for 19 (29%), linagliptin for 16 (24%) and telmisartan for 11 (17%). The individual best-performing drug reduced suPAR by 13.3% (95% confidence interval [CI] 3.7, 22.8; P = 0.007). The difference in suPAR response between the individual best-performing drug and the other three was -19.7% (95% CI -23.1, -16.3; P < 0.001).. We demonstrated no overall effect of 4-week treatment with telmisartan, empagliflozin, linagliptin or baricitinib on suPAR. However, individualization of treatment might significantly reduce suPAR levels.

Topics: Adult; Biomarkers; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Linagliptin; Receptors, Urokinase Plasminogen Activator; Telmisartan

To determine the effect of the dipeptidyl peptidase-4 inhibitor linagliptin on postprandial glomerular hyperfiltration compared with the sulphonylurea glimepiride in adults with type 2 diabetes (T2D).. In this predefined substudy within a randomized, double-blind, parallel-group, intervention trial, overweight people with T2D without renal impairment were treated with once-daily linagliptin 5 mg (N = 10) or glimepiride 1 mg (N = 13) as an add-on to metformin for 8 weeks. After a standardized liquid protein-rich meal, the glomerular filtration rate (GFR) and effective renal plasma flow were determined by inulin and para-aminohippuric acid clearance, respectively, based on timed urine sampling. Intrarenal haemodynamics were estimated using the Gomez equations. Glucoregulatory/vasoactive hormones, urinary pH and fractional excretions (FE) of sodium, potassium and urea were measured.. In contrast to our hypothesis, compared with glimepiride, linagliptin does not reduce postprandial hyperfiltration, yet appears to increase FF after meal ingestion by increasing blood pressure or R

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Double-Blind Method; Glycated Hemoglobin; Hemodynamics; Humans; Hypoglycemic Agents; Linagliptin; Sulfonylurea Compounds; Treatment Outcome

Remogliflozin Etabonate (RE) & Vildagliptin are twice-daily medications that are individually approved and widely used in India for the treatment of diabetes. A single pill fixed dose combination of RE & Vildagliptin was formulated as potential pharmaco-therapeutic agent that would not only offer beneficial pharmacologic effects, but also reduces the pill burden, leading to a simplified treatment regimen with better treatment compliance. The fixed dose combination (FDC) of Remogliflozin + Vildagliptin added on to Metformin has been evaluated in this pivotal phase III study.. This 16 week, multi-centric, prospective, double blind, double dummy, parallel group, randomized controlled study compared efficacy and safety of FDC of RE 100mg + Vildagliptin 50mg (RV) given twice daily with active comparator of Empagliflozin 25mg +Linagliptin 5mg (EL) given once daily. Adult T2DM patients with HbA1c 8-11% on Metformin stable dose of ≥1500mg for ≥8 weeks before screening were randomized to either of treatment arms. The study endpoints were mean changes from baseline (CFB) in HbA1c (primary), fasting plasma glucose (FPG), post-prandial plasma glucose (PPG), body weight (BW) and blood pressure (BP) for efficacy and adverse events (AE) monitoring for safety assessments.. Of 400 eligible subjects (200 in each arm), 357 (89.3%) subjects completed the study. The baseline demographic characteristics were well balanced between 2 treatment arms. In the mITT population, the least squares (LS) mean (SE) change from baseline in HbA1c levels at week 16 was -1.46% (0.098) in the RV arm and -1.38% (0.100) in the EL arm (p < 0.001 for within group change from baseline). The mean difference of -0.08% (95%CI: -0.28, 0.13) in HbA1c demonstrated non-inferiority (NI) of RV compared to EL (p<0.001 for NI test). Similarly, significant reduction was observed in FPG, PPG, BW and BP which was found to be comparable between the two treatment arms. Drug related AEs were observed in 5.5% and 4.5% subjects of EL and RV arm respectively, with low incidence of hypoglycemia, genital and urinary tract infections (0.5-3%).. Overall, FDC of Remogliflozin Etabonate + Vildagliptin added on to Metformin was found to be efficacious and well tolerated in the treatment of patients with T2DM, and demonstrated non-inferiority to Empagliflozin 25mg + Linagliptin 5mg treatment added on to Metformin.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Glucosides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Linagliptin; Metformin; Prospective Studies; Pyrazoles; Treatment Outcome; Vildagliptin

Type 2 diabetes causes cardio-renal complications and is treated with different combination therapies. The renal hemodynamics profile of such combination therapies has not been evaluated in detail.. Patients (N = 97) with type 2 diabetes were randomized to receive either empagliflozin and linagliptin (E+L group) or metformin and insulin glargine (M+I group) for 3 months. Renal hemodynamics were assessed with para-aminohippuric acid and inulin for renal plasma flow (RPF) and glomerular filtration rate (GFR). Intraglomerular hemodynamics were calculated according the Gomez´ model.. Treatment with E+L reduced GFR (p = 0.003), but RPF remained unchanged (p = 0.536). In contrast, M+I not only reduced GFR (p = 0.001), but also resulted in a significant reduction of RPF (p < 0.001). Renal vascular resistance (RVR) decreased with E+L treatment (p = 0.001) but increased with M+I treatment (p = 0.001). The changes in RPF and RVR were different between the two groups (both p. In patients with type 2 diabetes and preserved renal function treatment with M+I resulted in reduction of renal perfusion and increase in vascular resistance, in contrast to treatment with E+I that preserved renal perfusion and reduced vascular resistance. Moreover, different underlying effects on the resistance vessels have been estimated according to the Gomez model, with M+I increasing R. The study was registered at www.clinicaltrials.gov (NCT02752113) on April 26, 2016.

Topics: Aged; Benzhydryl Compounds; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Female; Germany; Glomerular Filtration Rate; Glucosides; Hemodynamics; Humans; Hypoglycemic Agents; Insulin Glargine; Linagliptin; Male; Metformin; Middle Aged; Prospective Studies; Renal Plasma Flow; Sodium-Glucose Transporter 2 Inhibitors; Time Factors; Treatment Outcome

Previous studies have suggested that linagliptin may represent renoprotective effects besides its anti-hyperglycemic properties in patients with type 2 diabetes. However, there is a lack of decisive evidence to support this assumption. This study aimed to address the effect of linagliptin in type 2 diabetic patients with severely increased albuminuria.. In this randomized double-blind, placebo-controlled clinical trial, type 2 diabetic patients with severely increased albuminuria (albuminuria ≥ 300 mg/24 h) were enrolled. Patients were randomized to linagliptin (5 mg/d) and placebo based on a computer-generated list of random numbers. Biochemical (fasting blood sugar (FBS) (mg/dL), hemoglobin A1c (HbA1c) (%), proteinuria (mg/24h), blood urea nitrogen (BUN) (mg/dL), serum creatinine (mg/dL)) and clinical variables (weight (kg), systolic, and diastolic blood pressure (mmHg)) were measured at baseline and 3 and 6 months post intervention.. At baseline, no statistically significant difference was detected in demographic characteristics between the two groups (P > .05). A significant decrease was observed in proteinuria, FBS, weight, SBP, and DBP in the intervention group after 6 months (Ptime < .05), however; none of the clinical and biochemical variables showed a significant difference between groups after 6 months (Pgroup > .05).. Linagliptin may serve as a renoprotective therapeutic option in diabetic patients with severely increased albuminuria due to its role in proteinuria reduction. Results of this study can be used for future large-scale, long-term studies investigating the renoprotective effects of linagliptin in patients with diabetic nephropathy. DOI: 10.52547/ijkd.6110.

Topics: Albuminuria; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Glycated Hemoglobin; Humans; Linagliptin

To assess the effect of linagliptin vs. standard therapy in improving clinical outcomes in patients hospitalized with diabetes and coronavirus disease 2019 (COVID-19).. We did an open-label, prospective, multicenter, randomized clinical trial in 3 Israeli hospitals between October 1, 2020, and April 4, 2021. Eligible patients were adults with type 2 diabetes mellitus and a diagnosis of COVID-19. A total of 64 patients, 32 in each group, were randomized to receive linagliptin 5 mg PO daily throughout the hospitalization or standard of care therapy. The primary outcome was time to clinical improvement within 28 days after randomization, defined as a 2-point reduction on an ordinal scale ranging from 0 (discharged without disease) to 8 (death).. The mean age was 67 ± 14 years, and most patients were male (59.4%). Median time to clinical improvement was 7 days (interquartile range (IQR) 3.5-15) in the linagliptin group compared with 8 days (IQR 3.5-28) in the standard of care group (hazard ratio, 1.22; 95% CI, 0.70-2.15; p = 0.49). In-hospital mortality was 5 (15.6%) and 8 (25.0%) in the linagliptin and standard of care groups, respectively (odds ratio, 0.56; 95% CI, 0.16-1.93). The trial was prematurely terminated due to the control of the COVID-19 outbreak in Israel.. In this randomized clinical trial of hospitalized adult patients with diabetes and COVID-19 who received linagliptin, there was no difference in the time to clinical improvement compared with the standard of care.. ClinicalTrials.gov, identifier NCT04371978.

Topics: Aged; COVID-19; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Hospitalization; Humans; Israel; Linagliptin; Male; Prospective Studies; SARS-CoV-2; Standard of Care; Treatment Outcome

Sodium-glucose cotransporter-2 (SGLT2) inhibitors and dipeptidyl peptidase (DPP)-4 inhibitors added to insulin regimens in patients with type 2 diabetes mellitus (T2DM) can improve glycaemic control. This study compared the efficacy and safety of empagliflozin and linagliptin added to premixed insulin therapy in patients with poorly controlled T2DM.. In this 24-week, open-label, parallel-design randomized controlled trial, patients with poorly controlled T2DM despite a premixed insulin regimen were randomized to receive 5mg of linagliptin (n=53) or 25mg of empagliflozin (n=53) for 24 weeks.. At week 24, changes in glycated haemoglobin (HbA1c) from baseline were -0.06±0.17% and -1.01±0.16% in the linagliptin and empagliflozin groups, respectively, and the mean treatment HbA1c difference was -0.88% (95% CI: -1.33, -0.43). At week 24, the empagliflozin group showed significant reductions, compared with the linagliptin group, in fasting plasma glucose (P<0.001), body weight (P<0.001), systolic blood pressure (P=0.003) and total daily insulin dose (P=0.042). Hypoglycaemia was reported to be slightly, and not significantly, higher in the empagliflozin group vs linagliptin group (30.2% vs 22.6%, respectively; P=0.51). Similar percentages of patients (1.9%) had urinary tract infections in the two groups.. In Asian patients with inadequately controlled T2DM while taking premixed insulin, the addition of empagliflozin for 24 weeks provided better glycaemic control and greater reductions in body weight and systolic blood pressure than the addition of linagliptin. Clinical Trial Registration #: NCT03458715.

Topics: Benzhydryl Compounds; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Glucosides; Humans; Hypoglycemic Agents; Insulin; Linagliptin; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

This 24-week, double-blind, placebo-controlled, phase III trial evaluated the efficacy and safety of linagliptin in 206 Chinese patients with inadequately controlled (glycated haemoglobin [HbA1c] 7.5%-10.0%) type 2 diabetes mellitus (T2DM) receiving insulin (basal or premixed) ± metformin. Patients were randomized (1:1) to receive linagliptin 5 mg/d or placebo. The decrease from baseline in HbA1c (primary endpoint) was greater with linagliptin than with placebo (-0.61% vs. -0.20%, adjusted mean difference -0.40%; P = 0.0016). Linagliptin demonstrated significantly greater improvement in 2-hour postprandial glucose (-1.77 mmol/L [-31.95 mg/dL]; P < 0.001), and a numerical reduction in fasting plasma glucose (-0.34 mmol/L [-6.2 mg/dL]; P = 0.2241) versus placebo. Proportionally more patients on linagliptin achieved a HbA1c reduction of ≥0.5% versus those on placebo (odds ratio 2.293, P < 0.01). Adverse events in both groups were similar, with no new safety findings or clinically relevant changes in body weight. Among investigator-defined hypoglycaemic events (linagliptin: 17.3%; placebo: 12.7%; odds ratio 1.48, P = 0.337), none were severe. In Chinese patients with T2DM, linagliptin add-on to insulin improved glycaemic control and was well tolerated, without increased risk of hypoglycaemia or weight gain.

Topics: Blood Glucose; China; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Linagliptin; Treatment Outcome

To compare the cardiovascular (CV) safety of linagliptin with glimepiride in older and younger participants in the CAROLINA trial in both prespecified and post hoc analyses.. People aged 40 to 85 years with relatively early type 2 diabetes, inadequate glycaemic control and elevated CV risk were randomly assigned to linagliptin 5 mg or glimepiride 1 to 4 mg. The primary endpoint was time to first occurrence of three-point major adverse CV events (MACE: CV death, non-fatal myocardial infarction, or non-fatal stroke). We evaluated clinical and safety outcomes across age groups.. Of 6033 participants, 50.7% were aged <65 years, 35.3% were aged 65 to 74 years, and 14.0% were aged ≥75 years. During the 6.3-year median follow-up, CV/mortality outcomes did not differ between linagliptin and glimepiride overall (hazard ratio [HR] for three-point MACE 0.98, 95.47% confidence interval [CI] 0.84, 1.14) or across age groups (interaction P >0.05). Between treatment groups, reductions in glycated haemoglobin were comparable across age groups but moderate-to-severe hypoglycaemia was markedly reduced with linagliptin (HR 0.18, 95% CI 0.15, 0.21) with no differences among age groups (P = 0.23). Mean weight was -1.54 kg (95% CI -1.80, -1.28) lower for linagliptin versus glimepiride. Adverse events increased with age, but were generally balanced between treatment groups. Significantly fewer falls or fractures occurred with linagliptin.. Linagliptin and glimepiride were comparable for CV/mortality outcomes across age groups. Linagliptin had significantly lower risk of hypoglycaemia and falls or fractures than glimepiride, including in "older-old" individuals for whom these are particularly important treatment considerations.

Topics: Adult; Aged; Aged, 80 and over; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Double-Blind Method; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Linagliptin; Middle Aged; Sulfonylurea Compounds; Treatment Outcome

We validated the effect of linagliptin, an oral dipeptidyl peptidase-4 inhibitor, on nonalcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM). A total of 50 patients with NAFLD and T2DM treated with metformin were randomized (1:1) to metformin plus add-on linagliptin (linagliptin group) or to an increased dose of metformin (metformin group) for 52 weeks. The primary endpoint was change in hepatic steatosis from baseline to week 52 as quantified by unenhanced computed tomography imaging. Secondary endpoints included changes in the levels of anthropometric, biochemical and adipokinetic markers. The linagliptin group showed no statistically significant reduction in hepatic steatosis as compared to the metformin group (P = 0.97), although changes in hepatic steatosis were significantly correlated with decreased liver enzymes in both groups. Body weight was significantly reduced in the metformin group but not in the linagliptin group (P = 0.002). Serum leptin levels were significantly increased in the linagliptin group compared to the metformin group (P = 0.003), and were correlated with the changes body weight in whole samples. Adverse events were not different between the two groups (P = 0.78). Add-on linagliptin demonstrated a safe profile but was not superior to increased metformin in reducing hepatic steatosis.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Linagliptin; Metformin; Non-alcoholic Fatty Liver Disease; Purines; Quinazolines; Treatment Outcome

This trial was conducted to assess the long-term safety, efficacy, and benefit of early add-on of linagliptin to insulin in patients with type 2 diabetes mellitus (T2DM).. This trial enrolled 246 subjects. The subjects were randomized to the linagliptin group or the control group and were observed for 156 weeks. After week 16, subjects in the control group were also allowed to add linagliptin to evaluate the benefit of early add-on of linagliptin to insulin. The primary end point was a change in HbA1c from baseline to week 16. Secondary end points included fasting plasma glucose, daily insulin dose, and frequency of adverse events.. HbA1c and fasting plasma glucose levels significantly decreased from baseline to week 16 in the linagliptin group compared with the control group. The significant improvement in HbA1c continued until week 52. The daily insulin dose significantly decreased in the linagliptin group compared with the control group. The frequency of hypoglycemia and adverse events was comparable in both groups.. Add-on of linagliptin to insulin was tolerated, improved glycemic control, and reduced the daily insulin dose. This study demonstrates the long-term safety, efficacy and benefit of early add-on of linagliptin to insulin in Japanese T2DM patients.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Japan; Linagliptin; Treatment Outcome

Type 2 diabetes, particularly with concomitant CVD, is associated with an increased risk of cognitive impairment. We assessed the effect on accelerated cognitive decline (ACD) of the DPP-4 inhibitor linagliptin vs the sulfonylurea glimepiride in individuals with type 2 diabetes.. In a large, international outcome trial in people with relatively early type 2 diabetes at elevated cardiovascular risk, no difference in risk for ACD was observed between linagliptin and glimepiride over 6.1 years.. This study was sponsored by Boehringer Ingelheim.. ClinicalTrials.gov NCT01243424.

Topics: Aged; Blood Glucose; Cognition; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Humans; Hypoglycemic Agents; Linagliptin; Male; Middle Aged; Neuropsychological Tests; Sulfonylurea Compounds; Treatment Outcome

To evaluate the effect of linagliptin on left ventricular systolic function beyond glycaemic control in type 2 diabetes mellitus.. A multicentre, randomised, double-blind, placebo controlled, parallel-group study, was performed (the DYDA 2 trial). Individuals with type 2 diabetes mellitus and asymptomatic impaired left ventricular systolic function were randomly allocated in a 1:1 ratio to receive for 48 weeks either linagliptin 5 mg daily or placebo, in addition to their diabetes therapy. Eligibility criteria were age 40 years and older, haemoglobin A1c 8.0% or less (≤64 mmol/mol), no history of cardiac disease, concentric left ventricular geometry (relative wall thickness ≥0.42), impaired left ventricular systolic function defined as midwall fractional shortening 15% or less at baseline echocardiography. The primary end point was the modification of midwall fractional shortening over time. The main secondary objectives were changes in diastolic and/or in longitudinal left ventricular systolic function as measured by tissue Doppler echocardiography. One hundred and eighty-eight patients were enrolled, predominantly men with typical insulin-resistance comorbidities. At baseline, mean midwall fractional shortening was 13.3%±2.5. At final evaluation, 88 linagliptin patients and 86 placebo patients were compared: midwall fractional shortening increased from 13.29 to 13.82 (+4.1%) in the linagliptin group, from 13.58 to 13.84 in the placebo group (+1.8%, analysis of covariance P = 0.86), corresponding to a 2.3-fold higher increase in linagliptin than the placebo group, although non-statistically significant. Also, changes in diastolic and longitudinal left ventricular systolic function did not differ between the groups. Serious adverse events or linagliptin/placebo permanent discontinuation occurred in very few cases and in the same percentage between the groups.. In the DYDA 2 patients the addition of linagliptin to stable diabetes therapy was safe and provided a modest non-significant increase in left ventricular systolic function measured as midwall fractional shortening.. ClinicalTrial.gov (ID NCT02851745).

Topics: Adult; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glycated Hemoglobin; Humans; Linagliptin; Male; Ventricular Dysfunction, Left; Ventricular Function, Left

Results of a post hoc analysis of urinary dipeptidyl peptidase-4 (DPP-4) protein as a predictor of urine albumin-to-creatinine ratio (UACR) response to linagliptin treatment based on MARLINA-T2D trial data are described. MARLINA was a 24-week, phase 3b, multinational, placebo-controlled clinical trial, in which patients with type 2 diabetes (T2D), HbA1c 6.5%-10.0% and UACR 30-3000 mg/g (n = 360) were treated with linagliptin or placebo. After 24 weeks of treatment, linagliptin significantly inhibited urinary DPP-4 activity and increased urinary DPP-4 protein. Furthermore, medium urinary DPP-4 protein levels (between 5.5 and 7.5 natural logarithmic [ln] μg/g creatinine) at baseline allowed for prediction of improved UACR in linagliptin-treated individuals. In patients with lower or higher levels of urinary DPP-4 protein at baseline, no association between linagliptin treatment and improved UACR was present. This might suggest a varying degree of importance of DPP-4 as a pathophysiological factor in T2D-associated kidney disease. In summary, urinary DPP-4 might be a useful predictive biomarker for UACR improvement by linagliptin.

Topics: Albumins; Biomarkers; Creatinine; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Humans; Linagliptin

Preserved vascular function represents a key prognostic factor in type 2 diabetes mellitus (T2DM), but data on vascular parameters in this patient cohort are scarce. Patients with T2DM often need more than one drug to achieve optimal glucose control. The aim of this study was to analyse the efficacy of two combination therapies on vascular function in subjects with T2DM.. This prospective, randomized study included 97 subjects with T2DM. Subjects were randomized to either the combination therapy empagliflozin (E) 10 mg with linagliptin (L) 5 mg once daily or metformin (M) 850 or 1000 mg twice daily with insulin glargine (I) once daily. At baseline and after 12 weeks, subjects had peripheral office and 24-h ambulatory blood pressure (BP) measurement and underwent vascular assessment by pulse wave analysis under office and ambulatory conditions. Office, 24-h ambulatory and central BP as well as pulse pressure (PP) decreased after 12 weeks of treatment with E + L, whereas no change was observed in M + I. There were greater decreases in 24-h ambulatory peripheral systolic (between-group difference: -5.2 ± 1.5 mmHg, P = 0.004), diastolic BP (-1.9 ± 1.0 mmHg, P = 0.036), and PP (-3.3 ± 1.0 mmHg, P = 0.007) in E + L than M + I. Central office systolic BP (-5.56 ± 1.9 mmHg, P = 0.009), forward pressure height of the pulse wave (-2.0 ± 0.9 mmHg, P = 0.028), 24-h ambulatory central systolic (-3.6 ± 1.4 mmHg, P = 0.045), diastolic BP (-1.95 ± 1.1 mmHg, P = 0.041), and 24-h pulse wave velocity (-0.14 ± 0.05m/s, P = 0.043) were reduced to a greater extent with E + L.. Beyond the effects on glycaemic control, the combination therapy of E + L significantly improved central BP and vascular function compared with the classic combination of M + I.. NCT02752113.

Topics: Aged; Arterial Pressure; Benzhydryl Compounds; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Female; Germany; Glucosides; Humans; Insulin Glargine; Linagliptin; Male; Metformin; Middle Aged; Prospective Studies; Sodium-Glucose Transporter 2 Inhibitors; Time Factors; Treatment Outcome; Vascular Stiffness

Prediabetes is a highly prevalent health problem with a high risk of complications and progression to type 2 diabetes (T2D). The goals of this study were to evaluate the effect of the combination of lingaliptin + metformin + lifestyle on glucose tolerance, pancreatic β-cell function and T2D incidence in patients with prediabetes.. A single center parallel double-blind randomized clinical trial with 24 months of follow-up in patients with impaired glucose tolerance plus two T2D risk factors which were randomized to linagliptin 5 mg + metformin 1700 mg daily + lifestyle (LM group) or metformin 1700 mg daily + lifestyle (M group). Primary outcomes were regression to normoglycemia and T2D incidence; glucose levels and pancreatic β-cell function were secondary outcomes.. Subjects were screened for eligibility by OGTT and 144 patients with prediabetes were randomized to LM group (n = 74) or M group (n = 70); 52 and 36 participants in the LM group and 52 and 27 participants in the M group, completed the 12 and 24 months of treatment, respectively; average follow-up was 17 ± 6 and 18 ± 7 months in M and LM group, respectively. Glucose levels during OGTT improved more in LM group. OGTT disposition index (DI) improved significantly better during the first months in LM group, increasing from 1·31 (95% CI: 1·14-1·49) to 2·41 (95% CI: 2.10-2.72) and to 2.07 (95% CI: 1.82-2.31) at 6 and 24 months in LM group vs from 1.21 (95% CI: 0.98-1.34) to 1.56 (95% CI: 1.17-1.95) and to 1.72 (95% CI: 1.45-1.98) at 6 and 24 months in M group (p < .05). T2D incidence was higher in M group in comparison to LM group (HR 4.0, 95% CI: 1.24-13.04, p = .020). The probability of achieving normoglycemia was higher in LM group (OR 3.26 CI 95% 1.55-6.84). No major side effects were observed during the study.. The combination of linagliptin, metformin and lifestyle improved significantly glucose metabolism and pancreatic β-cell function, and reduced T2D incidence in subjects with prediabetes as compared to metformin and lifestyle.

Topics: Adult; Aged; Blood Glucose; Combined Modality Therapy; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Follow-Up Studies; Glucose Intolerance; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Insulin-Secreting Cells; Life Style; Linagliptin; Male; Metformin; Middle Aged; Treatment Outcome

In CARMELINA®, linagliptin demonstrated cardiovascular and renal safety in patients with type 2 diabetes (T2D) with high renal and cardiovascular disease (CVD) risk. We investigated safety and efficacy of this dipeptidyl peptidase-4 inhibitor in older participants.. Subjects aged ≥18 years with T2D and established CVD with urinary albumin-to-creatinine ratio (UACR) >30 mg/g, and/or prevalent kidney disease, were randomized to linagliptin or placebo added to usual care. The primary endpoint (time to first occurrence of 3P-MACE: cardiovascular death, non-fatal myocardial infarction or non-fatal stroke) and other outcomes were evaluated across age groups <65 (n = 2968), 65 to <75 (n = 2800) and ≥75 years (n = 1211).. Mean age was 65.9 years (17.4% and 5.9% aged ≥75 and 80, respectively) and median follow-up was 2.2 years. The hazard ratio (HR) for 3P-MACE with linagliptin versus placebo was 1.02 [95% confidence interval (CI) 0.89, 1.17] with no significant interaction between age and treatment effect (P = 0.0937). HRs for participants aged <65, 65 to <75 and ≥75 years were 1.11 (95% CI 0.89, 1.40), 1.09 (0.89, 1.33) and 0.76 (0.57, 1.02), respectively. Linagliptin did not increase the risk of adverse kidney outcomes or hospitalization for heart failure across age groups. The incidence of adverse events, including hypoglycaemia, increased with age but was similar with linagliptin and placebo despite glycated haemoglobin A1c reduction with linagliptin.. Linagliptin did not increase risk for cardiovascular events or hypoglycaemia and kidney function remained stable in older people with T2D and established CVD with albuminuria and/or kidney disease.

Topics: Adolescent; Adult; Aged; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Kidney; Kidney Diseases; Linagliptin; Treatment Outcome

Topics: Aged; Albuminuria; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Hospitalization; Humans; Hypoglycemic Agents; Kidney Diseases; Linagliptin; Male; Middle Aged

Angiogenic T (Tang) cells are mediators of vascular repair, and are characterized by surface expression of CXCR4. This receptor for stromal cell-derived factor-1α (SDF-1α) is cleaved by dipeptidyl peptidase-4 (DPP-4). Tang cell levels were investigated in people with type 2 diabetes mellitus (T2DM) compared with matched healthy controls and after treatment with the DPP-4 inhibitor Linagliptin. People with T2DM were randomized to 5 mg/day Linagliptin (n = 20) or placebo (n = 21) for 26 weeks. Tang cell frequency was identified in peripheral blood mononuclear cells (CD3

Topics: Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Leukocytes, Mononuclear; Linagliptin; T-Lymphocytes

To assess the effects of early management of hyperglycaemia with antidiabetic drugs plus lifestyle intervention compared with lifestyle alone, on microvascular function in adults with pre-diabetes.. Trial design: International, multicenter, randomised, partially double-blind, placebo-controlled, clinical trial.. Males and females aged 45-74 years with IFG, IGT or IFG+IGT, recruited from primary care centres in Australia, Austria, Bulgaria, Greece, Kuwait, Poland, Serbia, Spain and Turkey.. Participants were randomized to placebo; metformin 1.700 mg/day; linagliptin 5 mg/day or fixed-dose combination of linagliptin/metformin. All patients were enrolled in a lifestyle intervention program (diet and physical activity). Drug intervention will last 2 years. Primary Outcome: composite end-point of diabetic retinopathy estimated by the Early Treatment Diabetic Retinopathy Study Score, urinary albumin to creatinine ratio, and skin conductance in feet estimated by the sudomotor index. Secondary outcomes in a subsample include insulin sensitivity, beta-cell function, biomarkers of inflammation and fatty liver disease, quality of life, cognitive function, depressive symptoms and endothelial function.. One thousand three hundred ninety one individuals with hyperglycaemia were assessed for eligibility, 424 excluded after screening, 967 allocated to placebo, metformin, linagliptin or to fixed-dose combination of metformin + linagliptin. A total of 809 people (91.1%) accepted and initiated the assigned treatment. Study sample after randomization was well balanced among the four groups. No statistical differences for the main risk factors analysed were observed between those accepting or rejecting treatment initiation. At baseline prevalence of diabetic retinopathy was 4.2%, severe neuropathy 5.3% and nephropathy 5.7%.. ePREDICE is the first -randomized clinical trial with the aim to assess effects of different interventions (lifestyle and pharmacological) on microvascular function in people with pre-diabetes. The trial will provide novel data on lifestyle modification combined with glucose lowering drugs for the prevention of early microvascular complications and diabetes.. - ClinicalTrials.Gov Identifier: NCT03222765 - EUDRACT Registry Number: 2013-000418-39.

Topics: Aged; Diabetes Complications; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Double-Blind Method; Europe; Female; Galvanic Skin Response; Humans; Hyperglycemia; International Cooperation; Life Style; Linagliptin; Male; Metformin; Microcirculation; Middle Aged; Patient Selection; Research Design; Risk Factors

To investigate the efficacy and safety of evogliptin compared with linagliptin in patients with type 2 diabetes.. In this 12-week, multicentre, randomized, double-blind, active-controlled, and 12-week open-label extension study, a total of 207 patients with type 2 diabetes who had HbA1c levels of 7.0%-10.0% were randomized 1:1 to receive evogliptin 5 mg (n = 102) or linagliptin 5 mg (n = 105) daily for 12 weeks. The primary efficacy endpoint was the change from baseline HbA1c at week 12. The secondary endpoint was the change in the mean amplitude of glycaemic excursion (MAGE) assessed by continuous glucose monitoring. In the extension study conducted during the following 12 weeks, evogliptin 5 mg daily was administered to both groups: evogliptin/evogliptin group (n = 95) and linagliptin/evogliptin group (n = 92).. After 12 weeks of treatment, the mean change in HbA1c in the evogliptin group and in the linagliptin group was -0.85% and -0.75%, respectively. The between-group difference was -0.10% (95% CI: -0.32 to 0.11), showing non-inferiority based on a non-inferiority margin of 0.4%. The change in MAGE was -24.6 mg/dL in the evogliptin group and -16.7 mg/dL in the linagliptin group. These values were significantly lower than the baseline values in both groups. However, they did not differ significantly between the two groups. In the evogliptin/evogliptin group at week 24, HbA1c decreased by -0.94%, with HbA1c values of <7.0% in 80.2% of the patients. The incidence and types of adverse events were comparable between the two groups for 24 weeks.. In this study, the glucose-lowering efficacy of evogliptin was non-inferior to linagliptin. It was maintained at week 24 with a 0.94% reduction in HbA1c. Evogliptin therapy improved glycaemic variability without causing any serious adverse events in patients with type 2 diabetes.

Topics: Blood Glucose; Blood Glucose Self-Monitoring; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Linagliptin; Piperazines; Treatment Outcome

Fixed-dose combination (FDC) therapy can improve outcomes in type 2 diabetes (T2D). We evaluated the bioequivalence of 2 doses of an FDC of extended-release metformin (metformin XR), empagliflozin, a sodium-glucose co-transporter 2 inhibitor, and linagliptin, a dipeptidyl peptidase-4 inhibitor, versus corresponding free tablet combinations.. Two randomized, open-label, two-way crossover studies in healthy adults compared: 2 FDC tablets of empagliflozin 5 mg/linagliptin 2.5 mg/metformin XR 1000 mg (Study 1; N = 30), 1 FDC tablet of empagliflozin 25 mg/linagliptin 5 mg/metformin XR 1000 mg (Study 2; N = 30) versus corresponding dose of free combinations. Subjects received study medication under fed conditions; washout was ≥35 days between treatments. Primary endpoints: area under the plasma concentration-time curve (AUC) from time 0 to last quantifiable data point for empagliflozin and metformin; AUC from time 0 to 72 hours for linagliptin, and peak plasma concentration (C. Study 1: 27/29 and 28/30 treated participants were included in the pharmacokinetic analysis for the FDC and free combination periods, respectively. Study 2: 29/29 treated participants were included in the pharmacokinetic analysis for both periods. The adjusted geometric mean ratios of FDCs to their respective free tablet combinations and two-sided 90% CIs were all within the predefined range. The shapes of the mean plasma concentration-time profile of empagliflozin, linagliptin, and metformin XR were similar for subjects in the FDC and free combination groups in both studies. No serious adverse events were reported.. The evaluated doses of empagliflozin/linagliptin/metformin XR FDC tablets were bioequivalent to the corresponding free combinations. Based on these two bioequivalence studies and existing phase 3 data, the FDA has recently approved this triple FDC to improve glycemic control in adults with T2D.

Topics: Adolescent; Adult; Area Under Curve; Benzhydryl Compounds; Cross-Over Studies; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Drug Combinations; Female; Glucosides; Humans; Hypoglycemic Agents; Linagliptin; Male; Medication Adherence; Metformin; Middle Aged; Therapeutic Equivalency; Young Adult

Type 2 diabetes is a leading cause of kidney failure, but few outcome trials proactively enrolled individuals with chronic kidney disease (CKD). We performed secondary analyses of cardiovascular (CV) and kidney outcomes across baseline estimated glomerular filtration rate (eGFR) categories (≥60, 45 to <60, 30 to <45, and <30 mL/min/1.73 m. Participants with CV disease and/or CKD were included. The primary outcome was time to first occurrence of CV death, nonfatal myocardial infarction, or nonfatal stroke (three-point major adverse CV event [3P-MACE]), with a secondary outcome of renal death, end-stage kidney disease, or sustained ≥40% decrease in eGFR from baseline. Other end points included progression of albuminuria, change in HbA. A total of 6,979 subjects (mean age 65.9 years; eGFR 54.6 mL/min/1.73 m. Across all GFR categories, in participants with type 2 diabetes and CKD and/or CV disease, there was no difference in risk for linagliptin versus placebo on CV and kidney events. Significant reductions in risk for albuminuria progression and HbA

Topics: Aged; Cardiovascular Diseases; Cardiovascular System; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Female; Glomerular Filtration Rate; Humans; Hypoglycemic Agents; Incidence; Kidney; Kidney Failure, Chronic; Linagliptin; Male; Middle Aged; Mortality; Prognosis; Renal Insufficiency, Chronic; Retrospective Studies; Treatment Outcome

To determine the glucose-independent effect of the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin versus the sulphonylurea glimepiride on systemic haemodynamics in the fasting and postprandial state in patients with type 2 diabetes (T2D).. In this prespecified secondary analysis of a phase IV, double-blind trial, 46 metformin-treated, overweight patients with T2D were included and randomly assigned (1:1) to once-daily linagliptin (5 mg) or glimepiride (1 mg) for 8 weeks. In a sub-study involving 26 patients, systemic haemodynamics were also assessed following a standardized liquid meal (Nutridrink Yoghurt style). Systemic haemodynamics (oscillometric device and finger photoplethysmography), arterial stiffness (applanation tonometry) and cardiac sympathovagal balance (heart rate variability [HRV]) were measured in the fasting state and repetitively following the meal. Ewing tests were performed in the fasting state.. From baseline to week 8, linagliptin compared with glimepiride did not affect systemic haemodynamics, arterial stiffness or HRV in the fasting state. Linagliptin increased parasympathetic nervous activity, as measured by the Valsalva manoeuvre (P = .021) and deep breathing test (P = .027) compared with glimepiride. Postprandially, systolic blood pressure (SBP) dropped an average of 7.6 ± 1.6 mmHg. Linagliptin reduced this decrease to 0.7 ± 2.3 mmHg, which was significant to glimepiride (P = .010).. When compared with glimepiride, linagliptin does not affect fasting blood pressure. However, linagliptin blunted the postprandial drop in SBP, which could benefit patients with postprandial hypotension.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Double-Blind Method; Glycated Hemoglobin; Hemodynamics; Humans; Hypoglycemic Agents; Linagliptin; Overweight; Sulfonylurea Compounds; Treatment Outcome

Endothelial Progenitor cells (EPCs) has been shown to be dysfunctional in both type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) leading to poor regeneration of endothelium and renal perfusion. EPCs have been shown to be a robust cardiovascular disease (CVD) risk indicator. Cellular mechanisms of DPP4 inhibitors such as linagliptin (LG) on CVD risk, in patients with T2DM with established CKD has not been established. Linagliptin, a DPP4 inhibitor when added to insulin, metformin or both may improve endothelial dysfunction in a diabetic kidney disease (DKD) population.. 31 subjects taking metformin and/or Insulin were enrolled in this 12 weeks, double blind, randomized placebo matched trial, with 5 mg LG compared to placebo. Type 2 diabetes subjects (30-70 years old), HbA1c of 6.5-10%, CKD Stage 1-3 were included. CD34+ cell number, migratory function, gene expression along with vascular parameters such as arterial stiffness, biochemistry, resting energy expenditure and body composition were measured. Data were collected at week 0, 6 and 12. A mixed model regression analysis was done with p value < 0.05 considered significant.. A double positive CD34/CD184 cell count had a statistically significant increase (p < 0.02) as determined by flow cytometry in LG group where CD184 is SDF1a cell surface receptor. Though mRNA differences in CD34+ve was more pronounced CD34- cell mRNA analysis showed increase in antioxidants (superoxide dismutase 2 or SOD2, Catalase and Glutathione Peroxidase or GPX) and prominent endothelial markers (PECAM1, VEGF-A, vWF and NOS3). Arterial stiffness measures such as augmentation Index (AI) (p < 0.04) and pulse wave analysis (PWV) were improved (reduced in stiffness) in LG group. A reduction in LDL: HDL ratio was noted in treatment group (p < 0.04). Urinary exosome protein examining podocyte health (podocalyxin, Wilms tumor and nephrin) showed reduction or improvement.. In DKD subjects, Linagliptin promotes an increase in CXCR4 expression on CD34 + progenitor cells with a concomitant improvement in vascular and renal parameters at 12 weeks. Trial Registration Number NCT02467478 Date of Registration: 06/08/2015.

Topics: Adult; Aged; Antigens, CD34; Biomarkers; Cells, Cultured; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; District of Columbia; Double-Blind Method; Drug Therapy, Combination; Endothelial Progenitor Cells; Female; Humans; Hypoglycemic Agents; Insulin; Linagliptin; Male; Metformin; Middle Aged; Pilot Projects; Receptors, CXCR4; Renal Insufficiency, Chronic; Time Factors; Treatment Outcome

To compare effects of the dipeptidyl peptidase 4 (DPP-4) inhibitor linagliptin with those of a sulfonylurea on renal physiology in metformin-treated patients with type 2 diabetes mellitus (T2DM).. In this double-blind randomized trial, 46 overweight T2DM patients without renal impairment received once-daily linagliptin (5 mg) or glimepiride (1 mg) for 8 weeks. Fasting glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were determined by inulin and para-aminohippuric acid clearances. Fractional excretions, urinary damage markers, and circulating DPP-4 substrates (among others, glucagon-like peptide 1 and stromal cell-derived factor-1α [SDF-1α]) were measured.. HbA. Linagliptin does not affect fasting renal hemodynamics compared with glimepiride in T2DM patients. DPP-4 inhibition promotes modest natriuresis, possibly mediated by SDF-1α, likely distal to the macula densa.

Topics: Adult; Aged; Chemokine CXCL12; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Glycated Hemoglobin; Humans; Kidney; Linagliptin; Male; Metformin; Middle Aged; Natriuresis; Overweight; Sulfonylurea Compounds; Treatment Outcome

Type 2 diabetes is associated with cognitive dysfunction and an increased dementia risk, particularly in individuals with concomitant cardiovascular and/or kidney disease. Incretin therapies may modulate this risk via glycemic and nonglycemic pathways. We explored if the dipeptidyl peptidase 4 inhibitor linagliptin could prevent cognitive decline in people with type 2 diabetes with cardiorenal disease.. The CArdiovascular and Renal Microvascular outcomE study with LINAgliptin (CARMELINA)-COG substudy was an integral part of CARMELINA (NCT01897532) that randomized participants with cardiorenal disease to linagliptin 5 mg or placebo once daily (1:1), in addition to standard of care. The primary cognitive outcome was the occurrence of accelerated cognitive decline at the end of treatment, defined as a regression-based index score ≤16th percentile on the Mini-Mental State Examination (MMSE) or a composite measure of attention and executive functioning and analyzed in participants with a baseline MMSE ≥24. Effects across subgroups by baseline factors, as well as absolute cognitive changes, were also assessed.. In a large international cardiovascular outcome trial in people with type 2 diabetes and cardiorenal disease, linagliptin did not modulate cognitive decline over 2.5 years.

Topics: Aged; Blood Glucose; Cardiovascular Diseases; Cognition; Cognitive Dysfunction; Comorbidity; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Glomerular Filtration Rate; Humans; Incretins; Kidney; Kidney Diseases; Linagliptin; Male; Middle Aged; Treatment Outcome

A multicentre, randomized, double-blind, placebo-controlled, parallel-group study aimed to define the potential positive effect of dipeptidyl peptidase-4 inhibition on left ventricular systolic function (LVSF) beyond glycemic control in type 2 diabetes mellitus (T2DM) (DYDA 2™ trial).. Individuals with fairly controlled T2DM and asymptomatic impaired LVSF were randomized in a 1:1 ratio to receive for 48 weeks either linagliptin 5 mg daily or placebo, in addition to their stable diabetes therapy. Eligibility criteria were age ≥ 40 years, history of T2DM with a duration of at least 6 months, HbA1c ≤ 8.0% (≤ 64 mmol/mol), no history or clinical signs/symptoms of cardiac disease, evidence at baseline echocardiography of concentric LV geometry (relative wall thickness ≥ 0.42), and impaired LVSF defined as midwall fractional shortening (MFS) ≤ 15%. The primary end-point was the modification from baseline to 48 weeks of MFS. As an exploratory analysis, significant changes in LV global longitudinal strain and global circumferential strain, measured by speckle tracking echocardiography, were also considered. Secondary objectives were changes in diastolic and/or in systolic longitudinal function as measured by tissue Doppler.. A total of 188 patients were enrolled. They were predominantly males, mildly obese, with typical insulin-resistance co-morbidities such as hypertension and dyslipidemia. Mean relative wall thickness was 0.51 ± 0.09 and mean MFS 13.3% ± 2.5.. DYDA 2 is the first randomized, double-blind, placebo-controlled trial to explore the effect of a dipeptidyl peptidase-4 inhibitor on LVSF in T2DM patients in primary prevention regardless of glycemic control. The main characteristics of the enrolled population are reported.. ClinicalTrial.gov Identifier: NCT02851745.

Topics: Adult; Aged; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Female; Glycated Hemoglobin; Humans; Italy; Linagliptin; Male; Middle Aged; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Time Factors; Treatment Outcome; Ventricular Dysfunction, Left; Ventricular Function, Left; Ventricular Remodeling

An estimated 4.3 million people aged ≥ 65 years with diabetes live in Japan. We evaluated the efficacy and safety of linagliptin in older Japanese patients with poorly controlled type 2 diabetes (T2DM).. In this phase 4, randomised, placebo-controlled national study (part of a global study) conducted in Japan over a period of 52 weeks, 102 patients on stable treatment with basal insulin ± metformin/alpha-glucosidase inhibitors were randomised (1:1) to receive linagliptin 5 mg qd or placebo. The primary end point was the change in glycated haemoglobin (HbA1c) after 24 weeks of treatment, with additional analyses at 52 weeks.. Mean age and HbA1c of the study population were 71 years and 8.1%, respectively. Approximately two-thirds of participants were aged ≥ 70 years, two-thirds had macrovascular complications, approximately half had a baseline estimated glomerular filtration rate < 60 ml/min/1.73 m. Linagliptin was effective in improving glucose control in Japanese patients aged ≥ 60 years with T2DM on stable glucose-lowering therapy with basal insulin. Linagliptin was well tolerated and no new safety concerns were raised. The results presented here are highly consistent with the results from the global study, which was conducted over a 24-week period.. ClinicalTrials.gov identifier, NCT02240680.. Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance.

Topics: Aged; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glomerular Filtration Rate; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Japan; Linagliptin; Male; Metformin; Middle Aged

This two-part, double-blind, double-dummy, randomized, placebo-controlled trial (83 sites) evaluated the efficacy and safety of empagliflozin (Empa) 10 or 25 mg and linagliptin (Lina) 5 mg fixed-dose combinations (FDCs) in Japanese patients with type 2 diabetes mellitus (T2DM) who were poorly controlled with Empa.. Patients (previously drug-naive or using one oral antidiabetic drug for ≥ 12 weeks) entered an open-label stabilization period (16 weeks, Empa 10 mg [Part A] or Empa 25 mg [Part B]). Subsequently, they received Empa 10 mg plus placebo (Plc) for Empa/Lina10/5 (Empa/Plc 10/5; Part A) or Empa 25 mg plus Plc for Empa/Lina 25/5 (Empa/Plc 25/5; Part B) for 2 weeks. Patients with HbA1c 7.5-10.0% were randomized (1:1) to a 24-week regimen of once-daily Empa/Lina 10/5 (n = 107) or Empa/Plc 10/5 (n = 108) in Part A, or to Empa/Lina 25/5 (n = 116) or Empa/Plc 25/5 (n = 116) in Part B, with a 28-week extension period in Part B.. Change from baseline in HbA1c at Week 24 was greater (P < 0.0001) with Empa/Lina than with Empa/Plc (primary outcome, Empa/Lina 10/5: -0.94 vs -0.12%; adjusted mean difference, -0.82%; Empa/Lina 25/5: -0.91 vs -0.33%; adjusted mean difference, -0.59%). Over 24- and 52-week periods, higher proportions of patients achieved HbA1c < 7.0% and greater decreases in fasting plasma glucose were observed with Empa/Lina compared with Empa/Plc. Empa/Lina was well tolerated, with no unexpected adverse events or diabetic ketoacidosis. One case of confirmed hypoglycaemia with Empa/Plc 25/5 was reported.. These results support Empa/Lina FDC as a potential option for Japanese patients with T2DM who require combination therapy. ClinicalTrials.gov NCT02489968.

Topics: Adult; Aged; Benzhydryl Compounds; Blood Glucose; Diabetes Mellitus, Type 2; Drug Combinations; Female; Glucosides; Humans; Hypoglycemic Agents; Japan; Linagliptin; Male; Middle Aged

The present study investigated the effect of high-dose metformin or low-dose metformin/linagliptin combination therapy on glycemic variability (GV) in type 2 diabetes patients with insufficient glycemic control despite low-dose metformin monotherapy in a cross-over study using continuous glucose monitoring.. The present study was carried out with 11 type 2 diabetes outpatients (7% < glycated hemoglobin < 10%) receiving low-dose metformin monotherapy (500-1,000 mg). All patients were assigned to either metformin 1,500 mg monotherapy (HMET) or combination therapy of low-dose (750 mg) metformin and linagliptin 5 mg (LMET + dipeptidyl peptidase-4 [DPP4]). GV was evaluated by continuous glucose monitoring after >4 weeks of the initial treatment and again after cross-over to the other treatment. GV metrics were compared between the treatments using the Wilcoxon signed-rank test.. Of the continuous glucose monitoring-derived GV metrics for the HMET versus LMET + DPP4, mean glucose levels, standard deviations and mean amplitude of glucose excursions were not significantly different. Although the pre-breakfast glucose levels were not significantly different among the treatments (P = 0.248), the 3-h postprandial glucose area under the curve (>160 mg/dL) after breakfast was significantly larger with HMET versus LMET + DPP4 (9,550 [2,075-11,395] vs 4,065 [1,950-8,895]; P = 0.041).. A comparison of GV with HMET versus LMET + DPP4 suggested that LMET + DPP4 might reduce post-breakfast GV to a greater degree than HMET in type 2 diabetes patients receiving low-dose metformin monotherapy.

Topics: Biomarkers; Blood Glucose; Blood Glucose Self-Monitoring; Cross-Over Studies; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Follow-Up Studies; Glycated Hemoglobin; Glycemic Index; Humans; Hypoglycemic Agents; Linagliptin; Male; Metformin; Middle Aged; Prognosis

Type 2 diabetes is associated with increased cardiovascular (CV) risk. Prior trials have demonstrated CV safety of 3 dipeptidyl peptidase 4 (DPP-4) inhibitors but have included limited numbers of patients with high CV risk and chronic kidney disease.. To evaluate the effect of linagliptin, a selective DPP-4 inhibitor, on CV outcomes and kidney outcomes in patients with type 2 diabetes at high risk of CV and kidney events.. Randomized, placebo-controlled, multicenter noninferiority trial conducted from August 2013 to August 2016 at 605 clinic sites in 27 countries among adults with type 2 diabetes, hemoglobin A1c of 6.5% to 10.0%, high CV risk (history of vascular disease and urine-albumin creatinine ratio [UACR] >200 mg/g), and high renal risk (reduced eGFR and micro- or macroalbuminuria). Participants with end-stage renal disease (ESRD) were excluded. Final follow-up occurred on January 18, 2018.. Patients were randomized to receive linagliptin, 5 mg once daily (n = 3494), or placebo once daily (n = 3485) added to usual care. Other glucose-lowering medications or insulin could be added based on clinical need and local clinical guidelines.. Primary outcome was time to first occurrence of the composite of CV death, nonfatal myocardial infarction, or nonfatal stroke. Criteria for noninferiority of linagliptin vs placebo was defined by the upper limit of the 2-sided 95% CI for the hazard ratio (HR) of linagliptin relative to placebo being less than 1.3. Secondary outcome was time to first occurrence of adjudicated death due to renal failure, ESRD, or sustained 40% or higher decrease in eGFR from baseline.. Of 6991 enrollees, 6979 (mean age, 65.9 years; eGFR, 54.6 mL/min/1.73 m2; 80.1% with UACR >30 mg/g) received at least 1 dose of study medication and 98.7% completed the study. During a median follow-up of 2.2 years, the primary outcome occurred in 434 of 3494 (12.4%) and 420 of 3485 (12.1%) in the linagliptin and placebo groups, respectively, (absolute incidence rate difference, 0.13 [95% CI, -0.63 to 0.90] per 100 person-years) (HR, 1.02; 95% CI, 0.89-1.17; P < .001 for noninferiority). The kidney outcome occurred in 327 of 3494 (9.4%) and 306 of 3485 (8.8%), respectively (absolute incidence rate difference, 0.22 [95% CI, -0.52 to 0.97] per 100 person-years) (HR, 1.04; 95% CI, 0.89-1.22; P = .62). Adverse events occurred in 2697 (77.2%) and 2723 (78.1%) patients in the linagliptin and placebo groups; 1036 (29.7%) and 1024 (29.4%) had 1 or more episodes of hypoglycemia; and there were 9 (0.3%) vs 5 (0.1%) events of adjudication-confirmed acute pancreatitis.. Among adults with type 2 diabetes and high CV and renal risk, linagliptin added to usual care compared with placebo added to usual care resulted in a noninferior risk of a composite CV outcome over a median 2.2 years.. ClinicalTrials.gov Identifier: NCT01897532.

Topics: Aged; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Kidney Failure, Chronic; Linagliptin; Male; Middle Aged; Proportional Hazards Models; Risk Factors

The use of incretin-based therapy, rather than or complementary to, insulin therapy is an active area of research in hospitalized patients with type 2 diabetes (T2D). We determined the glycaemic efficacy and safety of linagliptin compared to a basal-bolus insulin regimen in hospitalized surgical patients with T2D.. This prospective open-label multicentre study randomized T2D patients undergoing non-cardiac surgery with admission blood glucose (BG) of 7.8 to 22.2 mmol/L who were under treatment with diet, oral agents or total insulin dose (TDD) ≤ 0.5 units/kg/day to either linagliptin (n = 128) daily or basal-bolus (n = 122) with glargine once daily and rapid-acting insulin before meals. Both groups received supplemental insulin for BG > 7.8 mmol/L. The primary endpoint was difference in mean daily BG between groups.. Mean daily BG was higher in the linagliptin group compared to the basal-bolus group (9.5 ± 2.6 vs 8.8 ± 2.3 mmol/L/dL, P = 0.03) with a mean daily BG difference of 0.6 mmol/L (95% confidence interval 0.04, 1.2). In patients with randomization BG < 11.1 mmol/L (63% of cohort), mean daily BG was similar in the linagliptin and basal-bolus groups (8.9 ± 2.3 vs 8.7 ± 2.3 mmol/L, P = 0.43); however, patients with BG ≥ 11.1 mmol/L who were treated with linagliptin had higher BG compared to the basal-bolus group (10.9 ± 2.6 vs 9.2 ± 2.2 mmol/L, P < 0.001). Linagliptin resulted in fewer hypoglycaemic events (1.6% vs 11%, P = 0.001; 86% relative risk reduction), with similar supplemental insulin and fewer daily insulin injections (2.0 ± 3.3 vs 3.1 ± 3.3, P < 0.001) compared to the basal-bolus group.. For patients with T2D undergoing non-cardiac surgery who presented with mild to moderate hyperglycaemia (BG < 11.1 mmol/L), daily linagliptin is a safe and effective alternative to multi-dose insulin therapy, resulting in similar glucose control with lower hypoglycaemia.

Topics: Aged; Amputation, Surgical; Blood Glucose; Diabetes Mellitus, Type 2; Digestive System Surgical Procedures; Dipeptidyl-Peptidase IV Inhibitors; Female; Glycated Hemoglobin; Gynecologic Surgical Procedures; Hospitalization; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Insulin Glargine; Insulin, Short-Acting; Linagliptin; Male; Middle Aged; Orthopedic Procedures; Perioperative Care; Surgical Procedures, Operative; Treatment Outcome; Urologic Surgical Procedures

Concomitant treatment with angiotensin-converting enzyme (ACE) inhibitors and dipeptidyl peptidase-4 (DPP-4) inhibitors is increasingly common. Pharmacological studies have suggested a potential adverse drug interaction between ACE inhibitors and DPP-4 inhibitors resulting in unfavorable hemodynamic changes; very few studies have examined such an interaction between angiotensin II receptor blockers (ARBs) and DPP-4 inhibitors. We investigated blood pressure (BP) and heart rate (HR) during treatment with the DPP-4 inhibitor linagliptin in individuals receiving either ACE inhibitors or ARBs in the MARLINA-T2D trial.. In this study, 360 individuals with type 2 diabetes and albuminuria receiving unchanged doses of ACE inhibitors or ARBs were randomized to linagliptin or placebo. Twenty-four-hour ambulatory BP monitoring, an exploratory endpoint, was conducted at baseline and after 24 weeks.. Ambulatory BP monitoring data were available for 208 individuals (linagliptin: n = 111; placebo: n = 97). Baseline mean ± SD 24-h SBP and DBP were 132.5 ± 12.4 mmHg and 75.9 ± 9.4 mmHg, respectively; mean 24-h HR was 76.3 ± 10.1 bpm. At week 24, no overall effect of the DPP-4 inhibitor versus placebo was seen on mean 24-h SBP, DBP, or HR. Furthermore, in the subgroups receiving either an ACE inhibitor or an ARB, no effect on these hemodynamic parameters was seen as a result of concomitant DPP-4 inhibitor treatment.. Adding linagliptin to treatment with ACE inhibitors or ARBs was not associated with any hemodynamic changes, supporting their concomitant use in individuals with type 2 diabetes and albuminuria.

Topics: Aged; Albuminuria; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Interactions; Female; Humans; Hypoglycemic Agents; Linagliptin; Male; Middle Aged; Renin-Angiotensin System

Individuals with type 2 diabetes mellitus are at increased risk for heart failure (HF), particularly those with coexisting atherosclerotic cardiovascular disease and/or kidney disease. Some but not all dipeptidyl peptidase-4 inhibitors have been associated with increased HF risk. We performed secondary analyses of HF and related outcomes with the dipeptidyl peptidase-4 inhibitor linagliptin versus placebo in CARMELINA (The Cardiovascular and Renal Microvascular Outcome Study With Linagliptin), a cardiovascular outcomes trial that enrolled participants with type 2 diabetes mellitus and atherosclerotic cardiovascular disease and/or kidney disease.. Participants in 27 countries with type 2 diabetes mellitus and concomitant atherosclerotic cardiovascular disease and/or kidney disease were randomized 1:1 to receive once daily oral linagliptin 5 mg or placebo, on top of standard of care. All hospitalization for HF (hHF), cardiovascular outcomes, and deaths were prospectively captured and centrally adjudicated. In prespecified and post hoc analyses of HF and related events, Cox proportional hazards models adjusting for region and baseline history of HF were used. Recurrent hHF events were analyzed using a negative binomial model. In a subset of participants with left ventricular ejection fraction captured within the year before randomization, HF-related outcomes were assessed in subgroups stratified by left ventricular ejection fraction > or ≤50%.. In a large, international cardiovascular outcome trial in participants with type 2 diabetes mellitus and concomitant atherosclerotic cardiovascular disease and/or kidney disease, linagliptin did not affect the risk of hHF or other selected HF-related outcomes, including among participants with and without a history of HF, across the spectrum of kidney disease, and independent of previous left ventricular ejection fraction.. URL: https://www.clinicaltrials.gov . Unique identifier: NCT01897532.

Topics: Aged; Atherosclerosis; Biomarkers; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Female; Glomerular Filtration Rate; Glycated Hemoglobin; Heart Failure; Humans; Kidney; Kidney Diseases; Linagliptin; Male; Middle Aged; Prevalence; Prospective Studies; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome

To assess the addition of linagliptin as an alternative to insulin uptitration in older people with type 2 diabetes on stable insulin therapy.. This phase 4, randomized, multicentre, double-blinded, placebo-controlled, 24-week study recruited individuals on stable insulin, with baseline HbA1c 7.0%-10.0%, aged ≥60 years and body mass index ≤45 kg/m. Addition of linagliptin improves glucose control without an excess of hypoglycaemia in older patients with type 2 diabetes on stable insulin therapy.

Topics: Aged; Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Linagliptin; Male; Middle Aged

The long-term safety and efficacy of gemigliptin was evaluated in the present extension study after a 12-week study during a 40-week follow-up period.. The main study was a randomized, placebo-controlled, double-blinded, phase IIIb study in which 50 mg of gemigliptin (N = 66) or placebo (N = 66) was administered to patients with type 2 diabetes mellitus (T2DM) and moderate or severe renal impairment over a 12-week period. Patients with a glycated haemoglobin (HbA1c) level of 7% to 11% and an estimated glomerular filtration rate (eGFR) of 15 to 59 mL/min/1.73 m. The HbA1c levels of both groups were significantly reduced at week 52 compared with baseline. Specifically, the adjusted mean change ± standard error in HbA1c level in the gemigliptin and placebo/linagliptin groups was 1.00% ± 0.21% and 0.65% ± 0.22% lower at week 52 than at baseline (P < .001 and P = .003), respectively. No significant difference in the change in HbA1c level was found between the 2 groups (P = .148). Trends in fasting plasma glucose, fructosamine and glycated albumin levels in the 2 groups were similar to trends in HbA1c levels. The eGFR of both groups was also significantly lower at week 52 than at baseline, and no significant difference in change in eGFR was found between the 2 groups. In contrast, both drugs had little effect on urinary albumin excretion, although both drugs significantly reduced the urinary type IV collagen level. The overall rates of adverse events were similar between the 2 groups.. Gemigliptin and linagliptin did not differ with respect to safety and efficacy in patients with T2DM and renal impairment. The 2 drugs had similar glucose-lowering effects, and the changes in eGFR and albuminuria were also similar. Additionally, the risk of side effects, including hypoglycaemia, was similar between the 2 groups.

Topics: Aged; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Monitoring; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Kidney; Linagliptin; Male; Middle Aged; Patient Dropouts; Piperidones; Pyrimidines; Renal Insufficiency, Chronic; Severity of Illness Index; Sulfonylurea Compounds

To identify the dose of the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin in pediatric patients with type 2 diabetes (T2D).. Double-blind, randomized, controlled parallel group study comparing linagliptin 1 and 5 mg once daily, with placebo in 39 patients with T2D aged 10 to below 18 years. The primary efficacy endpoint was the change from baseline in glycated hemoglobin (HbA1c) after 12 weeks of treatment. The key pharmacodynamic endpoint was DPP-4 inhibition during steady-state.. Compared to placebo, there was a dose-dependent reduction in mean HbA1c of 0.48% and 0.63% with linagliptin 1 and 5 mg, respectively, associated with corresponding declines in mean fasting plasma glucose (FPG) of 5.6 and 34.2 mg/dL. Median DPP-4 inhibition was 38% with linagliptin 1 mg and 79% with linagliptin 5 mg. Geometric mean trough levels of linagliptin were 3.80 and 7.42 nmol/L in the 1 and 5 mg groups, respectively; levels that were slightly higher than in adult patients with T2D that were most likely caused by higher plasma DPP-4 concentrations in the study population. There were no drug-related adverse events during treatment with either dose of linagliptin.. Linagliptin was well tolerated and induced dose-dependent DPP-4 inhibition that was accompanied by corresponding reductions in HbA1c and FPG levels in young people with T2D. The results are consistent with the clinical efficacy and safety profile that have been reported for linagliptin in adult patients with T2D, favoring linagliptin 5 mg over 1 mg.

Topics: Adolescent; Age of Onset; Child; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Linagliptin; Male; Placebos

Safe and easily implemented treatment regimens are needed for the management of patients with type 2 diabetes mellitus (T2DM) in long-term care (LTC) and skilled nursing facilities.. This 6-month open-label randomized controlled trial compared the efficacy and safety of a DPP4 inhibitor (linagliptin) and basal insulin (glargine) in LTC residents with T2DM.. Three LTC institutions affiliated with a community safety-net hospital, US Department of Veterans Affairs and Emory Healthcare System in Atlanta, Georgia.. A total of 140 residents with T2DM treated with oral antidiabetic agents or low-dose insulin (≤0.1 U/kg/d), with fasting or premeal blood glucose (BG) > 180 mg/dL and/or HbA1c >7.5%.. Baseline antidiabetic therapy, except metformin, was discontinued on trial entry. Residents were treated with linagliptin 5 mg/d (n = 67) or glargine at a starting dose of 0.1 U/kg/d (n = 73). Both groups received supplemental rapid-acting insulin before meals for BG > 200 mg/dL.. Primary outcome was mean difference in daily BG between groups. Main secondary endpoints included differences in frequency of hypoglycemia, glycosylated hemoglobin (HbA1c), complications, emergency department visits, and hospital transfers.. Treatment with linagliptin resulted in no significant differences in mean daily BG (146 ± 34 mg/dL vs. 157 ± 36 mg/dL, P = .07) compared to glargine. Linagliptin treatment resulted in fewer mild hypoglycemic events <70 mg/dL (3% vs. 37%, P < .001), but there were no differences in BG < 54 mg/dL (P = .06) or <40 mg/dL (P = .05) compared to glargine. There were no significant between-group differences in HbA1c, length of stay, complications, emergency department visits, or hospitalizations.. Treatment with linagliptin resulted in noninferior glycemic control and in significantly lower risk of hypoglycemia compared to insulin glargine in long-term care and skilled nursing facility residents with type 2 diabetes.

Topics: Aged; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin Glargine; Linagliptin; Male; Residential Facilities; Skilled Nursing Facilities

Type 2 diabetes mellitus is associated with cognitive dysfunction and an increased risk of dementia. Linagliptin is a glucose-lowering agent of the dipeptidyl peptidase-IV (DPP-IV) inhibitor class that is of particular interest for the prevention of accelerated cognitive decline, because it may potentially benefit the brain through pleiotropic effects, beyond glucose lowering. This paper presents the design of a study that aims to establish if linagliptin is superior to the sulfonylurea glimepiride in the prevention of accelerated cognitive decline in patients with type 2 diabetes mellitus.. The cognition substudy is an integral part of the ongoing event-driven, randomised, double blind CARdiOvascular safety of LINAgliptin (CAROLINA®) trial, which evaluates the effect of treatment with linagliptin versus glimepiride on cardiovascular outcomes. CAROLINA® includes patients with type 2 diabetes mellitus with sub-optimal glycaemic control at elevated cardiovascular risk. The substudy will evaluate patients randomised and treated who have a baseline Mini Mental State Examination (MMSE) score ≥ 24, documented years of formal education with at least one valid cognitive assessment at baseline and during follow-up. The primary cognitive outcome is the occurrence of accelerated cognitive decline at the end of follow-up. The two treatment groups will be compared by using a logistic regression. Accelerated cognitive decline is defined as a rate of cognitive decline that falls at or below the 16th percentile of decline for the whole cohort on either the MMSE or a combined score of the trail making and verbal fluency test. Potential confounders are taken into account at an individual patient level, using a regression based index.. Between December 2010 and December 2012, 6042 patients were randomised and treated with either linagliptin (5 mg) or glimepiride (1-4 mg) once daily in CAROLINA®. Cognitive tests were conducted in nearly 4500 participants at baseline and are scheduled for two subsequent assessments, after 160 weeks of follow-up and end of follow-up. This substudy of the ongoing CAROLINA® trial will establish if linagliptin is superior to glimepiride in the prevention of accelerated cognitive decline in patients with type 2 diabetes mellitus. Final results are expected in 2019.. ClinicalTrials.gov Identifier: NCT 01243424 .

Topics: Aged; Cognitive Dysfunction; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Humans; Hypoglycemic Agents; Linagliptin; Male; Middle Aged; Research Design; Sulfonylurea Compounds; Treatment Outcome

Recently, we reported that linagliptin had equivalent efficacy to voglibose in reducing postprandial blood glucose levels in drug-naïve patients with type 2 diabetes (L-STEP Study). As a sub-study of the L-STEP Study we examined the effect of linagliptin on postprandial lipids profile. Between October 2012 and April 2014, the study enrolled patients with type 2 diabetes mellitus who had inadequate glycemic control. Patients were randomly assigned to either the linagliptin group (5 mg once daily, n = 85) or the voglibose group (0.2 mg/meal thrice daily, n = 71). Meal tolerance tests were performed at baseline (week 0) and endpoint (week 12). The increments in 4-h postprandial triglyceride, remnant lipoprotein cholesterol (RLP-C), and apolipoprotein B48 (ApoB48) from baseline to endpoint in the linagliptin group were lower (p < 0.001, p = 0.025 and p < 0.001). 4-h postprandial ApoB48 at endpoint was lower in the linagliptin group (p = 0.007), and positive correlation was detected between change of ApoB48 and changes in both triglyceride (r = 0.67, p < 0.001) and RLP-C (r = 0.73, p < 0.001) at 4 h. This study revealed that in drug-naïve Japanese patients with relatively mild type 2 diabetes mellitus, linagliptin improves not only postprandial blood glucose level but also levels of lipids such as TG and RLP-C by reducing the ApoB48 level compared with voglibose.

Topics: Aged; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Hypoglycemic Agents; Inositol; Linagliptin; Lipids; Male; Middle Aged; Postprandial Period; Treatment Outcome

Treatment-related quality of life (QOL) is an important aspect of diabetes management. However, no studies have compared the influence of dipeptidyl peptidase-4 inhibitors versus alpha-glucosidase inhibitors on treatment-related QOL. This prespecified sub-analysis of the Linagliptin Study of Effects on Postprandial blood glucose (L-STEP) compared the effects of linagliptin (5 mg once daily) and voglibose (0.2 mg/meal thrice daily) on treatment-related QOL in Japanese patients with type 2 diabetes (T2DM) inadequately controlled with diet and exercise therapy. Among 366 subjects in the original study, 182 in the linagliptin group and 173 in the voglibose group were included in this analysis. The outcome of this study was change in QOL as assessed by the Diabetes Therapy-Related Quality of Life 17 (DTR-QOL17) questionnaire from baseline to week 12. Compared with baseline data, total DTR-QOL17 scores were significantly higher after 12 weeks of linagliptin and voglibose treatment. The change in the total DTR-QOL17 score and the score of one domain, burden on social activities and daily activities, was significantly greater in the linagliptin group than in the voglibose group. In addition, only linagliptin treatment was identified as a factor associated with an increased total DTR-QOL17 score. Linagliptin is superior to voglibose in terms of improving treatment-related QOL in Japanese patients with T2DM.

Topics: Activities of Daily Living; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Inositol; Linagliptin; Male; Middle Aged; Quality of Life; Treatment Outcome

This double-blind, randomized, placebo-controlled trial (ClinicalTrials.gov NCT02453555) evaluated the efficacy and safety of empagliflozin (Empa) 10 or 25 mg as add-on to linagliptin (Lina) 5 mg (fixed-dose combination, Empa/Lina 10/5 or 25/5) in insufficiently controlled Japanese type 2 diabetes patients.. The trial (40 sites; May 2015-March 2017) involved screening 433 adults (≥20 years) who were treatment-naive or were using one oral antidiabetic drug for ≥12 weeks, which was discontinued at enrolment. Patients with HbA1c 7.5%-10.0% after ≥16 weeks of using Lina (pre-enrolment or during a 16-week, open-label period) and 2 weeks of using placebo (Plc) for Empa/Lina 10/5, plus Lina, were randomized (2:1) to once-daily Empa/Lina 10/5 (n = 182) or Plc/Lina 10/5 (n = 93) for 24 weeks. Patients with HbA1c ≥ 7.0% at Week 24 received Empa/Lina up-titrated to 25/5 (n = 126) or the corresponding placebo (n = 80), per randomization, from Week 28; 172 Empa/Lina and 84 Plc/Lina patients completed 52 weeks.. Change from baseline in HbA1c was greater (P < .0001) with Empa/Lina than with Plc/Lina at Week 24 (primary outcome, -0.93% vs 0.21%; adjusted mean difference, -1.14%) and Week 52 (-1.16% vs 0.06%; adjusted mean difference, -1.22%). More patients with HbA1c < 7.0% and greater decreases in fasting plasma glucose, body weight and systolic blood pressure were seen in the Empa/Lina group than in the Plc/Lina group. Empa/Lina was well tolerated. The adverse events that were more frequent with Empa/Lina were known empagliflozin-associated events (eg, increased urination, increased blood ketones). There were no adjudication-confirmed diabetic ketoacidosis events or lower limb amputations.. These results support the notion that empagliflozin-linagliptin in fixed-dose combination is a therapeutic option for Japanese patients with type 2 diabetes.

Topics: Aged; Benzhydryl Compounds; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glucosides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Linagliptin; Male; Middle Aged; Treatment Outcome

Early glucose lowering intervention in subjects with type 2 diabetes mellitus was demonstrated to be beneficial in terms of micro- and macrovascular risk reduction. However, most of currently ongoing cardiovascular outcome trials are performed in subjects with manifest atherosclerosis and long-standing diabetes. Therefore, the aim of this study is to investigate the effects of the dipeptidylpeptidase-4 inhibitor linagliptin in subjects with coronary artery disease (CAD) but early type 2 diabetes mellitus (T2DM) on a set of cardiovascular surrogate measurements.. In this randomized, placebo-controlled, double-blind, single-center study, we included subjects with early diabetes (postchallenge diabetes (2 h glucose > 200 mg/dl) or T2DM treated with diet only or on a stable dose of metformin monotherapy and an HbA1c < 75 mmol/mol) and established CAD. Participants were randomized to receive either linagliptin (5 mg) once daily orally or placebo for 12 weeks. The primary outcome was the change in flow mediated dilatation (FMD). The secondary objective was to investigate the effect of linagliptin treatment on arginine bioavailability ratios [Global arginine bioavailability ratio (GABR) and arginine to ornithine ratio (AOR)]. Arginine, ornithine and citrulline were measured in serum samples with a conventional usual amino acid analysis technique, involving separation of amino acids by ion exchange chromatography followed by postcolumn continuous reaction with ninhydrin. GABR was calculated by L-arginine divided by the sum of (L-ornithine plus L-citrulline). The AOR was calculated by dividing L-arginine by L-ornithine levels. Group comparisons were calculated by using a two-sample t-test with Satterthwaite adjustment for unequal variances.. We investigated 43 patients (21% female) with a mean age of 63.3 ± 8.2 years. FMD at baseline was 3.5 ± 3.1% in the linagliptin group vs. 4.0 ± 2.9% in the placebo group. The change in mean FMD in the linagliptin group was not significantly different compared to the change in the placebo group (0.43 ± 4.84% vs. - 0.45 ± 3.01%; p = 0.486). No significant improvements were seen in the arginine bioavailability ratios (GABR; p = 0.608 and AOR; p = 0.549).. Linagliptin treatment in subjects with CAD and early T2DM did not improve endothelial function or the arginine bioavailability ratios. Trial registration ClinicalTrials.gov, NCT02350478 ( https://clinicaltrials.gov/ct2/show/NCT02350478 ).

Topics: Aged; Arginine; Austria; Biomarkers; Blood Glucose; Citrulline; Coronary Artery Disease; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Endothelium, Vascular; Female; Glycated Hemoglobin; Humans; Linagliptin; Lipids; Male; Middle Aged; Ornithine; Postprandial Period; Prospective Studies; Time Factors; Treatment Outcome; Vasodilation

Two 52-week Phase III studies evaluated the efficacy and safety of once-daily combinations of empagliflozin/linagliptin as monotherapy or add-on to metformin in patients with type 2 diabetes (T2DM). The aim of this analysis was to further assess the safety and tolerability of empagliflozin/linagliptin compared with their individual components in patients with T2DM, using pooled data from these trials.. A total of 1363 patients were treated with empagliflozin 25 mg/linagliptin 5 mg (n = 273), empagliflozin 10 mg/linagliptin 5 mg (n = 272), empagliflozin 25 mg (n = 276), empagliflozin 10 mg (n = 275), or linagliptin 5 mg (n = 267). Adverse events (AEs) were assessed descriptively in patients who took ≥ 1 dose of study drug.. Total exposure was 251, 255, 256, 249, and 243 patient-years in the empagliflozin 25 mg/linagliptin 5 mg, empagliflozin 10 mg/linagliptin 5 mg, empagliflozin 25 mg, empagliflozin 10 mg, and linagliptin 5 mg groups, respectively. The proportion of patients with ≥ 1 AE was similar across groups (70.4-74.9%). The percentage of patients with confirmed hypoglycemic AEs (plasma glucose ≤ 70 mg/dL and/or requiring assistance) was low in all groups (1.1-2.2%); none required assistance. Events consistent with urinary tract infection were reported in similar percentages of patients in all groups (11.4-13.8%), and in a greater proportion of female than male patients. Events consistent with genital infection were reported in higher percentages of patients on empagliflozin/linagliptin or empagliflozin (4.0-6.5%) than linagliptin 5 mg (2.6%), and in a greater proportion of females than males. The risks of hypersensitivity reactions and events consistent with volume depletion were low across treatment groups.. Empagliflozin/linagliptin as monotherapy or add-on to metformin for 52 weeks was well tolerated in patients with T2DM, with safety profiles similar to individual components, including a low risk of hypoglycemia.. The Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance.. ClinicalTrials.gov identifiers, NCT01422876 & NCT01422876.

Topics: Benzhydryl Compounds; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Monitoring; Female; Glucosides; Humans; Hypoglycemia; Hypoglycemic Agents; Linagliptin; Male; Metformin; Middle Aged; Treatment Outcome

Dipeptidyl peptidase 4 (DPP4) inhibitors improve glycemic control by promoting GLP1-mediated glucose-dependent insulin secretion and suppression of glucagon. Sitagliptin and vildagliptin have been shown to improve insulin sensitivity in patients with type 2 diabetes mellitus (T2DM). However, these patients had uncontrolled blood glucose at inclusion; therefore, the improvement in insulin sensitivity observed in these studies could be attributed to the drug per se and/or reduction in glucotoxicity. This study examines the effect of linagliptin on insulin sensitivity and β-cell function in patients with well-controlled T2DM.. Thirty patients with T2DM of duration ≤5 years, and having HbA1c < 7.5% were randomized to receive linagliptin, voglibose or placebo (n = 10 each), and were followed up for 6 months. Insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp, and insulin secretory response was measured by basal (M. The median HbA1c of the study subjects at inclusion was 6.9% and there was no significant difference among the groups in terms of age, duration of diabetes, body mass index (BMI), HbA1c, insulin sensitivity, AUC of C-peptide and M. Linagliptin modestly improves glycemic profile in patients with well controlled T2DM; however, it may not have an effect on insulin sensitivity in these patients.. Retrospectively Registered in Clinicaltrials.gov (ID number, NCT02097342 ). Registered: March 27, 2014.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Inositol; Insulin Resistance; Insulin-Secreting Cells; Linagliptin; Male; Middle Aged; Postprandial Period

Chronic kidney disease (CKD) and type 2 diabetes mellitus (T2D) frequently coexist and are associated with poor clinical outcomes. Dipeptidyl peptidase-4 (DPP-4) inhibitors can be used for patients with T2D and CKD, and preclinical evidence suggests these agents may slow the progression of kidney disease in T2D. Although clinical evidence of the renal effects of DPP-4 inhibitors is limited, the recent publication of the MARLINA-T2D study provided important new data. In MARLINA-T2D, linagliptin was associated with significant improvements in glycemic control with a non-significant reduction in albuminuria and no evidence of renal adverse effects in a high-risk population of patients with T2D and early diabetic kidney disease. Although there was no conclusive evidence of renoprotective effects, previous research suggests that clinically apparent renal benefits might develop with longer term treatment. The results of ongoing trials with primary renal endpoints are awaited with interest.

Topics: Adult; Albuminuria; Blood Glucose; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Linagliptin; Treatment Outcome

Hepatocyte nuclear factor 1α (HNF1A)-diabetes is the most common monogenetic subtype of diabetes. Strict glycaemic control is crucial for a good prognosis for patients with HNF1A-diabetes. Sulfonylurea (SU) is used as a first-line therapy in HNF1A-diabetes. However, SU therapy may be problematic as it confers a high risk of hypoglycaemia. We hypothesise that low dose of SU in combination with a dipeptidyl peptidase 4 inhibitor provides a safer and more efficacious treatment in patients with HNF1A-diabetes compared with SU as monotherapy.. In a randomised, double-blinded, crossover study, patients with HNF1A-diabetes will randomly be assigned to 16 weeks of treatment with glimepiride+linagliptin, 4 weeks of washout and 16 weeks of treatment with glimepiride+placebo (or vice versa). Treatment will be evaluated with continuous glucose monitoring and combined meal and bicycle tests conducted at baseline and at the end of each of the two treatment periods. The primary end point is the absolute difference in the mean amplitude of glycaemic excursions between the two treatments (glimepiride+linagliptin vs glimepiride+placebo) at the end of each treatment period.. The study protocol is approved by the Danish Medicines Agency, The Scientific-Ethical Committee of the Capital Region of Denmark (H-17014518) and the Danish Data Protection Agency. The trial will be carried out and monitored in compliance with Good Clinical Practice guidelines and in accordance with the latest version of the Declaration of Helsinki. Positive, negative and inconclusive results will be published at scientific conferences and as one or more scientific manuscripts in peer-reviewed journals with authorship in accordance with the International Committee of Medical Journal Editors' recommendations.. 2017-000204-15.

Topics: Blood Glucose; Blood Glucose Self-Monitoring; Cross-Over Studies; Denmark; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Therapy, Combination; Glycated Hemoglobin; Hepatocyte Nuclear Factor 1-alpha; Humans; Hypoglycemic Agents; Linagliptin; Patient Reported Outcome Measures; Randomized Controlled Trials as Topic; Sulfonylurea Compounds; Treatment Outcome

Short-term studies have demonstrated potential therapeutic efficacy of dipeptidyl peptidase 4 inhibitors (DPP4 inhibitors) in patients with poorly controlled T1DM. In this study we evaluated the effect of DPP4 inhibitor, linagliptin, on glycaemic control and variability, and incretinaxis in well controlled T1DM patients to mitigate the effect of glucotoxicity on incretin secreting cells.. Twenty T1DM patients were randomized to receive either linagliptin (10 patients, dose-5 mg/day) or placebo (10 patients), in addition to insulin for 3 months. HbA1C, continuous glucose monitoring (CGM) and mixed meal test (MMT) were performed before and at the end of the study period.. HbA1C reduction and change in glycaemic variability and insulin requirement in the linagliptin group did not attain the level of statistical significance. The increase in AUC GLP1 (Area under curve for GLP1) and decrease in AUC glucagon (Area under curve for glucagon) during the MMT in linagliptin group were also statistically insignificant.. Linagliptin is not effective in reducing HbA1C and glycaemic variability in relatively well controlled T1DM patients.

Topics: Blood Glucose; Blood Glucose Self-Monitoring; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Incretins; Linagliptin; Purines; Quinazolines; Treatment Outcome

The MARLINA-T2D study (ClinicalTrials.gov, NCT01792518) was designed to investigate the glycaemic and renal effects of linagliptin added to standard-of-care in individuals with type 2 diabetes and albuminuria.. Baseline mean HbA1c and geometric mean (gMean) UACR were 7.8% ± 0.9% (62.2 ± 9.6 mmol/mol) and 126 mg/g, respectively; 73.7% and 20.3% of participants had microalbuminuria or macroalbuminuria, respectively. After 24 weeks, the placebo-adjusted mean change in HbA1c from baseline was -0.60% (-6.6 mmol/mol) (95% confidence interval [CI], -0.78 to -0.43 [-8.5 to -4.7 mmol/mol]; P < .0001). The placebo-adjusted gMean for time-weighted average of percentage change in UACR from baseline was -6.0% (95% CI, -15.0 to 3.0; P = .1954). The adverse-event profile, including renal safety and change in eGFR, was similar between the linagliptin and placebo groups.. In individuals at early stages of diabetic kidney disease, linagliptin significantly improved glycaemic control but did not significantly lower albuminuria. There was no significant change in placebo-adjusted eGFR. Detection of clinically relevant renal effects of linagliptin may require longer treatment, as its main experimental effects in animal studies have been to reduce interstitial fibrosis rather than alter glomerular haemodynamics.

Topics: Aged; Albuminuria; Blood Glucose; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Female; Humans; Hyperglycemia; Linagliptin; Male; Middle Aged; Renal Insufficiency; Standard of Care; Treatment Outcome

Topics: Aged; Asian People; Blood Glucose; Diabetes Mellitus, Type 2; Drug Monitoring; Female; Humans; Hypoglycemic Agents; Inositol; Japan; Linagliptin; Male; Middle Aged

To evaluate the efficacy and safety of linagliptin vs placebo as add-on to empagliflozin and metformin in patients with type 2 diabetes.. Patients with inadequate glycaemic control despite stable-dose metformin received open-label empagliflozin 10 mg (study 1) or 25 mg (study 2) as add-on therapy for 16 weeks. Subsequently, those with HbA1c ≥7.0 and ≤10.5% (>53 and ≤91 mmol/mol) (N = 482) were randomized to 24 weeks' double-blind, double-dummy treatment with linagliptin 5 mg or placebo in study 1, or to linagliptin 5 mg or placebo in study 2; all patients continued treatment with metformin and empagliflozin 10 mg (study 1) or metformin and empagliflozin 25 mg (study 2). The primary endpoint was change from baseline (defined as the last value before first intake of randomized, double-blind treatment) in HbA1c at week 24.. At week 24, HbA1c (mean baseline 7.82-8.04 [62-64 mmol/mol]) was significantly reduced with linagliptin vs placebo; adjusted mean (SE) differences in change from baseline in HbA1c with linagliptin vs placebo were -.32% (.10) (-3.59 [1.08] mmol/mol) ( P = .001) for patients on empagliflozin 10 mg and metformin, and -0.47% (0.10) (-5.15 [1.04] mmol/mol) ( P < 0.001) for patients on empagliflozin 25 mg and metformin. Adverse events were reported in more patients receiving placebo than in those receiving linagliptin: 55.5% vs 48.4% in study 1 and 58.9% vs 52.7% in study 2.. Linagliptin as add-on to empagliflozin and metformin for 24 weeks improved glycaemic control vs placebo, and was well tolerated.

Topics: Aged; Benzhydryl Compounds; Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glucosides; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Linagliptin; Male; Metformin; Middle Aged; Pancreatitis; Reproductive Tract Infections; Treatment Outcome; Urinary Tract Infections

Dipeptidyl peptidase-4 (DPP-4) inhibitors reduce the risk of hypoglycaemia, possibly through augmentation of glucose-dependent insulinotropic polypeptide (GIP) action, but not that of glucagon-like peptide-1 (GLP-1) on glucagon secretion. To examine this model in Japanese individuals with type 2 diabetes (T2D), the effects of the DPP-4 inhibitor linagliptin on glucagon and other counter-regulatory hormone responses to hypoglycaemia were evaluated and compared with those of the GLP-1 receptor agonist liraglutide in a multi-centre, randomized, open-label, 2-arm parallel comparative, exploratory trial. Three-step hypoglycaemic clamp glucose tests preceded by meal tolerance tests were performed before and after 2-week treatment with the drugs. Glucagon levels were increased during the hypoglycaemic clamp test at 2.5 mmol/L. This increase was similar in the linagliptin and liraglutide groups, both before and after the 2-week treatment. Changes in other counter-regulatory hormones (ie, growth hormone, cortisol, epinephrine and norepinephrine) were also similar between the groups, but were suppressed substantially after 2-week treatment compared to baseline. In conclusion, we confirmed that the glucagon response to hypoglycaemia was not affected by linagliptin or liraglutide treatment in Japanese individuals with T2D.

Topics: Aged; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Epinephrine; Female; Glucagon; Glucagon-Like Peptide-1 Receptor; Glucose Clamp Technique; Human Growth Hormone; Humans; Hydrocortisone; Hypoglycemia; Hypoglycemic Agents; Japan; Linagliptin; Liraglutide; Male; Middle Aged; Norepinephrine

The present multicenter, prospective, controlled, open and randomized three-arm parallel study was designed to compare the effects of linagliptin with those of metformin on endothelial function.. Type 2 diabetes patients treated with 750 mg of metformin (hemoglobin A1c ≥6.0% and <8.0%, n = 96) were randomized to continue metformin 750 mg/day (control group, n = 29), metformin at 1,500 mg/day (metformin group, n = 26) and metformin 750 mg/day supplemented with linagliptin 5 mg/day (linagliptin add-on group, n = 29) and treated for 16 weeks. Vascular endothelial function was evaluated by flow-mediated dilation. The primary end-point was changes in flow-mediated dilation at 16 weeks relative to baseline.. Linagliptin significantly improved flow-mediated dilation from baseline (4.9 ± 2.7%) to 16 weeks (6.3 ± 2.7%, P < 0.05), whereas the other groups did not show any changes. Hemoglobin A1c at 16 weeks was significantly lower in the metformin and linagliptin add-on groups compared with the control (6.6 ± 0.6%, 6.5 ± 0.5% and 7.0 ± 0.6%, respectively). Single and multiple regression analyses showed that apolipoprotein B correlated significantly with change in flow-mediated dilation, and apolipoprotein B was decreased only in the linagliptin add-on group (-6.0 ± 11.3 mg/dL, P < 0.01).. Linagliptin for 16 weeks improved endothelial function with a modest improvement in glycemic control. This effect was mediated, at least in part, by reduction in apolipoprotein B. Linagliptin has a protective role on endothelial function in patients with type 2 diabetes with moderate hyperglycemia.

Topics: Aged; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Linagliptin; Male; Metformin; Middle Aged; Prospective Studies; Treatment Outcome

To investigate the effect of sequential treatment escalation with empagliflozin and linagliptin on laboratory markers of α- and β-cell function in people with type 2 diabetes mellitus (T2DM) insufficiently controlled on metformin monotherapy.. A total of 44 people with T2DM received 25 mg empagliflozin for a duration of 1 month in an open-label fashion (treatment period 1 [TP1]). Thereafter, they were randomized to a double-blind add-on therapy with linagliptin 5 mg or placebo (treatment period 2 [TP2]) for 1 additional month. α- and β-cell function was assessed using a standardized liquid meal test and an intravenous (i.v.) glucose challenge. Efficacy measures comprised the areas under the curve for glucose, insulin, proinsulin and glucagon after the liquid meal test and the assessment of fast and late-phase insulin release after an i.v. glucose load with a subsequent hyperglycaemic clamp.. Empagliflozin reduced fasting and postprandial plasma glucose levels, associated with a significant reduction in postprandial insulin levels and an improvement in the conversion rate of proinsulin (TP1). The addition of linagliptin during TP2 further improved postprandial glucose levels, probably as a result of a marked reduction in postprandial glucagon concentrations (TP2). The insulin response to an i.v. glucose load increased during treatment with empagliflozin (TP1), and further improved after the addition of linagliptin (TP2).. After metformin failure, sequential treatment escalation with empagliflozin and linagliptin is an attractive treatment option because of the additive effects on postprandial glucose control, probably mediated by complementary effects on α- and β-cell function.

Topics: Aged; Benzhydryl Compounds; Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glucagon; Glucagon-Secreting Cells; Glucose Clamp Technique; Glucosides; Humans; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Linagliptin; Male; Middle Aged; Postprandial Period; Proinsulin; Treatment Outcome

To assess efficacy/safety of initial linagliptin/metformin single-pill combination (SPC) therapies versus individual drug components over 24weeks in treatment-naïve Asian patients with type 2 diabetes mellitus and insufficient glycemic control.. Patients (initial glycated hemoglobin [HbA1c] ⩾7.5% to <11.0% [58-97mmol/mol]; main group) were randomized to: linagliptin 5mg once daily (qd); metformin 500mg twice daily (bid); metformin 1000mg bid; linagliptin 2.5mg/metformin 500mg bid; or linagliptin 2.5mg/metformin 1000mg bid. Patients with severe hyperglycemia (HbA1c ⩾11.0% [97mmol/mol]) received linagliptin 2.5mg/metformin 1000mg bid or linagliptin 5mg qd (switched at week 12 from linagliptin to SPC if HbA1c >8.0% [64mmol/mol]). The main group primary endpoint was HbA1c change from baseline to week 24.. At week 24, adjusted mean change from baseline in HbA1c (main group, n=733) was: linagliptin 5mg qd, -1.3%; metformin 500mg bid, -1.6%; metformin 1000mg bid, -2.1%; linagliptin 2.5mg/metformin 500mg bid, -2.2%; linagliptin 2.5mg/metformin 1000mg bid, -2.3%. The first test of primary HbA1c analysis (linagliptin 2.5mg/metformin 1000mg bid vs. metformin 1000mg bid) was borderline non-significant; however, SPCs produced significantly greater reductions in HbA1c from baseline versus respective monotherapies in all but one pre-defined sensitivity analysis. In the severe hyperglycemia group (n=143), linagliptin 2.5mg/metformin 1000mg bid produced a superior HbA1c reduction (-4.7%) versus linagliptin 5mg qd (-3.5%) after 12weeks. Hypoglycemic adverse events were low across groups.. Initial linagliptin/metformin SPC significantly improved glycemic control in this population.

Topics: Adult; Aged; Asian People; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Combinations; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Linagliptin; Male; Metformin; Middle Aged; Tablets; Treatment Outcome

Studies of dipeptidyl peptidase (DPP)-4 inhibitors report heterogeneous effects on endothelial function in patients with type 2 diabetes (T2D). This study assessed the effects of the DPP-4 inhibitor linagliptin versus the sulphonylurea glimepiride and placebo on measures of macro- and microvascular endothelial function in patients with T2D who represented a primary cardiovascular disease prevention population.. This crossover study randomised T2D patients (n = 42) with glycated haemoglobin (HbA1c) ≤7.5%, no diagnosed macro- or microvascular disease and on stable metformin background to linagliptin 5 mg qd, glimepiride 1-4 mg qd or placebo for 28 days. Fasting and postprandial macrovascular endothelial function, measured using brachial flow-mediated vasodilation, and microvascular function, measured using laser-Doppler on the dorsal thenar site of the right hand, were analysed after 28 days.. Baseline mean (standard deviation) age, body mass index and HbA1c were 60.3 (6.0) years, 30.3 (3.0) kg/m. Linagliptin had no effect on macrovascular function in T2D, but significantly improved microvascular function in the fasting state. Trial registration ClinicalTrials.gov identifier-NCT01703286; registered October 1, 2012.

Topics: Aged; Biomarkers; Brachial Artery; Cross-Over Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Endothelium, Vascular; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Linagliptin; Male; Metformin; Microcirculation; Microvessels; Middle Aged; Sulfonylurea Compounds; Time Factors; Treatment Outcome; Vasodilation

Use of dipeptidyl peptidase-4 inhibitors (DPP4-i) for the treatment of type 2 diabetes (T2D) has been associated with a possible increase in the risk for heart failure (HF). B-type natriuretic peptide (BNP), which is both a biomarker of HF and a hemodynamically active hormone, is a substrate of DPP-4. We herein tested the acute effects of the DPP-4i linagliptin on BNP and NT-proBNP in a cross-over placebo-controlled trial in patients with T2D with and without chronic kidney disease (CKD).. B-type natriuretic peptide and NT-proBNP were measured using commercially available clinical-grade immune-assays at baseline and at the end of a 4-day treatment with placebo and linagliptin. Changes from baseline during each treatment arm, as well as placebo-subtracted effects of linagliptin on BNP and NT-proBNP were calculated.. 46 patients completed the study, 18 of whom were affected by CKD. Baseline BNP and NT-proBNP levels increased with age, were elevated in CKD patients, and inversely correlated with estimated glomerular filtration rate. No significant change was detected in BNP and NT-proBNP levels after treatment with linagliptin or placebo in patients with or without CKD. Only in CKD patients the placebo-subtracted effect of linagliptin indicated a significant reduction in NT-proBNP levels, but this finding was not statistically robust.. Acute treatment with a DPP-4i exerts no clinically-meaningful effects on BNP and NT-proBNP. As routinely used immunoassays do not discriminate between intact/active and cleaved BNP, these data cannot rule out an effect of DPP-4i on HF pathophysiology. Trial registration NCT01617824.

Topics: Aged; Biomarkers; Cross-Over Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Female; Glomerular Filtration Rate; Humans; Immunoassay; Kidney; Linagliptin; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Predictive Value of Tests; Renal Insufficiency, Chronic; Single-Blind Method; Time Factors; Treatment Outcome

BACKGROUND Although the efficacy of combination therapy consisting of basal insulin and oral hypoglycemic agents (OHAs) has been shown, which OHAs are the most efficient remains unclear. MATERIAL AND METHODS Five patients with type 2 diabetes were enrolled and treated with insulin degludec and metformin as a basal therapy. The patients were randomized in a cross-over fashion to receive a combination of mitiglinide (10 mg) and voglibose (0.2 mg) (M+V) 3 times daily or linagliptin (5 mg) (L) once daily for 8 weeks. After 8 weeks, 2 kinds of meal tolerance tests were performed as breakfast on 2 consecutive days. The first breakfast contained 460 kcal (carbohydrates, 49.1%; protein, 15.7%; fat, 35.2%), while the second contained 462 kcal (carbohydrates, 37.2%; protein, 19.6%; fat, 43.2%). Self-monitoring blood glucose levels were measured at 0, 30, 60, and 120 min after the meal tests, and the increase in the postprandial area under the curve (AUC)0-120 min was determined. The HbA1c, glycated albumin, and 1,5-anhydroglucitol (AG) levels were measured, and continuous glucose monitoring was performed. RESULTS The increase in the postprandial AUC0-120 min was significantly smaller in the M+V group than in the L group after both meals. The 24-h average, 24-h standard deviations, 24-h AUC, and mean amplitude of glycemic excursion (MAGE) were similar for both groups and after both meals. The change in 1,5-AG was higher in the M+V group than in the L group. CONCLUSIONS The combination of M+V with basal therapy improved postprandial glucose excursion more effectively than L in T2DM patients.

Topics: Aged; Blood Glucose; Cross-Over Studies; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Humans; Hypoglycemic Agents; Inositol; Insulin; Insulin, Long-Acting; Isoindoles; Linagliptin; Male; Metformin; Middle Aged; Postprandial Period

To evaluate the effects of the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin on aortic pulse wave velocity (PWV) as a surrogate marker of arterial stiffness and early atherosclerosis in people with early type 2 diabetes.. A total of 45 people with type 2 diabetes (median [interquartile range] age 63 [54-66] years, 61% men, mean ± standard deviation glycated haemoglobin [HbA1c] 6.3% ± 0.4% [45 ± 4.6 mmol/mol]), without cardiovascular disease and naïve to antidiabetic treatment, were randomized (1:1) to treatment with linagliptin 5 mg once daily or placebo for 26 weeks in a double-blind fashion. PWV was assessed at baseline, 4 and 26 weeks of treatment, and again at 30, 4 weeks after treatment. The primary endpoint was between-group difference in PWV (corrected for systolic blood pressure [SBP]) at week 26. Secondary endpoints included differences in central SBP and augmentation index (AIx).. Compared with placebo, 26 weeks of linagliptin decreased PWV by an average of 0.91 m/s (95% confidence interval -1.76 to -0.06; P = .035). PWV returned to baseline after 4 weeks washout. Differences in central SBP and AIx were not different between linagliptin and placebo. Linagliptin decreased HbA1c (-0.4%; P < .001), fasting plasma glucose (-0.7 mmol/L; P = .002) and triglycerides (-0.49 mmol/L; P = .019) as compared with placebo. The changes in body weight, cholesterol and high-sensitivity C-reactive protein did not differ between groups.. Linagliptin decreased aortic PWV in people with early-stage type 2 diabetes as compared with placebo after 26 weeks of treatment. These results suggest that linagliptin has a favourable effect on arterial stiffness.

Topics: Aorta; Atherosclerosis; Biomarkers; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Hyperglycemia; Hypertension; Hypertriglyceridemia; Hypoglycemia; Linagliptin; Male; Middle Aged; Pulse Wave Analysis; Severity of Illness Index; Vascular Stiffness

Despite the increasing prevalence of type 2 diabetes mellitus (T2DM) in Asia, clinical trials for glucose-lowering therapies are often dominated by Caucasian and/or Western populations. The present Phase III randomized placebo-controlled double-blind, 24-week study evaluated the efficacy and safety of the dipeptidyl peptidase-4 inhibitor linagliptin added to metformin in Asian T2DM patients.. In all, 306 patients (n = 265 Chinese; n = 24 Malaysian; n = 17 Filipino), aged 18-80 years with HbA1c between ≥7.0 and ≤10.0% and on metformin therapy were randomized (2:1) to either linagliptin 5 mg daily or placebo added to metformin. Antidiabetes drugs other than metformin were washed out prior to randomization. The primary endpoint was change in mean HbA1c from baseline after 24 weeks.. Baseline characteristics were well-matched between the groups (overall mean [±SD] HbA1c 8.0 ± 0.8%). Adjusted mean (±SE) HbA1c decreased in the linagliptin and placebo groups by -0.66 ± 0.05 and -0.14 ± 0.07%, respectively (placebo-corrected difference -0.52 ± 0.09%; 95% confidence interval [CI] -0.70, -0.34; P < 0.0001). In patients with baseline HbA1c ≥8.5%, the placebo-corrected decrease in HbA1c was -0.89 ± 0.17% (P < 0.0001). Adverse events occurred in similar proportions in the linagliptin and placebo patients (27.3% and 28.0%, respectively) and few were considered drug-related (2.4% and 0.0%, respectively). Hypoglycemia occurred in 1.0% of patients in both groups. Linagliptin therapy was weight neutral.. Linagliptin 5 mg was efficacious and well tolerated over 24 weeks in Asian patients with T2DM inadequately controlled by metformin.

Topics: Adult; Aged; Asian People; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Hyperlipidemias; Hypoglycemic Agents; Linagliptin; Male; Metformin; Middle Aged; Treatment Outcome

With the expanding armamentarium of noninsulin therapies for type 2 diabetes mellitus, the use of insulin with various oral agents is becoming more common. In this study, we assessed the efficacy and cardiovascular (CV) safety of the dipeptidyl peptidase-4 inhibitor linagliptin as add-on to insulin in patients with type 2 diabetes.. In this post hoc analysis, data for patients receiving basal or basal-bolus insulin were pooled from 4 randomized, double-blind, phase 3 clinical trials of linagliptin 5 mg once daily or placebo given as add-on to background glucose-lowering treatment. Changes in glycated hemoglobin (A1C) and CV risk factors were assessed from baseline to end of trial. The primary CV endpoint was a composite of CV death, nonfatal myocardial infarction, nonfatal stroke and hospitalization due to unstable angina.. The number of patients receiving basal or basal-bolus insulin as background therapy was 1613 (linagliptin: n=811; placebo: n=802). The placebo-adjusted mean (SE) change from baseline in A1C was -0.41 (0.05)% (95% CI -0.50, -0.32; p<0.0001). Treatment with linagliptin provided a relative weight benefit and reduced insulin requirements without affecting blood pressure, heart rate or lipids. The incidence of hypoglycemia with linagliptin was similar to that for placebo (38.7% vs. 39.4%, respectively). The hazard ratio (HR) for the primary endpoint showed that treatment with linagliptin was not associated with an increased CV risk (HR 1.07 [95% CI 0.62, 1.85]).. Linagliptin, when added to ongoing insulin treatment in patients with type 2 diabetes, improves glycemic control and has a neutral impact on major adverse CV events.

Topics: Aged; Cardiovascular Diseases; Cohort Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Cardiomyopathies; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Insulin; Kaplan-Meier Estimate; Linagliptin; Male; Middle Aged; Mortality; Risk Factors

Circulating cells, including endothelial progenitor cells (EPCs) and monocyte subtypes, are involved in diabetic complications. Modulation of these cells may mediate additional benefits of glucose-lowering medications.. We assessed whether the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin acutely modifies EPCs and monocyte subsets in patients with type 2 diabetes.. This was a randomized, crossover, placebo-controlled trial.. The study was conducted at a tertiary referral diabetes outpatient clinic.. Forty-six type 2 diabetes patients with (n = 18) or without (n = 28) chronic kidney disease (CKD) participated in the study.. Intervention included a 4-day treatment with linagliptin 5 mg or placebo during two arms separated by a 2-week washout.. Before and after each treatment, we determined the levels of circulating progenitor cells (CD34, CD133, KDR) and monocyte subtypes (CD14/CD16, chemokine and scavenger receptors) and the concentrations of soluble mediators.. Compared with placebo, linagliptin increased CD34(+)CD133(+) progenitor cells (placebo subtracted effect 40.4 ± 18.7/10(6); P = .036), CD34(+)KDR(+) EPCs (placebo subtracted effect 22.1 ± 10.2/10(6); P = .036), and CX3CR1(bright) monocytes (placebo subtracted effect 1.7 ± 0.8%; P = .032). Linagliptin abated DPP-4 activity by greater than 50%, significantly increased active glucagon-like peptide-1 and stromal cell-derived factor-1α, and reduced monocyte chemotactic protein-1, CCL22, and IL-12. Patients with CKD, as compared with those without, had lower baseline CD133(+) and CD34(+)CD133(+) cells and had borderline reduced CD34(+) and CD34(+)KDR(+) cells. The effects of linagliptin on progenitor cells and monocyte subtypes were similar in patients with or without CKD. Fasting plasma glucose, triglycerides and free fatty acids were unaffected.. DPP-4 inhibition with linagliptin acutely increases putative vasculoregenerative and antiinflammatory cells. Direct effects of DPP-4 inhibition may be important to lower vascular risk in diabetes, especially in the presence of CKD.

Topics: Aged; Cross-Over Studies; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Endothelial Cells; Female; Humans; Hypoglycemic Agents; Linagliptin; Male; Middle Aged; Monocytes; Phenotype; Renal Insufficiency, Chronic; Stem Cells

Linagliptin plus pioglitazone single-pill combinations were evaluated. Patients (n = 936) with insufficient glycaemic control, despite lifestyle interventions, were randomised for 30 weeks to either monotherapy with linagliptin 5 mg; pioglitazone 15, 30 or 45 mg; or single-pill combination with linagliptin 5 mg plus pioglitazone 15, 30 or 45 mg. An extension (⩽54 weeks) planned to evaluate linagliptin plus pioglitazone 30 or 45 mg single-pill combinations was not completed due to a protocol amendment. Adjusted mean (95% confidence interval) differences in HbA1c change from baseline at week 30 for linagliptin plus pioglitazone 15, 30 and 45 mg were -0.17% (-0.41, 0.07), -0.37% (-0.60, -0.14) and -0.41% (-0.64, -0.18) versus pioglitazone monotherapies, respectively, and -0.44% (-0.67, -0.20), -0.68% (-0.91, -0.44) and -0.89% (-1.12, -0.66) versus linagliptin monotherapy, respectively. Single-pill combinations were generally well tolerated. Hypoglycaemia frequency was ⩽1.5% per group. Linagliptin plus pioglitazone combinations were efficacious, with safety profiles comparable to the individual monotherapies.

Topics: Administration, Oral; Aged; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Combinations; Europe; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Linagliptin; Male; Middle Aged; Pioglitazone; Tablets; Thiazolidinediones; Time Factors; Treatment Outcome; United States

The dipeptidyl peptidase-4 inhibitor, linagliptin, possesses pleiotropic vasodilatory, antioxidant, and anti-inflammatory properties in animals, independent of its glucose-lowering properties. Although large, randomized clinical trials are being conducted to better evaluate the efficacy and safety of linagliptin on cardiovascular outcomes, little is known about its effects on vascular function in humans.. This study sought to evaluate the effect of linagliptin on surrogates of vascular and mitochondrial function.. This was a randomized, double-blind, placebo-controlled trial at a tertiary care center with a large type 2 diabetes referral base.. Forty participants with type 2 diabetes were included in a 12-wk treatment of either linagliptin 5mg/d or placebo.. Micro- and macrovascular functions were assessed using laser Doppler coupled with iontophoresis and with brachial flow-mediated dilation, respectively. Mitochondrial function was assessed by phosphorus-31 metabolites changes in the calf muscle measured by magnetic resonance spectroscopy. Circulating endothelial progenitor cells, as well as inflammatory cytokines, growth factors, and biomarkers of endothelial function were also quantified.. Linagliptin was associated with an increase in axon reflex-dependent vasodilation, a marker of neurovascular function (P = .05). A trend indicating increased endothelium-dependent microvascular reactivity was observed (P = .07). These were associated with decreases in concentrations of IFNγ (P < .05), IL-6 (P = .03), IL-12 (P < .03), and MIP-1 (P < .04) following linagliptin treatment when compared with placebo.. This study demonstrates that linagliptin tends to improve endothelial and neurovascular microvascular function and is associated with decreased markers of inflammation in patients with type 2 diabetes. There was no significant effect of linagliptin on mitochondrial function, macrovascular function, or endothelial progenitor cells.

Topics: Aged; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Linagliptin; Male; Middle Aged; Mitochondrial Diseases; Outcome Assessment, Health Care; Vascular Diseases

Endothelial dysfunction predicts cardiovascular damage and renal involvement. Animal experiments and human studies indicate an increased nitric oxide (NO) activity and endothelial NO synthase (NOS) expression in the early stage of type 2 diabetes. The aim of the study was to assess the effect of linagliptin on the endothelial function of the renal vasculature.. In this randomised, double-blind, parallel-group, investigator-initiated trial, 62 patients with type 2 diabetes were randomly assigned (by computer-generated random code) to receive linagliptin 5 mg (n = 30) or placebo (n = 32) for 4 weeks. The primary objective was to assess endothelial function of the renal vasculature, by constant-infusion input-clearance and urinary albumin/creatinine ratio (UACR), both before and after blockade of NOS with N. Our data suggest that treatment with the dipeptidyl peptidase-4 inhibitor linagliptin for 4 weeks prevented the impairment of renal endothelial function due to hyperglycaemia in type 2 diabetes.. ClinicalTrials.gov NCT01835678 FUNDING: : This study was funded by Boehringer Ingelheim.

Topics: Aged; Albuminuria; Blood Glucose; Creatinine; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glomerular Filtration Rate; Glycated Hemoglobin; Humans; Hyperglycemia; Kidney; Linagliptin; Male; Middle Aged; Postprandial Period; Treatment Outcome

Few studies of oral glucose-lowering drugs exist in newly diagnosed type 2 diabetes (T2D) patients with marked hyperglycemia, and insulin is often proposed as initial treatment. We evaluated the oral initial combination of metformin and linagliptin, a dipeptidyl peptidase-4 inhibitor, in this population.. We performed a pre-specified subgroup analysis of a randomized study in which newly diagnosed T2D patients with glycated hemoglobin A1c (HbA1c) 8.5%-12.0% received linagliptin/metformin or linagliptin monotherapy. Subgroups of baseline HbA1c, age, body-mass index (BMI), renal function, race, and ethnicity were evaluated, with efficacy measured by HbA1c change from baseline after 24 weeks.. HbA1c reductions from baseline (mean 9.7%) at week 24 in the overall population were an adjusted mean -2.81% ± 0.12% with linagliptin/metformin (n = 132) and -2.02% ± 0.13% with linagliptin (n = 113); treatment difference -0.79% (95% CI -1.13 to -0.46, P < 0.0001). In patients with baseline HbA1c ≥9.5%, HbA1c reduction was -3.37% with linagliptin/metformin (n = 76) and -2.53% with linagliptin (n = 61); difference -0.84% (95% CI -1.32 to -0.35). In those with baseline HbA1c <9.5%, HbA1c reduction was -2.08% with linagliptin/metformin (n = 56) and -1.39% with linagliptin (n = 52); difference -0.69% (95% CI -1.23 to -0.15). Changes in HbA1c and treatment differences between the linagliptin/metformin and linagliptin groups were of similar magnitudes to the overall population across patient subgroups based on age, BMI, renal function, and race. Drug-related adverse events occurred in 8.8% and 5.7% of linagliptin/metformin and linagliptin patients, respectively; no severe hypoglycemia occurred.. Linagliptin/metformin combination in newly diagnosed T2D patients with marked hyperglycemia was well tolerated and elicited substantial improvements in glycemic control regardless of baseline HbA1c, age, BMI, renal function, or race. Thus, newly diagnosed, markedly hyperglycemic patients may be effectively treated by combinations of oral agents.. www.clinicaltrials.gov identifier is NCT01512979.

Topics: Adult; Aged; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Kidney Function Tests; Linagliptin; Male; Metformin; Middle Aged; Racial Groups

To compare the efficacy on glycemic parameters between a 12-week administration of once-daily linagliptin and thrice-daily voglibose in Japanese patients with type 2 diabetes.. In a multi-center, randomized, parallel-group study, 382 patients with diabetes were randomized to the linagliptin group (n=192) or the voglibose group (n=190). A meal tolerance test was performed at weeks 0 and 12. Primary outcomes were the change from baseline to week 12 in serum glucose levels at 2h during the meal tolerance test, HbA1c levels, and serum fasting glucose levels, which were compared between the 2 groups.. Whereas changes in serum glucose levels at 2h during the meal tolerance test did not differ between the groups, the mean change in HbA1c levels from baseline to week 12 in the linagliptin group (-0.5±0.5% [-5.1±5.4mmol/mol]) was significantly larger than in the voglibose group (-0.2±0.5% [-2.7±5.4mmol/mol]). In addition, there was significant difference in changes in serum fasting glucose levels (-0.51±0.95mmol/L in the linagliptin group vs. -0.18±0.92mmol/L in the voglibose group, P<0.001). The incidences of hypoglycemia, serious adverse events (AEs), and discontinuations due to AEs were low and similar in both groups. However, gastrointestinal AEs were significantly lower in the linagliptin group (1.05% vs. 5.85%; P=0.01).. These data suggested that linagliptin monotherapy had a stronger glucose-lowering effect than voglibose monotherapy with respect to HbA1c and serum fasting glucose levels, but not serum glucose levels 2h after the start of the meal tolerance test.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follow-Up Studies; Humans; Hypoglycemic Agents; Inositol; Japan; Linagliptin; Male; Middle Aged; Postprandial Period; Retrospective Studies; Time Factors; Young Adult

Patients with type 2 diabetes (T2DM) are at increased risk for macrovascular events as well as for microvascular complications. There is evidence that in patients with coronary artery disease (CAD), about 35 % suffer from manifest T2DM. Early glucose-lowering intervention in subjects with T2DM has been demonstrated to be beneficial in terms of cardiovascular risk reduction. But thus far, no data are available regarding investigating the impact of linagliptin treatment in patients with early diabetes on cardiovascular endpoints or surrogate parameters. Therefore, the aim of this study is to investigate the effects of linagliptin in CAD patients with early T2DM on various cardiovascular surrogate measurements including mechanical and biochemical endothelial function assessments.. Forty-two subjects with early diabetes and CAD are included in this investigator-driven, randomized, placebo-controlled, double-blind, phase IV, single-center study. Participants will be randomized to receive either linagliptin (5 mg) administered once daily per os or placebo for 12 weeks. Before and after the intervention, evaluation of endothelial function (flow-mediated dilatation and biochemical biomarkers) and a Meal Tolerance Test are performed.. Cardiovascular surrogate parameters, such as endothelial function, are able to provide insights into the potential mechanisms of the cardiovascular effects of antihyperglycemic agents. Currently ongoing trials do not specifically focus on early diabetes as a target of intervention and we therefore believe that our study will contribute to a better understanding of the cardiovascular effects of dipeptidylpeptidase-4 (DPP-4) inhibitors in early diabetes.. NCT02350478 . Registered 26 January 2015. Protocol date/version 24 October 2014/version 2.4 EudraCT number: 2013-000330-35.

Topics: Adult; Aged; Aged, 80 and over; Arginine; Austria; Biological Availability; Biomarkers; Brachial Artery; Clinical Protocols; Coronary Artery Disease; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Endothelium, Vascular; Female; Humans; Linagliptin; Male; Middle Aged; Prospective Studies; Research Design; Risk Factors; Time Factors; Treatment Outcome

To evaluate glucose-lowering treatment strategies with linagliptin and metformin in people with newly diagnosed type 2 diabetes and marked hyperglycaemia, a prevalent population for which few dedicated studies of oral antidiabetes drugs have been conducted.. A total of 316 patients, with type 2 diabetes diagnosed for ≤12 months and with glycated haemoglobin (HbA1c) concentration in the range 8.5-12.0%, were randomized 1:1 to double-blind, free-combination treatment with linagliptin 5 mg once daily and metformin twice daily (uptitrated to 2000 mg/day maximum) or to linagliptin monotherapy. The primary endpoint was change in HbA1c concentration from baseline at week 24 (per-protocol completers' cohort: n = 245).. The mean (standard deviation) age and HbA1c at baseline were 48.8 (11.0) years and 9.8 (1.1)%, respectively. At week 24, the mean ± standard error (s.e.) HbA1c decreased from baseline by -2.8 ± 0.1% with linagliptin/metformin and -2.0 ± 0.1% with linagliptin; a treatment difference of -0.8% (95% confidence interval -1.1 to -0.5; p <0.0001). Similar results were observed in a sensitivity analysis based on intent-to-treat principles: adjusted mean ± s.e. changes in HbA1c of -2.7 ± 0.1% and -1.8 ± 0.1%, respectively; treatment difference of -0.9% (95% CI -1.3 to -0.6; p <0.0001). A treatment response of HbA1c <7.0% was achieved by 61 and 40% of patients in the linagliptin/metformin and linagliptin groups, respectively. Few patients experienced drug-related adverse events (8.8 and 5.7% of patients in the linagliptin/metformin and linagliptin groups, respectively). Hypoglycaemia occurred in 1.9 and 3.2% of patients in the linagliptin/metformin and linagliptin groups, respectively (no severe episodes). Body weight decreased significantly with the combination therapy (-1.3 kg between-group difference; p =0.0033).. Linagliptin in initial combination with metformin in patients with newly diagnosed type 2 diabetes and marked hyperglycaemia, an understudied group, elicited significant improvements in glycaemic control with a low incidence of hypoglycaemia, weight gain or other adverse effects. These results support early combination treatment strategies and suggest that newly diagnosed patients with marked hyperglycaemia may be effectively managed with oral, non-insulin therapy.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; International Cooperation; Linagliptin; Metformin; Purines; Quinazolines; Treatment Outcome

To evaluate the risk of documented hypoglycaemia with glimepiride versus linagliptin.. This was an exploratory analysis of data from a 2-year, randomized, double-blind study of the dipeptidyl peptidase-4 inhibitor linagliptin 5 mg once daily (n = 764) versus the sulphonylurea glimepiride 1-4 mg once daily (n = 755) in patients with type 2 diabetes uncontrolled by metformin. Patients randomized to glimepiride started on 1 mg and after 4 weeks were allowed to be individually uptitrated stepwise to glimepiride 4 mg if a fasting plasma glucose concentration ≤6.1 mmol/l was not achieved. Investigator-reported hypoglycaemia was evaluated by dose, over time, and by the degree of glycated haemoglobin (HbA1c) reduction.. The percentages of patients with at least one hypoglycaemic event at the individual maximum glimepiride dose were: 1 mg, 45.0%; 2 mg, 50.8%; 3 mg, 36.1%; and 4 mg, 27.7%. The incidence of hypoglycaemia was higher with glimepiride than with linagliptin (36.1 vs. 7.5%; p < 0.0001); after performing sensitivity analyses by excluding events during dose escalation (weeks 0-16), this difference remained significant (weeks 16-104: 25.8 vs. 5.9%; p < 0.0001). Notably, the incidence of hypoglycaemia was higher with glimepiride than with linagliptin in each quartile of HbA1c change from baseline (all p < 0.0001); the incidence of hypoglycaemic episodes was not increased with greater reductions in HbA1c in either group. In all 4-week intervals across the 2-year study, the incidence of hypoglycaemia was lower with linagliptin than with glimepiride.. Linagliptin was associated with a lower risk of hypoglycaemia than glimepiride at all dose levels and time intervals, and regardless of change in HbA1c level.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Linagliptin; Male; Middle Aged; Purines; Quinazolines; Risk; Sulfonylurea Compounds; Time Factors; Young Adult

To evaluate the efficacy and safety of combinations of empagliflozin/linagliptin as second-line therapy in subjects with type 2 diabetes inadequately controlled on metformin.. Subjects were randomized to a combination of empagliflozin 25 mg/linagliptin 5 mg (n = 137), empagliflozin 10 mg/linagliptin 5 mg (n = 136), empagliflozin 25 mg (n = 141), empagliflozin 10 mg (n = 140), or linagliptin 5 mg (n = 132) as add-on to metformin for 52 weeks. The primary end point was change from baseline in HbA1c at week 24.. At week 24, reductions in HbA1c (mean baseline 7.90-8.02% [62.8-64.1 mmol/mol]) with empagliflozin/linagliptin were superior to those with empagliflozin or linagliptin alone as add-on to metformin; adjusted mean (SE) changes from baseline were -1.19% (0.06) (-13.1 mmol/mol [0.7]) with empagliflozin 25 mg/linagliptin 5 mg, -1.08% (0.06) (-11.8 mmol/mol [0.7]) with empagliflozin 10 mg/linagliptin 5 mg, -0.62% (0.06) (-6.8 mmol/mol [0.7]) with empagliflozin 25 mg, -0.66% (0.06) (-7.2 mmol/mol [0.7]) with empagliflozin 10 mg, and -0.70% (0.06) (-7.6 mmol/mol [0.7]) with linagliptin 5 mg (P < 0.001 for all comparisons). In these groups, respectively, 61.8, 57.8, 32.6, 28.0, and 36.1% of subjects with baseline HbA1c ≥7% (≥53 mmol/mol) had HbA1c <7% (<53 mmol/mol) at week 24. Efficacy was maintained at week 52. The proportion of subjects with adverse events (AEs) over 52 weeks was similar across treatment arms (68.6-73.0%), with no hypoglycemic AEs requiring assistance.. Combinations of empagliflozin/linagliptin as second-line therapy for 52 weeks significantly reduced HbA1c compared with the individual components and were well tolerated.

Topics: Benzhydryl Compounds; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Glucosides; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Linagliptin; Male; Metformin; Middle Aged; Purines; Quinazolines; Treatment Outcome; Weight Loss

Topics: Aged; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Linagliptin; Male; Purines; Quinazolines; Sulfonylurea Compounds

To evaluate the efficacy and long-term safety of linagliptin added to basal insulin in Asian patients with type 2 diabetes mellitus (T2DM) inadequately controlled by basal insulin with/without oral agents.. This was a post hoc analysis of Asian patients from a global ≥52 week study in which patients on basal insulin were randomized (1:1) to double-blind treatment with linagliptin 5 mg once daily or placebo (NCT00954447). Basal insulin dose remained stable for 24 weeks, after which adjustments could be made according to the investigator's discretion to improve glycemic control. The primary endpoint was the mean change in glycated hemoglobin (HbA1c) from baseline to 24 weeks.. Data were available for 154 Asian patients (80 linagliptin, 74 placebo). Baseline HbA1c (standard deviation [SD]) was 8.6 (0.9)% (70 [10] mmol/mol). The placebo-corrected mean change (standard error [SE]) in HbA1c from baseline was -0.9 (0.1)% (-10 [1] mmol/mol) (95% confidence interval [CI]: -1.2, -0.7; p<0.0001) at Week 24 and -0.9 (0.1)% (-10 [1] mmol/mol) (95% CI: -1.1, -0.6; p<0.0001) at Week 52. The frequency of adverse events (linagliptin 81.3%, placebo 91.9%) and hypoglycemia (Week 24: linagliptin 25.0%, placebo 25.7%; treatment end: linagliptin 28.8%, placebo 35.1%) was similar between groups. By Week 52, changes (SE) in mean body weight were similar in both groups (linagliptin -0.67 [0.26] kg, placebo -0.38 [0.25] kg).. This study was limited by the post hoc nature of the analysis and the small number of patients in the subgroup. However, the results suggest that linagliptin significantly improves glycemic control in Asian patients with T2DM inadequately controlled by basal insulin, without increasing the risk for hypoglycemia or weight gain. ClinicalTrials identifier: NCT00954447.

Topics: Adult; Aged; Asian People; Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Monitoring; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Linagliptin; Male; Middle Aged; Purines; Quinazolines; Treatment Outcome; Weight Gain

To evaluate the efficacy and safety of empagliflozin/linagliptin in subjects with type 2 diabetes.. Subjects not receiving antidiabetes therapy for ≥12 weeks were randomized to empagliflozin 25 mg/linagliptin 5 mg (n = 137), empagliflozin 10 mg/linagliptin 5 mg (n = 136), empagliflozin 25 mg (n = 135), empagliflozin 10 mg (n = 134), or linagliptin 5 mg (n = 135) for 52 weeks. The primary end point was change from baseline in HbA1c at week 24.. Mean HbA1c at baseline was 7.99-8.05% (64 mmol/mol). At week 24, adjusted mean (SE) changes from baseline in HbA1c with empagliflozin 25 mg/linagliptin 5 mg, empagliflozin 10 mg/linagliptin 5 mg, empagliflozin 25 mg, empagliflozin 10 mg, and linagliptin 5 mg were -1.08 (0.06)% (-11.8 [0.7] mmol/mol), -1.24 (0.06)% (-13.6 [0.7] mmol/mol), -0.95 (0.06)% (-10.4 [0.7] mmol/mol), -0.83 (0.06)% (-9.1 [0.7] mmol/mol), and -0.67 (0.06)% (-7.3 [0.7] mmol/mol), respectively. Reductions in HbA1c were significantly greater for empagliflozin 25 mg/linagliptin 5 mg compared with linagliptin 5 mg (P < 0.001) but not compared with empagliflozin 25 mg and were significantly greater for empagliflozin 10 mg/linagliptin 5 mg compared with the individual components (P < 0.001 for both). At week 24, 55.4%, 62.3%, 41.5%, 38.8%, and 32.3% of subjects with baseline HbA1c ≥7% (≥53 mmol/mol) reached HbA1c <7% with empagliflozin 25 mg/linagliptin 5 mg, empagliflozin 10 mg/linagliptin 5 mg, empagliflozin 25 mg, empagliflozin 10 mg, and linagliptin 5 mg, respectively. Efficacy was maintained at week 52. The proportion of subjects with adverse events (AEs) over 52 weeks was similar across groups (68.9-81.5%), with no confirmed hypoglycemic AEs.. Reductions from baseline in HbA1c with empagliflozin/linagliptin were significantly different versus linagliptin and empagliflozin 10 mg but not versus empagliflozin 25 mg. Empagliflozin/linagliptin was well tolerated.

Topics: Benzhydryl Compounds; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Therapy, Combination; Female; Glucosides; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Linagliptin; Male; Middle Aged; Purines; Quinazolines; Treatment Outcome

Linagliptin is a dipeptidyl peptidase (DPP)-4 inhibitor, used to treat type 2 diabetes mellitus (T2DM). Population pharmacokinetic and pharmacodynamic analyses were performed to characterize the impact of clinically relevant intrinsic/extrinsic factors (covariates) on linagliptin exposure and DPP-4 inhibition in patients with T2DM.. Linagliptin plasma concentrations and DPP-4 activities were obtained from four studies (two phase 1, two phase 2b). Non-linear mixed-effects modelling techniques were implemented using NONMEM software. The covariates that were studied comprised demographic information and laboratory values, including liver enzyme levels and creatinine clearance, as well as study-related factors such as metformin co-treatment. Covariate effects on parameters describing the pharmacokinetics and pharmacokinetic/pharmacodynamic relationship were investigated using stepwise forward inclusion/backward elimination.. The pharmacokinetic analysis included 6,907 measurements of plasma linagliptin concentrations from 462 patients; the pharmacokinetic/pharmacodynamic analysis included 9,674 measurements of plasma DPP-4 activity and linagliptin plasma concentrations from 607 patients. The non-linear pharmacokinetics were described by a target-mediated drug disposition model accounting for the concentration-dependent binding of linagliptin to its target, DPP-4. The difference in exposure between the 5th and 95th percentiles of the covariate distributions and median was <20 % for each single covariate. Likewise, the impact of the covariates on both the half-maximum effect (EC50) and the concentration leading to 80 % DPP-4 inhibition was <20 %.. These analyses show that the investigated factors do not alter the pharmacokinetics and DPP-4 inhibitory activity of linagliptin to a clinically relevant extent and that dose adjustment is not necessary on the basis of factors including age, sex and weight.

Topics: Adult; Aged; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Female; Humans; Hypoglycemic Agents; Linagliptin; Male; Metformin; Middle Aged; Nonlinear Dynamics

CARdiovascular Outcome Trial of LINAgliptin Versus Glimepiride in Type 2 Diabetes (NCT01243424) is an ongoing, randomized trial in subjects with early type 2 diabetes and increased cardiovascular risk or established complications that will determine the long-term cardiovascular impact of linagliptin versus the sulphonylurea glimepiride. Eligible patients were sulphonylurea-naïve with HbA1c 6.5%-8.5% or previously exposed to sulphonylurea (in monotherapy or in a combination regimen <5 years) with HbA1c 6.5%-7.5%. Primary outcome is time to first occurrence of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke or hospitalization for unstable angina. A total of 631 patients with primary outcome events will be required to provide 91% power to demonstrate non-inferiority in cardiovascular safety by comparing the upper limit of the two-sided 95% confidence interval as being below 1.3 for a given hazard ratio. Hierarchical testing for superiority will follow, and the trial has 80% power to demonstrate a 20% relative cardiovascular risk reduction. A total of 6041 patients were treated with median type 2 diabetes duration 6.2 years, 40.0% female, mean HbA1c 7.2%, 66% on 1 and 24% on 2 glucose-lowering agents and 34.5% had previous cardiovascular complications. The results of CARdiovascular Outcome Trial of LINAgliptin Versus Glimepiride in Type 2 Diabetes may influence the decision-making process for selecting a second glucose-lowering agent after metformin in type 2 diabetes.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Blood Glucose; Cardiovascular Diseases; Clinical Protocols; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Female; Glycated Hemoglobin; Humans; Incretins; Linagliptin; Male; Middle Aged; Patient Selection; Research Design; Risk Factors; Sample Size; Sulfonylurea Compounds; Treatment Outcome

The aim of this study was to investigate the efficacy and safety of linagliptin + low-dose (LD) metformin once daily versus high-dose (HD) metformin twice daily in treatment-naïve patients with type 2 diabetes.. Patients (n = 689) were randomized (1:1) to double-blind treatment with linagliptin 5 mg + LD metformin (1000 mg) or HD metformin (2000 mg) for 14 weeks. Metformin was initiated at 500 mg/day and up-titrated within 2 weeks; the dose then remained unchanged. The primary endpoint was change in glycated hemoglobin (HbA1c) from baseline to Week 14 in patients who tolerated a daily metformin dose of ≥1000 mg after 2 weeks.. At Week 14, HbA1c changed from a mean baseline of 8.0% (64 mmol/mol) by -0.99% (-11 mmol/mol) for linagliptin + LD metformin, and -0.98% (-11 mmol/mol) for HD metformin [treatment difference -0.01% (95% confidence interval -0.13, 0.12) (0 mmol/mol), P = 0.8924]. The proportion of patients who achieved HbA1c <7.0% (53 mmol/mol) without occurrence of moderate or severe gastrointestinal (GI) events (including abdominal pain, nausea, vomiting, diarrhea, and decreased appetite) was the same in both groups (51.3% for both). Although the occurrence of moderate or severe GI events was similar, the linagliptin + LD metformin group had fewer mild GI events (18.5% versus 24.3%). The incidence of hypoglycemia was low in both groups.. Linagliptin + LD metformin combination showed similar efficacy and safety to HD metformin. This combination may be an alternative treatment option in patients who may have difficulty tolerating metformin doses >1000 mg/day.. Boehringer Ingelheim.

Topics: Adult; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Linagliptin; Male; Metformin; Middle Aged; Treatment Outcome

Glucose-lowering treatment options for type 2 diabetes mellitus patients with chronic kidney disease are limited. We evaluated the potential for linagliptin in combination with insulin in type 2 diabetes mellitus patients with mild-to-severe renal impairment. Data for participants in two phase 3 trials with linagliptin who were receiving insulin were analysed separately (n = 811). Placebo-adjusted mean HbA1c changes from baseline were -0.59% (mild renal impairment) and -0.69% (moderate renal impairment) after 24 weeks and -0.43% (severe renal impairment) after 12 weeks. Drug-related adverse events with linagliptin were similar to placebo (mild renal impairment: 19.9% vs. 26.5%; moderate renal impairment: 22.0% vs. 25.0%; severe renal impairment: 46.3% vs. 43.6%, respectively). Frequencies of hypoglycaemia in patients with mild, moderate and severe renal impairment were 34.9%, 35.6% and 66.7% with linagliptin and 37.5%, 39.7% and 49.1% with placebo, respectively. Episodes of severe hypoglycaemia were low (⩽5.6%). Adding linagliptin to insulin in type 2 diabetes mellitus patients with chronic kidney disease improved glucose control and was well tolerated.

Topics: Aged; Blood Glucose; Cohort Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Glycated Hemoglobin; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Linagliptin; Male; Metformin; Middle Aged; Pioglitazone; Renal Insufficiency, Chronic; Retrospective Studies; Severity of Illness Index; Sulfonylurea Compounds; Thiazolidinediones; Treatment Outcome

Efficacy, Safety & Modification of Albuminuria in Type 2 Diabetes Subjects with Renal Disease with LINAgliptin (MARLINA-T2D™), a multicentre, multinational, randomized, double-blind, placebo-controlled, parallel-group, phase 3b clinical trial, aims to further define the potential renal effects of dipeptidyl peptidase-4 inhibition beyond glycaemic control. A total of 350 eligible individuals with inadequately controlled type 2 diabetes and evidence of renal disease are planned to be randomized in a 1:1 ratio to receive either linagliptin 5 mg or placebo in addition to their stable glucose-lowering background therapy for 24 weeks. Two predefined main endpoints will be tested in a hierarchical manner: (1) change from baseline in glycated haemoglobin and (2) time-weighted average of percentage change from baseline in urinary albumin-to-creatinine ratio. Both endpoints are sufficiently powered to test for superiority versus placebo after 24 weeks with α = 0.05. MARLINA-T2D™ is the first of its class to prospectively explore both the glucose- and albuminuria-lowering potential of a dipeptidyl peptidase-4 inhibitor in patients with type 2 diabetes and evidence of renal disease.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Albuminuria; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Female; Humans; Hyperglycemia; Hypoglycemic Agents; Kidney Diseases; Linagliptin; Male; Middle Aged; Treatment Outcome; Young Adult

BACKGROUND This study aimed to evaluate the efficacy and safety of linagliptin (a novel dipeptidyl peptidase (DPP)-4 inhibitor) on glucose metabolism and β-cell function in Chinese patients with newly-diagnosed, drug-naïve type 2 diabetes mellitus (T2DM). MATERIAL AND METHODS Newly-diagnosed and drug-naïve T2DM patients were enrolled. After 4-week lifestyle modulation and 2-week placebo run-in, 57 patients were randomized to double-blind treatment with linagliptin (n=34) or placebo (n=23). The primary endpoint was the change from baseline in glycosylated hemoglobin A1c (HbA1c) after 24 weeks. Fasting plasma glucose (FPG), 2-h postprandial plasma glucose (2h-PPG), fasting insulin, proinsulin-to-insulin ratio, homeostasis model assessment of insulin resistance (HOMA-IR), and homeostasis model assessment of β-cell function (HOMA-β) were also evaluated. RESULTS Baseline characteristics were similar between the 2 groups. Compared with placebo, linagliptin therapy resulted in a significant decrease in HbA1C (-1.2±0.7% vs. -0.4±0.4%, P<0.001), FBG (-0.98±1.17 vs. -0.32±0.51 mmol/L, P=0.011, and 2h-PPG (-2.02±0.94 vs. -0.97±0.63 mmol/L, P<0.001). Significant differences were observed for the proinsulin/insulin ratio (P<0.001) and HOMA-β index (P=0.001). Rates of adverse events were similar between the 2 groups (30.3% vs. 27.3%). All adverse events were mild. One patient discontinued participation due to pregnancy. CONCLUSIONS Linagliptin treatment resulted in a significant and clinically meaningful improvement of glycemic control in drug-naïve Chinese patients with T2DM, as well as improved parameters of b-cell function. Linagliptin had an excellent safety profile.

Topics: Adult; Blood Glucose; Blood Pressure; Body Mass Index; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Female; Glycated Hemoglobin; Homeostasis; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin Resistance; Insulin-Secreting Cells; Life Style; Linagliptin; Male; Middle Aged; Postprandial Period; Time Factors

Glucose-lowering treatment options are limited for uncontrolled type 2 diabetes mellitus (T2DM) patients with advanced stages of renal impairment (RI). This retrospective analysis evaluated glycaemic efficacy and tolerability of the dipeptidyl peptidase-4 inhibitor linagliptin added to sulphonylurea. Three randomized phase 3 studies (n = 619) including T2DM subjects with moderate or severe RI [estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m²] were analysed; only sulphonylurea-treated subjects who received additional linagliptin (n = 58) or placebo (n = 33) were evaluated. Linagliptin provided meaningful placebo-adjusted HbA1c reductions of -0.68% (95% confidence interval: -1.19, -0.17), -1.08% (-2.02, -0.14) and -0.62% (-1.25, 0.01) after 24, 18 and 12 weeks, respectively. There was a similar incidence of overall adverse events (linagliptin: 79.3%, placebo: 75.8%) and hypoglycaemia (linagliptin: 37.9%, placebo: 39.4%). Severe hypoglycaemia was more common with placebo (linagliptin: 1.7%, placebo: 6.1%). These data suggest that linagliptin is a safe and effective glucose-lowering treatment in T2DM patients with moderate-to-severe RI for whom sulphonylurea treatment is no longer sufficient.

Topics: Aged; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Monitoring; Drug Resistance; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Kidney; Linagliptin; Male; Middle Aged; Purines; Quinazolines; Renal Insufficiency, Chronic; Retrospective Studies; Severity of Illness Index; Sulfonylurea Compounds

Although black/African American individuals are disproportionately affected by type 2 diabetes, there is scant clinical trial information available on antidiabetes therapies in this group. We compared linagliptin with placebo in black/African American adults who were treatment-naïve or receiving one oral antidiabetes drug.. Of 226 patients randomized to 24 weeks' linagliptin 5 mg/day or placebo, 208 had baseline and at least one on-treatment glycated hemoglobin (HbA1c) measurement. Mean baseline HbA1c was 8.6% in the linagliptin group (n = 98) and 8.68% in the placebo group (n = 110). The primary outcome was change in HbA1c from baseline to week 24.. By week 24, mean HbA1c changes were -0.84% with linagliptin and -0.25% with placebo (treatment difference, -0.58%; P<.001), and more patients in the linagliptin group achieved HbA1c <7.0% (26.8% vs. 8.3%; P = .001) or an HbA1c reduction ≥0.5% (54.1% vs. 30.0%; P<.001). Mean weight loss was -1.1 kg in both groups. During the treatment period, 8 of 98 linagliptin-group patients and 17 of 110 placebo-group patients required rescue therapy (odds ratio, 0.5; P = .14). For postprandial glucose, values were available for few patients (11 placebo, 10 linagliptin), and thus the between-group difference was associated with wide confidence intervals (CIs) (difference, -1.97 mg/dL; 95% CI, -53.80 to 49.86; P = .94). In the overall study population, a similar proportion of patients in both groups had adverse events (58.5% vs. 61.7%); most events were mild or moderate and considered unrelated to study drug. Investigator-defined hypoglycemia was rare (3 linagliptin-group patients and 1 placebo-group patient), with no severe events (requiring external assistance).. This study confirms that linagliptin is efficacious and well tolerated in black/African American patients with type 2 diabetes.

Topics: Adult; Aged; Black or African American; Black People; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Linagliptin; Male; Middle Aged

Topics: Adult; Aged; Autoimmunity; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Linagliptin; Male; Middle Aged; Purines; Quinazolines; Sulfonylurea Compounds

Inflammation and glycemic control are important prognosis-related factors for hemodialysis (HD) patients; moreover, inflammation affects insulin secretion. Here, we evaluated the anti-inflammatory effects of monotherapy with linagliptin-a dipeptidase-4 inhibitor-in HD patients with type 2 diabetes. We examined 21 diabetic HD patients who were not receiving oral diabetes drugs or insulin therapy and with poor glycemic control (glycated albumin [GA] level, >20%). Linagliptin (5 mg) was administered to the patients daily. The levels of prostaglandin E2 (PGE2), interleukin-6 (IL-6), high-sensitivity C-reactive protein, GA, blood glucose, and active glucagon-like peptide-1 were determined before and 6 months after treatment. Body weight and serum levels of albumin, hemoglobin, total cholesterol, and low-density lipoprotein cholesterol were also recorded before and after treatment. The levels of PGE2 and GA were significantly decreased 1 month after starting linagliptin therapy, whereas the IL-6 levels were significantly decreased 6 months after starting linagliptin therapy. After 6 months of treatment, the PGE2 levels decreased from 188 ± 50 ng/mL to 26 ± 5 ng/mL; IL-6 levels, from 1.5 ± 0.4 pg/mL to 0.6 ± 0.1 pg/mL; and GA levels, from 21.3% ± 0.6% to 18.0% ± 0.6%. Glucagon-like peptide-1 levels increased 2.5-fold during the treatment. Over the 6-month treatment period, body weight and levels of high-sensitivity C-reactive protein, blood glucose, albumin, hemoglobin, and cholesterol did not change; none of the patients exhibited hypoglycemia. The anti-inflammatory effects of linagliptin monotherapy indicate that it may serve as a useful glucose control strategy for HD patients with diabetes.

Topics: Aged; Anti-Inflammatory Agents; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Hypoglycemic Agents; Kidney Failure, Chronic; Linagliptin; Male; Purines; Quinazolines; Renal Dialysis

The goal of this study was to investigate the effects of linagliptin compared with glimepiride on alpha and beta cell function and several vascular biomarkers after a standardized test meal.. Thirty-nine patients on metformin alone (age, 64 ± 7 years; duration of type 2 diabetes mellitus, 7.8 ± 4.5years, 27 male, 12 female; HbA1c , 57.2 ± 6.9 mmol/mol; mean ± SD) were randomized to receive linagliptin 5 mg (n = 19) or glimepiride (n = 20) for a study duration of 12 weeks. Glucagon-like peptide 1, blood glucose, insulin, intact proinsulin, glucagon, plasminogen activator inhibitor-1 (PAI-1), cyclic guanosinmonophosphat and asymetric dimethylarginin levels were measured in the fasting state and postprandial at 30-min intervals for a duration of 5 h. The areas under the curve (AUC0-300 min ) were calculated for group comparisons.. HbA1c , fasting and postprandial glucose levels improved in both groups. An increase in postprandial insulin (22595 ± 5984 pmol/L*min), postprandial intact proinsulin (1359 ± 658 pmol/L*min), postprandial glucagon (317 ± 1136 pg/mL*min) and postprandial PAI-1 levels (863 ± 467 ng/mL*min) could be observed during treatment with glimepiride, whereas treatment with linagliptin was associated with a decrease in postprandial insulin (-8007 ± 4204 pmol/L*min), intact proinsulin (-1771 ± 426 pmol/L*min), postprandial glucagon (-1597 ± 1831 pg/mL*min) and PAI-1 levels (-410 ± 276 ng/mL*min).. Despite an improvement in blood glucose control in both groups, linagliptin reduced postprandial insulin, proinsulin, glucagon and PAI-levels. These results indicate an improvement in postprandial alpha and beta cell function, as well as a reduced postprandial vascular risk profile during treatment with linagliptin.

Topics: Aged; Biomarkers; Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glucagon; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Islets of Langerhans; Linagliptin; Male; Metformin; Middle Aged; Plasminogen Activator Inhibitor 1; Postprandial Period; Proinsulin; Purines; Quinazolines; Risk Factors; Sulfonylurea Compounds

To investigate the efficacy and safety of the dipeptidyl peptidase-4 inhibitor linagliptin in patients with Type 2 diabetes mellitus inadequately controlled by a combination of metformin and pioglitazone.. This was a multi-centre, phase 3, randomized, double-blind, placebo-controlled study comparing linagliptin 5 mg once daily (n = 183) and placebo (n = 89) as add-on to metformin and pioglitazone. The primary endpoint was the change from baseline in glycated haemoglobin (HbA1c ) after 24 weeks.. The placebo-corrected adjusted mean (se) change in HbA1c from baseline to 24 weeks was -6 (1) mmol/mol [-0.57 (0.13)%] (P < 0.0001). In patients with baseline HbA1c ≥ 53 mmol/mol (7.0%), 32.4% of patients in the linagliptin group and 13.8% in the placebo group achieved HbA1c < 53 mmol/mol (7.0%) (odds ratio 2.94; P = 0.0033). The placebo-corrected adjusted mean (se) change from baseline in fasting plasma glucose at week 24 was -0.57 (0.26) mmol/l [-10.4 (4.7) mg/dl] (P = 0.0280). The incidence of serious adverse events was 2.2% with linagliptin and 3.4% with placebo. Investigator-defined hypoglycaemia occurred in 5.5% of the linagliptin group and 5.6% of the placebo group. No meaningful changes in mean body weight were noted for either group.. Linagliptin as add-on therapy to metformin and pioglitazone produced significant and clinically meaningful improvements in glycaemic control, without an additional risk of hypoglycaemia or weight gain (Clinical Trials Registry No: NCT 00996658).

Topics: Adult; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Linagliptin; Male; Metformin; Middle Aged; Pioglitazone; Purines; Quinazolines; Thiazolidinediones; Treatment Failure; Treatment Outcome; Weight Gain

To investigate individual patient data from a comprehensive trials programme to evaluate the safety and efficacy of the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin across a range of glucose-lowering regimens in a large elderly population with type 2 diabetes mellitus (T2DM).. Data were pooled from individuals aged ≥ 65 years, who participated in seven phase III, placebo-controlled clinical trials of linagliptin (24-52 weeks). Safety was assessed by incidence and severity of adverse events (AEs) with a focus on hypoglycaemia. The primary efficacy endpoint was change in glycated haemoglobin (HbA1c).. In total, 841 subjects received linagliptin 5 mg once a day and 490 received placebo. At baseline, the population had a mean ± s.d. age of 71.0 ± 4.6 years and a mean HbA1c concentration of 8.0 ± 0.8%; 63.5% of subjects received ≥ 2 antidiabetes drugs. Overall AEs and drug-related AEs were experienced by similar proportions of patients (linagliptin 71.3, placebo 73.3; linagliptin 18.1, placebo 19.8%, respectively). The incidence of investigator-reported hypoglycaemia was 21.4% with linagliptin and 25.7% with placebo. Severe hypoglycaemic events were rare and there were fewer in the linagliptin group (1.0 vs. 1.8%). At week 24, the placebo-corrected adjusted mean ± s.e. reduction in HbA1c with linagliptin was -0.62 ± 0.06% (95% CI: -0.73, -0.51).. Data from this large cohort show that linagliptin is a well-tolerated and efficacious therapy for elderly patients with T2DM. Treatment with linagliptin may support individualized treatment goals, while effectively managing the risk of hypoglycaemia or drug-related side effects.

Topics: Aged; Aged, 80 and over; Blood Glucose; Comorbidity; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Incidence; Linagliptin; Male; Purines; Quinazolines; Treatment Outcome

Individuals carrying variants of the transcription factor 7-like 2 gene (TCF7L2) are at increased risk for type 2 diabetes. These metabolic genetic risk factors have been linked to diminished pancreatic islet-cell responsiveness to incretins, thus pharmacological interventions aimed at amplifying endogenous incretin biology may be affected. However, clinical evidence from randomised controlled trials so far is lacking. We investigated the influence of TCF7L2 risk alleles on the response to treatment with the dipeptidylpeptidase-4 (DPP-4) inhibitor linagliptin from four 24 week, phase III, placebo-controlled trials.. Pharmacogenomic samples and clinical data were available from 961 patients with type 2 diabetes. Whole-blood DNA samples were genotyped for TCF7L2 single-nucleotide polymorphisms in conjunction with assessments of 24 week changes in HbA1c.. Linagliptin lowered HbA1c meaningfully in all three genotypes of rs7903146 (non-risk variant carriers CC [n = 356]: -0.82% [-9.0 mmol/mol], p < 0.0001; heterozygous CT [n = 264]: -0.77% [-8.4 mmol/mol], p < 0.0001; homozygous risk variant carriers TT [n = 73]: -0.57% [-6.2 mmol/mol], p < 0.0006). No significant treatment differences were seen between CC and CT patients, although HbA1c response was reduced in TT compared with CC patients (~0.26% [~2.8 mmol/mol], p = 0.0182).. Linagliptin significantly improved hyperglycaemia in patients with type 2 diabetes both with and without the TCF7L2 gene diabetes risk alleles. However, differences in treatment response were observed, indicating that diabetes susceptibility genes may be an important contributor to the inter-individual variability of treatment response.

Topics: Alleles; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Genetic Predisposition to Disease; Humans; Linagliptin; Purines; Quinazolines; Transcription Factor 7-Like 2 Protein

Linagliptin treatment for 104 weeks was recently reported to achieve non-inferior glucose-lowering effects compared with glimepiride in patients with type 2 diabetes inadequately controlled with metformin. Additional analyses from this randomised, active-controlled, double-blind trial have been performed in individuals completing the study on study drug without requiring rescue therapy. In this population, significantly more patients receiving linagliptin achieved HbA1c < 7% without hypoglycaemia and without body weight gain after 2 years compared with those receiving glimepiride (54% and 23%, respectively; odds ratio of 3.9, 95% confidence interval 2.6-5.7, p < 0.0001).

Topics: Analysis of Variance; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Administration Schedule; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Linagliptin; Male; Middle Aged; Purines; Quinazolines; Sulfonylurea Compounds; Treatment Outcome; Weight Gain

To evaluate the long-term safety and efficacy of linagliptin as add-on therapy to one approved oral antidiabetic drug (OAD) in Japanese patients with type 2 diabetes mellitus and insufficient glycaemic control.. This 52-week, multicentre, open-label, parallel-group study evaluated once-daily linagliptin 5 mg as add-on therapy to one OAD [biguanide, glinide, glitazone, sulphonylurea (SU) or α-glucosidase inhibitors (A-GI)] in 618 patients. After a 2-week run-in, patients on SU or A-GI were randomized to either linagliptin (once daily, 5 mg) or metformin (twice or thrice daily, up to 2250 mg/day) as add-on therapy. Patients receiving the other OADs received linagliptin add-on therapy (non-randomized).. Adverse events were mostly mild or moderate, and rates were similar across all groups. Hypoglycaemic events were rare, except in the SU group. Overall, 26 (5.8%) hypoglycaemic events were reported in patients receiving linagliptin (non-randomized). Hypoglycaemic events were similar for linagliptin and metformin added to A-GI (1/61 vs. 2/61, respectively) or SU (17/124 vs. 10/63, respectively). Significant reductions in glycated haemoglobin (HbA1c) levels (between -0.7 and -0.9%) occurred throughout the study period for the background therapy groups that received linagliptin (baseline HbA1c 7.9-8.1%). The decline in HbA1c levels was indistinguishable between linagliptin and metformin groups when administered as add-on therapy to A-GI or SU.. Once-daily linagliptin showed safety and tolerability over 1 year and provided effective add-on therapy leading to significant HbA1c reductions, similar to metformin, over 52 weeks in Japanese patients.

Topics: Asian People; Biguanides; Blood Glucose; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Japan; Linagliptin; Male; Metformin; Middle Aged; Purines; Quinazolines; Sulfonylurea Compounds; Thiazolidinediones; Time Factors; Treatment Outcome

To evaluate the efficacy and safety of linagliptin in Chinese patients with type 2 diabetes mellitus (T2DM) inadequately controlled by metformin and sulphonylurea.. Data for a pre-defined Chinese subgroup who participated in a Phase III randomised, placebo-controlled, 24 week trial (NCT00602472) were analysed. The primary endpoint was change in HbA1c from baseline to 24 weeks. Apart from safety endpoints, secondary endpoints included changes in FPG and measures of insulin secretion and resistance.. A total of 192 Chinese patients with T2DM participated in the pre-defined analysis; 144 and 48 patients received linagliptin or placebo, respectively, added to metformin and sulphonylurea. Baseline characteristics (mean [±SD]) for linagliptin and placebo were similar: HbA1c: 8.1% (±0.85) and 8.1% (±0.84); body mass index: 25.9 (±3.2) and 25.6 (±3.4) kg/m², respectively. Placebo-corrected mean (±SE) change in HbA1c from baseline at 24 weeks was -0.68% (0.14) with linagliptin-based treatment (95% CI: -0.96 to -0.39; P<0.0001). Placebo-corrected mean (±SE) change in FPG from baseline at 24 weeks with linagliptin was -18.8 (6.5) mg/dL (-1.0 [0.4] mmol/L; 95% CI: -31.7 to -5.9; P=0.0044). Overall adverse event (AE) rates with linagliptin and placebo including background medication were similar (38.9% and 43.8%, respectively). Drug-related AEs were reported by 12.5% and 2.1% of linagliptin and placebo patients, respectively. Differences were due to hypoglycaemia (10.4% and 0.0%, respectively). No severe hypoglycaemia was reported in either group of this sub-population.. Linagliptin in combination with metformin and sulphonylurea has a favourable safety profile and is an efficacious and well tolerated treatment option for Chinese patients with inadequately controlled T2DM. Reduction of sulphonylurea dose should be considered to minimise risk of hypoglycaemia. Although the findings of this pre-specified sub-analysis may be limited by the number of patients in the subgroup, the results were generally consistent with those for the overall population. CLINICALTRIALS IDENTIFIER: NCT00602472.

Topics: Aged; China; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Humans; Hypoglycemic Agents; Linagliptin; Male; Metformin; Middle Aged; Placebos; Purines; Quinazolines; Sulfonylurea Compounds

A substantial proportion of patients with type 2 diabetes are elderly (≥65 years) but this group has been largely excluded from clinical studies of glucose-lowering drugs. We aimed to assess the effectiveness of linagliptin, a dipeptidyl peptidase-4 inhibitor, in elderly patients with type 2 diabetes.. In this randomised, double-blind, parallel-group, multinational phase 3 study, patients aged 70 years or older with type 2 diabetes, glycated haemoglobin A1c (HbA1c) of 7·0% or more, receiving metformin, sulfonylureas, or basal insulin, or combinations of these drugs, were randomised (by computer-generated randomisation sequence, concealed with a voice-response system, stratified by HbA1c level [<8·5% vs ≥8·5%] and insulin use [yes vs no], block size four) in a 2:1 ratio to once-daily oral treatment with linagliptin 5 mg or matching placebo for 24 weeks. Investigators and participants were masked to assignment throughout the study. The primary endpoint was change in HbA1c from baseline to week 24. This trial is registered with ClinicalTrials.gov, number NCT01084005.. 241 community-living outpatients were randomised (162 linagliptin, 79 placebo). Mean age was 74·9 years (SD 4·3). Mean HbA1c was 7·8% (SD 0·8). At week 24, placebo-adjusted mean change in HbA1c with linagliptin was -0·64% (95% CI -0·81 to -0·48, p<0·0001). Overall safety and tolerability were much the same between the linagliptin and placebo groups; 75·9% of patients in both groups had an adverse event (linagliptin n=123, placebo n=60). No deaths occurred. Serious adverse events occurred in 8·6% (14) of patients in the linagliptin group and 6·3% (five) patients in the placebo group; none were deemed related to study drug. Hypoglycaemia was the most common adverse event in both groups, but did not differ between groups (24·1% [39] in the linagliptin group, 16·5% [13] in the placebo group; odds ratio 1·58, 95% CI 0·78-3·78, p=0·2083).. In elderly patients with type 2 diabetes linagliptin was efficacious in lowering glucose with a safety profile similar to placebo. These findings could inform treatment decisions for achieving individualised glycaemic goals with minimal risk in this important population of patients.. Boehringer Ingelheim.

Topics: Aged; Aged, 80 and over; Analysis of Variance; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Linagliptin; Male; Purines; Quinazolines; Treatment Outcome

Preclinical data suggest that linagliptin, a dipeptidyl peptidase-4 inhibitor, may lower urinary albumin excretion. The ability of linagliptin to lower albuminuria on top of renin-angiotensin-aldosterone system (RAAS) inhibition in humans was analyzed by pooling data from four similarly designed, 24-week, randomized, double-blind, placebo-controlled, phase III trials.. A pooled analysis of four completed studies identified 217 subjects with type 2 diabetes and prevalent albuminuria (defined as a urinary albumin-to-creatinine ratio [UACR] of 30-3,000 mg/g creatinine) while receiving stable doses of RAAS inhibitors. Participants were randomized to either linagliptin 5 mg/day (n = 162) or placebo (n= 55). The primary end point was the percentage change in geometric mean UACR from baseline to week 24.. UACR at week 24 was reduced by 32% (95% CI -42 to -21; P < 0.05) with linagliptin compared with 6% (95% CI -27 to +23) with placebo, with a between-group difference of 28% (95% CI -47 to -2; P = 0.0357). The between-group difference in the change in HbA1c from baseline to week 24 was -0.61% (-6.7 mmol/mol) in favor of linagliptin (95% CI -0.88 to -0.34% [-9.6 to -3.7 mmol/mol]; P < 0.0001). The albuminuria-lowering effect of linagliptin, however, was not influenced by race or HbA1c and systolic blood pressure (SBP) values at baseline or after treatment.. Linagliptin administered in addition to stable RAAS inhibitors led to a significant reduction in albuminuria in patients with type 2 diabetes and renal dysfunction. This observation was independent of changes in glucose level or SBP. Further research to prospectively investigate the renal effects of linagliptin is underway.

Topics: Aged; Albuminuria; Blood Pressure; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Female; Glycated Hemoglobin; Humans; Linagliptin; Male; Middle Aged; Purines; Quinazolines; Renin-Angiotensin System; Treatment Outcome

To evaluate the efficacy and long-term safety of linagliptin added to basal insulins in type 2 diabetes inadequately controlled on basal insulin with or without oral agents.. A total of 1,261 patients (HbA1c ≥7.0% [53 mmol/mol] to ≤10.0% [86 mmol/mol]) on basal insulin alone or combined with metformin and/or pioglitazone were randomized (1:1) to double-blind treatment with linagliptin 5 mg once daily or placebo for ≥52 weeks. The basal insulin dose was kept unchanged for 24 weeks but could thereafter be titrated according to fasting plasma glucose levels at the investigators' discretion. The primary end point was the mean change in HbA1c from baseline to week 24. The safety analysis incorporated data up to a maximum of 110 weeks.. At week 24, HbA1c changed from a baseline of 8.3% (67 mmol/mol) by -0.6% (-6.6 mmol/mol) and by 0.1% (1.1 mmol/mol) with linagliptin and placebo, respectively (treatment difference -0.65% [95% CI -0.74 to -0.55] [-7.1 mmol/mol]; P < 0.0001). Despite the option to uptitrate basal insulin, it was adjusted only slightly upward (week 52, linagliptin 2.6 IU/day, placebo 4.2 IU/day; P < 0.003), resulting in no further HbA1c improvements. Frequencies of hypoglycemia (week 24, linagliptin 22.0%, placebo 23.2%; treatment end, linagliptin 31.4%, placebo 32.9%) and adverse events (linagliptin 78.4%, placebo 81.4%) were similar between groups. Mean body weight remained unchanged (week 52, linagliptin -0.30 kg, placebo -0.04 kg).. Linagliptin added to basal insulin therapy significantly improved glycemic control relative to placebo without increasing hypoglycemia or body weight.

Topics: Adult; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Linagliptin; Male; Metformin; Middle Aged; Pioglitazone; Purines; Quinazolines; Retrospective Studies; Thiazolidinediones; Treatment Outcome

To determine the efficacy and safety of linagliptin in initial combination with metformin in patients with type 2 diabetes.. This 1-year randomised, double-blind study was an extension of a 6-month randomised controlled trial, in which adults with type 2 diabetes received one of six treatment regimens (linagliptin 2.5 mg plus metformin 500 mg bid, linagliptin 2.5 mg plus metformin mg 1000 bid, metformin 1000 mg bid, metformin 500 mg bid, linagliptin 5 mg qd or placebo). In the extension, patients in the first three treatment groups continued their regimen (non-switched group, n = 333) while the metformin 500 mg bid, linagliptin 5 mg qd and placebo groups were re-randomised to one of the three continuing regimens (switched group, n = 233).. All three non-switched groups maintained reductions in glycosylated haemoglobin (HbA1c; mean ± standard deviation reductions across the 1.5-year period: linagliptin 2.5 plus metformin 1000 bid, -1.63 ± 1.05%; linagliptin 2.5 plus metformin 500 bid, -1.32 ± 1.06%; metformin 1000 bid, -1.25 ± 0.91%) while the switched groups showed additional HbA1c reductions. During the extension, there were no clinically meaningful changes in body weight in any group. Adverse event rates were similar between groups, with most events being mild or moderate, and the incidence of investigator-defined hypoglycaemia was low, with no severe events.. Initial combination of linagliptin and metformin was well tolerated over the 1-year extension period, with low risk of hypoglycaemia, and improved glycaemic control vs. metformin alone.. The initial combination of linagliptin and metformin appears to provide a useful treatment option in patients whose blood glucose levels are increased to an extent that metformin monotherapy may not achieve treatment targets.

Topics: Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Linagliptin; Male; Metformin; Middle Aged; Purines; Quinazolines; Treatment Outcome

Linagliptin is a novel, highly selective and long acting DPP-4 inhibitor for the treatment of type 2 diabetes mellitus (T2DM). Linagliptin exhibits non-linear pharmacokinetics (PK) due to saturable binding to plasma and tissue DPP-4. The aim of this study was to characterize the PK and PK/DPP-4 inhibition relationship of linagliptin in Japanese patients with T2DM using a population PK/DPP-4 model and to support the rationale for the therapeutic dose in Japanese patients by simulation.. Linagliptin plasma concentration and DPP-4 inhibition measurements from a placebo-controlled, parallel group multiple (28 days) dose trial that included 36 T2DM patients (18 patients each in 2.5 mg and 10 mg dose group) were used for analysis. Modeling was performed using FOCE INTERACTION estimation method implemented in NONMEM V. The linagliptin plasma concentration- and DPP-4 inhibition- time profiles were simulated for Japanese patients receiving 5 mg linagliptin once daily by the model established.. Nonlinear PK of linagliptin in T2DM patients were well described by a 2-compartment model assuming concentration-dependent binding to DPP-4 in the central and peripheral compartment. Plasma DPP-4 inhibition was integrated in the model by relating the model-predicted DPP-4 occupancy with linagliptin linearly to DPP-4 inhibition. The simulation predicted that for the 5 mg dose group the trough DPP-4 inhibition at steady-state was 84.2%, which is higher than the target inhibition (≥80%) for an effective dose of DPP-4 inhibitor. In 2.5 mg dose group, steady-state DPP-4 inhibition of >80% was not maintained over 24 hours (observed and simulated).. The nonlinear PK of linagliptin and its plasma DPP-4 inhibition in patients were well characterized by a target-mediated drug disposition model relating DPP-4 occupancy with linagliptin to DPP-4 inhibition. Simulations of plasma DPP-4 inhibition suggest that 5 mg linagliptin once daily is an appropriate therapeutic dose for Japanese patients with T2DM.

Topics: Adult; Aged; Asian People; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Female; Humans; Hypoglycemic Agents; Linagliptin; Male; Middle Aged; Models, Biological; Purines; Quinazolines

This placebo-controlled study assessed long-term efficacy and safety of the dipeptidyl peptidase-4 inhibitor linagliptin in patients with type 2 diabetes and severe renal impairment (RI).. In this 1-year, double-blind study, 133 patients with type 2 diabetes (HbA(1c) 7.0-10.0%) and severe RI (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m(2)) at screening were randomized to linagliptin 5 mg (n = 68) or placebo (n = 65) once daily, added to existing background therapy. The primary efficacy end point was HbA(1c) change from baseline to week 12. Efficacy and safety end points were assessed after 1 year.. At week 12, adjusted mean HbA(1c) decreased by -0.76% with linagliptin and -0.15% with placebo (treatment difference, -0.60%; 95% CI -0.89 to -0.31; P < 0.0001). HbA(1c) improvements were sustained with linagliptin (-0.71%) over placebo (0.01%) at 1 year (treatment difference -0.72%, -1.03 to -0.41; P < 0.0001). Mean insulin doses decreased by -6.2 units with linagliptin and -0.3 units with placebo. Overall adverse event incidence was similar over 1 year (94.1 vs. 92.3%). Incidence of severe hypoglycemia with linagliptin and placebo was comparably low (three patients per group). Linagliptin and placebo had little effect on renal function (median change in eGFR, -0.8 vs. -2.2 mL/min/1.73 m(2)), and no drug-related renal failure occurred.. In patients with type 2 diabetes and severe RI, linagliptin provided clinically meaningful improvements in glycemic control with very low risk of severe hypoglycemia, stable body weight, and no cases of drug-related renal failure. The potential for linagliptin to spare insulin and provide long-term renal safety warrants further investigations.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Kidney; Linagliptin; Male; Middle Aged; Purines; Quinazolines; Renal Insufficiency; Young Adult

In a phase III study conducted among Japanese patients with type 2 diabetes mellitus (T2DM), linagliptin 5 and 10 mg showed clinically meaningful improvements in glycaemic parameters after 12 and 26 weeks compared with placebo and voglibose, respectively. This extension study assessed long-term tolerability of linagliptin over 52 weeks.. Japanese patients with T2DM who completed either phase of a 12-week/26-week study comparing linagliptin monotherapy with placebo or voglibose were eligible to enrol. In the extension study, the comparator groups switched to linagliptin 5 or 10 mg, while the linagliptin groups maintained dosage.. In all, 540 patients received at least one dose of linagliptin 5 or 10 mg and 494 completed the extension. Long-term treatment with linagliptin was well tolerated; adverse events (AEs) of special interest and serious AEs occurred in small percentages of patients. Drug-related AEs occurred in 10.2 and 10.6% of patients in the linagliptin 5- and 10-mg groups, respectively, and discontinuations due to drug-related AEs occurred in 1.1 and 0.7%, respectively. Only one (0.4%) patient in each dose group experienced investigator-defined hypoglycaemia during the treatment period (both events were non-severe). Body weight was not clinically altered in either group. The glycated haemoglobin A1c profiles over time were similar with linagliptin 5 and 10 mg.. These findings provide evidence for the safety and tolerability of oral linagliptin at either 5 or 10 mg for up to 52 weeks for the treatment of Japanese patients with T2DM, without clinically relevant increase in the risk of hypoglycaemia or weight gain.

Topics: Adult; Aged; Aged, 80 and over; Asian People; Blood Glucose; Body Mass Index; Body Weight; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Inositol; Linagliptin; Male; Middle Aged; Purines; Quinazolines; Time Factors

This was an open label, multicentre phase I trial to study the pharmacokinetics and pharmacodynamics of the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin in African American patients with type 2 diabetes mellitus (T2DM).. Forty-one African American patients with T2DM were included in this study. Patients were admitted to a study clinic and administered 5 mg linagliptin once daily for 7 days, followed by 7 days of outpatient evaluation.. Primary endpoints were area under the plasma concentration-time curve (AUC), maximum plasma concentration (Cmax ) and plasma DPP-4 trough inhibition at steady-state. Linagliptin geometric mean AUC was 194 nmol l(-1) h (geometric coefficient of variation, 26%), with a Cmax of 16.4 nmol l(-1) (41%). Urinary excretion was low (0.5% and 4.4% of the dose excreted over 24 h, days 1 and 7). The geometric mean DPP-4 inhibition at steady-state was 84.2% at trough and 91.9% at maximum. The exposure range and overall pharmacokinetic/pharmacodynamic profile of linagliptin in this study of African Americans with T2DM was comparable with that in other populations. Laboratory data, vital signs and physical examinations did not show any relevant findings. No safety concerns were identified.. The results of this study in African American patients with T2DM support the use of the standard 5 mg dose recommended in all populations.

Topics: Black or African American; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Female; Humans; Hypoglycemic Agents; Linagliptin; Male; Purines; Quinazolines

To evaluate the efficacy and safety of linagliptin 5 and 10 mg vs. placebo and voglibose in Japanese patients with type 2 diabetes mellitus (T2DM).. This study enrolled patients with inadequately controlled T2DM who were previously treated with one or two oral antidiabetics or were drug naÏve. After a 2 to 4-week washout and placebo run-in, 561 patients were randomized (2 : 2 : 2 : 1) to double-blind treatment with linagliptin 5 or 10 mg qd, voglibose 0.2 mg tid or placebo. The primary endpoint was the change from baseline in haemoglobin A1c (HbA1c) with linagliptin vs. placebo after 12 weeks and vs. voglibose after 26 weeks.. Baseline characteristics were well balanced across treatment groups (overall mean HbA1c was 8.01%). The adjusted mean (95% confidence interval) treatment differences at week 12 were -0.87% (-1.04, -0.70; p < 0.0001) and -0.88% (-1.05, -0.71; p < 0.0001) for linagliptin 5 and 10 mg vs. placebo and at week 26 were -0.32% (-0.49, -0.15; p = 0.0003) and -0.39% (-0.56, -0.21; p < 0.0001) for linagliptin 5 and 10 mg vs. voglibose. At week 12, mean HbA1c was 7.58, 7.48 and 8.34% in patients receiving linagliptin 5 mg, linagliptin 10 mg and placebo, respectively. At week 26, mean HbA1c was 7.63% with linagliptin 5 mg, 7.50% with linagliptin 10 mg and 7.91% with voglibose. Drug-related adverse event rates were comparable across treatment groups over 12 weeks (9.4% linagliptin 5 mg, 8.8% linagliptin 10 mg and 10.0% placebo) and 26 weeks (11.3% linagliptin 5 mg, 10.6% linagliptin 10 mg and 18.5% voglibose). There were no documented cases of hypoglycaemia.. Linagliptin showed superior glucose-lowering efficacy and comparable safety and tolerability to both placebo and voglibose in Japanese patients with T2DM.

Topics: Adult; Aged; Aged, 80 and over; Analysis of Variance; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Humans; Hypoglycemic Agents; Inositol; Japan; Linagliptin; Male; Middle Aged; Purines; Quinazolines; Treatment Outcome

To evaluate the efficacy and safety of initial combination therapy with linagliptin plus metformin versus linagliptin or metformin monotherapy in patients with type 2 diabetes.. In this 24-week, double-blind, placebo-controlled, Phase III trial, 791 patients were randomized to one of six treatment arms. Two free combination therapy arms received linagliptin 2.5 mg twice daily (bid) + either low (500 mg) or high (1000 mg) dose metformin bid. Four monotherapy arms received linagliptin 5 mg once daily, metformin 500 mg or 1000 mg bid or placebo. Patients with haemoglobin A1c (HbA1c) ≥11.0% were not eligible for randomization and received open-label linagliptin + high-dose metformin.. The placebo-corrected mean (95% confidence interval) change in HbA1c from baseline (8.7%) to week 24 was -1.7% (-2.0, -1.4) for linagliptin + high-dose metformin, -1.3% (-1.6, -1.1) for linagliptin + low-dose metformin, -1.2% (-1.5, -0.9) for high-dose metformin, -0.8% (-1.0, -0.5) for low-dose metformin and -0.6 (-0.9, -0.3) for linagliptin (all p < 0.0001). In the open-label arm, the mean change in HbA1c from baseline (11.8%) was -3.7%. Hypoglycaemia occurred at a similar low rate with linagliptin + metformin (1.7%) as with metformin alone (2.4%). Adverse event rates were comparable across treatment arms. No clinically significant changes in body weight were noted.. Initial combination therapy with linagliptin plus metformin was superior to metformin monotherapy in improving glycaemic control, with a similar safety and tolerability profile, no weight gain and a low risk of hypoglycaemia.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Linagliptin; Male; Metformin; Middle Aged; Purines; Quinazolines; Treatment Outcome

Addition of a sulphonylurea to metformin improves glycaemic control in type 2 diabetes, but is associated with hypoglycaemia and weight gain. We aimed to compare a dipeptidyl peptidase-4 inhibitor (linagliptin) against a commonly used sulphonylurea (glimepiride).. In this 2-year, parallel-group, non-inferiority double-blind trial, outpatients with type 2 diabetes and glycated haemoglobin A(1c) (HbA(1c)) 6·5-10·0% on stable metformin alone or with one additional oral antidiabetic drug (washed out during screening) were randomly assigned (1:1) by computer-generated random sequence via a voice or web response system to linagliptin (5 mg) or glimepiride (1-4 mg) orally once daily. Study investigators and participants were masked to treatment assignment. The primary endpoint was change in HbA(1c) from baseline to week 104. Analyses included all patients randomly assigned to treatment groups who received at least one dose of treatment, had a baseline HbA(1c) measurement, and had at least one on-treatment HbA(1c) measurement. This trial is registered at ClinicalTrials.gov, number NCT00622284.. 777 patients were randomly assigned to linagliptin and 775 to glimepiride; 764 and 755 were included in analysis of the primary endpoint. Reductions in adjusted mean HbA(1c) (baseline 7·69% [SE 0·03] in both groups) were similar in the linagliptin (-0·16% [SE 0·03]) and glimepiride groups (-0·36% [0·03]; difference 0·20%, 97·5% CI 0·09-0·30), meeting the predefined non-inferiority criterion of 0·35%. Fewer participants had hypoglycaemia (58 [7%] of 776 vs 280 [36%] of 775 patients, p<0·0001) or severe hypoglycaemia (1 [<1%] vs 12 [2%]) with linagliptin compared with glimepiride. Linagliptin was associated with significantly fewer cardiovascular events (12 vs 26 patients; relative risk 0·46, 95% CI 0·23-0·91, p=0·0213).. The results of this long-term randomised active-controlled trial advance the clinical evidence and comparative effectiveness bases for treatment options available to patients with type 2 diabetes mellitus. The findings could improve decision making for clinical treatment when metformin alone is insufficient.. Boehringer Ingelheim.

Topics: Adult; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Linagliptin; Male; Metformin; Middle Aged; Purines; Quinazolines; Research Design; Sulfonylurea Compounds; Treatment Failure; Treatment Outcome

Glycaemic control in patients with type 2 diabetes (T2DM) is often not achieved or not sustained using monotherapy such as metformin, necessitating the addition of other antihyperglycaemic agents. Linagliptin, a dipeptidyl peptidase-4 inhibitor, is licensed for 5 mg once-daily dosing. As metformin is administered twice daily, a fixed-dose combination of these compounds would require twice-daily administration of linagliptin. This study evaluated whether 2.5 mg twice-daily dosing of linagliptin has comparable efficacy and safety to 5 mg once-daily dosing when given in addition to metformin twice daily in patients with inadequate glycaemic control.. A total of 491 T2DM patients with glycated haemoglobin (HbA1c) 7.0-10.0% were randomised (5:5:1) to double-blind treatment with linagliptin 2.5 mg twice daily, 5 mg once daily or placebo, respectively, in addition to continuing metformin twice daily (≥1500 mg/day or maximally tolerated dose). The primary endpoint was change from baseline in HbA1c after 12 weeks. ClinicalTrials.gov, NCT01012037.. Mean baseline HbA1c for all patients was 7.97%. After 12 weeks, linagliptin 2.5 mg twice daily and 5 mg once daily both significantly reduced HbA1c (placebo-adjusted changes from baseline -0.74% (95% CI -0.97, -0.52) and -0.80% (95% CI -1.02, -0.58), respectively, both p<0.0001). The treatment difference (twice daily-once daily) between the linagliptin regimens was 0.06 (95% CI -0.07, 0.19), the upper bound of which was less than the predefined noninferiority margin (0.35%). The overall incidence of adverse events with linagliptin 2.5 mg twice daily, 5 mg once daily and placebo was 43.0%, 34.8%, and 38.6% respectively. Hypoglycaemia was rare (3.1% with linagliptin 2.5 mg twice daily, 0.9% with 5 mg once daily, 2.3% with placebo) with no severe episodes. Study limitations include duration, patient population (mainly white) and absence of postprandial glucose data.. Linagliptin 2.5 mg twice daily had non-inferior HbA1c-lowering effects after 12 weeks compared to 5 mg once daily, with comparable safety and tolerability, in T2DM patients inadequately controlled with metformin.

Topics: Aged; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Administration Schedule; Female; Glycated Hemoglobin; Humans; Linagliptin; Male; Middle Aged; Placebos; Purines; Quinazolines

Some patients with type 2 diabetes mellitus (T2DM) receiving monotherapy with a sulfonylurea (SU) are unable to meet recommended glycemic targets over the long term and require additional pharmacologic agents to maintain glycemic control. This study was designed to assess the utility of adjunctive therapy with the dipeptidyl peptidase (DPP)-4 inhibitor linagliptin in patients with T2DM inadequately controlled with SU monotherapy.. To assess the efficacy and tolerability of linagliptin as add-on therapy in patients with inadequately controlled T2DM despite background therapy with an SU.. In this Phase III, multicenter, randomized, double-blind, placebo-controlled trial, patients with inadequately controlled T2DM on SU monotherapy were randomly assigned to receive treatment with linagliptin 5 mg once daily (n = 161) or placebo (n = 84) for 18 weeks. The primary end point was the mean change in hemoglobin (Hb) A(1c) from baseline to week 18, evaluated using ANCOVA. Tolerability was assessed using laboratory analysis, spontaneous reporting, and physical examination and interview.. Mean baseline characteristics were similar in the linagliptin and placebo groups. Linagliptin treatment was associated with a placebo-corrected mean (95% CI) change in HbA(1c) from baseline (8.6%) to 18 weeks of -0.47% (-0.70 to -0.24; P < 0.0001). Patients in the linagliptin group were more likely compared with placebo to achieve the HbA(1c) target level of <7.0% after 18 weeks of treatment (15.2% vs 3.7%, respectively; odds ratio [OR] = 6.5; 95% CI, 1.7-24.8; P = 0.007). Similarly, patients in the linagliptin group were more likely to achieve an HbA(1c) reduction of ≥0.5% compared with those in the placebo group (57.6% vs 22.0%; OR = 5.1, 95% CI 2.7-9.6; P < 0.0001). The overall frequency of adverse events was similar between the linagliptin and placebo groups (42.2% vs 42.9%). The incidences of hypoglycemic events were not significantly different between the 2 groups (5.6% vs 4.8%), and none of the hypoglycemic episodes were assessed as severe by the investigator. The difference in the changes in mean body weight was not significant (+0.43 vs -0.01 kg; P = 0.12).. The addition of linagliptin to SU therapy for 18 weeks in these patients with T2DM was associated with statistically significant and clinically meaningful reductions in HbA(1c) compared with placebo. The overall tolerability of linagliptin was similar to that of placebo, with a low risk for hypoglycemia and no significant weight gain. These findings support the use of linagliptin as adjunctive therapy in patients with T2DM inadequately controlled on SU monotherapy. ClinicalTrials.gov identifier: NCT00819091.

Topics: Aged; Analysis of Variance; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Therapy, Combination; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Linagliptin; Male; Middle Aged; Purines; Quinazolines; Sulfonylurea Compounds; Treatment Outcome

To investigate the efficacy and safety of linagliptin, a dipeptidyl peptidase-4 inhibitor, in type 2 diabetes mellitus (T2DM) patients for whom metformin was inappropriate.. This 1-year double-blind study (ClinicalTrials.gov, NCT00740051) enrolled T2DM patients with inadequate glycaemic control, treatment-naïve [glycated haemoglobin (HbA1c) 7.0-10.0%] or previously treated with one oral antidiabetes drug (HbA1c 6.5-9.0% before washout), ineligible for metformin because of contraindications (e.g. renal impairment) or previous intolerable side effects. Patients were randomized to monotherapy with linagliptin 5 mg once daily (n = 151) or placebo (n = 76) for 18 weeks, after which placebo patients switched to glimepiride 1-4 mg once daily and treatments continued for another 34 weeks. The primary endpoint was change from baseline in HbA1c after 18 weeks (full-analysis set, last observation carried forward).. At week 18, adjusted mean difference in change from baseline HbA1c (8.1%) was -0.60% (95% confidence interval -0.88, -0.32; p < 0.0001) (-0.39% with linagliptin, +0.21% with placebo). At week 52, mean HbA1c was decreased from baseline in both groups [linagliptin: -0.44%; placebo/glimepiride: -0.72% (observed cases)]. Adverse events occurred in 40.4 and 48.7% of linagliptin and placebo patients, respectively, during the initial 18 weeks. During the 34-week extension, patients receiving linagliptin experienced less hypoglycaemia (2.2% vs. 7.8%) and no weight gain (mean change from baseline of -0.2 and +1.3 kg, respectively) compared with glimepiride patients.. In T2DM patients for whom metformin was inappropriate, linagliptin improved glycaemic control and was well tolerated, with less hypoglycaemia and relative weight loss compared with glimepiride.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Administration Schedule; Female; Humans; Hypoglycemia; Hypoglycemic Agents; Linagliptin; Male; Metformin; Middle Aged; Purines; Quinazolines; Sulfonylurea Compounds; Treatment Outcome

In the United States, black/African American individuals are more likely than whites to develop type 2 diabetes mellitus (T2DM), and have higher rates of complications, but are under-represented in clinical trials. The design of a trial comparing the efficacy and safety of the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin 5 mg/day with placebo in this patient group, and the characteristics of the patients enrolled are reported.. This United States, multicenter, 24-week, randomized, double-blind study enrolled adults with T2DM who self-reported their race as black or African American, were receiving ≤ 1 oral antidiabetes drug, had a body mass index ≤ 45 kg/m(2) and glycosylated hemoglobin (HbA(1c)) of 7.5 - 11% at screening.. The primary efficacy endpoint is the change of HbA(1c) from baseline to week 24.. A total of 226 patients were randomized and received ≥ 1 study drug dose. The mean age was 54 years (standard deviation: 9.9 years), and 54% were men. The mean HbA(1c) was 8.75% (standard deviation: 1.10%). Approximately half the patients (52%) had mild or moderate renal impairment and the majority (72%) had hypertension.. To the authors' knowledge, this is the first trial of any oral antidiabetes drug specifically conducted in black/African American patients.

Topics: Adult; Aged; Aged, 80 and over; Black or African American; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Female; Humans; Linagliptin; Male; Middle Aged; Purines; Quinazolines; Treatment Outcome; Young Adult

The aim of this study was to investigate the effect of the dipeptidyl peptidase-4 inhibitor linagliptin on the pharmacokinetics of glyburide (a CYP2C9 and CYP3A4 substrate) and vice versa. This randomized, open-label, three-period, two-way crossover study examined the effects of co-administration of multiple oral doses of linagliptin (5 mg/day × 6 days) and single doses of glyburide (1.75 mg/day × 1 day) on the relative bioavailability of either compound in healthy subjects (n = 20, age 18-55 years). Coadministration of glyburide did not alter the steady-state pharmacokinetics of linagliptin. Geometric mean ratios (GMRs) [90% CI] for (linagliptin + glyburide)/linagliptin AUC(τ,ss) and C(max,ss) were 101.7% [97.7-105.8%] and 100.8% [89.0-114.3%], respectively. For glyburide, there was a slight reduction in exposure of ∼14% when coadministered with linagliptin (GMRs [90% CI] for (glyburide + linagliptin)/glyburide AUC(0-∞) and C(max) were 85.7% [79.8-92.1%] and 86.2% [79.6-93.3%], respectively). However, this was not seen as clinically relevant due to the absence of a reliable dose-response relationship and the known large pharmacokinetic interindividual variability of glyburide. These results further support the assumption that linagliptin is not a clinically relevant inhibitor of CYP2C9 or CYP3A4 in vivo. Coadministration of linagliptin and glyburide had no clinically relevant effect on the pharmacokinetics of linagliptin or glyburide. Both agents were well tolerated and can be administered together without the need for dosage adjustments.

Topics: Adolescent; Adult; Area Under Curve; Aryl Hydrocarbon Hydroxylases; Biological Availability; Cross-Over Studies; Cytochrome P-450 CYP2C9; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Interactions; Female; Glyburide; Humans; Hypoglycemic Agents; Linagliptin; Male; Middle Aged; Purines; Quinazolines; Sulfonylurea Compounds

To evaluate the efficacy and safety of the potent and selective dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin administered as add-on therapy to metformin in patients with type 2 diabetes with inadequate glycaemic control.. This 24-week, randomized, placebo-controlled, double-blind, parallel-group study was carried out in 82 centres in 10 countries. Patients with HbA1c levels of 7.0-10.0% on metformin and a maximum of one additional antidiabetes medication, which was discontinued at screening, continued on metformin ≥1500 mg/day for 6 weeks, including a placebo run-in period of 2 weeks, before being randomized to linagliptin 5 mg once daily (n = 524) or placebo (n = 177) add-on. The primary outcome was the change from baseline in HbA1c after 24 weeks of treatment, evaluated with an analysis of covariance (ANCOVA).. Mean baseline HbA1c and fasting plasma glucose (FPG) were 8.1% and 9.4 mmol/l, respectively. Linagliptin showed significant reductions vs. placebo in adjusted mean changes from baseline of HbA1c (-0.49 vs. 0.15%), FPG (-0.59 vs. 0.58 mmol/l) and 2hPPG (-2.7 vs. 1.0 mmol/l); all p < 0.0001. Hypoglycaemia was rare, occurring in three patients (0.6%) treated with linagliptin and five patients (2.8%) in the placebo group. Body weight did not change significantly from baseline in both groups (-0.5 kg placebo, -0.4 kg linagliptin).. The addition of linagliptin 5 mg once daily in patients with type 2 diabetes inadequately controlled on metformin resulted in a significant and clinically meaningful improvement in glycaemic control without weight gain or increased risk of hypoglycaemia.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Linagliptin; Male; Metformin; Middle Aged; Purines; Quinazolines; Young Adult

To assess the safety and efficacy of the potent and selective dipeptidyl peptidase-4 inhibitor linagliptin 5 mg when given for 24 weeks to patients with type 2 diabetes who were either treatment-naive or who had received one oral antidiabetes drug (OAD).. This multicentre, randomized, parallel group, phase III study compared linagliptin treatment (5 mg once daily, n = 336) with placebo (n = 167) for 24 weeks in type 2 diabetes patients. Before randomization, patients pretreated with one OAD underwent a washout period of 6 weeks, which included a placebo run-in period during the last 2 weeks. Patients previously untreated with an OAD underwent a 2-week placebo run-in period. The primary endpoint was the change in HbA1c from baseline after 24 weeks of treatment.. Linagliptin treatment resulted in a placebo-corrected change in HbA1c from baseline of -0.69% (p < 0.0001) at 24 weeks. In patients with baseline HbA1c ≥ 9.0%, the adjusted reduction in HbA1c was 1.01% (p < 0.0001). Patients treated with linagliptin were more likely to achieve a reduction in HbA1c of ≥0.5% at 24 weeks than those in the placebo arm (47.1 and 19.0%, respectively; odds ratio, OR = 4.2, p < 0.0001). Fasting plasma glucose improved by -1.3 mmol/l (p < 0.0001) with linagliptin vs. placebo, and linagliptin produced an adjusted mean reduction from baseline after 24 weeks in 2-h postprandial glucose of -3.2 mmol/l (p < 0.0001). Statistically significant and relevant treatment differences were observed for proinsulin/insulin ratio (p = 0.025), Homeostasis Model Assessment-%B (p = 0.049) and disposition index (p = 0.0005). There was no excess of hypoglycaemic episodes with linagliptin vs. placebo and no patient required third-party intervention. Mild or moderate renal impairment did not influence the trough plasma levels of linagliptin.. Monotherapy with linagliptin produced a significant, clinically meaningful and sustained improvement in glycaemic control, accompanied by enhanced parameters of β-cell function. The safety profile of linagliptin was comparable with that of placebo.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin-Secreting Cells; Linagliptin; Male; Middle Aged; Placebos; Purines; Quinazolines; Treatment Outcome; Young Adult

To investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of linagliptin in patients with type 2 diabetes mellitus (T2DM).. After screening and a 14-day washout, subjects received linagliptin 2.5, 5 or 10 mg or placebo once-daily for 28 days in this randomized, double-blind, parallel, placebo-controlled within-dose groups study.. Seventy-seven patients entered the study (linagliptin: 61; placebo: 16). Four patients withdrew prematurely. There was little evidence of linagliptin accumulation. Exposure, maximum and trough plasma concentrations of linagliptin increased less than dose-proportionally. Rapid and sustained inhibition of dipeptidyl peptidase-4 reached 91-93% across linagliptin doses at steady state. At the end of the 24-h dosing interval, inhibition was still high (82-90%). There were marked increases in plasma glucagon-like peptide-1 after 28 days of dosing. Compared to placebo, all linagliptin doses resulted in statistically significant decreases of the area under the glucose curve following a meal tolerance test on day 29, that is, 24 h after the last study drug intake. After 28 days of treatment with linagliptin the placebo-corrected mean change in haemoglobin A1c (HbA1c) (median baseline 7.0%) was -0.31% (2.5-mg dose), -0.37% (5-mg dose) and -0.28% (10-mg dose). The frequency of adverse events was similar for linagliptin (31%) and placebo (34%). There were no notable safety concerns.. Linagliptin administration led to attenuation of postprandial glucose excursions and, despite a low HbA1c at baseline, statistically significant reductions in HbA1c after only 4 weeks of treatment. Linagliptin had a safety and tolerability profile similar to placebo in T2DM patients.

Topics: Adult; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Double-Blind Method; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Linagliptin; Male; Middle Aged; Placebos; Postprandial Period; Purines; Quinazolines; Treatment Outcome; Young Adult

To compare the efficacy, safety and tolerability of linagliptin or placebo administered for 24 weeks in combination with pioglitazone in patients with type 2 diabetes mellitus (T2DM) exhibiting insufficient glycaemic control (HbA1c 7.5-11.0%).. Patients were randomized to receive the initial combination of 30 mg pioglitazone plus 5 mg linagliptin (n = 259) or pioglitazone plus placebo (n = 130), all once daily. The primary endpoint was change from baseline in HbA1c after 24 weeks of treatment, adjusted for baseline HbA1c and prior antidiabetes medication.. After 24 weeks of treatment, the adjusted mean change (±s.e.) in HbA1c with the initial combination of linagliptin plus pioglitazone was -1.06% (±0.06), compared with -0.56% (±0.09) for placebo plus pioglitazone. The difference in adjusted mean HbA1c in the linagliptin group compared with placebo was -0.51% (95% confidence interval [CI] -0.71, -0.30; p < 0.0001). Reductions in fasting plasma glucose (FPG) were significantly greater for linagliptin plus pioglitazone than with placebo plus pioglitazone; -1.8 and -1.0 mmol/l, respectively, equating to a treatment difference of -0.8 mmol/l (95% CI -1.2, -0.4; p < 0.0001). Patients taking linagliptin plus pioglitazone, compared with those receiving placebo plus pioglitazone, were more likely to achieve HbA1c of <7.0% (42.9 vs. 30.5%, respectively; p = 0.0051) and reduction in HbA1c of ≥0.5% (75.0 vs. 50.8%, respectively; p < 0.0001). β-cell function, exemplified by the ratio of relative change in adjusted mean HOMA-IR and disposition index, improved. The proportion of patients that experienced at least one adverse event was similar for both groups. Hypoglycaemic episodes (all mild) occurred in 1.2% of the linagliptin plus pioglitazone patients and none in the placebo plus pioglitazone group.. Initial combination therapy with linagliptin plus pioglitazone was well tolerated and produced significant and clinically meaningful improvements in glycaemic control. This combination may offer a valuable additive initial treatment option for T2DM, particularly where metformin either is not well tolerated or is contraindicated, such as in patients with renal impairment.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Linagliptin; Male; Middle Aged; Pioglitazone; Placebos; Purines; Quinazolines; Thiazolidinediones; Treatment Outcome; Young Adult

The dipeptidyl-peptidase-4 (DPP-4) inhibitor linagliptin is under clinical development for treatment of type 2 diabetes mellitus (T2DM). In previous studies in white populations it showed potential as a once-daily oral antidiabetic drug.. In compliance with regulatory requirements for new drugs intended for use in the Japanese population, this study investigated the pharmacokinetics, pharmacodynamics, and tolerability of multiple oral doses of linagliptin in Japanese patients with T2DM.. In this randomized, double-blind, placebo-controlled multiple dose study, 72 Japanese patients with T2DM were assigned to receive oral doses of linagliptin 0.5, 2.5, or 10 mg or placebo (1:1:1:1 ratio) once daily for 28 days. For analysis of pharmacokinetic properties, linagliptin concentrations were determined from plasma and urinary samples obtained throughout the treatment phase, with more intensive samplings on days 1 and 28. DPP-4 inhibition, glycosylated hemoglobin A1c (HbA(1c)) levels, and plasma glucose and glucagon-like peptide-1 (GLP-1) levels were compared by mixed effect model. Tolerability was assessed throughout the study by physical examination, including blood pressure and pulse rate measurements, 12-lead ECG, and laboratory analysis.. Baseline demographic characteristics were well balanced across the 4 treatment groups (mean [SD] age, 59.7 [6.4] years in the placebo group, 60.8 [9.2] years in the 0.5 mg group, 60.2 [6.4] years in the 2.5 mg group, and 59.1 [8.6] years in the 10 mg group; mean [SD] weight, 67.2 [10.0] kg in the placebo group, 64.5 [9.0] kg in the 0.5 mg group, 69.6 [9.4] kg in the 2.5 mg group, and 63.5 [12.2] kg in the 10 mg group; mean [SD] duration of T2DM diagnosis, 5.1 [4.2] years in the placebo group, 5.2 [4.7] years in the 0.5 mg group, 5.9 [4.8] years in the 2.5 mg group, and 2.6 [2.3] years in the 10 mg group). The majority of the patients treated were male (76.4%). Use of previous antidiabetic medication was more common in the 2.5 mg linagliptin group (44%) than in the 0.5 or 10 mg linagliptin (15.8% and 22.2%, respectively) or placebo groups (35.3%). Total systemic exposure in terms of linagliptin AUC and C(max) (which occurred at 1.25-1.5 hours) increased in a less than dose-proportional manner. The terminal half-life was long (223-260 hours) but did not reflect the accumulation half-life (10.0-38.5 hours), resulting in a moderate accumulation ratio of <2.9 that decreased with increasing dose. Urinary excretion increased with linagliptin doses but was <7% at steady state for all dose groups. Inhibition of plasma DPP-4 at 24 hours after the last dose on day 28 was approximately 45.8%, 77.8%, and 89.7% after linagliptin 0.5, 2.5, and 10 mg, respectively. At steady state, linagliptin was associated with dose-dependent increases in plasma GLP-1 levels, and the postprandial GLP-1 response was enhanced. Statistically significant dose-dependent reductions were observed in fasting plasma glucose levels at day 29 for all linagliptin groups (-11.5, -13.6, and -25.0 mg/dL for the 0.5, 2.5, and 10 mg groups, respectively; P < 0.05 for all linagliptin groups). Linagliptin also produced statistically significant dose-dependent reductions from baseline for glucose area under the effect curve over 3 hours after meal tolerance tests (-29.0 to -68.1 mg × h/dL; P < 0.05 for all 3 linagliptin groups). For the 0.5 and 10 mg linagliptin-treated groups, there were statistically significant reductions in HbA(1c) from baseline compared with placebo, despite the relatively low baseline HbA(1c) (7.2%) and small sample size (P < 0.01 for both groups). The greatest reduction in HbA(1c) (-0.44%) was seen in the highest linagliptin dose group (10 mg). On dosing for up to 28 days, linaglip. Linagliptin demonstrated a nonlinear pharmacokinetic profile in these Japanese patients with T2DM consistent with the findings of previous studies in healthy Japanese and white patients. Linagliptin treatment resulted in statistically significant and clinically relevant reductions in HbA(1c) as soon as 4 weeks after starting therapy in these Japanese patients with T2DM, suggesting that clinical studies of longer duration in Japanese T2DM patients are warranted.

Topics: Adult; Aged; Area Under Curve; Asian People; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Double-Blind Method; Female; Glycated Hemoglobin; Half-Life; Humans; Hypoglycemic Agents; Japan; Linagliptin; Male; Middle Aged; Nonlinear Dynamics; Purines; Quinazolines; Time Factors

To examine the efficacy and safety of the dipeptidyl peptidase-4 inhibitor linagliptin in persons with Type 2 diabetes mellitus inadequately controlled [HbA(1c) 53-86 mmol/mol (7.0-10.0%)] by metformin and sulphonylurea combination treatment.. A multi-centre, 24-week, randomized, double-blind, parallel-group study in 1058 patients comparing linagliptin (5 mg once daily) and placebo when added to metformin plus sulphonylurea. The primary endpoint was the change in HbA(1c) after 24 weeks.. At week 24, the linagliptin placebo-corrected HbA(1c) adjusted mean change from baseline was -7 mmol/mol (-0.62%) [95% CI -8 to -6 mmol/mol (-0.73 to -0.50%); P < 0.0001]. More participants with baseline HbA(1c) ≥ 53 mmol/mol (≥ 7.0%) achieved an HbA(1c) < 53 mmol/mol (<7.0%) with linagliptin compared with placebo (29.2% vs. 8.1%, P< 0.0001). Fasting plasma glucose was reduced with linagliptin relative to placebo (-0.7 mmol/l, 95% CI -1.0 to -0.4; P<0.0001). Improvements in homeostasis model assessment of β-cell function were seen with linagliptin (P<0.001). The proportion of patients who reported a severe adverse event was low in both groups (linagliptin 2.4%; placebo 1.5%). Symptomatic hypoglycaemia occurred in 16.7 and 10.3% of the linagliptin and placebo groups, respectively. Hypoglycaemia was generally mild or moderate; severe hypoglycaemia was reported in 2.7 and 4.8% of the participants experiencing hypoglycaemic episodes in the linagliptin and placebo groups, respectively. No significant weight changes were noted.. In patients with Type 2 diabetes, adding linagliptin to metformin given in combination with a sulphonylurea significantly improved glycaemic control and this was well tolerated. Linagliptin could provide a valuable treatment option for individuals with inadequate glycaemic control despite ongoing combination therapy with metformin and a sulphonylurea.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers; Blood Glucose; Body Mass Index; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Therapy, Combination; Fasting; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Linagliptin; Male; Metformin; Middle Aged; Purines; Quinazolines; Sulfonylurea Compounds; Treatment Outcome; Young Adult

The dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin is in clinical development for the treatment of type 2 diabetes mellitus (T2DM). In previous studies in non-Japanese populations, linagliptin showed potential as a once-daily oral antidiabetic drug.. This study investigated the tolerability, pharmacokinetics, and pharmacodynamics of linagliptin in healthy adult male Japanese volunteers, in compliance with Japanese regulatory requirements for new drugs intended for use in humans.. This was a Phase I, randomized, doubleblind, placebo-controlled study in healthy volunteers. Linagliptin or placebo was administered as single escalating doses of 1, 2.5, 5, and 10 mg, or as multiple escalating doses of 2.5, 5, and 10 mg once daily for 12 days. Three quarters of subjects in each dose group were randomized to active drug and one quarter to placebo. Blood and urine samples for determination of pharmacokinetic parameters were obtained before administration of the first dose of study drug and at regular time points after administration, with more frequent blood sampling on days 1 and 12 in subjects receiving multiple doses. Inhibition of DPP-4 activity and plasma concentrations of glucagon-like peptide-1 (GLP-1) and glucose were also determined. Tolerability was assessed throughout the study based on physical examinations, 12-lead ECGs, and standard laboratory tests.. Eight subjects were enrolled in each dose group, 6 receiving active drug and 2 receiving placebo. Baseline demographic characteristics were comparable in the single-dose groups (mean [SD] age, 24.5 [3.6] years; mean weight, 61.2 [6.2] kg; mean height, 171.5 [5.3] cm) and multiple-dose groups (mean age, 25.4 [3.7] years; mean weight, 61.6 [5.2] kg; mean height, 170.9 [4.9] cm). Linagliptin displayed nonlinear pharmacokinetics. Total systemic exposure (AUC and C(max)) increased in a manner that was less than dose proportional. T(max) ranged from 1.50 to 6.00 hours, and elimination t((1/2)) ranged from 96.9 to 175.0 hours. Total CL increased with increasing dose (from 140 mL/min in the 1-mg group to 314 mL/min in the 10-mg group), as did apparent V(d) (from 1260 to 3060 L with doses up to 10 mg). Steady state was attained within 2 to 3 days. The accumulation t((1/2)) ranged from approximately 10 to 15 hours. The accumulation ratio with multiple dosing was <1.5 and decreased with increasing dose (approximately 1.2 in the 10-mg dose). Urinary excretion increased with increasing dose and over time in all dose groups, although it did not exceed 7% in any dose group on day 12. Linagliptin inhibited plasma DPP-4 activity in a dose-dependent manner. Mean DPP-4 inhibition was >or=80% over 24 hours after a single dose of 10 mg and after multiple doses of 5 and 10 mg for 12 days. Postprandial plasma GLP-1 concentrations increased from preprandial concentrations by 2- to 4-fold after administration of single doses and by 2- to 2.5-fold on day 12 after administration of multiple doses. Baseline (premeal) plasma GLP-1 concentrations were higher on day 12 than on day 1 in all linagliptin groups. A total of 3 adverse events were reported in 1 subject each: an increase in histamine concentration in a subject receiving a single dose of linagliptin 5 mg, vasovagal syncope in a subject receiving a single dose of linagliptin 10 mg, and pharyngitis in a subject receiving multiple doses of linagliptin 10 mg. None of these events was considered drug related. No episodes of hypoglycemia occurred during the study.. In this short-term study in healthy adult male Japanese volunteers, multiple oral doses of linagliptin inhibited plasma DPP-4 activity and elevated active GLP-1 concentrations in a dose-dependent manner, with no episodes of hypoglycemia. Multiple dosing of linagliptin for 12 days was well tolerated and exhibited a pharmacokinetic/pharmacodynamic profile consistent with a once-daily regimen. Clinical studies in Japanese patients with T2DM appear to be warranted.

Topics: Adult; Area Under Curve; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Double-Blind Method; Half-Life; Humans; Hypoglycemic Agents; Japan; Linagliptin; Male; Metabolic Clearance Rate; Purines; Quinazolines

The efficacy and safety of the dipeptidyl peptidase-4 inhibitor, linagliptin, added to ongoing metformin therapy, were assessed in patients with Type 2 diabetes who had inadequate glycaemic control (HbA(1c) ≥ 7.5 to ≤ 10%; ≥ 58.5 to ≤ 85.8 mmol/mol) with metformin alone.. Patients (n=333) were randomized to receive double-blind linagliptin (1, 5 or 10 mg once daily) or placebo or open-label glimepiride (1-3 mg once daily). The primary outcome measure was the change from baseline in HbA(1c) at week 12 in patients receiving combination therapy compared with metformin alone.. Twelve weeks of treatment resulted in a mean (sem) placebo-corrected lowering in HbA(1c) levels of 0.40% (± 0.14); 4.4 mmol/mol (± 1.5) for 1 mg linagliptin, 0.73% (± 0.14); 8.0 mmol/mol (± 1.5) for 5 mg, and 0.67% (± 0.14); 7.3 mmol/mol (± 1.5) for 10 mg. Differences between linagliptin and placebo were statistically significant for all doses (1 mg, P = 0.01; 5 mg and 10 mg, P < 0.0001). The change in mean (sem) placebo-corrected HbA(1c) from baseline was -0.90% (± 0.13); -9.8 mmol/mol (± 1.4) for glimepiride. Adjusted and placebo-corrected mean changes in fasting plasma glucose were -1.1 mmol/l for linagliptin 1 mg (P = 0.002), -1.9 mmol/l for 5 mg and -1.6 mmol/l for 10 mg (both P < 0.0001). One hundred and six (43.1%) patients reported adverse events; the incidence was similar across all five groups. There were no hypoglycaemic events for linagliptin or placebo, whereas three patients (5%) receiving glimepiride experienced hypoglycaemia.. The addition of linagliptin to ongoing metformin treatment in patients with Type 2 diabetes was well tolerated and resulted in significant and clinically relevant improvements in glycaemic control, with 5 mg linagliptin being the most effective dose.

Topics: Adult; Aged; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Linagliptin; Male; Metformin; Middle Aged; Purines; Quinazolines; Treatment Outcome

To investigate the safety, tolerability, pharmacokinetic and pharmacodynamic properties of multiple oral doses of the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin (BI 1356) in patients with type 2 diabetes mellitus.. Forty-seven male type 2 diabetic patients received linagliptin 1, 2.5, 5 or 10 mg, or placebo, once daily for 12 days.. Linagliptin exposure [area under the plasma concentration-time curve and maximum plasma concentration (Cmax)] increased less than proportionally with dose. Accumulation half-life was short (8.6-23.9 h), resulting in rapid attainment of steady state (2-5 days) and little accumulation (range: 1.18-2.03). The long terminal half-life (113-131 h) led to a sustained inhibition of DPP-4 activity. Renal excretion was below 1% on day 1 in all dose groups. Inhibition of plasma DPP-4 activity correlated well with linagliptin plasma concentrations, resulting in DPP-4 inhibition >90% in the two highest dose groups; even 24 h postdose, DPP-4 inhibition was >80%. Following an oral glucose tolerance test, 24 h after the last dose, statistically significant reductions of glucose excursions were observed with linagliptin (2.5, 5 and 10 mg doses) compared with placebo. Linagliptin was well tolerated. The frequency of adverse events (AEs) was not higher with linagliptin (54%) than with placebo (75%). No serious AEs and no episodes of hypoglycaemia were reported.. In type 2 diabetic patients, multiple rising doses of linagliptin were well tolerated and resulted in significant improvements of glucose parameters. Together with the favourable pharmacokinetics, these results confirm the unique profile of linagliptin in the DPP-4 inhibitor class.

Topics: Administration, Oral; Adult; Area Under Curve; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Double-Blind Method; Half-Life; Humans; Linagliptin; Male; Metabolic Clearance Rate; Middle Aged; Purines; Quinazolines; Young Adult

Fixed-dose combination (FDC) of the sodium-glucose co-transporter 2 inhibitor empagliflozin and the dipeptidyl peptidase-4 inhibitor linagliptin was approved for type 2 diabetes (T2D) treatment in Japan in 2018. We conducted a post-marketing surveillance study of empagliflozin/linagliptin FDC in routine clinical practice in Japan.. This one-year, prospective, multicenter, observational study investigated the safety and effectiveness of empagliflozin/linagliptin FDC in Japanese patients with T2D. The primary outcome was incidence of adverse drug reactions (ADRs).. Among 1146 patients, mean (SD) age was 63.8 (12.8) years and 22.08% were aged ≥75 years. Mean (SD) glycated hemoglobin (HbA1c) was 7.66% (1.21); fasting plasma glucose (FPG) was 142.90 mg/dl (43.75). ADRs were experienced by 32 (2.79%) patients (1 serious ADR); ADRs of important identified risk included urinary tract infection (7 patients [0.61%]), hypoglycemia (2 [0.17%]), ketoacidosis (0), genital infection (1 [0.09%]), and volume depletion (1 [0.09%]). Overall mean (SD) change from baseline in body weight, HbA1c, and FPG were -1.08 kg (3.21), -0.39% (1.11), and -7.90 mg/dl (39.12), respectively.. Empagliflozin/linagliptin FDC was effective and generally well tolerated in Japanese patients with T2D; no new safety concerns were identified.. The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT03761797) [Figure: see text] [Figure: see text].

Topics: Benzhydryl Compounds; Blood Glucose; Diabetes Mellitus, Type 2; East Asian People; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Linagliptin; Product Surveillance, Postmarketing; Prospective Studies; Sodium-Glucose Transporter 2 Inhibitors

Microvascular pathology in the brain is one of the suggested mechanisms underlying the increased incidence and progression of neurodegenerative diseases in people with type 2 diabetes (T2D). Although accumulating data suggest a neuroprotective effect of antidiabetics, the underlying mechanisms are unclear. Here, we investigated whether two clinically used antidiabetics, the dipeptidyl peptidase-4 inhibitor linagliptin and the sulfonylurea glimepiride, which restore T2D-induced brain vascular pathology. Microvascular pathology was examined in the striatum of mice fed for 12 months with either normal chow diet or a high-fat diet (HFD) to induce T2D. A subgroup of HFD-fed mice was treated with either linagliptin or glimepiride for 3 months before sacrifice. We demonstrate that T2D caused leakage of the blood-brain barrier (BBB), induced angiogenesis, and reduced pericyte coverage of microvessels. However, linagliptin and glimepiride recovered the BBB integrity and restored the pericyte coverage differentially. Linagliptin normalized T2D-induced angiogenesis and restored pericyte coverage. In contrast, glimepiride enhanced T2D-induced angiogenesis and increased pericyte density, resulting in proper vascular coverage. Interestingly, glimepiride reduced microglial activation, increased microglial-vascular interaction, and increased collagen IV density. This study provides evidence that both DPP-4 inhibition and sulfonylurea reverse T2D-induced BBB leakage, which may contribute to antidiabetic neurorestorative effects.

Topics: Animals; Blood-Brain Barrier; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Hypoglycemic Agents; Linagliptin; Mice; Pericytes; Sulfonylurea Compounds

Topics: Cognitive Dysfunction; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Humans; Hypoglycemic Agents; Linagliptin

Linagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor used for the treatment of type 2 diabetes, with additional beneficial effects for the kidney. Treatment of mice with linagliptin revealed increased storage of cobalamin (Cbl, Vitamin B12) in organs if a standard Cbl diet (30 µg Cbl/kg chow) is given. In order to translate these findings to humans, we determined methylmalonic acid (MMA), a surrogate marker of functional Cbl homeostasis, in human plasma and urine samples (n = 1092) from baseline and end of trial (6 months after baseline) of the previously completed MARLINA-T2D clinical trial. We found that individuals with medium Cbl levels (MMA between 50 and 270 nmol/L for plasma, 0.4 and 3.5 µmol/mmol creatinine for urine, at baseline and end of trial) exhibited higher MMA values at the end of study in placebo compared with linagliptin. Linagliptin might inhibit the N-terminal degradation of the transcobalamin receptor CD320, which is necessary for uptake of Cbl into endothelial cells. Because we demonstrate that linagliptin led to increased organ levels of Cbl in mice, sustained constant medium MMA levels in humans, and inhibited CD320 processing by DPP-4 in-vitro, we speculate that linagliptin promotes intra-cellular uptake of Cbl by prolonging half-life of CD320.

Topics: Animals; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Endothelial Cells; Homeostasis; Humans; Hypoglycemic Agents; Linagliptin; Mice; Vitamin B 12

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Fluorescent Dyes; Humans; Hypoglycemic Agents; Linagliptin; Tablets

Although the association between dipeptidyl peptidase-4 (DPP-4) inhibitors and bullous pemphigoid (BP) has begun to be established, some studies have suggested there are risk differences among DPP-4 inhibitors. We conducted a population-based cohort study to examine the risk differences.. Using the claims databases of the Fukuoka Prefecture Wide-Area Association of Latter-Stage Elderly Healthcare between April 1, 2013 and March 31, 2017, we conducted a retrospective cohort study to compare patients receiving one DPP-4 inhibitor with those who were prescribed another antidiabetic drug. The primary outcome was an adjusted hazard ratio (HR) of the development of bullous pemphigoid during a 3-year follow-up. The secondary outcome was the development of BP requiring systemic steroids immediately after the diagnosis. These were estimated using Cox proportional hazards regression models.. The study comprised 33,241 patients, of which 0.26% (n = 88) developed bullous pemphigoid during follow-up. The percentages of patients with bullous pemphigoid who required immediate systemic steroid treatment was 0.11% (n = 37). We analyzed four DPP-4 inhibitors: sitagliptin, vildagliptin, alogliptin, and linagliptin. Vildagliptin and linagliptin raised the risk of BP significantly (primary outcome, vildagliptin, HR 2.411 [95% confidence interval (CI) 1.325-4.387], linagliptin, HR 2.550 [95% CI 1.266-5.136], secondary outcome, vildagliptin HR 3.616 [95% CI 1.495-8.745], linagliptin HR 3.556 [95% CI 1.262-10.024]). A statistically significant risk elevation was not observed with sitagliptin and alogliptin (primary outcome, sitagliptin, HR 0.911 [95% CI 0.508-1.635], alogliptin, HR 1.600 [95% CI 0.714-3.584], secondary outcome, sitagliptin, HR 1.192 [95% CI 0.475-2.992], alogliptin, HR 2.007 [95% CI 0.571-7.053]).. Not all the DPP-4 inhibitors could induce bullous pemphigoid significantly. Therefore, the association warrants further investigations before generalization.

Topics: Aged; Cohort Studies; Delivery of Health Care; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; East Asian People; Humans; Hypoglycemic Agents; Linagliptin; Pemphigoid, Bullous; Retrospective Studies; Sitagliptin Phosphate; Vildagliptin

Alzheimer's disease (AD) is an age-related, multifactorial progressive neurodegenerative disorder manifested by cognitive impairment and neuronal death in the brain areas like hippocampus, yet the precise neuropathology of AD is still unclear. Continuous failure of various clinical trial studies demands the utmost need to explore more therapeutic targets against AD. Type 2 Diabetes Mellitus and neuronal insulin resistance due to serine phosphorylation of Insulin Receptor Substrate-1 at 307 exhibits correlation with AD. Dipeptidyl Peptidase-4 inhibitors (DPP-4i) have also indicated therapeutic effects in AD by increasing the level of Glucagon-like peptide-1 in the brain after crossing Blood Brain Barrier. The present study is hypothesized to examine Linagliptin, a DPP-4i in intracerebroventricular streptozotocin induced neurodegeneration, and neuroinflammation and hippocampal insulin resistance in rat model of AD. Following infusion on 1st and 3rd day, animals were treated orally with Linagliptin (0.513 mg/kg, 3 mg/kg, and 5 mg/kg) and donepezil (5 mg/kg) as a standard for 8 weeks. Neurobehavioral, biochemical and histopathological analysis was done at the end of treatment. Dose-dependently Linagliptin significantly reversed behavioral alterations done through locomotor activity (LA) and morris water maze (MWM) test. Moreover, Linagliptin augmented hippocampal GLP-1 and Akt-ser473 level and mitigated soluble Aβ (1-42), IRS-1 (s307), GSK-3β, TNF-α, IL-1β, IL-6, AchE and oxidative/nitrosative stress level. Histopathological analysis also exhibited neuroprotective and anti-amylodogenic effect in Hematoxylin and eosin and Congo red staining respectively. The findings of our study concludes remarkable dose-dependent therapeutic potential of Linagliptin against neuronal insulin resistance via IRS-1 and AD-related complication. Thus, demonstrates unique molecular mechanism that underlie AD.

Topics: Alzheimer Disease; Animals; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Glycogen Synthase Kinase 3 beta; Insulin Resistance; Linagliptin; Neuroinflammatory Diseases; Rats; Streptozocin

Type 2 diabetes can be cured by using tradjenta (also known as Linagliptin), a new therapeutic drug that is an inhibitor of the dipeptidyl peptidase-4 enzyme. Tradjenta is administered orally alone or in combination with metiguanide or empagliflozin. An easy and specific fluorimetric analysis of Tradjenta was developed and demonstrated in the present investigation. The Hantzsch reaction method, which generates a fluorescent dihydropyridine derivative, is the basis of this assay. In a Toerell-Stenhagen buffered solution, the unsubstituted amine group of Tradjenta interacted with 2,4-Pentadione/Oxomethane. Spectrofluorimetry was utilized for this investigation at an excitation/emission wavelength of 421/480 nm. When comparing the Tradjenta concentration to the tracked fluorimetric signal, the method revealed linearity over the concentration range of 0.05 to 1.2 µg/mL. By strictly altering system parameters and analyzing the validation factors following International Council for Harmonisation (ICH) requirements, the outcomes were achieved. Finally, the proposed approach was successfully applied to assay the drug not only in its raw form and prescribed formulations but also to evaluate the tablet's uniformity of content.

Topics: Diabetes Mellitus, Type 2; Fluorescent Dyes; Fluorometry; Humans; Linagliptin; Spectrometry, Fluorescence

Topics: Albuminuria; Benzhydryl Compounds; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Inflammation; Linagliptin

Patients with type 2 diabetes (T2D) and cardiovascular disease are at increased risk for recurrent ischemic events. Cardiovascular risk factor control is vital for secondary prevention, but how this compares among individuals with different T2D macrovascular complications is unknown. We aimed to determine if there might be differences in risk factor control in patients with T2D with previous stroke versus coronary artery disease (CAD).. Cross-sectional analyses were performed on 12 856 patients with T2D with prior history of stroke with or without CAD from 3 diabetes cardiovascular outcome trials: CARMELINA (The Cardiovascular and Renal Microvascular Outcome Study With Linagliptin), EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), and CAROLINA (The Cardiovascular Outcome Study of Linagliptin vs Glimepiride in Type 2 Diabetes). Risk factors at baseline assessed included dyslipidemia, hypertension, smoking, and current antiplatelet/anticoagulant therapy. Control, respectively, was defined as LDL (low-density lipoprotein)-C <100 mg/dL or statin use, systolic blood pressure <140 and diastolic blood pressure <90 mm Hg, not currently smoking, and use of an antiplatelet/anticoagulant medication. The odds ratio of 3 to 4 (or good) versus 0 to 2 (or suboptimal) risk factors controlled was analyzed by logistic regression models.. The odds for good versus suboptimal risk factor control in patients with CAD alone was higher than in those with stroke alone across all 3 trials odds ratios (95% CI): CARMELINA, 2.05 (1.67-2.51), EMPA-REG OUTCOME, 2.50 (2.10-2.99), and CAROLINA, 1.63 (1.21-2.20). The respective odds ratios were lower (and rendered nonsignificant in CAROLINA) when cardiovascular risk factor control in patients with both CAD and stroke were compared with those with stroke alone: CARMELINA, 1.45 (1.13-1.87); EMPA-REG OUTCOME, 1.62 (1.25-2.08); and CAROLINA, 1.16 (0.74-1.83).. In contemporary populations of patients with T2D, there was significant discordance in control of cardiovascular risk factors between patients with stroke versus CAD, with the former having less optimal control. The intermediate results in patients with both CAD and stroke suggest that these differences could be related at least in part to clinician factors.. URL: https://www.. gov; Unique identifiers: NCT01243424, NCT01131676, NCT01897532.

Topics: Cardiovascular Diseases; Coronary Artery Disease; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Heart Disease Risk Factors; Humans; Linagliptin; Risk Factors; Stroke; Treatment Outcome

The control of diabetes mellitus is multifactorial, the different therapeutic options make it necessary to compare the effectiveness with previous therapeutic schemes.. Analize the indicators of control of diabetes mellitus after incorporating liraglutide, sitagliptin/metformin, linagliptin, and sitagliptin.. Observational, analytical, longitudinal study. Glucose, glycosylated hemoglobin, and blood pressure were compared after the inclusion of new cues in patients with diabetes mellitus; in addition to the control indicators reported in the unit in october, november, and december 2000, with those of 2021 in the same months. A descriptive analysis was performed, T for related samples and McNemar, a value of < .05 was considered significant, a confidence level of 95%, with the IBM-SPSS 24 software.. 352 files were analyzed, 59% women, aged 26 to 88 years, and the percentage of control decreased after the change of scheme (38.4% vs 35.8%) without a statistical difference (p .503). There was no statistical difference between the levels of glucose, glycated hemoglobin, weight, and blood pressure before and six months after the change. In the unit, the regimen glycemic control indicator improved in October, November, and December 2020 compared to the same months in 2021, it increased (from 17.2, 18.7, and 16.3, to 41.6, 47.2, and 46.5%). Blood pressure control went from 64.5, 66.7, and 67 to 82.4, 85.1, and 83.1%.. The control indicators in the unit improved, however, the patients who used the new keys did not show any difference.. el control de la diabetes mellitus es multifactorial, las diferentes opciones terapéuticas hacen necesario comparar la efectividad con esquemas terapéuticos previos.. analizar los indicadores de control de diabetes mellitus posterior a incorporar liraglutida, sitagliptina/metformina, linagliptina y sitagliptina.. estudio observacional, analítico, longitudinal. Se compararon glucosa, hemoglobina glucosilada y presión arterial posterior a la inclusión de nuevas claves en pacientes con diabetes mellitus; además de los indicadores de control reportados en la unidad en los meses octubre, noviembre y diciembre 2020, con los del 2021 en los mismos meses. Se realizó un análisis descriptivo, T para muestras relacionadas y McNemar, se consideró un valor de p ≤ 0.05 como significativo, un nivel de confianza de 95%, con el programa informático IBM-SPSS 24.. se analizaron 352 expedientes, el 59% correspondía a mujeres, con edades de 26 a 88 años, el porcentaje de control disminuyó después del cambio de esquema (38.4% frente a 35.8%) sin diferencia estadística (p = 0.503). No hubo diferencia estadística entre los niveles de glucosa, hemoglobina glucosilada, peso y presión arterial previos y seis meses después del cambio de esquema. En la unidad, el indicador de control de glucemia en los meses de octubre, noviembre y diciembre 2020 comparados con los mismos meses en el 2021 incrementaron (17.2, 18.7 y 16.3, a 41.6, 47.2 y 46.5%). El control de presión arterial pasó del 64.5, 66.7 y 67 a 82.4, 85.1 y 83.1%.. los indicadores de control en la unidad mejoraron, sin embargo los pacientes que utilizaron las nuevas claves no mostraron diferencia.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glucose; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Linagliptin; Liraglutide; Longitudinal Studies; Male; Metformin; Sitagliptin Phosphate; Treatment Outcome

The burden of type 2 diabetes mellitus (T2DM) is raising dramatically both internationally and in India. It is often observed that multiple therapies or combinations of different drugs are usually required to successfully control hyperglycemia in patients with T2DM. To facilitate effective control of glucose levels, many new agents have been developed over the past few years.. Multiple Advisory Board Meetings were conducted with 87 leading key opinion leaders (KOLs) from diabetes specialty PAN India to understand the simplicity aspect of linagliptin therapy in T2DM patients.. Linagliptin is a xanthine-based, non-peptidomimetic, selective dipeptidyl peptidase 4 (DPP-4) inhibitor with a different pharmacological profile when compared to other DPP-4 inhibitors already available in India. It is known to decrease the risk of hypoglycemia compared to sulphonylurea (SU), is weight neutral, and no dose modification is required over a broad range of patient populations. This consensus paper discusses the clinical efficacy of DPP-4 inhibitors and linagliptin in T2DM. It also highlights the evidence for the safety of linagliptin in T2DM patients with renal impairment (RI), cardiovascular (CV) risk, and heart failure (HF).. Linagliptin therapy is simplifying the management of T2DM with good efficacy and its use across a wide range of patients without any dose modification.

Topics: Antiviral Agents; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Linagliptin

Older patients managed with intensive antidiabetic therapy are more likely to be harmed. Our study's primary endpoint was to analyze the safety and efficacy of linagliptin in combination with basal insulin versus basal-bolus insulin in patients with 75 years of age or older hospitalized in medicine and surgery departments in real-world clinical practice.. We retrospectively enrolled non-critically patients ≥75 years with type 2 diabetes admitted to medicine and non-cardiac surgery departments with admission glycated hemoglobin <8%, admission blood glucose <240 mg/dL, and without at-home injectable therapies managed with our hospital's antihyperglycemic protocol (basal-bolus or linagliptin-basal regimens) between January 2016 and December 2018. To match each patient who started on the basal-bolus regimen with a patient who started on the linagliptin-basal regimen, a propensity matching analysis was used.. Postmatching, 198 patients were included in each group. There were no significant differences in mean daily blood glucose levels after admission (P=0.203); patients with mean blood glucose 100-140mg/dL (P=0.134), 140-180mg/dL (P=0.109), or >200mg/dL (P=0.299); and number and day of treatment failure (P=0.159 and P=0.175, respectively). The total insulin dose and the number of daily injections were significantly lower in the linagliptin-basal group (both, P<0.001). Patients on the basal-bolus insulin regimen had more total hypoglycemic events than patients on the linagliptin-basal insulin regimen (P<0.001).. The linagliptin-basal insulin regimen was an effective alternative with fewer hypoglycemic events and daily insulin injections than intensive basal-bolus insulin in very old patients with type 2 diabetes with mild-to-moderate hyperglycemia treated at home without injectable therapies.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Linagliptin; Retrospective Studies; Treatment Outcome

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Linagliptin; Pemphigoid, Bullous; Rituximab

Dipeptidyl peptidase (DPP)-4 plays a complex role in immune regulation and its inhibition can have effects on the pathogenesis of various skin diseases. Studies have shown that DPP-4 inhibitors are associated with an increased risk of bullous pemphigoid (BP).. To analyse the clinical and histopathological features of cutaneous adverse events in patients on DPP-4 inhibitors.. We performed a retrospective review of patients with suspected DPP-4 inhibitor-associated cutaneous adverse events, at a tertiary teaching hospital from 1 January 2017 to 31 December 2020. Exclusion criteria included previous history of chronic skin disease and lack of histopathological reports or follow-up records. The clinical characteristics, latency period, Naranjo Adverse Drug Reaction Probability Scale and clinical outcomes were evaluated.. In total, 18 patients (10 men, 8 women; mean age 68.6 years, range 38-89 years) were included. The DPP-4 inhibitors used were teneligliptin (n = 6), vildagliptin (n = 6), sitagliptin (n = 4), linagliptin (n = 1) and saxagliptin (n = 1). The mean interval between therapy initiation and lesion onset was 8.8 months (range 1-24 months). The dermatoses noted were BP (n = 12; 66.6%), lichenoid dermatitis (n = 4; 22.2%), psoriasiform dermatitis (n = 1; 5.6%) and spongiotic dermatitis (n = 1; 5.6%). Eight patients (44.4%) had necrotic keratinocytes as one of the distinct histological features. Causality assessment using the Naranjo scale rated the causative role of DPP-4 inhibitors as 'possible' in all patients. Of the 18 patients, 11 (61.1%) noted improvement in their condition following discontinuation of DPP-4 inhibitors, with 5 having complete remission within 6 months of stopping the drug.. DPP-4 inhibitor-associated dermatoses are not necessarily limited to BP. It is necessary to recognize the possibility of other dermatoses in patients on DPP-4 inhibitors as drug substitution/cessation may improve disease morbidity.

Topics: Adult; Aged; Aged, 80 and over; Dermatitis; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exanthema; Female; Humans; Hypoglycemic Agents; Linagliptin; Male; Middle Aged; Pemphigoid, Bullous; Retrospective Studies

To examine the prescription pattern of the different dipeptidyl peptidase-4 inhibitors (DPP4is), depending on the estimated glomerular filtration rate (eGFR) under real-world clinical practice conditions.. This was a descriptive, observational study using a population database (SIDIAP Catalonia). Subjects diagnosed with T2DM with kidney function assessed and on active treatment with DPP4is were enrolled. Patients were included at the time of the measurement of eGFR (CKD-epi) and were monitored for 6 months after enrolment. For each subject, the prescribed daily dose (PDD) of DPP4i, the theoretical dose according to the degree of renal failure established by the recommendations in the summary of product characteristics (DDD-adj), and the PDR ratio (PDD/DDD-adj) were estimated. A subject was considered overtreated if his/her RDR was greater than 1.2 (>20%).. The study sample consisted of 72,135 subjects with a mean age of 69.7 (±11.6) years and 55.9% males. The proportion of patients overtreated varied depending on the type of DPP4i and the renal function stage. Overall, overdosage was recorded in 7.15% of all DPP4i treatments. In advanced stages (IIIb, IV, and V), overdosage was much higher (36.8% for all DPP4is, and 58.7% if linagliptin is excluded).. Under real-world clinical practice conditions, more than one third of T2DM patients with advanced renal failure were overdosed with DPP4is because the doses were not adequately adjusted to the glomerular filtration rate of each patient.

Topics: Aged; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Glomerular Filtration Rate; Humans; Kidney; Linagliptin; Male

Type 2 diabetes (T2D) is a common comorbidity in people living with HIV (PLWH). Anti-hyperglycemic treatment in PLWH is still a challenge, and no randomized controlled studies using new glucose-lowering agents are currently available.. A 55-year-old-women was admitted to our Diabetes Unit because of hyperosmolar hyperglycemic state (HHS) and sepsis. The medical history included HIV infection and insulin-treated diabetes. On clinical examination, the lady appeared dehydrated with dry buccal mucosa, tachycardia, altered mental status, genital infection, and fever. On admission, plasma glucose was 54.5 mmol/L, HbA1c 155 mmol/mol, osmolarity 389.4 mOsm/kg, bicarbonate 24.6 mmol/L with no detectable serum ketones. The patient was treated with i.v. fluid and insulin, and antibiotic therapy commenced. Upon HHS and sepsis resolution, a basal-bolus insulin therapy was implemented that was followed by significant improvement of daily glucose profiles and progressive reduction of insulin requirement until complete discontinuation. A low dose of metformin plus linagliptin was started. Since a severe atherosclerotic disease was diagnosed, a GLP-1 receptor agonist, dulaglutide, was added to metformin upon linagliptin withdrawal with maintenance of good glycemic control, treatment adherence and amelioration of quality of life and no side effects.. This case suggests that GLP-1 receptor agonist therapy may be effective and safe for treatment of T2D with high cardiovascular risk in PLWH, supporting the need of clinical trials directly assessing the safety and the efficacy of GLP-1 receptor agonist in these individuals.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Female; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Glucose; Glycated Hemoglobin; Heart Disease Risk Factors; HIV Infections; Humans; Hypoglycemic Agents; Immunoglobulin Fc Fragments; Insulin; Linagliptin; Metformin; Middle Aged; Quality of Life; Recombinant Fusion Proteins; Risk Factors; Sepsis

Fish skin collagen hydrolyzate has demonstrated the potent inhibition of dipeptidyl peptidase-IV (DPP-IV), one of the treatments for type-2 diabetes mellitus (type-2 DM), but the precise mechanism is still unclear. This study used in silico method to evaluate the potential of the active peptides from tilapia skin collagen (Oreochromis niloticus) for DPP-IV inhibitor. The methodology includes collagen hydrolysis using BIOPEP, which is the database of bioactive peptides; active peptide selection; toxicity, allergenicity, sensory analysis of active peptides; and binding of active peptides to DPP-IV compared with linagliptin. The result indicated that in silico enzymatic hydrolysis of collagen produced active peptides with better prediction of biological activity than intact collagen. There are 13 active peptides were predicted as non-toxic and non-allergenic, some of which have a bitter, salty, and undetectable taste. Docking simulations showed all active peptides interacted with DPP-IV through hydrogen bonds, van der Waals force, hydrophobic interaction, electrostatic force, π-sulfur, and unfavorable interaction, where WF (Trp-Phe), VW (Val-Trp), WY (Trp-Tyr), and WG (Trp-Gly) displayed higher binding affinities of 0.8; 0.5; 0.4; and 0.3 kcal/mol compared with linagliptin. In this study, we successfully demonstrated antidiabetic type-2 DM potential of the active peptides from tilapia skin collagen. The obtained data provided preliminary data for further research in the utilization of fish skin waste as a functional compound to treat the type-2 DM patients. Alternatively, this treatment can be synergistically combined with the available antidiabetic drugs to improve the insulin secretion of the type-2 DM patients.

Topics: Animals; Collagen; Diabetes Mellitus, Type 2; Humans; Linagliptin; Molecular Docking Simulation; Peptides; Proteolysis; Skin; Tilapia

A recent 3-year post-marketing surveillance (PMS) study reaffirmed the safety and effectiveness of linagliptin in linagliptin-naïve Japanese patients with type 2 diabetes (T2D). We present further analyses from this study by body mass index (BMI).. Safety and effectiveness were assessed across BMI subgroups (<25, 25 to <30, and ≥30 kg/m. Data were available for 876, 566, and 201 patients in the BMI subgroups, respectively. Incidence of adverse drug reactions [ADR] with linagliptin was 11.42%, 11.31%, 10.45%, respectively. The most common ADR of special interest was hepatic disorders (n [%]: 6 [0.68], 7 [1.24], and 3 [1.49], respectively). Additional use of glucose-lowering drugs (GLDs) increased with BMI (15.0%, 19.1%, 24.4% of patients;. In this study of linagliptin in Japanese patients with T2D, across BMI subgroups no new safety concerns were observed. The proportion of patients with additional GLD use increased with baseline BMI. Decreases in HbA1c were observed in all subgroups, including in patients with no additional GLD use.. NCT01650259.

Topics: Body Mass Index; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; Japan; Linagliptin; Product Surveillance, Postmarketing

There is no published data on linagliptin, a dipeptidyl peptidase-4 inhibitor, on its cardiovascular risk reduction in Thai population. This study, therefore, aimed to investigate the effect of linagliptin on cardiovascular risk reduction in Thai patients with diabetes mellitus.. Patient profiles of all patients treated with linagliptin in a hospital in Thailand were reviewed. Patients who had used linagliptin for at least 12 months were recruited for analysis. Their cardiovascular risk scores were calculated using the Atherosclerotic Cardiovascular Disease Risk Estimator Plus tool and were compared between pre-treatment and 12-month post-treatment of linagliptin.. There were a total of 73 patients recruited for analysis. At 12 months of treatment, the results indicated no significant reduction in the cardiovascular risk score of all patients compared to pre-treatment (25.67% vs. 23.37%, p-value 0.442). The atherosclerotic cardiovascular disease risk reduction with linagliptin was significantly higher in patients with high baseline atherosclerotic cardiovascular disease risk and in the elderly population. A significant reduction in patients with ≥20% baseline cardiovascular risk score (6.36% decrease, p-value 0.017) was observed. Significant decreases in fasting blood sugar, haemoglobin A1c, and triglyceride were observed, but not in total and LDL-cholesterol levels. Additionally, HDL-cholesterol was significantly increased.. The mean cardiovascular risk score of all patients was not significantly changed with 12-month linagliptin treatment. However, linagliptin could significantly reduce the 10-year cardiovascular risk score in patients with ≥20% baseline risk. Also, patients with advanced age gained more benefit from linagliptin treatment. A limitation of this study was the drugs which might affect cardiovascular risk were not collected at 12-month post-treatment.

Topics: Aged; Cardiovascular Diseases; Cholesterol; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glycated Hemoglobin; Heart Disease Risk Factors; Humans; Hypoglycemic Agents; Linagliptin; Risk Factors; Thailand; Treatment Outcome

Studies have shown that the DPP-4 inhibitor was effective in improving skin damage in patients with psoriasis, but the exact mechanism was not known. To investigate the therapeutic effects of linagliptin in mice with type 2 diabetes mellitus (T2DM) with psoriasis and its possible therapeutic mechanisms. A total of 32 db/db mice and 16 db/m mice were randomly divided into six groups: normal group, psoriasis group, diabetes group, diabetes combined with psoriasis group, linagliptin-treated diabetes group, and linagliptin-treated diabetes combined with psoriasis group. The levels of serum fasting blood glucose, total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol were measured; the levels of serum FINS were determined by enzyme-linked immunoassay and the insulin resistance index was calculated. Basic parameters of diabetes, Psoriasis Area and Severity Index, histopathology of skin, the expression of interleukin (IL)-17A, IL-23, IL-22, and tumor necrosis factor (TNF)-α, and expression levels of measuring p-ERK, p-MAPK and p-nuclear factor kappa B (NF-κB) in skin tissues were measured. After treatment with linagliptin, insulin resistance, and TC and TG levels were reduced in mice with T2DM and psoriasis (p < .05). Moreover, the degree of epidermal tissue thickening, number of keratinized layers, and inflammatory cell infiltration were also reduced (p < .05), as well as the expression levels of inflammatory factors: TNF-α, IL-1β, IL-17A, IL-23, and p-P38/P38, p-ERK/ERK, p-P65/P65 proteins (p < .05). Linagliptin significantly reduced the extent of skin lesions and skin inflammation. The underlying mechanism of this compound may be related to the inhibition of MAPK/NF-κB inflammatory pathways and the consequential improvement of insulin resistance.Significance Statement: In this study, we evaluated the therapeutic effect of the DPP-4 inhibitor linagliptin using a murine model of type 2 diabetes combined with psoriasis, and its potential mechanisms of action were further explored. The results of this study will help to uncover the pathogenesis of type 2 diabetes and psoriasis and, more importantly, provide a theoretical basis for the search for safe and effective drugs in the treatment of this specific patient population.

Topics: Animals; Cholesterol; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Hypoglycemic Agents; Imiquimod; Insulin Resistance; Interleukin-23; Linagliptin; Mice; NF-kappa B; Psoriasis; Tumor Necrosis Factor-alpha

Nanosponges are porous solid nanoparticles composed of hyper-cross-linked polymers that serve as specific micro-domains designed for the co-encapsulation of two drugs with different chemical structures. Our goal was to engineer a novel assembly of multilayer nanosponges (MLNS) based on a layer-by-layer approach. This MLNS was engineered to incorporate two drugs (linagliptin and empagliflozin) in a new drug delivery route. Linagliptin has a low oral bioavailability due to intestinal degradation and low permeability. Its pharmacokinetics shows a non-linear profile which leads to a disproportionate increase in its effectiveness with increasing the dose frequency. Empagliflozin has a low permeability and is very slightly soluble in aqueous media between pH 1-7.5. MLNS could improve their bioavailability along with resolving possible risks due to the non-linear pharmacokinetics of linagliptin and maximizing its dose efficiency. 2

Topics: Benzhydryl Compounds; Cardiovascular Diseases; Chitosan; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucosides; Humans; Hypoglycemic Agents; Linagliptin; Pharmaceutical Preparations

To probe into the efficacy of Yishen Huashi granules combined with linagliptin tablets in the treatment of type 2 diabetic nephropathy (DN) and its effect on blood glucose and renal function in patients.. 70 patients with type 2 DN at our hospital between May 2020 and May 2022 were chosen as the research objects and separated into the control group and the research group based on their treatments. With 35 cases in each group, the patients treated with initial therapy and linagliptin tablets were enrolled in the control group, and those who received the above treatments and also Yishen Huashi granules were included in the research group. Their clinical indexes such as blood glucose and renal function were compared with both groups after treatment.. After treatment, the research group had remarkably lower fasting blood glucose (FPG), 2 h-postprandial blood glucose (2 h-PBG), and glycosylated hemoglobin A1c (HbA1c) levels than those in the control group (. The combination of Yishen Huashi granules and linagliptin tablets can reduce the blood glucose and blood lipid levels in patients with type 2 DN and lower UPro and protect renal function at the same time, which provides a new idea and a method for clinical treatment of type 2 DN with integrated traditional Chinese and Western medicine.

Topics: Albumins; Blood Glucose; Cholesterol; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drugs, Chinese Herbal; Glycated Hemoglobin; Humans; Kidney; Linagliptin; Lipoproteins, HDL; Lipoproteins, LDL; Tablets; Triglycerides

Insulin therapy often increases body weight and leads to visceral fat accumulation. Progression in diabetes is also associated with accelerated loss of muscle mass. Little is known about body composition changes in type 2 diabetes mellitus (T2DM) patients on insulin therapy who use sodium-glucose cotransporter-2 (SGLT2) inhibitors versus dipeptidyl peptidase-4 (DPP4) inhibitors. This study examined the effect of 25 mg of empagliflozin compared with 5 mg of linagliptin for 24 weeks on body weight and body composition in patients with T2DM on premixed insulin. Body composition was assessed with bioelectrical impedance analysis. The mean difference between the linagliptin and empagliflozin groups in terms of mean body weight change from baseline to 24 weeks was - 1.80 kg (95% CI - 2.57, - 1.03). Empagliflozin also significantly reduced muscle mass (- 1.39 kg, 95% CI - 2.49, - 0.29) and total body water (- 1.07 kg, 95% CI - 1.88, - 0.27) compared with linagliptin. Compared to linagliptin, empagliflozin decreased body fat mass more from baseline to week 24, but this was not significant (- 0.31 kg, 95% CI - 1.51, 0.90). Further research on insulin-treated T2DM patients is necessary to investigate the long-term effects of SGLT2 and DPP4 inhibitors on body composition, as well as their effects on muscle strength and physical function.Trial registration: ClinicalTrials.gov no. NCT03458715, registration date: March 8, 2018.

Topics: Benzhydryl Compounds; Blood Glucose; Body Composition; Body Weight; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucose; Glucosides; Humans; Hypoglycemic Agents; Insulin; Linagliptin; Sodium; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Treatment Outcome

Topics: Adenosine; Albumins; Animals; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dinoprostone; Dipeptidyl-Peptidase IV Inhibitors; Hemodynamics; Insulin; Linagliptin; Male; Mice; Natriuresis; Sodium-Glucose Transporter 2 Inhibitors

In contrast to Western population, glucagon-like peptide-1 (GLP-1) levels are preserved in some East Asian population with type 2 diabetes (T2D), explaining why dipeptidyl peptidase-IV (DPP-IV) inhibitors are more effective in East Asians. We assessed whether differences in endogenous GLP-1 levels resulted in different treatment responses to DPP-IV inhibitors in prediabetes and T2D.. A prospective 12-week study using linagliptin 5mg once daily in 50 subjects (28 prediabetes and 22 T2D) who were stratified into high versus low fasting GLP-1 groups. A 75-g oral glucose tolerance test (OGTT) was performed at week 0 and 12. Primary outcomes were changes in HbA1c, fasting and post-OGTT glucose after 12 weeks. Secondary outcomes included changes in insulin resistance and beta cell function indices.. There was a greater HbA1c reduction in subjects with high GLP-1 compared to low GLP-1 levels in both the prediabetes and T2D populations [least-squares mean (LS-mean) change of -0.33% vs. -0.11% and -1.48% vs. -0.90% respectively)]. Linagliptin significantly reduced glucose excursion by 18% in high GLP-1 compared with 8% in low GLP-1 prediabetes groups. The reduction in glucose excursion was greater in high GLP-1 compared to low GLP-1 T2D by 30% and 21% respectively. There were significant LS-mean between-group differences in fasting glucose (-0.95 mmol/L), 2-hour glucose post-OGTT (-2.4 mmol/L) in the high GLP-1 T2D group. Improvement in insulin resistance indices were seen in the high GLP-1 T2D group while high GLP-1 prediabetes group demonstrated improvement in beta cell function indices. No incidence of hypoglycemia was reported.. Linagliptin resulted in a greater HbA1c reduction in the high GLP-1 prediabetes and T2D compared to low GLP-1 groups. Endogenous GLP-1 level play an important role in determining the efficacy of DPP-IV inhibitors irrespective of the abnormal glucose tolerance states.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Insulin Resistance; Linagliptin; Prediabetic State; Prospective Studies

Hyperglycaemia in hospitalized patients with type 2 diabetes is preferably managed with insulin. We aimed to analyse the glycaemic efficacy, treatment simplicity, and safety of our hospital's antihyperglycemic regimens (linagliptin-basal insulin versus basal-bolus insulin) in patients with type 2 diabetes admitted for heart failure decompensation.. In this real-world study, we included patients with mild-to-moderate hyperglycaemia managed with our antihyperglycemic regimens between 2016 and 2018. To match patients who started one of the regimens, a propensity matching analysis was used.. After propensity matching, 146 patients were included in each group. There were no differences in mean blood glucose levels (163.6±21.2 vs 159.6±19.2mg/dl, p=.210). Patients on the linagliptin-basal insulin regimen had a lower total number of hypoglycaemic episodes (36 vs 64, p<.001), lower total insulin dose (24.1±5.3 vs 32.0±5.6 units, p<.001), and lower number of daily injections (2.4±.8 vs 4.0±.0, p<.001) than those on the basal-bolus regimen.. Linagliptin-basal insulin was a safe, simple, and efficacious regimen and could be considered standard of care for these vulnerable, high complex patients to simplify in-hospital management.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Heart Failure; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Linagliptin; Treatment Outcome

Dipeptidylpeptidase-4 (DPP-4) inhibitors, including linagliptin, alogliptin, saxagliptin, sitagliptin, and vildagliptin, are used for the treatment of type 2 diabetes mellitus (T2DM) patients in China. This study assessed the economic outcomes of different DPP-4 inhibitors in patients with T2DM inadequately controlled with metformin in the Chinese context.. In this study, the validated Chinese Outcomes Model for T2DM (COMT) was conducted to project economic outcomes from the perspective of Chinese healthcare service providers. Efficacy and safety, medical expenditure, and utility data were derived from the literature, which were assigned to model variables. The primary outputs of the model included the lifetime costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER). One-way and probability sensitivity analysis was conducted to assess the potential uncertainties of parameters.. Of the five competing strategies, alogliptin 25 mg strategy yielded the most significant health outcome, which associated with improvements in discounted QALY of 0.007, 0.014, 0.011, and 0.022. These results suggested that alogliptin was a preferred treatment option compared with other DPP-4 inhibitors for Chinese patients whose T2DM are inadequately controlled on metformin monotherapy.

Topics: Adamantane; China; Cost-Benefit Analysis; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Drug Resistance; Drug Therapy, Combination; Humans; Linagliptin; Metformin; Middle Aged; Piperidines; Randomized Controlled Trials as Topic; Sitagliptin Phosphate; Uracil; Vildagliptin

Linagliptin is prescribed as a dipeptidyl peptidase-4 (DPP-4) inhibitor. Azithromycin is specified as an antibiotic that binds with 23s rRNA of the 50s ribosomal subunit, obstructing the microbial protein synthesis. Our study focuses on the drug-drug interactions of these drugs.. The purpose of the study is to understand the bioavailability and physicochemical approaches of Linagliptin and Azithromycin interaction mediated through the strength and nature of the complexation.. TheIn vitro assessment of drug interaction was conducted using Ultraviolet-visible spectroscopy (UV/VIS), Ultra-Performance Liquid Chromatography (UPLC), Fourier transform infrared spectroscopy (FT-IR), and Differential scanning calorimetry (DSC), while the Oral Glucose Tolerance Test (OGTT) was performed for theIn vivo assessment of drug interaction in a mouse model.. Hence, the concomitant administration of Linagliptin and Azithromycin simultaneously might reduce the therapeutic effect of the drug complex.

Topics: Animals; Azithromycin; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Linagliptin; Mice; Spectroscopy, Fourier Transform Infrared

Topics: Aged, 80 and over; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Linagliptin; Male; Pemphigoid, Bullous

Linagliptin (LGP), a novel anti-diabetic drug, is a DPP-4 inhibitor used in the treatment of type II diabetes. One of the major disadvantages of LGP is its low oral bioavailability (29.5%) due to first-pass metabolism and P-gp efflux. In an attempt to increase the oral bioavailability, LGP solid lipid nanoparticles (LGP-SLNs) were developed with poloxamer 188 and Tween 80 as P-gp inhibitors. LGP-SLNs were formulated using palmitic acid, poloxamer 188 and Tween 80 as lipid, surfactant and co-surfactant, respectively, by hot homogenization ultrasonication method and optimized using 3

Topics: Administration, Oral; Animals; Biological Availability; Caco-2 Cells; Diabetes Mellitus, Type 2; Drug Carriers; Humans; Linagliptin; Lipids; Liposomes; Nanoparticles; Particle Size; Rats

Dipeptidyl peptidase 4 (DPP-4) inhibitors are a class of oral glucose-lowering drugs used in the treatment of type 2 diabetes. In a pilot study using human kidney biopsies, we observed high DPP-4 expression in early crescent formation. This glomerular lesion occurs in different kidney diseases and is a hallmark in the pathogenesis of renal dysfunction. Therefore, we investigated the potential involvement of DPP-4 in the pathogenesis of nephritis induced by anti-glomerular basement membrane (GBM) antibody in rats.. Linagliptin and vehicle were used to treat anti-GBM nephritis in a 2- and 8-week regimen, that is either preventive or therapeutic (treatment started 7 days or 4 weeks after disease induction). Kidney function, morphologic changes, inflammation and fibrosis were monitored.. In the long-term experiment, linagliptin preventive treatment in anti-GBM nephritic rats significantly reduced the number of crescents, glomerulosclerosis, tubular injury and renal fibrosis, compared with those in untreated nephritic rats. Both linagliptin regimes significantly lowered the number of Pax8+ cells on the glomerular tuft in anti-GBM nephritis, indicating accelerated resolution of the cellular crescents. The linagliptin treatment did not change the podocyte stress in both therapeutic groups. Therapeutic intervention with linagliptin resulted in weaker amelioration of renal disease on Week 8 than did preventive intervention.. DPP-4 inhibition with linagliptin ameliorates renal injury in a rat model of anti-GBM, indicating that linagliptin not only is a secure therapy in diabetes but also can improve resolution of glomerular injury and healing in non-diabetic renal disease.

Topics: Animals; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Kidney; Linagliptin; Nephritis; Pilot Projects; Rats

We investigated the long-term safety and effectiveness of linagliptin in Japanese type 2 diabetes (T2D) patients starting linagliptin add-on therapy in routine clinical practice.. This 3-year prospective, observational, post-marketing surveillance (PMS) was conducted in Japanese patients starting linagliptin add-on therapy. The primary outcome was the incidence of adverse drug reactions (ADRs). The secondary outcome was the change from baseline in HbA1c.. The safety analysis set comprised of 3,372 patients. Mean ± standard deviation (SD) age was 66.5 ± 12.4 years. Most patients (63.2%) received linagliptin in combination with another antidiabetic drug, most commonly a sulfonylurea (38.6%). The incidence of ADRs was 11.39%; the most common ADRs according to MedDRA preferred terms were diabetes mellitus (1.25%), hypertension (0.83%), and hypoglycemia (0.80%). In the effectiveness analysis set (n = 3,029), mean ± SD HbA1c was 7.76 ± 1.37% at baseline and 7.26 ± 1.19% at last observation; mean change from baseline to last observation was - 0.49 ± 1.33%; sustained reductions in HbA1c were observed. These results were consistent across patient subgroups.. In this PMS, linagliptin add-on therapy for Japanese T2D patients had a safety profile consistent with its known profile and HbA1c reductions over 3 years were observed.. NCT01904383.

Topics: Aged; Asian People; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Japan; Linagliptin; Male; Middle Aged; Product Surveillance, Postmarketing; Prospective Studies

Empagliflozin and linagliptin are newly approved FDA combination that used for the treatment of type 2 diabetes mellitus (T2DM) under trade name Glxambi. Two spectroflourimetric methods were developed for simple quantitative determination of empagliflozin and linagliptin in their pharmaceutical formulation and human plasma without need any tedious processing operations. Empagliflozin has a native fluorescence nature, therefore can be directly determined by measuring emission peak at 305 nm after excitation at 234 nm. There is no any interference from linagliptin at this emission wavelength. On the other hand, linagliptin is a very weak florescent compound that needs to react with fluorogenic reagent to be quantitatively determined without any reaction of empagliflozin. So, quantitative analysis of linagliptin was achieved by coupling with NBD-Cl which is an electro active halide reagent (targeting only Linagliptin with no effect on empagliflozin). Dark yellow fluorophore with high fluorescence is a result of this reaction and can be measured at emission wavelength 538 nm after excition at wavelength 469 nm. Experimental conditions of the suggested methods were well checked and optimized. The regression plots were found to be linear over the range of 40-1200 ng/mL and 3-700 ng/mL for empagliflozin and linagliptin, respectively. The obtained results by the suggested methods were statistically compared with those obtained by the reported methods, showing no significant difference with respect to accuracy and precision at p = 0.05.

Topics: Benzhydryl Compounds; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Compounding; Glucosides; Humans; Hypoglycemic Agents; Linagliptin

We designed a postmarketing surveillance study of linagliptin for patients with type 2 diabetes (T2D) in Korea. This prospective, observational, multicentre study investigated the safety and glycaemic effectiveness of linagliptin as monotherapy or combination therapy with other antidiabetic drugs in routine clinical practice. Endpoints were the incidence of adverse drug reactions (ADRs) and the change in HbA1c. Overall, 3119 and 2171 patients were included in the safety and effectiveness analysis sets, respectively. A total of 56 patients (1.8%) experienced ADRs. The most common ADR was gastrointestinal disorders (0.7%), followed by metabolism and nutrition disorders (0.5%). ADRs of special interest, including pancreatic diseases, cardiac diseases and hypoglycaemia, occurred in 12 patients, 11 of whom had hypoglycaemia, while one had a skin lesion. Mean HbA1c change during the study period was -0.8%. Lower body mass index, shorter diabetes duration and higher baseline HbA1c were independently associated with a better effectiveness, while the presence of diabetic complications, dyslipidaemia and the use of sulphonylureas were associated with a poor response. In conclusion, linagliptin showed an excellent safety profile and glycaemic effectiveness in Korean patients with T2D.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Linagliptin; Prospective Studies; Republic of Korea; Treatment Outcome

Sodium-glucose cotransporter 2 (SGLT2) inhibitors, which are used for treatment of type 2 diabetes, are associated with risk of urogenital infections. FDA issued a black box warning about multiple case reports of Fournier's gangrene (FG) observed in patients taking SGLT2 inhibitors. FG is a type of necrotising fasciitis that occurs in the anogenital area. We report a case of a 71-year-old woman with type 2 diabetes on dapagliflozin, presenting with foul-smelling discharge and a large abscess in the perianal area. Her risk factors for FG included her advanced age, obesity, diabetes and trauma to the site. During her stay, dapagliflozin was discontinued and she received procedural debridement, wound care and broad-spectrum intravenous antibiotics. Due to possible association between FG and SGLT2 inhibitors, patients presenting with signs and symptoms of FG who are taking SGLT2 inhibitors should be examined for infection in the urogenital area and treated promptly.

Topics: Abscess; Accidental Falls; Aged; Anti-Bacterial Agents; Benzhydryl Compounds; Debridement; Diabetes Mellitus, Type 2; Drainage; Female; Fournier Gangrene; Glucosides; Hospitals, Rural; Humans; Hypoglycemic Agents; Insulin; Linagliptin; Obesity; Perineum; Sodium-Glucose Transporter 2 Inhibitors; Sulfonylurea Compounds

Dipeptidyl peptidase 4 inhibitors (DPP-4i) are associated with an increased risk of developing bullous pemphigoid (BP) in patients with diabetes. Autoantibodies targeting epitopes on the processed BP180, 120-kDa (LAD-1), and 97-kDa (LABD97) linear immunoglobulin (Ig)A dermatosis antigens are the major autoantibodies in DPP-4i-associated BP. However, no case of mucous membrane pemphigoid (MMP) developing during treatment with DPP-4i has been reported. We report a case of MMP associated with DPP-4i. A man in his late 70s presented with oral mucous membrane erosion and a few blisters on his upper chest and back. He had used linagliptin for diabetes for over 1 year when he presented. The immunological characteristics were similar to DPP4i-associated BP: higher reactivity to LAD-1 and LABD97 than to the full-length BP180. The aphthae achieved remission after oral linagliptin was replaced with sitagliptin. However, 6 months later, the aphthae relapsed and any DPP-4i was discontinued. The aphthae disappeared, and now he is completely free from lesions associated with MMP. This case suggests that the DPP-4i may have shared roles in the production of IgG antibodies to LAD-1 or to LABD97 in the pathogenesis of DPP-4i-associated BP and MMP. Our case highlights the possibility of overlooking the mild MMP in DPP-4i-treated diabetes patients with mucosal lesions.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Linagliptin; Male; Mucous Membrane; Pemphigoid, Benign Mucous Membrane; Pemphigoid, Bullous

Effects of combination therapy of dipeptidyl peptidase-4 (DPP-4) inhibitor and sodium-glucose co-transporter 2 (SGLT2) inhibitor on β-cells are still unclear, although combination agent of these two drugs has become common in clinical practice. Therefore, we aimed to elucidate the effects of DPP-4 inhibitor and/or SGLT2 inhibitor on β-cell mass and function and compared their effects between in an early and advanced phase of diabetes. We used 7-week-old db/db mice as an early phase and 16-week-old mice as an advanced phase and treated them for 2 weeks with oral administration of linagliptin, empagliflozin, linagliptin + empagliflozin (L + E group), and 0.5% carboxymethylcellulose (Cont group). Blood glucose levels in Empa and L + E group were significantly lower than Cont group after treatment. In addition, β-cell mass in L + E group was significantly larger than Cont group only in an early phase, accompanied by increased Ki67-positive β-cell ratio. In isolated islets, mRNA expression levels of insulin and its transcription factors were all significantly higher only in L + E group in an early phase. Furthermore, mRNA expression levels related to β-cell differentiation and proliferation were significantly increased only in L + E group in an early phase. In conclusion, combination of DPP-4 inhibitor and SGLT2 inhibitor exerts more beneficial effects on β-cell mass and function, especially in an early phase of diabetes rather than an advanced phase.

Topics: Animals; Benzhydryl Compounds; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Drug Combinations; Glucosides; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Linagliptin; Male; Mice; Mice, Inbred NOD; Mice, Inbred Strains; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors

The incidence and prevalence of end-stage renal disease (ESRD) is increasing. The most common cause of ESRD is diabetes mellitus (DM). Kidney transplantation offers better quality of life and survival for patients with ESRD. Because of the use of immunosuppressive therapy and steroids post-kidney transplantation, the patients are at an increased risk for the development of posttransplant DM (PTDM). Management of DM after transplantation (whether pre-existing or transplant related) remains a challenge. Multiple treatment options are currently available to manage PTDM. Those medications have good safety and efficacy record in the general population and in patients with mild degrees of kidney disease.. We conducted a retrospective single center analysis of safety and efficacy of linagliptin post-kidney transplantation. The study was approved by the institutional review board. We collected data (demographics, laboratory tests, and any symptoms or hospitalizations) for 42 patients for a period of 12 months.. All 42 patients received linagliptin throughout the study period. Patients' average age was 62 years. Twenty-three were women and all were of Middle Eastern descent and had kidney transplants on average of 25 months when they were included in the study. Nineteen patients had DM before the transplant, and the rest had PTDM. Eighteen patients were on metformin and 15 were on insulin, whereas the rest were not on any other medications at the start of the study. Baseline average creatinine was 1.5 mg/dL (132.9 mmol/L) and glycated hemoglobin (HbA1c) was 8.2 g/dL at the start of the study, whereas creatinine was 1.6 mg/dL (138.5 mmol/L) and HbA1c was 7.4 g/dL at the end. HbA1c dropped 0.8 on average within 3 months of starting linagliptin and remained at the same level for the rest of the study. Urine protein did not change significantly throughout the study. Three patients developed acute myocardial infarction during the study, and a fourth one was hospitalized with an opportunistic infection. Two patients had urinary tract infections. Adverse effects were minimal. No allergic reactions, hypoglycemia, or acute pancreatitis episodes were reported. The average weight and body mass index did not change throughout the study. None of the patients stopped the medication.. In this retrospective analysis, linagliptin seems to be safe and efficacious after kidney transplantation. It can be considered as a treatment option to manage DM after transplantation.

Topics: Acute Disease; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Kidney Transplantation; Linagliptin; Male; Middle Aged; Pancreatitis; Quality of Life; Retrospective Studies

The efficacy and safety of empagliflozin and linagliptin (Empa/Lina), is demonstrated in adults with T2DM in the various trials. The study was planned to investigate the clinical effectiveness and safety of Empa/Lina in a more representative population of the Indian outpatient setting.. The study was conducted in poorly controlled T2DM patients being treated with Empa/Lina once daily (25/5mg) as an add on in a tertiary care institute in Jammu, India. Various efficacy and safety parameters were assessed prior to the initiation of Empa/Lina and thereafter at periodic intervals until week 12. Appropriate statistical tests were applied.. In a total of 347 eligible patients, the mean age (SD) was 57.84 ±7.3 years, Males were 49%, average body weight was 79.81±9.72 kg. The median duration of diabetes was 6.42±2.05 years. Empa/Lina as an add on therapy to other glucose-lowering treatment was associated with a significant lowering in HbA1c (-1.1 ±0.64 mg/dl), FPG level -47.11(±20.42) mg/dl, PPG level (-71.32± 26.56), body weight -2.64 (±1.97) kg and blood pressure parameters (systolic BP -7.68 ±5.2 and Diastolic BP -3.16±1.7) from baseline at 12 weeks. A total of 47.55 percent of patients responded to Empa/Lina (25/5mg) added in conjunction with other antidiabetes agents. There was no significant difference in glycemic parameters of various subgroups assessed based on concurrent antidiabetes drugs. However, a significant reduction in body weight of subjects on insulin therapy was noticed. There was an improvement in eGFR level which was maintained across the study period. Genital mycotic infection was reported in 8.6% of patients. Empa/Lina (25/5 mg) as an add-on therapy was well tolerated with less hypoglycemic events.. Thus, the combination of empagliflozin and linagliptin (25/5 mg) significantly improved the glycemic and non-glycemic measures in combination with one or more commonly prescribed antidiabetic drugs in inadequately controlled diabetes patients and is well tolerated.

Topics: Adult; Aged; Benzhydryl Compounds; Diabetes Mellitus, Type 2; Glucosides; Humans; Linagliptin; Male; Middle Aged; Retrospective Studies; Treatment Outcome

Linagliptin is a selective dipeptidyl peptidase-4 (DPP-4) inhibitor which suppresses the rapid degradation of endogenous glucagon-like peptide-1 (GLP-1). In clinical practice, it is used as an antidiabetic drug, but recent studies have confirmed its role in the activity of the central nervous system (CNS). The reported study focused on the role of linagliptin (10 and 20 mg/kg, ip) in the morphine rewarding effect, analyzing how the agent had influenced the conditioned place preference (CPP) in rats via the expression, acquisition, extinction and reinstatement of the morphine rewarding effect. The obtained results clearly demonstrated linagliptin to inhibit the expression and acquisition, to accelerate the extinction and, eventually, to reduce the reinstatement of morphine-induced CPP. The undertaken experiments significantly extended our knowledge on the mechanisms behind the morphine rewarding effect.

Topics: Animals; Behavior, Animal; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Hypoglycemic Agents; Linagliptin; Male; Morphine; Rats, Wistar; Reward

Recent studies revealed the risk of bullous pemphigoid (BP) in patients with diabetes mellitus (DM) taking dipeptidyl peptidase 4 (DPP-4) inhibitors. To clarify the relationship between taking DPP-4 inhibitors and the risk of BP among patients with DM, we conducted a cohort study by using the National Health Insurance Research Database of Taiwan from 1 January 2009 to 31 December 2015. We identified 6340 patients with DM taking DPP-4 inhibitors and 25 360 DM patients who had not taken DPP-4 inhibitors during the 7-year follow-up period. Compared with the non-DPP-4 inhibitor group, patients taking DDP-4 inhibitors had a higher risk of BP (adjusted hazard ratio [aHR], 2.382; 95% confidence interval (CI), 1.163-4.883; P = 0.017]. Among the DPP-4 inhibitors available in Taiwan, vildagliptin showed the highest risk of BP (aHR, 2.849; 95% CI, 1.893-4.215; P < 0.001), followed by saxagliptin (aHR, 2.657; 95% CI, 1.770-3.934; P < 0.001). Subgroup analysis revealed that the higher risk of BP was observed in patients older than 65 years (aHR, 2.403; 95% CI, 1.590-3.627; P < 0.001). This study revealed that treatment with DPP-4 inhibitors, especially vildagliptin, was significantly associated with an increased risk of BP among DM patients.

Topics: Adamantane; Adult; Age Factors; Aged; Case-Control Studies; Databases, Factual; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Incidence; Linagliptin; Male; Middle Aged; Pemphigoid, Bullous; Piperidines; Risk Factors; Sitagliptin Phosphate; Taiwan; Uracil; Vildagliptin; Young Adult

Bullous pemphigoid (BP) is the most common autoimmune subepidermal bullous diseases. Autoantibodies against hemidesmosomal adhesion proteins might be involved in the developing process. BP usually affects the elderly with high mortality whereas the drug-induced BP is often improved and rarely relapses after the withdrawal of the suspected drug. An accumulated evidence suggests that dipeptidyl peptidase-4 inhibitor (DPP-4I), which has been widely used as the antidiabetic drug improves glycemic control with little risk for hypoglycemia, could be an inducer of DPP-4I-associated BP (DPP-4I-BP). While the precise mechanism remains unclear, a unique immunological profile with human leukocyte antigen (HLA)-DQB1*03:01 could be a biomarker of genetic susceptibility to DPP-4I-BP. Here, we encountered an interesting case of DPP-4I-BP with HLA-DQB1*03:01, which was likely triggered by scabies. A 56-year-old Japanese male with type 2 diabetes on hemodialysis was referred to our hospital due to worsened blisters. Prior to his admission, he had been on linagliptin, a DPP-4I, for 5 months. He then suffered from scabies 2 weeks before his admission while the treatment with ivermectin failed to improve his symptom. Based on his clinical symptom, positive for anti-BP180 autoantibody in serum, and the pathological alterations of skin biopsy specimens, he was diagnosed with DPP-4I-BP. Importantly, he also carried an HLA-DQB1*03:01 allele. Oral prednisolone was subsequently administered after the discontinuation of linagliptin, and his symptom gradually disappeared. Given the fact that the DPP-4I-BP could be a life-threating disease, we should be cautious of prescribing DPP-4I in hemodialysis patients, whose immune system could be impaired.

Topics: Alleles; Autoantibodies; Biopsy; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucocorticoids; HLA-DQ beta-Chains; Humans; Linagliptin; Male; Middle Aged; Pemphigoid, Bullous; Prednisolone; Renal Dialysis; Scabies; Treatment Outcome

To assess whether dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists are associated with an increased lung cancer risk among individuals with type 2 diabetes.. We conducted a population-based cohort study using the UK Clinical Practice Research Datalink. We identified 130 340 individuals newly treated with antidiabetes drugs between January 2007 and March 2017, with follow-up until March 2018. We used a time-varying approach to model use of dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists compared with use of other second- or third-line antidiabetes drugs. We used Cox proportional hazards models to estimate the adjusted hazard ratios, with 95% CIs, of incident lung cancer associated with use of dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists, separately, by cumulative duration of use, and by time since initiation.. A total of 790 individuals were newly diagnosed with lung cancer (median follow-up 4.6 years, incidence rate 1.5/1000 person-years, 95% CI 1.4-1.6). Compared with use of second-/third-line drugs, use of dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists was not associated with an increased lung cancer risk (hazard ratio 1.07, 95% CI 0.87-1.32, and hazard ratio 1.02, 95% CI 0.68-1.54, respectively). There was no evidence of duration-response relationships.. In individuals with type 2 diabetes, use of incretin-based drugs was not associated with increased lung cancer risk.

Topics: Adamantane; Aged; Diabetes Complications; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Female; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incidence; Incretins; Linagliptin; Liraglutide; Lung Neoplasms; Male; Middle Aged; Proportional Hazards Models; Pulmonary Disease, Chronic Obstructive; Risk Factors; Sitagliptin Phosphate; Smoking

The nigrostriatal dopaminergic system (NDS) controls motor activity, and its impairment during type 2 diabetes (T2D) progression could increase Parkinson's disease risk in diabetics. If so, whether glycemia regulation prevents this impairment needs to be addressed. We investigated whether T2D impairs the NDS and whether dipeptidyl peptidase-4 inhibition (DPP-4i; a clinical strategy against T2D but also neuroprotective in animal models) prevents this effect, in middle-aged mice. Neither T2D (induced by 12 months of high-fat diet) nor aging (14 months) changed striatal dopamine content assessed by high-performance liquid chromatography. However, T2D reduced basal and amphetamine-stimulated striatal extracellular dopamine, assessed by microdialysis. Both the DPP-4i linagliptin and the sulfonylurea glimepiride (an antidiabetic comparator unrelated to DPP-4i) counteracted these effects. The functional T2D-induced effects did not correlate with NDS neuronal/glial alterations. However, aging itself affected striatal neurons/glia, and the glia effects were counteracted mainly by DPP-4i. These findings show NDS functional pathophysiology in T2D and suggest the preventive use of two unrelated anti-T2D drugs. Moreover, DPP-4i counteracted striatal age-related glial alterations suggesting striatal rejuvenation properties.

Topics: Aging; Animals; Corpus Striatum; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Disease Progression; Dopamine; Linagliptin; Male; Mice; Mice, Inbred C57BL; Models, Animal; Parkinson Disease; Risk; Substantia Nigra; Sulfonylurea Compounds

Linagliptin, a dipeptidyl peptidase (DPP)-4 inhibitor, for type 2 diabetes exhibits nonlinear plasma protein binding in the therapeutic concentration range due to its high affinity binding to the pharmacological target DPP-4, and its pharmacokinetics both in plasma and urine is also nonlinear. The purpose of the present study was to explain the nonlinear pharmacokinetic profiles using a physiologically based pharmacokinetic (PBPK) model with saturable binding of linagliptin to soluble and membrane-bound DPP-4 in blood and organs including kidneys. The model was first fitted to previously reported full-scale plasma concentrations and urinary excretion data at 4 intravenous (iv) dose levels. Additional fitting to the data from 4 oral (po) dose levels was then performed to yield the final iv-po based model including gastrointestinal absorption-associated parameters. Data from [

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Linagliptin; Purines; Quinazolines

The purpose of this study was to evaluate and compare the effects on laboratory parameters among monotherapy with five DPP-4 inhibitors in patients with type 2 diabetes mellitus (DM).. We identified cohorts of new sitagliptin users (n = 879), vildagliptin users (n = 253), teneligliptin users (n = 260), alogliptin users (n = 237), and linagliptin users (n = 180) in patients with type 2 DM. We used a multivariate regression model to evaluate and compare the effects of the drugs on laboratory parameters including HbA1c concentration and serum concentrations of creatinine, estimated glomerular filtration rate, high density lipoprotein, total cholesterol, triglyceride, aspartate aminotransferase, and alanine aminotransferase among the five DPP-4 inhibitors up to 12 months.. Our study showed a favorable effect on HbA1c concentration and a slightly unfavorable effect on serum creatinine concentration in users of the five DPP-4 inhibitors, a favorable effect on lipid metabolism in sitagliptin, vildagliptin, and alogliptin users, and a favorable effect on hepatic parameters in sitagliptin, alogliptin, and linagliptin users, in comparison of the baseline and exposure periods. However, there was no significant difference in mean change in the concentration of any laboratory parameter among the five groups of DPP-4 inhibitor users.. In this study, we showed the effect of five DPP-4 inhibitors on glycemic, renal, and lipid metabolism, and hepatic parameters. DPP-4 inhibitors are well-tolerated hypoglycemic drugs.

Topics: Aged; Alanine Transaminase; Aspartate Aminotransferases; Cholesterol; Creatinine; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Glomerular Filtration Rate; Glycated Hemoglobin; Humans; Linagliptin; Lipid Metabolism; Lipoproteins, HDL; Male; Middle Aged; Piperidines; Pyrazoles; Sitagliptin Phosphate; Thiazolidines; Triglycerides; Uracil; Vildagliptin

Recent data have indicated the emerging role of glomerular autophagy in diabetic kidney disease. We aimed to assess the effect of the SGLT2 inhibitor empagliflozin, the DPP4 inhibitor linagliptin, and their combination, on glomerular autophagy in a model of type 2 diabetes. Eight-week-old male

Topics: Animals; Apoptosis; Autophagy; Benzhydryl Compounds; Biomarkers; Body Weight; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Gene Expression; Glucosides; Immunohistochemistry; Kidney Function Tests; Kidney Glomerulus; Linagliptin; Mice; Mice, Inbred Strains; Mice, Transgenic; Podocytes; Sodium-Glucose Transporter 2 Inhibitors

Dipeptidyl peptidase 4 (DPP-4) inhibitors have anti-inflammatory and atheroprotective effects. We evaluated the effects of the DPP-4 inhibitor linagliptin on atherosclerotic plaque and hepatic inflammation using histology and 2-deoxy-2-[. Igf2/Ldlr. Mice in linagliptin and HFD groups had similar fasting glucose concentrations, but linagliptin improved glucose tolerance. Aortas of linagliptin and HFD groups showed advanced atherosclerotic plaques with no difference in the mean intima-to-media ratio or number of macrophages in the plaques. Autoradiography showed similar. Linagliptin therapy improved glucose tolerance and reduced hepatic inflammation but had no effect on plaque burden or atherosclerotic inflammation, as determined by histology and

Topics: Animals; Atherosclerosis; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Fluorodeoxyglucose F18; Inflammation; Linagliptin; Mice; Mice, Knockout; Plaque, Atherosclerotic; Positron-Emission Tomography

Data regarding the clinical characteristics of patients with dipeptidyl-peptidase IV inhibitors (DPP4i)-associated BP is inconclusive. We aimed to characterize the clinical features of patients with DPP4i-associated BP, and to assess whether there are phenotypic differences associated with different agents belonging to the DPP4i class. A retrospective prevalence study was performed, including all consecutive patients diagnosed with BP throughout the years 2000 to 2019. The study included 397 patients with BP, of whom 58 (14.6%) were DPP4i-associated. Compared to other patients with BP, patients with DPP4i-associated BP had a more prominent male preponderance (60.3% vs 41.0%; P = .006), presented more frequently with extensive disease (60.3% vs 46.3%; P = .049), had greater truncal (96.6% vs 85.5%; P = .019) and cephalic (51.7% vs 33.6%; P = .008) involvement, and had less frequent peripheral eosinophilia (25.9% vs 51.9%; P < .001). Compared to patients with vildagliptin-associated BP, those with linagliptin-associated BP were managed by higher dosage of systemic corticosteroids in order to achieve disease control (prednisone > 1 mg/kg: 68.2% vs 40.0%; P = .046). In conclusion, DPP4i-associated BP seems to have a unique clinical profile characterized by male predominance, extensive disease, truncal and cephalic involvement, and less peripheral eosinophilia. Linagliptin may be associated with a harder course necessitating more aggressive therapy.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Linagliptin; Male; Pemphigoid, Bullous; Retrospective Studies

Topics: Administration, Oral; Adult; Benzhydryl Compounds; Diabetes Mellitus, Type 2; Drug Combinations; Glucosides; Humans; Hypoglycemic Agents; Linagliptin; Metformin

Topics: Animals; Atherosclerosis; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Fluorodeoxyglucose F18; Inflammation; Linagliptin; Mice; Plaque, Atherosclerotic

Despite several recent reports on the elevated risk of bullous pemphigoid in patients with type 2 diabetes treated with dipeptidyl peptidase-4 (DPP-4) inhibitors, evidence on the absolute risk and comparative safety against other antidiabetics is limited.. To characterize the incidence rate of bullous pemphigoid associated with DPP-4 inhibitor use compared with second-generation sulfonylureas.. This cohort study used data from 2 large commercial insurance claims databases (Optum Clinformatics Data Mart from October 17, 2006, to December 31, 2018, and IBM MarketScan Research Database from October 17, 2006, to December 31, 2017) and Medicare data from January 1, 2006, to December 31, 2016. Patients with type 2 diabetes who initiated treatment with DPP-4 inhibitors or second-generation sulfonylurea were included.. The primary outcome of the study was bullous pemphigoid, identified using diagnosis codes. After 1:1 propensity score matching, the incidence rates of bullous pemphigoid and the hazard ratios (HRs) with 95% CIs comparing patients who initiated DPP-4 inhibitor and second-generation sulfonylurea therapy were estimated. Subgroup analyses by age, sex, race, and individual DPP-4 agents were performed. The results from each database were pooled using inverse-variance fixed-effects meta-analysis.. A total of 1 664 880 patients who initiated DPP-4 inhibitors (51.0% female; mean [SD] age, 63.9 [9.7] years) and sulfonylurea (50.4% female; mean [SD] age, 63.9 [9.9] years) were included. The incidence rate of bullous pemphigoid per 1000 person-years was 0.42 in the DPP-4 inhibitor group vs 0.31 in the sulfonylurea group (HR, 1.42; 95% CI, 1.17-1.72). Higher rates per 1000 person-years for DPP-4 inhibitor vs sulfonylurea groups were seen in those who were 65 years or older (0.79 vs 0.49; HR, 1.62; 95% CI, 1.32-1.99), white (0.93 vs 0.54; HR, 1.70; 95% CI, 1.30-2.24), and treated with linagliptin (1.20 vs 0.55; HR, 1.68; 95% CI, 1.16-2.43).. This study found that patients who initiated DPP-4 inhibitor therapy had higher risk of bullous pemphigoid than those who initiated second-generation sulfonylurea therapy. Clinicians should be aware of this rare adverse effect of DPP-4 inhibitors in subgroups of patients who are older, white, and linagliptin users.

Topics: Administrative Claims, Healthcare; Age Factors; Aged; Case-Control Studies; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Prescriptions; Female; Humans; Incidence; Linagliptin; Male; Middle Aged; Pemphigoid, Bullous; Retrospective Studies; Risk Assessment; Risk Factors; Sulfonylurea Compounds; United States

For the recently introduced single-pill combination of empagliflozin and linagliptin, real-world evidence has not been available. This observational study aims to assess real-world effectiveness of this combination, in the Indian outpatient setting of type-2 diabetes.. This was a prospective cohort study design, involving patients from 4 centres across western India. Patients with type-2 diabetes and uncontrolled HbA1c, were categorized into 4 groups, including: (1) Naïve to DPP-4i or SGLT-2i; (2) Receiving DPP-4i; (3) Receiving SGLT-2i; (4) Receiving SGLT-2i and DPP-4i as individual pills. Patients were initiated on the fixed-dose combination of empagliflozin + linagliptin, and followed-up over 12-week duration. Clinical parameters of changes in glycaemia, body-weight, and blood-pressure were observed.. 251 patients were included in the analysis, with just over half of them being males (57%), or having pre-existing cardiovascular disease (54%). The group-wise patient distribution was approximately 47%, 18%,15%, and 20% respectively. The study represented patients across broad range of duration of type-2 diabetes, use of background antidiabetic therapies, and comorbid cardiovascular risk. The use of combination demonstrated significant and clinically meaningful reductions in HbA1c, fasting and postprandial glycaemia levels across all the study groups. Reductions in body-weight and blood-pressure levels were also demonstrated. Interestingly, patients in group 4, who were switched from free drug combination to the fixed-dose combination, also demonstrated significant and meaningful improvements in HbA1c, fasting as well as postprandial glycaemia levels, suggestive of possible improvement in medication-adherence.. This real-world evidence complements the results observed in randomized controlled trials, for meaningful effectiveness with the use of empagliflozin-linagliptin fixed dose combination in the Indian outpatient setting. More evidence may facilitate further characterization of clinical value of this promising combination.

Topics: Benzhydryl Compounds; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Glucosides; Humans; Hypoglycemic Agents; India; Linagliptin; Male; Prospective Studies

Linagliptin demonstrates substantial nonlinear pharmacokinetics due to its saturable binding to its pharmacological target dipeptidyl peptide 4 (DPP-4), a phenomenon known as target-mediated drug disposition (TMDD). In the current study, we established a novel whole-body physiologically-based pharmacokinetic (PBPK)-TMDD model for linagliptin. This comprehensive model contains plasma and 14 tissue compartments, among which TMDD binding process was incorporated in 9 of them, namely the plasma, kidney, liver, spleen, lung, skin, salivary gland, thymus, and reproductive organs. Our final model adequately captured the concentration-time profiles of linagliptin in both plasma and various tissues in both wildtype rats and DPP4-deficient rats following different doses. The association rate constant (k

Topics: Administration, Intravenous; Administration, Oral; Animals; Computer Simulation; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Hepatobiliary Elimination; Humans; Linagliptin; Models, Animal; Models, Biological; Rats; Rats, Transgenic; Tissue Distribution

Recently, it has been suggested that glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1), which play important roles in the homeostasis of glucose metabolism, could be involved in the regulation of bone metabolism. Inhibitors of dipeptidyl peptidase 4 (DPP-4), an enzyme that degrades GIP and GLP-1, are widely used clinically as a therapeutic agent for diabetes. However, the effects of DPP-4 inhibitors on bone metabolism remain unclear. In this study, we investigated the effects of linagliptin, a DPP-4 inhibitor, on bone fragility induced by type 2 diabetes mellitus (T2DM). Non-diabetic mice were used as controls, and T2DM mice were administered linagliptin orally on a daily basis for 12 weeks. In T2DM mice, decreased bone mineral density was observed in the lower limb bones along with low serum osteocalcin levels and high serum tartrate-resistant acid phosphatase-5b (TRAP) levels. In contrast, the decreased serum osteocalcin levels and increased serum TRAP levels observed in T2DM mice were significantly suppressed after the administration of linagliptin 30 mg/kg. Bone histomorphometric analysis revealed a reduced osteoid volume and osteoblast surface with an increase in the eroded surface and number of osteoclasts in T2DM mice. This decreased bone formation and increased bone resorption observed in the T2DM mice were suppressed and trabecular bone volume increased following the administration of 30 mg/kg linagliptin. Collectively, these findings suggest that linagliptin may improve the microstructure of trabecular bone by inhibiting both a decrease in bone formation and an increase in bone resorption induced by T2DM.

Topics: Administration, Oral; Animals; Bone and Bones; Bone Density; Case-Control Studies; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Linagliptin; Male; Mice; Mice, Obese; Osteocalcin; Tartrate-Resistant Acid Phosphatase

Angiotensin-1 converting enzyme inhibitors (ACEIs) improve insulin sensitivity. Inhibitors of dipeptidyl peptidase-4 (DPP-4) are anti-diabetic drugs with several cardio-renal effects. Both ACE and DPP-4 share common features. Thus, we tested if they could be inhibited by one inhibitor. First, in silico screening was used to investigate the ability of different DPP-4 inhibitors or ACEIs to interact with DPP-4 and ACE. The results of screening were then extrapolated into animal study. Fifty Sprague Dawley rats were randomly assigned into 5 groups treated with vehicle, captopril, enalapril, linagliptin or sitagliptin. Both low and high doses of each drug were tested. Baseline blood samples and samples at days 1, 8, 10, 14 were used to measure plasma DPP-4 and ACE activities and angiotensin II levels. Active glucagon-like peptide-1 (GLP-1) levels were measured after oral glucose challenge. All tested DPP-4 inhibitors could interact with ACE at a relatively reasonable binding energy while most of the ACEIs only interacted with DPP-4 at a predicted high inhibition constant. In rats, high dose of sitagliptin was able to inhibit ACE activity and reduce angiotensin II levels while linagliptin had only a mild effect. ACEIs did not significantly affect DPP-4 activity or prevent GLP-1 degradation. It seems that some DPP-4 inhibitors could inhibit ACE and this could partially explain the cardio-renal effects of these drugs. Further studies are required to determine if such inhibition could take place in clinical settings.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Captopril; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Enalapril; Female; Glucagon-Like Peptide 1; Humans; Hypertension; Linagliptin; Peptidyl-Dipeptidase A; Protein Binding; Rats; Rats, Sprague-Dawley; Sitagliptin Phosphate

Outcomes in type 2 diabetes mellitus (T2DM) could be optimized by identifying which treatments are likely to produce the greatest improvements in glycemic control for each patient.. We aimed to identify patient characteristics associated with achieving and maintaining a target glycated hemoglobin (HbA1c) of ≤ 7% using machine learning methodology to analyze clinical trial data on combination therapy for T2DM. By applying a new machine learning methodology to an existing clinical dataset, the practical application of this approach was evaluated and the potential utility of this new approach to clinical decision making was assessed.. Data were pooled from two phase III, randomized, double-blind, parallel-group studies of empagliflozin/linagliptin single-pill combination therapy versus each monotherapy in patients who were treatment-naïve or receiving background metformin. Descriptive analysis was used to assess univariate associations between HbA1c target categories and each baseline characteristic. After the descriptive analysis results, a machine learning analysis was performed (classification tree and random forest methods) to estimate and predict target categories based on patient characteristics at baseline, without a priori selection.. In the descriptive analysis, lower mean baseline HbA1c and fasting plasma glucose (FPG) were both associated with achieving and maintaining the HbA1c target. The machine learning analysis also identified HbA1c and FPG as the strongest predictors of attaining glycemic control. In contrast, covariates including body weight, waist circumference, blood pressure, or other variables did not contribute to the outcome.. Using both traditional and novel data analysis methodologies, this study identified baseline glycemic status as the strongest predictor of target glycemic control attainment. Machine learning algorithms provide an hypothesis-free, unbiased methodology, which can greatly enhance the search for predictors of therapeutic success in T2DM. The approach used in the present analysis provides an example of how a machine learning algorithm can be applied to a clinical dataset and used to develop predictions that can facilitate clinical decision making.. What did this study look at? This study looked at whether a computer program could predict which people with type 2 diabetes would respond best to a particular treatment. The study treatment was a single-pill combination of two medicines, empagliflozin [em-PAH-gli-FLOW-zin] and linagliptin [LYNN-nah-GLIP-tin]. It is used to lower blood sugar (blood glucose) in people with type 2 diabetes. The researchers used machine learning to analyze data from people who received this treatment. Machine learning uses computer models to find patterns in information. The results helped to predict which people might respond best to the treatment. Who took part in this study? The researchers looked at results collected from two earlier studies of the treatment. 1363 people took part. Approximately half of them were male. Their average age was 55 years. Approximately half of them had not received any previous diabetes treatment, and approximately half (50.3%) had received metformin treatment for diabetes. What did the study show? The researchers found that two blood tests commonly used in clinical practice helped them predict who would have the best response to treatment. These tests were HbA1c levels (a measure of long-term blood glucose control), and their fasting plasma glucose (blood glucose levels when they had not eaten for 10–16 h). This study suggests that machine learning could be a useful tool to help doctors decide which treatments will work best for individuals with type 2 diabetes.

Topics: Benzhydryl Compounds; Blood Glucose; Clinical Decision-Making; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Combinations; Glucosides; Glycated Hemoglobin; Humans; Linagliptin; Machine Learning; Middle Aged; Randomized Controlled Trials as Topic; Treatment Outcome

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Heart Failure; Humans; Linagliptin

Topics: Aged; Aged, 80 and over; Diabetes Mellitus, Type 2; Female; Glucocorticoids; Humans; Hypoglycemic Agents; Linagliptin; Male; Pemphigoid, Bullous; Prednisone; Renal Insufficiency, Chronic; Withholding Treatment

To evaluate linagliptin prescribing in type 2 diabetes mellitus patients with different comorbidities, an expanded Japanese post-marketing surveillance also collected baseline data for patients initiating other glucose-lowering drugs.. Patients initiating linagliptin monotherapy were enrolled, then the next patient starting monotherapy with another glucose-lowering drug was enrolled (2012-2014). Baseline data were collected and analyzed by the Medical Dictionary for Regulatory Activities system organ class. Analyses were descriptive, and meaningful differences defined as absolute standardized difference >10%.. Over 4,200 type 2 diabetes mellitus patients were enrolled. Most system-organ class comorbidities were more common in patients initiating linagliptin versus other glucose-lowering drugs, with meaningful differences observed for metabolism/nutritional (50.5 vs 45.5%, respectively), cardiac (12.2 vs 8.6%, respectively), vascular (56.4 vs 51.3%, respectively) and renal/urinary disorders (9.9 vs 5.7%, respectively).. Expanding the linagliptin Japanese post-marketing surveillance revealed linagliptin prescribing to a type 2 diabetes mellitus population with more comorbidities versus other glucose-lowering drugs. Although such preferential prescribing might be expected, as linagliptin requires no dose adjustment or monitoring in renally or hepatically impaired patients, this innovative post-marketing surveillance approach generated important evidence that could only be shown in such a non-randomized comparative study. These data generated insights important for the design and interpretation of observational studies and spontaneous reports, which are key for public health.

Topics: Aged; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Drug Prescriptions; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Japan; Linagliptin; Male; Middle Aged; Practice Patterns, Physicians'; Product Surveillance, Postmarketing; Prognosis

Early prediction and clinical intervention are extremely important in order to delay or hinder diabetic nephropathy (DN) progression.. This study aimed to detect early signs of DN and study the potential ameliorating effect of the dipeptidyl peptidase-4 inhibitor, linagliptin, on some early markers for DN in fructose-streptozotocin (Fr-STZ)-induced diabetic rats.. Fr-STZ rats were treated with either linagliptin (3 mg/kg p.o. daily), metformin (350 mg/kg p.o. daily), or their combination for 6 weeks.. Fr-STZ DN rats exhibited obvious tubular renal damage and glomerular podocyte injury as confirmed by renal kidney -injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and vanin-1 mRNA, as well as urinary N-acetyl-β-D-glucosaminidase elevation and nephrin mRNA suppression, associated with the appearance of marked renal interstitial fibrosis and glomerulosclerosis despite the absence of microalbuminuria. Initiation of oxidative, inflammatory, fibrotic, and apoptotic reactions was evident in the settings of renal hyperglycemia. Linagliptin significantly modulated the aforementioned renal tubular injury makers and restored glomerular nephrin expression as well as reversed renal histopathological alterations. Oxidative, inflammatory, fibrotic and apoptotic processes were also alleviated.. This study suggests that linagliptin exerts renoprotection against early features of DN in rats probably by inhibition of high glucose-induced renal tubular and glomerular injury thereby hampering KIM-1 and NGAL as well as vanin-1 associated with renal inflammation, fibrosis and oxidative stress.

Topics: Animals; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Fructose; Hypoglycemic Agents; Kidney Function Tests; Linagliptin; Male; Oxidative Stress; Rats; Rats, Wistar; Streptozocin

To evaluate the safety of linagliptin versus other glucose-lowering medications in a multi-year monitoring programme using insurance claims data.. In two commercial US claims databases, we identified three pairwise 1:1 propensity-score (PS)-matched cohorts of patients with type 2 diabetes (T2D) aged ≥18 years initiating linagliptin or a comparator (other dipeptidyl peptidase-4 [DPP-4] inhibitors [n = 31 492 pairs], pioglitazone [n = 23 316 pairs], or second-generation sulphonylureas [n = 19 731 pairs]) between May 2011 and December 2015. The primary endpoint was the risk of a composite cardiovascular (CV) outcome (hospitalization for myocardial infarction, stroke, unstable angina, or coronary revascularization). We estimated pooled hazard ratios (HRs) and 95% confidence intervals (CIs), controlling for >100 baseline characteristics.. Patient characteristics were well balanced after PS-matching. The mean age was 55 years and mean follow-up was 0.8 years. Linagliptin conferred a similar risk of the composite CV outcome compared to other DPP-4 inhibitors (HR 0.91, 95% CI 0.79-1.05) and pioglitazone (HR 0.98, 95% CI 0.84-1.15), and showed a reduced risk of CV outcomes compared to second-generation sulphonylureas (HR 0.76, 95% CI 0.64--0.92). Key findings were signalled at the first interim analysis in June 2013 and solidified during ongoing monitoring until 2015.. Analyses from a large monitoring programme in routine care of patients with T2D, showed that linagliptin had similar CV safety compared to other DPP-4 inhibitors and pioglitazone, and a reduced CV risk compared to sulphonylureas.

Topics: Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Hypoglycemic Agents; Linagliptin; Male; Middle Aged; Pioglitazone; Propensity Score; Sulfonylurea Compounds; Treatment Outcome; United States

We studied the effects of dipeptidyl peptidase 4 (DPP4) inhibitor linagliptin on the expression of apoptosis regulator proteins Bcl-2 and Bad in the liver of db/db mice with genetically determined obesity and type 2 diabetes mellitus. The mice received daily linagliptin or saline (placebo) by gavage from week 10 to week 18 of life. In the liver of non-treated mice, the area positively stained for Bad was greater than the area of Bcl-2 expression, which created the conditions for apoptosis activation in liver at this age. Administration of linagliptin decreased Bad stained area and increased Bcl-2 stained area in the liver cells. At the same time, Bad stained area remained larger in treated mice than the area of Bcl-2 expression area, which attested to partial normalization of pro- and antiapoptotic protein balance.

Topics: Animals; Apoptosis; bcl-Associated Death Protein; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Linagliptin; Liver; Male; Mice; Non-alcoholic Fatty Liver Disease; Obesity; Proto-Oncogene Proteins c-bcl-2

Using real-world data (RWD) from three U.S. claims data sets, we aim to predict the findings of the CARdiovascular Outcome Trial of LINAgliptin Versus Glimepiride in Type 2 Diabetes (CAROLINA) comparing linagliptin versus glimepiride in patients with type 2 diabetes (T2D) at increased cardiovascular risk by using a novel framework that requires passing prespecified validity checks before analyzing the primary outcome.. Within Medicare and two commercial claims data sets (May 2011-September 2015), we identified a 1:1 propensity score-matched (PSM) cohort of T2D patients 40-85 years old at increased cardiovascular risk who initiated linagliptin or glimepiride by adapting eligibility criteria from CAROLINA. PSM was used to balance >120 confounders. Validity checks included the evaluation of expected power, covariate balance, and two control outcomes for which we expected a positive association and a null finding. We registered the protocol (NCT03648424, ClinicalTrials.gov) before evaluating the composite cardiovascular outcome based on CAROLINA's primary end point. Hazard ratios (HR) and 95% CIs were estimated in each data source and pooled with a fixed-effects meta-analysis.. We identified 24,131 PSM pairs of linagliptin and glimepiride initiators with sufficient power for noninferiority (>98%). Exposure groups achieved excellent covariate balance, including key laboratory results, and expected associations between glimepiride and hypoglycemia (HR 2.38 [95% CI 1.79-3.13]) and between linagliptin and end-stage renal disease (HR 1.08 [0.66-1.79]) were replicated. Linagliptin was associated with a 9% decreased risk in the composite cardiovascular outcome with a CI including the null (HR 0.91 [0.79-1.05]), in line with noninferiority.. In a nonrandomized RWD study, we found that linagliptin has noninferior risk of a composite cardiovascular outcome compared with glimepiride.

Topics: Adult; Aged; Aged, 80 and over; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Glycated Hemoglobin; Humans; Linagliptin; Medicare; Middle Aged; Sulfonylurea Compounds; Treatment Outcome; United States

We compared the effects of linagliptin (Lina, a DPP4 inhibitor) and GLP-1 receptor activation by exenatide followed by exendin-4 in an infusion pump (EX) on infarct size (IS), post-infarction activation of the inflammasome and remodeling in wild-type (WT) and db/db diabetic mice. Mice underwent 30 min ischemia followed by 24 h reperfusion. IS was assessed by TTC. Additional mice underwent permanent coronary artery occlusion. Echocardiography was performed 2w after infarction. Activation of the inflammasome in the border zone of the infarction was assessed by rt-PCR and ELISA 2w after reperfusion. Further in vitro experiments were done using primary human cardiofibroblasts and cardiomyocytes exposed to simulated ischemia-reoxygenation. Lina and EX limited IS in both the WT and the db/db mice. Lina and EX equally improved ejection fraction in both the WT and the db/db mice. mRNA levels of ASC, NALP3, IL-1β, IL-6, Collagen-1, and Collagen-3 were higher in the db/db mice than in the WT mice. Infarction increased these levels in the WT and db/db mice. Lina more than EX attenuated the increase in ASC, NALP3, IL-1β, IL-6, Collagen-1 and Collagen-3, TNFα and IL-1β, and decreased apoptosis, especially in the db/db mice. In vitro experiments showed that Lina, but not EX, attenuated the increase in TLR4 expression, an effect that was dependent on p38 activation with downstream upregulation of Let-7i and miR-146b levels. Lina and EX had similar effects on IS and post-infarction function, but Lina attenuated the activation of the inflammasome and the upregulation of collagen-1 and collagen-3 more than direct GLP-1 receptor activation. This effect depends on p38 activation with downstream upregulation of miR-146b levels that suppresses TLR4 expression.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Inflammasomes; Linagliptin; Mice; Mice, Inbred C57BL; Myocardial Infarction; NLR Family, Pyrin Domain-Containing 3 Protein; Signal Transduction

Bullous pemphigoid (BP) is an autoimmune blistering skin disorder. Recently, BP induced by dipeptidyl peptidase-4 (DPP-4) inhibitors has been a concern. Although DPP-4 inhibitors are commonly used in the Asian population because of their safety and efficacy, BP associated with DPP-4 inhibitors is sometimes seen in clinical settings. Here, we report five Japanese cases of BP associated with the agents. In the present cases, BP occurred in older adults using four different DPP-4 inhibitors, which showed various clinical manifestations in terms of latency period for BP, sex, glycemic control and diabetes duration. Withdrawal of DPP-4 inhibitors was effective in improving BP, and achieved remission even in cases requiring oral steroid administration and intravenous immunoglobulin therapy. Clinicians should note the importance of early diagnosis of this clinical condition and initiate prompt withdrawal of DPP-4 inhibitors.

Topics: Aged, 80 and over; Asian People; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Hypoglycemic Agents; Japan; Linagliptin; Male; Pemphigoid, Bullous; Pyrimidines; Sitagliptin Phosphate

To evaluate the extent to which balance in unmeasured characteristics of patients with type 2 diabetes (T2DM) was achieved in claims data, by comparing against more detailed information from linked electronic health records (EHR) data.. Within a large US commercial insurance database and using a cohort design, we identified patients with T2DM initiating linagliptin or a comparator agent within class (ie, another dipeptidyl peptidase-4 inhibitor) or outside class (ie, pioglitazone or a sulphonylurea) between May 2011 and December 2012. We focused on comparators used at a similar stage of diabetes to linagliptin. For each comparison, 1:1 propensity score (PS) matching was used to balance >100 baseline claims-based characteristics, including proxies of diabetes severity and duration. Additional clinical data from EHR were available for a subset of patients. We assessed representativeness of the claims-EHR-linked subset, evaluated the balance of claims- and EHR-based covariates before and after PS-matching via standardized differences (SDs), and quantified the potential bias associated with observed imbalances.. From a claims-based study population of 166 613 patients with T2DM, 7219 (4.3%) patients were linked to their EHR data. Claims-based characteristics in the EHR-linked and EHR-unlinked patients were similar (SD < 0.1), confirming the representativeness of the EHR-linked subset. The balance of claims-based and EHR-based patient characteristics appeared to be reasonable before PS-matching and generally improved in the PS-matched population, to be SD < 0.1 for most patient characteristics and SD < 0.2 for select laboratory results and body mass index categories, which was not large enough to cause meaningful confounding.. In the context of pharmacoepidemiological research on diabetes therapy, choosing appropriate comparison groups paired with a new-user design and 1:1 PS matching on many proxies of diabetes severity and duration improves balance in covariates typically unmeasured in administrative claims datasets, to the extent that residual confounding is unlikely.

Topics: Administration, Oral; Administrative Claims, Healthcare; Adult; Aged; Blood Glucose; Clinical Trials as Topic; Cohort Studies; Databases, Factual; Diabetes Mellitus, Type 2; Electronic Health Records; Female; Humans; Hypoglycemic Agents; Linagliptin; Male; Middle Aged; United States

To estimate the proportion of patients with moderate to severe chronic kidney disease (CKD) whose initial dipeptidyl-peptidase-4 inhibitor (DPP4-i) dosage was concordant with prescribing information (label) recommendations in the United States.. Adult patients with type 2 diabetes mellitus (T2DM) who initiated a DPP4-i (linagliptin, sitagliptin, saxagliptin) between 1 January 2011 and 30 June 2014 were identified using electronic medical records and administrative claims, with index date being the date of first observed DPP4-i treatment. Patients were required to have chronic kidney disease (CKD) stage 3b, 4 or 5 (estimated Glomerular Filtration Rate [eGFR] value <45 ml/min/1.73 m. Of the 492 patients (323 sitagliptin, 57 saxagliptin, 112 linagliptin), 36.2% were prescribed doses that were not concordant with label recommendations (44.9% for sitagliptin, 57.9% for saxagliptin and 0% for linagliptin [which does not require dosage adjustment]). Concordant patients were slightly older (mean age 71 years vs. 68, p = .01) but had similar gender distribution (55% vs. 60% female, p = .31) compared to those who were not concordant. They had lower general health status (Charlson Comorbidity Score 2.6 vs. 2.2, p = .03), and had similar pre-index all-cause total costs ($25,245 vs. $21,972, p = .68) and lower pre-index T2DM-related costs ($1618 vs. $1922, p = .05).. More than a third of DPP4-i patients with CKD stage 3b or higher were prescribed doses not concordant with DPP4-i label dosage recommendations.

Topics: Adamantane; Aged; Aged, 80 and over; Cohort Studies; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Hypoglycemic Agents; Linagliptin; Male; Middle Aged; Renal Insufficiency, Chronic; Retrospective Studies; Sitagliptin Phosphate

The cardiovascular safety and efficacy of linagliptin, a dipeptidyl peptidase-4 inhibitor, in patients with type 2 diabetes mellitus (T2DM) after acute coronary syndrome (ACS) or acute ischemic stroke (AIS) are unclear. The aim of our real-world cohort study was to evaluate the cardiovascular outcomes of linagliptin in patients with T2DM after ACS or AIS.. An open observational noncrossover retrospective cohort study was conducted between June 1, 2012 and December 31, 2013 utilizing Taiwan National Health Insurance Research Database. A total of 1203 patients with T2DM after ACS or AIS were selected as the study cohort. Cardiovascular safety and efficacy of linagliptin were evaluated by comparing outcomes of 401 subjects receiving linagliptin after ACS or AIS to 802 matched control subjects not receiving any incretin-based therapy after ACS or AIS. The primary composite outcome included cardiovascular death, non-fatal myocardial infarction and non-fatal ischemic stroke.. The primary composite outcome after 15-month follow-up was 7% (28 patients) in the linagliptin group compared with 6.1% (49 patients) in the control group [hazard ratio (HR) 1.06; 95% confidence interval (CI) .66-1.68]. The linagliptin group also had similar risks of all-cause mortality, hospitalization for heart failure, percutaneous coronary intervention and coronary artery bypass grafting compared to the control group in terms of the secondary outcomes.. In T2DM patients after ACS or AIS, treatment with linagliptin was not associated with increased risks of cardiovascular death, non-fatal myocardial infarction, or non-fatal ischemic stroke.

Topics: Acute Coronary Syndrome; Aged; Aged, 80 and over; Brain Ischemia; Comorbidity; Databases, Factual; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Linagliptin; Male; Middle Aged; Retrospective Studies; Risk Factors; Stroke; Taiwan; Time Factors; Treatment Outcome

Endothelial dysfunction contributes to poor cardiovascular prognosis in patients with type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD). The effect of dipeptidyl peptidase-4 inhibitors on endothelial function remains controversial. We sought to compare the effects of linagliptin and voglibose on endothelial function, as assessed by reactive hyperemia-peripheral arterial tonometry (RH-PAT). Sixteen patients with newly diagnosed T2DM and CAD were randomized 1:1 to linagliptin (5 mg, once-daily) or voglibose (0.9 mg, thrice-daily). The RH-PAT and laboratory parameters, including 75 g oral glucose tolerance test, were measured at baseline and 3 months. Linagliptin increased serum levels of active glucagon-like peptide-1 and high-molecular-weight adiponectin. Age-, sex-, and baseline-adjusted changes in logarithmic RH-PAT index (LnRHI) after 3 months were significant between groups (linagliptin, 0.135 ± 0.097; voglibose, - 0.124 ± 0.091; P = 0.047). In the linagliptin group, change in LnRHI was positively correlated with change in high-density lipoprotein cholesterol and negatively correlated with changes in both urine albumin-to-creatinine ratio and high-sensitivity C-reactive protein. Furthermore, linagliptin treatment for 3 months reduced serum levels of both glucose and insulin at 2 h, relative to voglibose, in the age-, sex-, and baseline-adjusted model. Linagliptin improved endothelial function relative to voglibose, accompanied by amelioration of glycemic, renal, and cardiometabolic parameters, in patients with newly diagnosed T2DM and CAD.Trial registration Unique Trial Number, UMIN 000029169 ( https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000012442 ).

Topics: Aged; Coronary Artery Disease; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Endothelium, Vascular; Female; Humans; Hypoglycemic Agents; Inositol; Linagliptin; Male; Middle Aged; Pilot Projects; Prognosis; Prospective Studies; Vasodilation

Recent data suggest that olfactory deficits could represent an early marker and a pathogenic mechanism at the basis of cognitive decline in type 2 diabetes (T2D). However, research is needed to further characterize olfactory deficits in diabetes, their relation to cognitive decline and underlying mechanisms.The aim of this study was to determine whether T2D impairs odour detection, olfactory memory as well as neuroplasticity in two major brain areas responsible for olfaction and odour coding: the main olfactory bulb (MOB) and the piriform cortex (PC), respectively. Dipeptidyl peptidase-4 inhibitors (DPP-4i) are clinically used T2D drugs exerting also beneficial effects in the brain. Therefore, we aimed to determine whether DPP-4i could reverse the potentially detrimental effects of T2D on the olfactory system.Non-diabetic Wistar and T2D Goto-Kakizaki rats, untreated or treated for 16 weeks with the DPP-4i linagliptin, were employed. Odour detection and olfactory memory were assessed by using the block, the habituation-dishabituation and the buried pellet tests. We assessed neuroplasticity in the MOB by quantifying adult neurogenesis and GABAergic inhibitory interneurons positive for calbindin, parvalbumin and carletinin. In the PC, neuroplasticity was assessed by quantifying the same populations of interneurons and a newly identified form of olfactory neuroplasticity mediated by post-mitotic doublecortin (DCX) + immature neurons.We show that T2D dramatically reduced odour detection and olfactory memory. Moreover, T2D decreased neurogenesis in the MOB, impaired the differentiation of DCX+ immature neurons in the PC and altered GABAergic interneurons protein expression in both olfactory areas. DPP-4i did not improve odour detection and olfactory memory. However, it normalized T2D-induced effects on neuroplasticity.The results provide new knowledge on the detrimental effects of T2D on the olfactory system. This knowledge could constitute essentials for understanding the interplay between T2D and cognitive decline and for designing effective preventive therapies.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Doublecortin Protein; GABAergic Neurons; Interneurons; Linagliptin; Male; Memory Disorders; Neurogenesis; Neuronal Plasticity; Nootropic Agents; Olfactory Bulb; Olfactory Perception; Piriform Cortex; Rats, Wistar

In 2008, the US Food and Drug Administration (FDA) issued Draft Guidance on investigating cardiovascular risk with oral diabetic drugs, including dipeptidyl peptidase-4 inhibitors (DPP-4i). In 2014, underpowered, post hoc analyses of clinical trials suggested an increased risk of heart failure with the use of these products. As such, we assessed disproportionate reporting of major adverse cardiac events (MACE) among reports for DPP-4i submitted to the FDA Adverse Event Reporting System (FAERS) from 2006 to 2015.. We assessed the empirical Bayes geometric mean (EBGM) and its lower bound (EB05) of the relative reporting ratio for MACE among DPP-4i reports in the full FAERS database and in a subset of reports limited to cardiovascular and diabetic drugs. We then compared the EB05 in these 2 analyses and calculated the percent positive agreement for signals of disproportional reporting (SDRs) involving MACE.. Of 180.3 million adverse event reports, 13.4 million were for diabetic and cardiovascular drugs. In the cardiovascular subset, there was an SDR for heart failure with linagliptin (EB05 = 2782.47) and saxagliptin (EB05 = 2.40), myocardial infarction with alogliptin (EB05 = 290.11), and cerebral infarction with sitagliptin (EB05 = 2.80). Of the 14 MACE, 8 had a percent positive agreement ≥50% for an SDR in both analyses. Overall, the cardiovascular subset elicited 11 more SDRs for DPP-4i than the full dataset.. Postmarketing surveillance of DPP-4i through FAERS suggest increased reporting of MACE, supporting the current FDA warning of heart failure risk. This suggests the need for additional longitudinal, observational research into the association of DPP-4i and other MACE.

Topics: Adamantane; Administration, Oral; Adverse Drug Reaction Reporting Systems; Aged; Bayes Theorem; Databases, Factual; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Female; Heart Failure; Humans; Linagliptin; Male; Middle Aged; Piperidines; Practice Guidelines as Topic; Sitagliptin Phosphate; United States; United States Food and Drug Administration; Uracil

The association of bullous pemphigoid (BP) with the use of dipeptidyl-peptidase 4 (DPP-4) inhibitors among patients with diabetes has recently emerged. The risk of developing BP during treatment with new DPP-4 inhibitor agents like linagliptin is yet to be established. The clinical features and the prognostic outcomes of patients with DPP-4 inhibitor-associated BP are yet to be established.. Primarily to estimate the association between DPP-4 inhibitor exposure and the development of BP, and secondarily to characterize the clinical features and history of patients with DPP-4 inhibitor-associated BP.. A retrospective case-control study of the intake of different DPP-4 inhibitor agents and metformin and occurrence of BP among patients with diabetes in a tertiary care referral center for autoimmune bullous diseases in northern Israel. Included were 82 consecutive patients with diabetes and immunopathologically validated BP diagnosed between January 1, 2011, and December 31, 2017, and 328 age-, sex-, and ethnicity-matched control participants with diabetes but without BP.. Patients with diabetes and BP and exposure to DPP-4 inhibitors were followed up for a median of 2.0 years and compared with other patients with diabetes and BP who were not exposed to DPP-4 inhibitors regarding clinical and immunological features, laboratory analyses, treatments, and clinical outcomes.. Eighty-two patients with BP and 328 age- and sex-matched control participants were enrolled; mean (SD) age, 79.1 (9.1) years; and 44 patients were female (53.7%). Overall, DPP-4 inhibitor intake was associated with a 3-fold increased risk for BP (adjusted odds ratio [OR], 3.2; 95% CI, 1.9-5.4). The adjusted ORs for vildagliptin and linagliptin were 10.7 (95% CI, 5.1-22.4) and 6.7 (95% CI, 2.2-19.7), respectively. The association of DPP-4 inhibitor use with BP was independent of the use of metformin and was stronger among male (OR, 4.46; 95% CI, 2.11-9.40) than female (OR, 1.88; 95%, CI 0.92-3.86) patients and strongest in patients younger than 70 years (OR, 5.59; 95% CI, 1.73-18.01). Patients with DPP-4 inhibitor-associated BP presented with higher mucosal involvement (22.2% vs 6.5%; P = .04) and lower mean (SD) peripheral eosinophil counts (399.8 [508.0] vs 1117.6 [1847.6] cells/μL; P = .01) than those with BP who had not been exposed to DPP-4 inhibitor. Discontinuation of DPP-4 inhibitor treatment was followed by improved clinical outcomes.. Vildagliptin and, to a lesser extent, linagliptin are associated with an increased risk of BP. This may partly explain the increasing incidence of BP in Israel. Discontinuation of DPP-4 inhibitor treatment in patients with diabetes should be considered when BP is diagnosed.

Topics: Age Factors; Aged; Aged, 80 and over; Case-Control Studies; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Eruptions; Eosinophils; Female; Humans; Hypoglycemic Agents; Israel; Leukocyte Count; Linagliptin; Male; Metformin; Mucous Membrane; Pemphigoid, Bullous; Retrospective Studies; Risk Assessment; Sex Factors; Vildagliptin

Dipeptidyl peptidase-4 inhibitors are commonly used drugs for the treatment of type 2 diabetes mellitus. While acute pancreatitis cases induced by saxagliptin, sitagliptin, and vildagliptin (all of which are members of the dipeptidyl peptidase-4 group) have been reported, there is no clear evidence suggesting that linagliptin may cause pancreatitis, and information in this regard is limited to a few studies. Moreover, no pancreatitis cases have been reported that were directly associated with linagliptin.. We present a case of linagliptin-related pancreatitis in a 79-year-old male diabetic patient with biliary calculi. The patient, who was diagnosed with acute pancreatitis 4 months after initiating linagliptin 5 mg/d treatment, was admitted to our hospital.. The patient's pancreatic enzymes were high. Ultrasonography showed multiple biliary calculi, and abdominal computed tomography showed edematous pancreatitis.. Linagliptin was discontinued and clinical improvement was achieved with standard acute pancreatitis treatment.. This is the 1st case report suggesting that linagliptin might be associated with the risk of pancreatitis and could be an etiologic cause of pancreatitis, similar to the other members of its group.. While the results of previous studies stated that there was no data to prove a causal relationship between dipeptidyl peptidase-4 inhibitors and pancreatitis, concerns regarding this subject have continued to arise. Therefore, new and comprehensive studies are needed to determine the long-term effects of dipeptidyl peptidase-4 inhibitors on type 2 diabetes mellitus patients and to shed light on the side effects of these medications.

Topics: Aged; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug-Related Side Effects and Adverse Reactions; Humans; Linagliptin; Male; Pancreatitis; Tomography, X-Ray Computed; Ultrasonography

The mortality rate of patients who develop sepsis-related cardiac dysfunction is high. Many disease conditions (e.g., diabetes) increase the susceptibility to infections and subsequently sepsis. Activation of the NF-κB pathway plays a crucial role in the pathophysiology of sepsis-associated cardiac dysfunction and diabetic cardiomyopathy. The effect of diabetes on outcomes in patients with sepsis is still highly controversial. We here hypothesized that type 2 diabetes (T2DM) augments the cardiac (organ) dysfunction associated with sepsis, and that inhibition of the NF-κB pathway with linagliptin attenuates the cardiac (organ) dysfunction in mice with T2DM/sepsis. To investigate this, 10-week old male C57BL/6 mice were randomized to receive normal chow or high fat diet (HFD), 60% of calories derived from fat). After 12 weeks, mice were subjected to sham surgery or cecal ligation and puncture (CLP) for 24 h. At 1 hour after surgery, mice were treated with linagliptin (10 mg/kg, i.v.), IKK-16 (1 mg/kg, i.v.), or vehicle (2% DMSO, 3 ml/kg, i.v.). Mice also received analgesia, fluids and antibiotics at 6 and 18 h after surgery. Mice that received HFD showed a significant increase in body weight, impairment in glucose tolerance, reduction in ejection fraction (%EF), and increase in alanine aminotransferase (ALT). Mice on HFD subjected to CLP showed further reduction in %EF, increase in ALT, developed acute kidney dysfunction and lung injury. They also showed significant increase in NF-κB pathway, iNOS expression, and serum inflammatory cytokines compared to sham surgery group. Treatment of HFD-CLP mice with linagliptin or IKK-16 resulted in significant reductions in (i) cardiac, liver, kidney, and lung injury associated with CLP-sepsis, (ii) NF-κB activation and iNOS expression in the heart, and (iii) serum inflammatory cytokine levels compared to HFD-CLP mice treated with vehicle. Our data show that pre-existing type 2 diabetes phenotype worsens the organ dysfunction/injury associated with CLP-sepsis in mice. Most notably, inhibition of NF-κB reduces the organ dysfunction/injury associated with sepsis in mice with pre-existing T2DM.

Topics: Animals; Cecum; Diabetes Mellitus, Type 2; Diet, High-Fat; Disease Models, Animal; Heart Diseases; Humans; Linagliptin; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Piperidines; Pyrrolidines; Sepsis; Signal Transduction

Type 2 diabetes mellitus (T2DM) is typically progressive, with sequential addition of therapies often needed to address increasing hyperglycemia over the disease course. Using treatments in combination may be preferred to sequential addition, as a means of providing a more rapid clinical response and potentially avoiding clinical inertia. In such cases, a single-pill combination can help to reduce pill burden. Although various single-pill combinations of oral glucose-lowering agents are available, empagliflozin/linagliptin was the first approved combination of a sodium glucose co-transporter 2 (SGLT2) inhibitor with a dipeptidyl peptidase 4 (DPP-4) inhibitor in the United States. Areas covered: Two publications of the clinical trial investigating the efficacy and safety of single-pill combinations of empagliflozin/linagliptin in treatment-naive or metformin-treated patients with T2DM (NCT01422876) are reviewed, and their potential impact on clinical practice is discussed. Expert opinion: The study discussed provides evidence for the efficacy and safety of empagliflozin/linagliptin single pills. Addition of an empagliflozin/linagliptin single pill may be considered in patients with inadequate glycemic control on metformin, or as an alternative to first-line treatment with empagliflozin or linagliptin when metformin is not suitable, particularly in patients with very poor glycemic control, or those who need to achieve target more quickly.

Topics: Adult; Benzhydryl Compounds; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Combinations; Glucosides; Humans; Hyperglycemia; Hypoglycemic Agents; Linagliptin; Metformin; Randomized Controlled Trials as Topic; Sodium-Glucose Transporter 2 Inhibitors

Previous studies suggest that dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium glucose cotransporter 2 (SGLT2) inhibitors have different effects on the lipid profile in patients with type 2 diabetes. We investigated the effects of DPP-4 inhibitors and SGLT2 inhibitors on the lipid profile in patients with type 2 diabetes.. From January 2013 to December 2015, a total of 228 patients with type 2 diabetes who were receiving a DPP-4 inhibitor or SGLT2 inhibitor as add-on therapy to metformin and/or a sulfonylurea were consecutively enrolled. We compared the effects of DPP-4 inhibitors and SGLT2 inhibitors on the lipid profile at baseline and after 24 weeks of treatment. To compare lipid parameters between the two groups, we used the analysis of covariance (ANCOVA).. A total of 184 patients completed follow-up (mean age: 53.1 ± 6.9 years, mean duration of diabetes: 7.1 ± 5.7 years). From baseline to 24 weeks, HDL-cholesterol (HDL-C) levels were increased by 0.5 (95% CI, -0.9 to 2.0) mg/dl with a DPP-4 inhibitor and by 5.1 (95% CI, 3.0 to 7.1) mg/dl with an SGLT2 inhibitor (p = 0.001). LDL-cholesterol (LDL-C) levels were reduced by 8.4 (95% CI, -14.0 to -2.8) mg/dl with a DPP-4 inhibitor, but increased by 1.3 (95% CI, -5.1 to 7.6) mg/dl with an SGLT2 inhibitor (p = 0.046). There was no significant difference in the mean hemoglobin A1c (8.3 ± 1.1 vs. 8.0 ± 0.9%, p = 0.110) and in the change of total cholesterol (TC) (p = 0.836), triglyceride (TG) (p = 0.867), apolipoprotein A (p = 0.726), apolipoprotein B (p = 0.660), and lipoprotein (a) (p = 0.991) between the DPP-4 inhibitor and the SGLT2 inhibitor.. The SGLT2 inhibitor was associated with a significant increase in HDL-C and LDL-C after 24 weeks of SGLT2 inhibitor treatment in patients with type 2 diabetes compared with those with DPP-4 inhibitor treatment in this study.. This study was conducted by retrospective medical record review.

Topics: Benzhydryl Compounds; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Cardiomyopathies; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Female; Follow-Up Studies; Glucosides; Glycated Hemoglobin; Humans; Hyperglycemia; Hyperlipidemias; Linagliptin; Male; Membrane Transport Modulators; Middle Aged; Piperidones; Pyrimidines; Republic of Korea; Retrospective Studies; Risk Factors; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors

We present the case of 60-year-old man with type 2 diabetes who developed blistering after two sequential exposures to linagliptin. Linagliptin is one of the dipeptidyl peptidase 4 (DPP-4) inhibitors, a group of oral hypoglycaemic agents used commonly for the treatment of type 2 diabetes. On the first exposure to linagliptin, he developed blisters on the hands which resolved after stopping the drug. After repeat exposure, he developed two large blisters on the left foot, which burst giving rise to secondary infection, requiring hospital admission for treatment. We discuss the latest research linking DPP-4 inhibitors with adverse skin reactions and the effect of ulcers on the morbidity and mortality of patients with diabetes. This case report highlights skin reactions as an important, rare and lesser known side effect of DPP-4 inhibitors.

Topics: Administration, Oral; Blister; Diabetes Mellitus, Type 2; Diagnosis, Differential; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Linagliptin; Male; Middle Aged; Skin Diseases, Vesiculobullous

To compare healthcare costs of adults with type 2 diabetes (T2D) after initiation of saxagliptin or linagliptin, two antidiabetic medications in the dipeptidyl peptidase-4 inhibitor medication class.. Patients with T2D who were at least 18 years old and initiated saxagliptin or linagliptin (index date) between 1 June 2011 and 30 June 2014 were identified in the MarketScan Commercial and Medicare Supplemental Databases. All-cause healthcare costs and diabetes-related costs (T2D diagnosis on a medical claim and/or an antidiabetic medication claim) were measured in the 1 year follow-up period. Saxagliptin and linagliptin initiators were matched using propensity score methods. Cost ratios (CRs) and predicted costs were estimated from generalized linear models and recycled predictions.. There were 34,560 saxagliptin initiators and 18,175 linagliptin initiators identified (mean ages 57 and 59; 55% and 56% male, respectively). Before matching, saxagliptin initiators had significantly lower all-cause total healthcare costs than linagliptin initiators (mean = $15,335 [SD $28,923] vs. mean = $20,069 [SD $48,541], p < .001) and significantly lower diabetes-related total healthcare costs (mean = $6109 [SD $13,851] vs. mean = $7393 [SD $26,041], p < .001). In matched analyses (n = 16,069 per cohort), saxagliptin initiators had lower all-cause follow-up costs than linagliptin initiators (CR = 0.953, 95% CI = 0.932-0.974, p < .001; predicted costs = $17,211 vs. $18,068). There was no significant difference in diabetes-related total costs after matching; however, diabetes-related medical costs were significantly lower for saxagliptin initiators (CR = 0.959, 95% CI = 0.927-0.993, p = 0.017; predicted costs = $3989 vs. $4159).. Adult patients with T2D initiating treatment with saxagliptin had lower total all-cause healthcare costs and diabetes-related medical costs over 1 year compared with patients initiating treatment with linagliptin.

Topics: Adamantane; Adult; Diabetes Mellitus, Type 2; Dipeptides; Female; Health Care Costs; Humans; Hypoglycemic Agents; Insurance Claim Review; Linagliptin; Male; Middle Aged; Retrospective Studies; United States

Topics: Aged; Chemical and Drug Induced Liver Injury; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Linagliptin; Liver Function Tests; Male

Linagliptin is a dipeptidyl Peptidase-4 (DPP-4) inhibitor that inhibits the degradation of glucagon-like peptide 1 (GLP-1), and has been approved for the treatment of type 2 diabetes (T2D) in clinic. Previous studies have shown linagliptin improves β cell function using animal models and isolated islets from normal subjects. Since β cell dysfunction occurs during diabetes development, it was not clear how human islets of T2D patients would respond to linagliptin treatment. Therefore, in this study we employed human islets isolated from donors with and without T2D and evaluated how they responded to linagliptin treatment. Our data showed that linagliptin significantly improved glucose-stimulated insulin secretion for both non-diabetic and diabetic human islets, but its effectiveness on T2D islets was lower than on normal islets. The differential effects were attributed to reduced GLP-1 receptor expression in diabetic islets. In addition, linagliptin treatment increased the relative GLP-1 vs glucagon production in both non-diabetic and diabetic islets, suggesting a positive role of linagliptin in modulating α cell function to restore normoglycemia. Our study indicated that, from the standpoint of islet cell function, linagliptin would be more effective in treating early-stage diabetic patients before they develop severe β cell dysfunction.

Topics: Cells, Cultured; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Glucagon-Secreting Cells; Humans; Hypoglycemic Agents; Insulin Secretion; Insulin-Secreting Cells; Linagliptin

Diabetic patients suffer an increased risk of restenosis and late stent thrombosis after angioplasty, complications which are related to a defective reendothelialization. Dipeptidyl peptidase-4 inhibitors have been suggested to exert a direct effect on endothelial and smooth muscle cells (SMCs). Therefore, the objective was to study if the dipeptidyl peptidase-4 inhibitor linagliptin could influence vascular repair and accelerate reendothelialization after arterial injury in healthy and diabetic animals. Diabetic Goto-Kakizaki and healthy Wistar rats were subjected to arterial injury and treated with linagliptin or vehicle. Vessel wall healing was monitored noninvasively using ultrasound, and on sacrifice, with Evans blue staining and immunohistochemistry. The effect of linagliptin on SMCs was also studied in vitro. We found that linagliptin reduced the proliferation and dedifferentiation of SMCs in vitro, and modulated the inflammatory response in the SMCs after arterial injury in vivo. However, these effects of linagliptin did not affect the neointima formation or the reendothelialization under normal and diabetic conditions. Although linagliptin did not influence vessel wall healing, it seems to possess a desirable antiproliferative influence on SMCs in vitro and an antiinflammatory effect in vivo. These pharmacological properties might carry a potential significance for favorable outcome after vascular interventions in diabetic patients.

Topics: Animals; Blood Glucose; Carotid Artery Injuries; Carotid Artery, External; Cell Proliferation; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Hypoglycemic Agents; Linagliptin; Male; Random Allocation; Rats; Rats, Wistar; Treatment Outcome; Wound Healing

A high hemoglobin glycation index (HGI) and glycated hemoglobin (HbA1c) level are associated with greater inflammatory status, and dipeptidyl peptidase-4 (DPP-4) inhibitors can suppress inflammation. We aimed to evaluate the relationship between HGI and the therapeutic effect of DPP-4 inhibitors.. This retrospective cohort study followed 468 patients with type 2 diabetes receiving DPP-4 inhibitor treatment for 1 year. Estimated HbA1c was calculated using a linear regression equation derived from another 2969 randomly extracted patients with type 2 diabetes based on fasting plasma glucose (FPG) level. The subjects were divided into two groups based on HGI (HGI = observed HbA1c - estimated HbA1c). Mixed model repeated measures were used to compare the treatment efficacy after 1 year in patients with a low (HGI<0, n = 199) and high HGI (HGI≧0, n = 269).. There were no significant group differences in mean changes of FPG after 1 year (-12.8 and -13.4 mg/dL in the low and high HGI groups, respectively). However, the patients with a high HGI had a significantly greater reduction in HbA1c from baseline compared to those with a low HGI (-1.9 versus -0.3% [-20.8 versus -3.3 mmol/mol]). Improvements in glycemic control were statistically significantly associated with the tested DPP-4 inhibitors in the high HGI group (-2.4, -1.4, -1.2 and -2.2% [-26.2, -15.3, -13.1 and -24.0 mmol/mol] for vildagliptin, linagliptin, saxagliptin and sitagliptin, respectively) but not in the low HGI group.. The HGI index derived from FPG and HbA1c may be able to identify who will have a better response to DPP-4 inhibitors.

Topics: Adamantane; Adult; Aged; Biomarkers, Pharmacological; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Female; Glycated Hemoglobin; Health Status Indicators; Humans; Linagliptin; Male; Middle Aged; Nitriles; Predictive Value of Tests; Prognosis; Pyrrolidines; Retrospective Studies; Sitagliptin Phosphate; Treatment Outcome; Vildagliptin

Topics: Administration, Oral; Aged; Arteries; Atherosclerosis; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Fluorodeoxyglucose F18; Humans; Linagliptin; Middle Aged; Positron-Emission Tomography; Radiopharmaceuticals; Randomized Controlled Trials as Topic; Vascular Stiffness

Topics: Aged; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Linagliptin; Male; Middle Aged; Pemphigoid, Bullous

The present study aimed to investigate the synergistic action of telmisartan and linagliptin in ameliorating pancreatic islet functions and morphology in type 2 diabetes mellitus and to delineate the molecular signaling pathway involved.. db/db mice were given telmisartan (3 mg/kg) or linagliptin (3 mg/kg) alone or in combination, daily for 8 weeks, and were studied in vivo by fasting and random blood glucose tests, oral glucose tolerance tests, and intraperitoneal insulin tolerance tests, as well as ex vivo by glucose-stimulated insulin secretion and morphology of pancreatic islets. The underlying signaling pathways were examined by Western blot, real-time quantitative polymerase chain reaction, and dihydroethidium staining analyses using mouse pancreatic islets and rat β-insulinoma cells.. Telmisartan/linagliptin combination induced significantly better glucose homeostasis than the monotherapies. Posttreatment reactive oxygen species level was suppressed most significantly after the telmisartan/linagliptin combined therapy, whereas no significant change in peroxisome proliferator-activated receptor γ expressions was observed after treatments.. The telmisartan/linagliptin combination preserved pancreatic islet cell functions and morphology via reduction of oxidative stress but independent of the peroxisome proliferator-activated receptor γ pathway. Our data shed light on the therapeutic potential of using the telmisartan/linagliptin combination in the treatment of human type 2 diabetes mellitus and its related complications.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Benzimidazoles; Benzoates; Blotting, Western; Cell Line, Tumor; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Drug Therapy, Combination; Female; Glucose Tolerance Test; Humans; Immunohistochemistry; Islets of Langerhans; Linagliptin; Mice; Mice, Inbred C57BL; Oxidative Stress; Pancreas; PPAR gamma; Reactive Oxygen Species; Telmisartan

Diabetic nephropathy has a significant socioeconomic impact, but its mechanism is unclear and needs to be examined. Hibiscus sabdariffa polyphenols (HPE) inhibited high glucose-induced angiotensin II receptor-1 (AT-1), thus attenuating renal epithelial mesenchymal transition (EMT). Recently, we reported HPE inhibited dipeptidyl-peptidase-4 (DPP-4, the enzyme degrades type 1 glucagon-like peptide (GLP-1)), which mediated insulin resistance signals leading to EMT. Since free fatty acids can realistically bring about insulin resistance, using the palmitate-stimulated cell model in contrast with type 2 diabetic rats, in this study we examined if insulin resistance causes renal EMT, and the preventive effect of HPE. Our findings reveal that palmitate hindered 30% of glucose uptake. Treatment with 1 mg mL(-1) of HPE and the DPP-4 inhibitor linagliptin completely recovered insulin sensitivity and palmitate-induced signal cascades. HPE inhibited DPP-4 activity without altering the levels of DPP-4 and the GLP-1 receptor (GLP-1R). HPE decreased palmitate-induced phosphorylation of Ser307 of insulin receptor substrate-1 (pIRS-1 (S307)), AT-1 and vimentin, while increasing phosphorylation of phosphatidylinositol 3-kinase (pPI3K). IRS-1 knockdown revealed its essential role in mediating downstream AT-1 and EMT. In type 2 diabetic rats, it suggests that HPE concomitantly decreased the protein levels of DPP-4, AT-1, vimentin, and fibronectin, but reversed the in vivo compensation of GLP-1R. In conclusion, HPE improves insulin sensitivity by attenuating DPP-4 and the downstream signals, thus decreasing AT-1-mediated tubular-interstitial EMT. HPE could be an adjuvant to prevent diabetic nephropathy.

Topics: Animals; Cell Differentiation; Cell Line; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Epithelial Cells; Gene Expression Regulation; Glucagon-Like Peptide-1 Receptor; Hibiscus; Humans; Insulin Receptor Substrate Proteins; Insulin Resistance; Kidney; Linagliptin; Mesenchymal Stem Cells; Palmitates; Polyphenols; Rats; Vimentin

To evaluate the efficacy and safety of linagliptin in people with Type 2 diabetes inadequately controlled on basal insulin and metformin.. This was a post hoc subanalysis of participants who received basal insulin and metformin in a global phase III study that randomized participants (1:1) to receive linagliptin 5 mg once daily or placebo for ≥52 weeks as add-on therapy to basal insulin alone or in combination with metformin and/or pioglitazone. During the first 24 weeks, the background dose of basal insulin remained stable; thereafter, adjustments based on glucose concentrations were recommended. The primary endpoint of the subanalysis was the change from baseline in HbA1c after 24 weeks. The safety analysis incorporated data up to a maximum of 110 weeks.. A total of 950 participants receiving background insulin and metformin were included in this subanalysis (linagliptin and placebo, both n = 475). At week 24, the placebo-corrected adjusted mean (±se) change from baseline in HbA1c with linagliptin was -7 (±1) mmol/mol [-0.7 (±0.1) %; 95% CI -0.8, -0.6; P < 0.0001]. The overall frequency of drug-related adverse events (linagliptin, 18.9%; placebo, 21.9%) and investigator-reported hypoglycaemia (linagliptin, 30.7%; placebo, 31.6%) were similar in both groups at the end of treatment. The frequency of severe hypoglycaemia was low (linagliptin, 1.7%; placebo, 0.8%). No meaningful changes in mean (±sd) body weight were noted in either group [week 52: linagliptin, -0.5 (±3.2) kg; placebo, 0.0 (±3.1) kg].. Linagliptin added to basal insulin and metformin improved glycaemic control, without increasing the risk of hypoglycaemia or body weight gain.

Topics: Aged; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Insulin; Linagliptin; Male; Metformin; Middle Aged; Treatment Outcome; Weight Gain; Weight Loss

Hypoglycemia poses a significant clinical and economic burden to patients with type 2 diabetes mellitus (T2DM). Minimizing the risk of hypoglycemia is an important component when managing patients with T2DM. Understanding hypoglycemia rates and the associated economic consequences can help to inform health care decision makers.. To assess hypoglycemia incidence rates and associated costs in patients who initiated second-line treatment with the antidiabetic agents linagliptin or a sulfonylurea (SU) after metformin.. A large U.S. administrative claims database was used to identify patients with T2DM (during the identification period July 2011-October 2013) who initiated linagliptin or a SU after metformin use. The date of the first prescription for linagliptin or a SU during the identification period was designated as the index date. Linagliptin users were matched to SU users based on demographic and clinical characteristics identified within a 12-month period before the index date using propensity scores (1:3 ratio, caliper: ±0.001). Rates and costs (2013 U.S. dollars) of hypoglycemia resulting in any health care resource use were quantified during a variable follow-up period (i.e., end of the study, end of the 12-month follow-up, treatment regimen change, or disenrollment, whichever came first). Hypoglycemia rates per 100 person-years were compared using univariate Poisson regression, and hazard of hypoglycemia was obtained from multivariate Cox proportional hazards regression. Mean monthly hypoglycemia-related costs, all-cause costs, and T2DM-related costs were computed for patients with hypoglycemia and compared using t-tests.. Propensity-score matching resulted in a sample of 11,536 patients (linagliptin = 2,884; SU = 8,652) with a mean age of 56 years and 59% male. The rate of hypoglycemia (per 100 person-years) was lower in the linagliptin than the SU user groups (2.51 vs. 3.63; P= 0.049). Linagliptin users had a 33% lower risk of hypoglycemia compared with SU users (HR = 0.67; 95% CI = 0.47-0.97; P= 0.031). Among patients who had hypoglycemia, linagliptin users showed numerically lower mean monthly hypoglycemia-related costs compared with SU users ($300 vs. $890; P= 0.092), which was primarily driven by differences in hypoglycemia-related costs in the hospital setting. A similar theme was observed with monthly all-cause costs (linagliptin users, $1,971 vs. SU users, $3,758; P= 0.092).. Linagliptin use was associated with a lower incidence rate of hypoglycemia compared with SU use in patients initiating second-line therapy after metformin monotherapy. Among patients who experienced hypoglycemia, linagliptin users appeared to have lower monthly hypoglycemia-related and all-cause costs than SU users. Careful consideration of newer treatment alternatives may be prudent for optimal T2DM management, especially with regard to hypoglycemia.. Funding for the research study and resultant publication was provided by Boehringer Ingelheim. Shetty is an employee of Boehringer Ingelheim. Cai was an employee of Boehringer Ingelheim at the time of the study. Raju and D'Souza are employees of Xcenda, which received research funding from Boehringer Ingelheim for the conduct of this study and for the preparation of this manuscript. All authors contributed to concept and study design. Raju took the lead in data analysis, along with D'Souza, and all authors contributed equally to data interpretation. The manuscript was written by Raju, D'Souza, Cai, and Shetty and revised primarily by Raju, along with Shetty and D'Souza.

Topics: Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Health Care Costs; Humans; Hypoglycemia; Hypoglycemic Agents; Incidence; Linagliptin; Male; Metformin; Middle Aged; Propensity Score; Sulfonylurea Compounds

The efficacy and safety of drugs can vary between different races or ethnic populations because of differences in the relationship of dose to exposure, pharmacodynamic response or clinical efficacy and safety. In the present post-hoc analysis, we assessed the influence of race on the pharmacokinetics, pharmacodynamics, efficacy and safety of monotherapy with the dipeptidyl peptidase-4 inhibitor, linagliptin, in patients with type 2 diabetes enrolled in two comparable, previously reported randomized phase III trials.. Study 1 (with a 12-week placebo-controlled phase) recruited Japanese patients only (linagliptin, n = 159; placebo, n = 80); study 2 (24-week trial) enrolled Asian (non-Japanese; linagliptin, n = 156; placebo, n = 76) and white patients (linagliptin, n = 180; placebo, n = 90).. Linagliptin trough concentrations were equivalent across study and race groups, and were higher than half-maximal inhibitory concentration, resulting in dipeptidyl peptidase-4 inhibition >80% at trough. Linagliptin inhibited plasma dipeptidyl peptidase-4 activity to a similar degree in study 1 and study 2. Linagliptin reduced fasting plasma glucose concentrations by a similar magnitude across groups, leading to clinically relevant reductions in glycated hemoglobin in all groups. Glycated hemoglobin levels decreased to a slightly greater extent in study 1 (Japanese) and in Asian (non-Japanese) patients from study 2. Linagliptin had a favorable safety profile in each race group.. Trough exposure, pharmacodynamic response, and efficacy and safety of linagliptin monotherapy were comparable among Japanese, Asian (non-Japanese) and white patients, confirming that the recommended 5-mg once-daily dose of linagliptin is appropriate for use among different race groups.

Topics: Aged; Asian People; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Linagliptin; Male; Middle Aged; Randomized Controlled Trials as Topic; Treatment Outcome; White People

The antihyperglycemic agent linagliptin, a dipeptidyl peptidase-4 (DPP-IV) inhibitor, has been shown to reduce inflammation and improve endothelial cell function. In this study, we hypothesized that DPP-IV inhibition with linagliptin would improve impaired cerebral perfusion in diabetic rats, as well as improve insulin-induced cerebrovascular relaxation and reverse pathological cerebrovascular remodeling. We further postulated that these changes would lead to a subsequent improvement of cognitive function. Male Type-2 diabetic and nondiabetic Goto-Kakizaki rats were treated with linagliptin for 4 wk, and blood glucose and DPP-IV plasma levels were assessed. Cerebral perfusion was assessed after treatment using laser-Doppler imaging, and dose response to insulin (10(-13) M-10(-6) M) in middle cerebral arteries was tested on a pressurized arteriograph. The impact of DPP-IV inhibition on diabetic cerebrovascular remodeling was assessed over a physiologically relevant pressure range, and changes in short-term hippocampus-dependent learning were observed using a novel object recognition test. Linagliptin lowered DPP-IV activity but did not change blood glucose or insulin levels in diabetes. Insulin-mediated vascular relaxation and cerebral perfusion were improved in the diabetic rats with linagliptin treatment. Indices of diabetic vascular remodeling, such as increased cross-sectional area, media thickness, and wall-to-lumen ratio, were also ameliorated; however, improvements in short-term hippocampal-dependent learning were not observed. The present study provides evidence that linagliptin treatment improves cerebrovascular dysfunction and remodeling in a Type 2 model of diabetes independent of glycemic control. This has important implications in diabetic patients who are predisposed to the development of cerebrovascular complications, such as stroke and cognitive impairment.

Topics: Animals; Blood Flow Velocity; Cerebrovascular Circulation; Cerebrovascular Disorders; Cognition; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Hypoglycemic Agents; Linagliptin; Male; Rats; Treatment Outcome; Vascular Remodeling

We aimed to determine if patient baseline characteristics affect responses to linagliptin and identify relevant predictors of glycated hemoglobin (HbA1c) reduction in patients with type 2 diabetes mellitus (T2DM).. Data were pooled from three 24-week, placebo-controlled trials of similar design (linagliptin, n = 1651; placebo, n = 607). Patients were categorized according to baseline characteristics: age, T2DM duration, gender, body mass index (BMI), Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), and metabolic syndrome (MetS). Changes from baseline in HbA1c after 24 weeks were assessed with analysis of covariance (ANCOVA). The proportion of patients with baseline HbA1c >7% achieving HbA1c of ≤7% at week 24 were evaluated. Independent predictors of HbA1c response with linagliptin were analyzed in a multivariate analysis with ANCOVA. Linagliptin treatment led to significant mean (SE) placebo-corrected reductions from baseline in HbA1c across all subgroups (-0.42% [±0.11] to -0.79% [0.08]; all p < 0.001). Within subgroups, HbA1c reduction was more pronounced in patients without MetS (-0.74% [0.06]; treatment interaction p = 0.0489). The proportion of patients with baseline HbA1c >7% achieving a target HbA1c ≤7% was greater with linagliptin versus placebo (30.2% vs 11.5%; odds ratio 3.82; 95% CI 2.82 to 5.17; p < 0.001). Characteristics significantly predicting HbA1c reductions after 24 weeks were fasting plasma glucose and race (both p < 0.05).. This post-hoc analysis supports that linagliptin achieved clinically meaningful improvements in hyperglycemia in patients with diverse clinical characteristics. These improvements were more pronounced in patients without MetS.

Topics: Aged; Biomarkers; Blood Glucose; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Linagliptin; Logistic Models; Male; Middle Aged; Multivariate Analysis; Odds Ratio; Randomized Controlled Trials as Topic; Retrospective Studies; Time Factors; Treatment Outcome

The majority of people with type 2 diabetes mellitus (T2DM) will develop chronic kidney disease in their lifetime. Because most dipeptidyl peptidase (DPP)-4 inhibitors require dose adjustment in patients with T2DM and renal impairment, we aimed to understand how these treatments are prescribed in UK clinical practice, and to determine whether recommended dose adjustments are being made at initial prescription.. This retrospective, descriptive cohort study analyzed data from the Clinical Practice Research Datalink (CPRD). Patients of interest were those with T2DM and renal impairment initiated on a DPP-4 inhibitor between 2014 and 2015. Patients under 40 years of age and with type 1 diabetes were excluded. Descriptive statistics were calculated for baseline demographic and clinical characteristics, and the study protocol was approved by the Independent Scientific Advisory Committee for Medicines and Healthcare products Regulatory Agency database research.. A total of 3425 patients diagnosed with T2DM and renal impairment and initiated on a DPP-4 inhibitor were identified. The percentages of patients prescribed the high dose of saxagliptin, alogliptin,sitagliptin, and vildagliptin were 48%, 43%, 41%, and 27%, respectively, which is not recommended given their renal dysfunction. These are conservative estimates, as they do not include patients with severe renal impairment on sitagliptin and alogliptin, whose doses should be further reduced. No patients were prescribed an inappropriately high dose of linagliptin, as there is no requirement for dose adjustment in patients with renal impairment.. In this study, a considerable number of patients with T2DM and renal impairment were prescribed an inappropriately high dose of saxagliptin, alogliptin, sitagliptin, or vildagliptin for their level of renal impairment at treatment initiation. This prescribing could have been due to the complexity of different dosing requirements, or a lack of awareness of the need for dose adjustment of most DPP-4 inhibitors in patients with renal impairment. Linagliptin may be used in patients with moderate or severe renal impairment without dose adjustment.

Topics: Adamantane; Aged; Aged, 80 and over; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Female; General Practice; Humans; Hypoglycemic Agents; Linagliptin; Male; Middle Aged; Nitriles; Piperidines; Pyrrolidines; Retrospective Studies; Sitagliptin Phosphate; Uracil; Vildagliptin

Hyperglycemia is associated with increased mortality and morbidity in patients with type 2 diabetes mellitus (T2DM) who are undergoing dialysis. Although dipeptidyl peptidase-4 (DPP-4) inhibitors have been widely used in end-stage renal disease (ESRD) patients with T2DM, there are few studies on their efficacy in this population. We studied the effect of 3 different DPP-4 inhibitors on metabolic parameters in ESRD patients with T2DM.Two hundred ESRD patients with T2DM who were treated with DPP-4 inhibitors (sitagliptin, vildagliptin, or linagliptin) were enrolled and analyzed retrospectively. The changes in glycated hemoglobin (HbA1c), fasting plasma glucose, and lipid profiles were assessed before and after 3 months of treatment with DPP-4 inhibitors. Subgroup analysis was done for each hemodialysis (HD) and peritoneal dialysis (PD) group.There was no significant difference in the decrease in the HbA1c level among sitagliptin, vildagliptin, and linagliptin treatment groups (-0.74 ± 1.57, -0.39 ± 1.45, and -0.08 ± 1.40, respectively, P = 0.076). The changes in fasting blood glucose and lipid profiles were also not significantly different. In HD patients (n = 115), there was no difference in the HbA1c level among the 3 groups. In contrast, in PD patients (n = 85), HbA1c was reduced more after 3 months of treatment with sitagliptin compared with vildagliptin and linagliptin (-1.58 ± 0.95, -0.46 ± 0.98, -0.04 ± 1.22, respectively, P = 0.001).There was no significant difference in the glucose-lowering effect between the different DPP-4 inhibitors tested in ESRD patients. In PD patients, sitagliptin tends to lower the HbA1c level more than the other inhibitors. The glucose-lowering efficacy of the 3 DPP-4 inhibitors was comparable.

Topics: Adamantane; Blood Glucose; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Female; Glycated Hemoglobin; Humans; Kidney Failure, Chronic; Linagliptin; Lipids; Male; Middle Aged; Nitriles; Peritoneal Dialysis; Pyrrolidines; Renal Dialysis; Retrospective Studies; Sitagliptin Phosphate; Treatment Outcome; Vildagliptin

Linagliptin, a xanthine derivative, is a highly potent, selective, long-acting and orally bioavailable DPP-4 inhibitor for the treatment of type 2 diabetes. During the process development of linagliptin, five new process-related impurities were detected by high performance liquid chromatography (HPLC). All these impurities were identified, synthesized, and subsequently characterized by their respective spectral data (MS, HRMS, ¹H-NMR, (13)C-NMR and IR) as described in this article. The identification of these impurities should be useful for quality control and the validation of the analytical method in the manufacture of linagliptin.

Topics: Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Linagliptin

Our previous clinical indicated that urinary cyclophilin A was a good marker for diabetic nephropathy.. We used animal and cell models of diabetic nephropathy to examine the role of cyclophilin A in disease progression.. Significantly increased urinary cyclophilin A could be detected in db/db at the 8th week. Linagliptin (3mg/kg/day and 15mg/kg/day) could suppress urinary 8-hydroxy-2'-deoxyguanosine at the 8th and 16th week but only the high dose Linagliption could suppress cyclophilin A at the 8th week. Compared to 8-hydroxy-2'-deoxyguanosine, cyclophilin A was a stronger, earlier, and more sensitive marker. Immunohistochemical staining for cyclophilin A was also positive for db/db. In cell studies, oxidative stress and hyperglycemia could stimulate MES-13 and HK-2 cells to secrete cyclophilin A. Hyperglycemia stimulated HK-2 cells to secrete TGFβ1, which caused secretion of cyclophilin A. The secreted cyclophilin A further stimulated CD 147 to move outward from cytosol onto cell membrane in confocal microscopy, which was associated with the p38 MAPK pathway in the downstream.. Secreted cyclophilin A may play an important role in diabetic nephropathy in the mouse model and is associated with TGFβ1, CD 147, and the p38 MAPK pathway.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Cells, Cultured; Cyclophilin A; Deoxyguanosine; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Kidney Diseases; Linagliptin; Mice; Mice, Transgenic

A new series of DPP-4 inhibitors with imidazo[1,2-a]pyridine scaffold were designed by exploiting scaffold hopping strategy and docking study. Based on docking binding model, structural modifications of 2-benzene ring and pyridine moieties of compound 5a led to the identification of compound 5d with 2, 4-dichlorophenyl group at the 2-position as a potent (IC50  = 0.13 μm), selective (DPP-8/DPP-4 = 215 and DPP-9/DPP-4 = 192) and in vivo efficacious DPP-4 inhibitor. Further, molecular docking revealed that compound 5d could retain key binding features of DPP-4 with the pyridine moiety of imidazo[1,2-a]pyridine ring providing an additional π-π interaction with Phe357 of DPP-4. Compound 5d might be a promising lead for further development of novel DPP-4 inhibitor treating T2DM.

Topics: Animals; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Imidazoles; Male; Mice; Mice, Inbred ICR; Molecular Docking Simulation; Pyridines; Structure-Activity Relationship

The objective of the present research was to cultivate an oral formulation of an anti-diabetic drug using polymeric nanofiber. A biodegradable polymer i.e. poly (vinyl alcohol) (PVA) nanofiber loaded linagliptin was prepared using electro spinning technique. The drug entrapment in the developed nanofibers was confirmed by scanning electron microscopy and X-ray diffraction. The in vivo study was performed on male Wistar rats to establish the pharmacodynamics behavior of developed formulation. The mucoadhesive strength results confirmed that the drug loaded PVA nanofiber patch had the highest mucoadhesion strength compare to PVA film and blank PVA nanofiber, due to its higher water holding capacity and surface area. The in vitro release study suggested that controlled release array of the drug from the nanofiber patch. In vivo activity validated the fact that linagliptin was delivered in its active state and showed visible results when compared to the commercial formulation. Additionally an encapsulation efficacy of 92% of the experimental formulation provides sufficient suggestion that the nanofibers serve as an ideal carrier for the delivery of linagliptin via the sublingual route.

Topics: Administration, Sublingual; Animals; Chemistry, Pharmaceutical; Delayed-Action Preparations; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Goats; Hypoglycemic Agents; Linagliptin; Male; Microscopy, Electron, Scanning; Nanofibers; Polyvinyl Alcohol; Rats; Rats, Wistar; X-Ray Diffraction

The clinical course > 6 months after the initiation of linagliptin in patients with type 2 diabetes was compared among the groups divided by their renal function.. Two hundred and sixteen Japanese patients with type 2 diabetes treated with 5 mg once daily linagliptin were studied as the treated set. One hundred and forty-five subjects whose medications were not changed during the observation period were investigated as the full analysis set to assess the effectiveness. The subjects were divided into three groups based on an eGFR: eGFR ≥ 60, 59 - 45 and < 45 ml/min/1.73 m(2). The parameters were analyzed separately in the patients receiving monotherapy and additional therapy of linagliptin.. The HbA1c (NGSP) levels significantly improved in both the patients receiving monotherapy and additional therapy. The changes in the HbA1c levels at 6 months were not significantly different between the groups with an eGFR ≥ 60, 59 - 45 and < 45 ml/min/1.73 m(2) receiving monotherapy (-1.0, -0.8 and -0.8%, respectively). Similarly, those were not significantly different between the different groups receiving additional therapy (-0.6, -0.5 and -0.7%, respectively).. Linagliptin is considered to be effective for patients with type 2 diabetes and renal impairment in the present analysis performed at our institution.

Topics: Aged; Aged, 80 and over; Asian People; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Glomerular Filtration Rate; Humans; Hypoglycemic Agents; Linagliptin; Male; Purines; Quinazolines; Renal Insufficiency; Retrospective Studies

It is unclear whether dipeptidylpeptidase-4 (DPP-4) inhibition can counteract the impairment of cognitive function and brain injury caused by transient cerebral ischemia in type 2 diabetes. The present study was undertaken to test our hypothesis that linagliptin, a DPP-4 inhibitor, administration following transient cerebral ischemia can ameliorate cognitive impairment and brain injury in diabetic mice.. db/db mice, a model of obese type 2 diabetes, were subjected to transient cerebral ischemia by 17 min of bilateral common carotid artery occlusion (BCCAO), and were administered (1) vehicle or (2) linagliptin for 8 weeks or 1 week. For the long-term experiment on 8 weeks of linagliptin treatment, cognitive function, and volume and neuronal cell number of hippocampus and cortex were estimated in each group of mice. For the short-term experiment on 1 week of linagliptin treatment, cerebral IgG extravasation, Iba-1 positive cell number (reactive microglia), oxidative stress, and claudin-5 and gp91phox protein levels were measured in each group of mice.. Linagliptin administration almost completely suppressed the circulating DPP-4 activity in db/db mice, but did not significantly reduce blood glucose or ameliorate glucose intolerance in db/db mice. Linagliptin administration following transient cerebral ischemia significantly counteracted cognitive impairment in diabetic mice, as estimated by water maze test and passive avoidance test. Linagliptin administration ameliorated the decrease in cerebral volume and neuronal cell number in hippocampus and cortex of diabetic mice. Linagliptin administration significantly reduced the increase in cerebral IgG extravasation and the increase in reactive microglia caused by transient cerebral ischemia in diabetic mice. Furthermore, linagliptin significantly suppressed the increase in cerebral oxidative stress in transient cerebral ischemia-subjected diabetic mice. Furthermore, linagliptin significantly increased cerebral claudin-5 and significantly decreased gp91phox in diabetic mice subjected to transient cerebral ischemia.. DPP-4 inhibition with linagliptin counteracted cognitive impairment and brain atrophy induced by transient cerebral ischemia in diabetic mice, independently of blood glucose lowering effect. This cerebroprotective effect of linagliptin was associated with the suppression of blood-brain barrier disruption and the attenuation of cerebral oxidative stress. Thus, our present work highlights DPP-4 inhibition as a promising therapeutic strategy for cognitive impairment and cerebral vascular complications in type 2 diabetes.

Topics: Animals; Atrophy; Brain; Carotid Artery, Common; Cerebral Cortex; Cognition; Cognition Disorders; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Hippocampus; Immunoglobulin G; Ischemic Attack, Transient; Linagliptin; Mice; Microglia; Organ Size

The effects of the dipeptidyl peptidase-4 (DPP-4) inhibitor, linagliptin, alone and in combination with voglibose or exendin-4, on glycaemic control and body weight were assessed in an animal model of type 2 diabetes. Voglibose is an α-glucosidase inhibitor but also increases glucagon-like peptide 1 (GLP-1). Exendin-4 is a GLP-1 receptor agonist. Male Zucker Diabetic Fatty (ZDF) rats were dosed for 3 days, fasted overnight and a sucrose/glucose tolerance test was performed. Linagliptin (1mg/kg po) improved glucose tolerance by increasing plasma GLP-1 (active) and insulin secretion, whilst having no effect on body weight. Voglibose (1 and 10mg/kg po) reduced body weight, improved glycaemic control, reduced plasma insulin and increased total but not active GLP-1. The combination of linagliptin and voglibose significantly reduced body weight, improved glycaemic control and reduced plasma insulin compared to linagliptin alone. Furthermore, linagliptin plus voglibose produced a marked increase in GLP-1 (active) at 5min post-sucrose, compared to linagliptin, possibly because linagliptin prevented the degradation of GLP-1 secreted in response to voglibose. Exendin-4 (10μg/kg sc) significantly reduced body weight, improved glucose tolerance but reduced GLP-1 (active). The combination of linagliptin and exendin-4 significantly reduced body weight and improved glycaemic control but had no effect on plasma GLP-1. Overall it did not markedly improve glycaemic control compared to the individual drugs. The improved glucose control, reduced body weight and markedly increased plasma GLP-1 levels in animals given linagliptin with voglibose, suggests that this combination may be particularly beneficial in the treatment of type 2 diabetes.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Exenatide; Hypoglycemic Agents; Inositol; Linagliptin; Male; Peptides; Purines; Quinazolines; Rats; Rats, Zucker; Treatment Outcome; Venoms

Dipeptidyl peptidase 4 (DPP-4) inhibitors are current drugs for the treatment of type 2 diabetes (T2D) based on their main property to enhance endogenous glucagon-like peptide-1 (GLP-1) levels, thus increasing insulin secretion. However, the mechanism of action of DPP-4 inhibition in extra pancreatic tissues has been poorly investigated and it might occur differently from that induced by GLP-1R agonists. Increased adult neurogenesis by GLP-1R agonists has been suggested to play a role in functional recovery in animal models of brain disorders. We recently showed that the DPP-4 inhibitor linagliptin reduces brain damage after stroke in normal and type 2 diabetic (T2D) mice. The aim of this study was to determine whether linagliptin impacts stroke-induced neurogenesis. T2D was induced by 25 weeks of high-fat diet. Linagliptin treatment was carried out for 7 weeks. Standard diet fed-mice were used as controls. Stroke was induced by middle cerebral artery occlusion 4 weeks into the linagliptin treatment. Neural stem cell (NSC) proliferation/neuroblast formation and striatal neurogenesis/gliogenesis were assessed 3 weeks after stroke. The effect of linagliptin on NSC viability was also determined in vitro. The results show that linagliptin enhances NSC proliferation in T2D mice but not in normal mice. Linagliptin did not increase NSC number in vitro indicating that the effect of linagliptin on NSC proliferation in T2D is indirect. Neurogenesis and gliogenesis were not affected. In conclusion, we found no correlation between acute neuroprotection (occurring in both T2D and normal mice) and increased NSC proliferation (occurring only in T2D mice). However, our results show that linagliptin evokes a differential response on NSC proliferation after stroke in normal and T2D mice suggesting that DPP-4 inhibition effect in the CNS might go beyond the well known increase of GLP-1.

Topics: Animals; Cell Proliferation; Cell Survival; Cells, Cultured; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Hypoglycemic Agents; Linagliptin; Male; Mice; Mice, Inbred C57BL; Neural Stem Cells; Purines; Quinazolines; Stroke; Structure-Activity Relationship

Highly potent DPP-4 inhibitors have been identified by hybrid compound design based on linagliptin and alogliptin. The most promising compound 2h (IC50 = 0.31 nM) exhibited 8.5-fold and 2.5-fold more potent activity than that of alogliptin (IC50 = 2.63 nM) and linagliptin (IC50 = 0.77 nM), respectively. Compound 2h had a good inhibition selectivity for DPP-4 over DPP-8/9 and thus was selected for further biological evaluation, including oral glucose tolerance, plasma DPP-4 inhibitory activity, pharmacokinetic profile, acute toxicity and hERG inhibition. The assay results showed that 2h displayed significant in vivo glucose-lowering effect and low risk of toxicity. Further studies are expected to confirm 2h as a potential drug candidate for the treatment of type 2 diabetes.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Drug Design; Humans; Linagliptin; Models, Molecular; Piperidines; Protein Conformation; Purines; Quinazolines; Structure-Activity Relationship; Substrate Specificity; Uracil

Dipeptidyl peptidase (DPP)-4 inhibitors are an increasingly used antihyperglycemic therapy for patients with type 2 diabetes mellitus (T2DM). Linagliptin, an orally administered DPP-4 inhibitor, has demonstrated favorable efficacy/safety in clinical trials. The aim of this post hoc pooled analysis was to expand current knowledge of the safety of linagliptin.. Safety data for once-daily linagliptin 5 mg (1 study of linagliptin 2.5 mg twice daily) were analyzed from 22 randomized, double-blind, Phase I-III, placebo-controlled clinical trials of ≤102 weeks' duration. Assessments of pooled data included incidence of patient-reported adverse events (AEs).. Data from 7400 patients (linagliptin, 4810; placebo, 2590) were pooled. Most patients (58.4%) had T2DM diagnosis for >5 years; approximately 75% were receiving ≥1 type of background therapy in addition to linagliptin/placebo. Overall exposure to the study drug was 2412.8 years for linagliptin and 1481.4 years for placebo (mean [SD], 183 [120] days and 209 [150] days, respectively). Overall frequencies of AEs were similar for linagliptin- and placebo-treated patients (57.3% and 61.8%, respectively). The incidence of neoplastic AEs was low (0.6% and 0.9%, respectively); there were no reports of pancreatic neoplasia. Pancreatitis was observed in 2 linagliptin-treated patients (<0.1%) and 1 placebo-treated patient (<0.1%). The occurrence of cardiac disorder AEs was similar in linagliptin- and placebo-treated patients (3.2% [n = 153] and 3.3% [n = 83], respectively); the incidence of heart failure AEs for linagliptin- and placebo-treated patients was 0.2% (n = 11) and 0.3% (n = 7), respectively. Overall, linagliptin was weight neutral. Occurrence of investigator-defined hypoglycemic AEs was low for both linagliptin and placebo (11.5% vs 14.0%). In patients receiving concomitant sulfonylurea therapy, investigator-defined hypoglycemic AEs were more frequent with linagliptin versus placebo (22.1% [238/1079] vs 14.5% [61/421], respectively). Subgroup analyses showed similar frequencies of AEs for linagliptin- and placebo-treated patients across different age groups and renal function levels.. This updated and expanded pooled, post hoc analysis of 22 placebo-controlled trials of linagliptin 5 mg daily supports previous findings of the acceptable overall safety/tolerability profile of linagliptin when administered to a broad range of patients with T2DM. Linagliptin-treated patients demonstrated a low overall risk of hypoglycemia (risk increased by concomitant sulfonylurea therapy). As with all pooled analyses, this study is limited by the use of data from different studies, and the relatively short duration of some included studies, although use of individual patient data from consistently designed trials should minimize methodological differences between trials. Results from ongoing clinical trials will provide additional insight into the long-term safety/tolerability of linagliptin.

Topics: Aged; Body Weight; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Therapy, Combination; Female; Heart Failure; Humans; Hypoglycemia; Hypoglycemic Agents; Incidence; Linagliptin; Male; Middle Aged; Neoplasms; Pancreatitis; Randomized Controlled Trials as Topic; Sulfonylurea Compounds

To clarify the role of dipeptidyl peptidase-4 (DPP-4) inhibition in vascular tissues, we compared the effects of the poorly tissue-penetrative DPP-4 inhibitor sitagliptin to the highly tissue-penetrative DPP-4 inhibitor linagliptin in Zucker diabetic fatty (ZDF) rats. Six-week-old ZDF rats were orally treated with placebo, sitagliptin (10 mg/kg), or linagliptin (3 mg/kg) for 4 weeks. Sitagliptin and linagliptin produced equivalent decreases in blood glucose concentrations and increased plasma insulin concentrations during oral glucose tolerance tests after the first and the last treatments. In isolated arteries, acetylcholine-induced vascular relaxation was significantly augmented by sitagliptin and linagliptin, with significantly stronger relaxation observed with linagliptin compared to sitagliptin. Vascular DPP-4 activity was attenuated by these drugs, with linagliptin producing significant greater attenuation than sitagliptin. Vascular malondialdehide levels were significantly lower with linagliptin compared to sitagliptin. Significantly greater attenuation of vascular gene expressions of p22(phox) and monocyte chemoattractant protein-1 by linagliptin, compared with sitagliptin, was also observed. In conclusion, the superior vascular protection by linagliptin compared with sitagliptin was unrelated to the regulation of circulating glucose and insulin levels, and the stronger vascular DPP-4 inhibition by linagliptin may contribute to the mechanism of vascular protection.

Topics: Animals; Atherosclerosis; Blood Glucose; Carotid Arteries; Chemokine CCL2; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Gene Expression; Glucose Tolerance Test; In Vitro Techniques; Insulin; Linagliptin; Malondialdehyde; NADPH Oxidases; Purines; Pyrazines; Quinazolines; Rats, Zucker; Sitagliptin Phosphate; Triazoles; Vasodilation

Topics: Aged; Aged, 80 and over; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Humans; Hypoglycemic Agents; Linagliptin; Male; Middle Aged; Prospective Studies; Purines; Quinazolines; Uric Acid; Xanthine Oxidase

Despite the beneficial effects of type 4 dipeptidyl peptidase (DPP-4) inhibitors on glucose levels, its effects on diabetic nephropathy remain unclear.. This study examined the long-term renoprotective effects of DPP-4 inhibitor linagliptin in db/db mice, a model of type 2 diabetes. Results were compared with the known beneficial effects of renin-angiotensin system blockade by enalapril. Ten-week-old male diabetic db/db mice were treated for 3 months with either vehicle (n = 10), 3 mg linagliptin/kg per day (n = 8), or 20 mg enalapril/kg per day (n = 10). Heterozygous db/m mice treated with vehicle served as healthy controls (n = 8).. Neither linagliptin nor enalapril had significant effects on the parameters of glucose metabolism or blood pressure in diabetic db/db mice. However, linagliptin treatment reduced albuminuria and attenuated kidney injury. In addition, expression of podocyte marker podocalyxin was normalized. We also analysed DPP-4 expression by immunofluorescence in human kidney biopsies and detected upregulation of DPP-4 in the glomeruli of patients with diabetic nephropathy, suggesting that our findings might be of relevance for human kidney disease as well.. Treatment with DPP-4 inhibitor linagliptin delays the progression of diabetic nephropathy damage in a glucose-independent and blood-pressure-independent manner. The observed effects may be because of the attenuation of podocyte injury and inhibition of myofibroblast transformation.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Enalapril; Glucose; Hypoglycemic Agents; Kidney; Kidney Glomerulus; Linagliptin; Male; Mice; Mice, Inbred Strains; Renin-Angiotensin System

The epithelial to mesenchymal transition (EMT) is important in renal fibrosis. Ser307 phosphorylation of insulin receptor substrate-1 (IRS-1 (S307)) is a hallmark of insulin resistance. We report that polyphenol extracts of Hibiscus sabdariffa (HPE) ameliorate diabetic nephropathy and EMT. Recently it has been observed that type 4 dipeptidyl peptidase (DPP-4) inhibitor linagliptin is effective for treating type 2 diabetes and albuminuria. We investigated if DPP-4 and insulin resistance are involved in renal EMT and explored the role of HPE. In high glucose-stimulated tubular cells, HPE, like linagliptin, inhibited DPP-4 activation, thereby regulating vimentin (EMT marker) and IRS-1 (S307). IRS-1 knockdown revealed its essential role in mediating downstream EMT. In type 2 diabetic rats, pIRS-1 (S307) abundantly surrounds the tubular region, with increased vimentin in kidney. Both the expressions were reduced by HPE. In conclusion, HPE exerts effects similar to those of linagliptin, which improves insulin resistance and EMT, and could be an adjuvant to prevent diabetic nephropathy.

Topics: Animals; Cells, Cultured; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Epithelial-Mesenchymal Transition; Glucose; Hibiscus; Insulin Receptor Substrate Proteins; Insulin Resistance; Kidney; Linagliptin; Male; Phosphorylation; Polyphenols; Purines; Quinazolines; Rats, Sprague-Dawley; Vimentin

Long duration of type 2 diabetes mellitus (T2DM) is associated with progressive β-cell loss and may pose a challenge to maintenance of good glycemic control. This study aimed to assess the efficacy and safety of the dipeptidyl peptidase-4 inhibitor linagliptin in an understudied population of patients with long-standing T2DM.. Data from 202 individuals with T2DM for >10 years were pooled from 2 randomized, placebo-controlled, Phase III trials. Participants received either linagliptin 5 mg once daily (n = 122) or placebo (n = 80) for 24 weeks as an add-on to their current glucose-lowering therapy.. Long-standing T2DM was associated with older age (mean [SD], 69.1 [10.0] years) and a high prevalence of diabetes-related complications (78% with diabetic kidney disease and 83% with macrovascular disease). The mean baseline glycosylated hemoglobin (HbA1c) level was 8.22% (1.08%), and mean baseline fasting plasma glucose level was 161.8 (49.2) mg/dL. Linagliptin significantly improved glycemic control after 24 weeks, with a placebo-adjusted mean change in HbA1c from baseline of -0.66% (95% CI, -0.95 to -0.38; P < 0.0001). This change was accompanied by a significant reduction in fasting plasma glucose, with a placebo-adjusted mean change from baseline of -15.5 mg/dL (95% CI, -29.6 to -1.3; P = 0.0323) at week 24. Overall, linagliptin was well tolerated, with drug-related adverse events in 21.3% and 16.3% of the linagliptin and placebo groups, respectively. Investigator-reported hypoglycemia occurred more often with linagliptin (25.4%) compared with placebo (12.5%). However, no severe hypoglycemic events were reported with linagliptin. Moreover, in patients not receiving concomitant sulfonylureas, the incidence of hypoglycemia with linagliptin (12.5%) was similar to that with placebo (12.2%). Patients' mean weight remained unchanged in both groups.. This pooled analysis found that linagliptin was well tolerated and significantly improved hyperglycemia in a clinically challenging population of patients with long-standing T2DM (>10 years). Although T2DM is commonly associated with diminished β-cell function, the extent of glucose lowering was similar to that in linagliptin trials, which largely included patients in earlier stages of the disease. Thus, this observation supports the hypothesis that regulation of glucagon release from pancreatic α cells may be of particular relevance for improving hyperglycemia in patients with long-term T2DM (NCT01194830 and NCT01084005).

Topics: Adult; Aged; Aged, 80 and over; Blood Glucose; Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Female; Glucagon; Glycated Hemoglobin; Humans; Hypoglycemia; Hypoglycemic Agents; Linagliptin; Male; Middle Aged; Randomized Controlled Trials as Topic; Retrospective Studies; Sulfonylurea Compounds; Treatment Outcome

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Hypoglycemic Agents; Linagliptin; Male; Purines; Quinazolines

Novel deazaxanthine-based DPP-4 inhibitors have been identified that are potent (IC(50) <10nM) and highly selective versus other dipeptidyl peptidases. Their synthesis and SAR are reported, along with initial efforts to improve the PK profile through decoration of the deazaxanthine core. Optimisation of compound 3a resulted in the identification of compound (S)-4i, which displayed an improved in vitro and ADME profile. Further enhancements to the PK profile were possible by changing from the deazahypoxanthine to the deazaxanthine template, culminating in compound 12g, which displayed good ex vivo DPP-4 inhibition and a superior PK profile in rat, suggestive of once daily dosing in man.

Topics: Animals; Caco-2 Cells; Crystallography, X-Ray; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Enzyme Activation; Heterocyclic Compounds; Humans; Inhibitory Concentration 50; Male; Models, Molecular; Molecular Structure; Rats; Structure-Activity Relationship

In recent years, dipeptidyl peptidase IV inhibitors have been noted as valuable agents for treatment of type 2 diabetes. Herein, we report the discovery of a novel potent DPP-4 inhibitor with 3H-imidazo[4,5-c]quinolin-4(5H)-one as skeleton. After efficient optimization of the lead compound 2a at the 7- and 8-positions using a docking study, we found 28 as a novel DPP-4 inhibitor with excellent selectivity against various DPP-4 homologues. Compound 28 showed strong DPP-4 inhibitory activity compared to marketed DPP-4 inhibitors. We also found that a carboxyl group at the 7-position could interact with the residue of Lys554 to form a salt bridge. Additionally, introduction of a carboxyl group to 7-position led to both activity enhancement and reduced risk for hERG channel inhibition and induced phospholipidosis. In our synthesis of compounds with 7-carboxyl group, we achieved efficient regioselective synthesis using bulky ester in the intramolecular palladium coupling reaction.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Humans; Imidazoles; Molecular Docking Simulation; Quinolines

Linagliptin is a selective, competitive dipeptidyl peptidase-4 (DPP-4) inhibitor, recently approved in the USA, Japan and Europe for the treatment of type 2 diabetes. It has non-linear pharmacokinetics and, unlike other DPP-4 inhibitors, a largely non-renal excretion route. It was hypothesised that P-glycoprotein (P-gp)-mediated intestinal transport could influence linagliptin bioavailability, and might contribute to its elimination. Two studies evaluated the role of P-gp-mediated transport in the bioavailability and intestinal secretion of linagliptin in rats. In the bioavailability study, male Wistar rats received single oral doses of linagliptin, 1 or 15 mg/kg, plus either the P-gp inhibitor, zosuquidar trihydrochloride, or vehicle. For the intestinal secretion study, rats underwent bile duct cannulation, and urine, faeces, and bile were collected. At the end of the study, gut content was sampled. Inhibition of intestinal P-gp increased the bioavailability of orally administered linagliptin, indicating that this transport system plays a role in limiting the uptake of linagliptin from the intestine. This effect was dependent on linagliptin dose, and could play a role in its non-linear pharmacokinetics after oral dosing. Systemically available linagliptin was mainly excreted unchanged via bile (49% of i.v. dose), but some (12%) was also excreted directly into the gut independently of biliary excretion. Thus, direct excretion of linagliptin into the gut may be an alternative excretion route in the presence of liver and renal impairment. The primarily non-renal route of excretion is likely to be of benefit to patients with type 2 diabetes, who have a high prevalence of renal insufficiency.

Topics: Animals; Area Under Curve; ATP Binding Cassette Transporter, Subfamily B, Member 1; Bile; Biliary Tract; Biological Availability; Biological Transport; Diabetes Mellitus, Type 2; Dibenzocycloheptenes; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Intestinal Mucosa; Linagliptin; Male; Purines; Quinazolines; Quinolines; Rats; Rats, Wistar

• Linagliptin is an oral, highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor that was approved in the United States, Europe and elsewhere in 2011 for the treatment of type 2 diabetes mellitus. • The elimination of linagliptin is primarily non-renal. Therefore, a potential effect of hepatic impairment on the elimination of linagliptin may have important implications for dosing recommendations.. • This study shows that mild, moderate or severe hepatic impairment did not result in an increase in linagliptin exposure after single and multiple dosing as compared with normal hepatic function. • No linagliptin dose adjustment is required in patients with any degree of hepatic impairment.. To investigate whether hepatic impairment affects linagliptin pharmacokinetics, pharmacodynamics and tolerability.. This open label, parallel group, single centre study enrolled patients with mild (n= 8), moderate (n= 9) or severe (n= 8) hepatic impairment and healthy subjects (n= 8). Groups were matched with regard to age, weight and gender. Primary endpoints were linagliptin exposure following 5 mg linagliptin once daily for 7 days in patients with mild and moderate hepatic impairment vs. healthy subjects or after a single 5 mg dose for patients with severe hepatic impairment vs. healthy subjects.. In mild hepatic impairment, steady-state linagliptin exposure was slightly lower than in healthy subjects [AUC(τ,ss) geometric mean ratio (GMR) 75.5%, 90% confidence interval (CI) 61.6%, 92.5%, and C(max,ss) GMR 64.4%, 90% CI 43.2%, 96.0%]. Exposure also tended to be lower in moderate hepatic impairment (AUC(τ,ss) GMR 85.5%, 90% CI 70.2%, 104.2% and C(max,ss) GMR 92.3%, 90% CI 62.8%, 135.6%). After a single dose, AUC(0,24 h) in patients with severe hepatic impairment was similar to that in healthy subjects (GMR 100.4%, 90% CI 75.0%, 134.3%) and C(max) was lower (GMR 77.0%, 90% CI 44.9%, 132.3%). Accumulation based on AUC or C(max) and renal excretion of unchanged linagliptin (≤ 7%) were comparable across groups. Median plasma DPP-4 inhibition was similar in healthy subjects (91%), and patients with mild (90%) and moderate (89%) hepatic impairment at steady-state trough concentrations, and in patients with severe hepatic impairment 24 h after a single dose (84%). Linagliptin was well tolerated.. Mild, moderate or severe hepatic impairment did not result in an increase in linagliptin exposure after single and multiple dosing compared with normal hepatic function. Dose adjustment with linagliptin is not required in patients with hepatic impairment.

Topics: Adult; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Female; Humans; Linagliptin; Liver Diseases; Male; Middle Aged; Purines; Quinazolines; Severity of Illness Index

Linagliptin (Trajenta) is a selective inhibitor of dipeptidyl peptidase-4, an enzyme that degrades two incretin hormones, GLP-1 ("Glucagon-Like Peptide-1") and GIP ("Glucose-dependent Insulinotropic Polypeptide"). As other molecules belonging to this pharmacological class, linagliptin improves blood glucose control of type 2 diabetic patients, without increasing hypoglycaemic risk, without promoting weight gain and with a good clinical and biological tolerance profile. Both efficacy and safety have been demonstrated in randomized controlled trials as monotherapy or in combination with other glucose-lowering agents, independent of demographic or clinical patient's characteristics. The pharmacokinetics specificity of linagliptin comprises its biliary excretion, with low hepatic metabolism (no drug-drug interactions) and, in contrast to other gliptins, its negligible renal elimination. Because of these favourable properties, linagliptin may be used without dose adjustment (5 mg once a day) in patients with renal impairment, as well as in elderly people.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Linagliptin; Purines; Quinazolines; Renal Insufficiency

Linagliptin (BI 1356) is a dipeptidyl peptidase-4 (DPP-4) inhibitor for treatment of Type 2 diabetes which recently gained approval in the US, Europe, and Japan. Linagliptin showed nonlinear pharmacokinetics after intravenous and oral administration, which is due to a concentration-dependent protein binding of linagliptin to its target enzyme DPP-4. The aim of this analysis was to investigate this target-mediated binding of linagliptin and its implication on efficacy and safety.. Pharmacokinetic modeling and simulations were performed using a two-compartment model with concentration-dependent binding in the central and in one peripheral compartment. The optimum therapeutic dose with minimal off-target side effects was simulated assuming that an antidiabetic effect of linagliptin was due to the linagliptin concentration bound to DPP-4 and that off-target side effects were related to free linagliptin.. The difference between steady state AUCs of specifically bound and free linagliptin was maximized at oral doses of 2 - 5 mg. Since plasma DPP-4 inhibition increased slightly from 2.5 to 10 mg, pharmacokinetic simulations and the pharmacodynamic measurements taken together suggest that 5 mg linagliptin could be considered an optimum dose. Simulations with missed doses and additional doses at steady state showed the effect on DPP-4 bound linagliptin and change in DPP-4 inhibition was minimal after missing one 5 mg oral dose of linagliptin while two doses of 5 mg linagliptin resulted in a less than proportional increase of steady state AUC of free linagliptin.. Results from modeling and simulation support a stable antidiabetic effect of linagliptin over 24 h at steady state and further indicate a low risk for off-target side effects.

Topics: Blood Proteins; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Humans; Hypoglycemic Agents; Linagliptin; Models, Biological; Purines; Quinazolines

Topics: Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Linagliptin; Male; Metformin; Purines; Quinazolines; Sulfonylurea Compounds

Topics: Adamantane; Aged; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Incretins; Linagliptin; Liraglutide; Nitriles; Peptides; Piperidines; Purines; Pyrazines; Pyrrolidines; Quinazolines; Sitagliptin Phosphate; Triazoles; Uracil; Venoms; Vildagliptin

Dipeptidyl peptidase-4 (DPP-4) inhibitors enhance incretin actions and beta-cell function. Concurrently, sodium-glucose co-transporter 2 (SGLT2) inhibitors block renal glucose reabsorption promoting excretion. In this study, we investigated the effects of linagliptin (a DPP-4 inhibitor) and BI-38335 (an SGLT2 inhibitor), individually and in combination, on glucose homeostasis, islet function, and pancreatic islet morphology in db/db mice. Diabetic and non-diabetic mice received linagliptin (3 mg/kg), BI-38335 (1 mg/kg), the two drugs in combination or control once daily for 8 weeks. Blood glucose homeostasis and insulin sensitivity were assessed. Pancreatic islet function and morphology as well as inflammatory factors and toll like receptor 2 (TLR2) pathways involved in islet inflammation were investigated. Active treatments markedly reduced blood glucose and glycated hemoglobin A1c (HbA(1c)) levels, with the combined treatment showing the greater effects. Insulin resistance was improved in the BI-38335 and combination groups with the enhancement of insulin sensitivity and significant increase of serum adiponectin levels. The combined treatment exhibited greater effects on enhanced islet glucose-stimulated insulin secretion and improved glucose tolerance. Moreover, the combination restored the islet beta-/alpha-cell ratio, reduced beta-cell apoptosis, decreased expression of islet immune cell markers, and suppressed factors related to the TLR2 pathway. In addition, all active treatments reduced serum lipid profiles, though the combination produced more robust effects. Collectively, our data show that combined treatment with BI-38335 and linagliptin work, at least in part, synergistically to benefit islet cell function/architecture and insulin resistance, thus improving glycemic control.

Topics: Animals; Apoptosis Regulatory Proteins; Blood Glucose; Cell Proliferation; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Evaluation, Preclinical; Drug Therapy, Combination; Female; Gene Expression; Hypoglycemic Agents; Inflammation Mediators; Insulin; Insulin Secretion; Islets of Langerhans; Linagliptin; Lipids; Mice; Mice, Inbred C57BL; Molecular Targeted Therapy; Pancreatitis; Purines; Quinazolines; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Tissue Culture Techniques

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Linagliptin; Metformin; Purines; Quinazolines; Sulfonylurea Compounds

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Germany; Humans; Linagliptin; Purines; Quinazolines

Topics: Clinical Trials as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Approval; Humans; Linagliptin; Purines; Quinazolines

This study assessed the influence of various degrees of renal impairment on the exposure of linagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor with a primarily non-renal route of excretion, in subjects with type 2 diabetes mellitus (T2DM).. Linagliptin pharmacokinetics was studied under single-dose and steady-state conditions in subjects with mild, moderate and severe renal impairment (with and without T2DM) and end-stage renal disease and compared with the pharmacokinetics in subjects with normal renal function (with and without T2DM).. Renal excretion of unchanged linagliptin was <7% in all groups. Under single-dose conditions, the degree of renal impairment did not affect mean plasma linagliptin concentration-time profiles. These showed a similar decline and almost identical plasma concentrations 24 h postdosing in subjects with mild, moderate or severe renal impairment and in subjects with T2DM with and without renal impairment. Although there was a tendency towards slightly higher (20-60%) exposure in renally impaired subjects (with and without T2DM) compared with subjects with normal renal function, the steady-state AUC and C(max) values showed a large overlap and were not affected by the degree of renal impairment. The accumulation half-life of linagliptin ranged from 14-15 h in subjects with normal renal function to 18 h in severe renal impairment. Only a weak correlation (r(2) = 0.18) was seen between creatinine clearance and steady-state exposure.. Renal impairment has only a minor effect on linagliptin pharmacokinetics. Consequently, there will be no need for adjusting the linagliptin dose in renally impaired patients with T2DM.

Topics: Analysis of Variance; Area Under Curve; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Female; Half-Life; Humans; Kidney Failure, Chronic; Linagliptin; Male; Middle Aged; Purines; Quinazolines; Treatment Outcome

The dipeptidyl peptidase-4 (DPP-4) inhibitors linagliptin, sitagliptin, saxagliptin, vildagliptin and alogliptin are being developed and have been approved for the treatment of type-2 diabetes. These agents may be used either as monotherapy for the treatment of type-2 diabetes or in combination with other anti-diabetic drugs. The present review highlights the use of linagliptin and other new (DPP-4) inhibitors in the management of type-2 diabetes. The review also highlights advantages, comparative pharmacokinetic, safety profile and other potential uses including potential newer indications of DPP-4 inhibitors and relevant patents. The other potential uses that are not restricted to diabetes include obesity, cardiovascular disease, neurological disease, hepatobiliary disease, wound healing, and other inflammatory illnesses.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drugs, Investigational; Humans; Hypoglycemic Agents; Linagliptin; Patents as Topic; Purines; Quinazolines

The pharmacokinetics of the novel dipeptidyl-peptidase 4 (DPP-4) inhibitor linagliptin is nonlinear. Based on in vitro experiments, concentration-dependent binding to DPP-4 is the most likely cause for the nonlinearity. Population pharmacokinetic/pharmacodynamic modeling was performed using linagliptin plasma concentrations and plasma DPP-4 activities from 2 phase 2a studies. In these studies, type 2 diabetic patients received either 1, 2.5, 5, or 10 mg of linagliptin once daily over 12 days (study 1) or 2.5, 5, or 10 mg of linagliptin once daily over 28 days (study 2). The modeling results supported the hypothesis that linagliptin exhibits target-mediated drug disposition. The linagliptin plasma concentrations were best described by a 2-compartment model including concentration-dependent protein binding in the central and peripheral compartment. The plasma DPP-4 activity was included in the model in a semi-mechanistic way by relating it to the model-calculated plasma DPP-4 occupancy with linagliptin. The target binding has a major impact on linagliptin pharmacokinetics. Although unbound linagliptin is cleared efficiently (CL/F 220 L/h), the concentration-dependent binding is responsible for the long terminal half-life (approximatelly 120 hours) of linagliptin and its nonlinear pharmacokinetics. The model allowed a comprehensive understanding of the impact of target-mediated drug disposition and provides a useful tool to support clinical development.

Topics: Clinical Trials, Phase II as Topic; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Humans; Linagliptin; Metabolic Clearance Rate; Models, Biological; Protein Binding; Purines; Quinazolines; Tissue Distribution

The purpose of this study was to characterise the plasma protein binding of BI 1356.. BI 1356 (proposed trade name ONDERO) is a novel dipeptidyl peptidase 4 (DPP-4) inhibitor, which is under clinical development for the treatment of type 2 diabetes. DPP-4 is expressed in various tissues but soluble DPP-4 is also present in plasma. Therefore, binding to soluble DPP-4 may influence the pharmacokinetics of BI 1356. Plasma protein binding of BI 1356 was determined in vitro for wild type mice and rats and the results compared with those for DPP-4 knockout mice and DPP-4 deficient Fischer rats. In addition, protein binding of BI 1356 was examined in plasma from healthy human volunteers and renal excretion of the compound in the DPP-4 knockout mice was compared with that occurring in wild type mice.. The results showed that BI 1356 exhibited a prominent concentration-dependent plasma protein binding due to a saturable high affinity binding to the DPP-4 target in plasma. Differences in renal excretion of BI 1356 between DPP-4 knockout mice and wild type mice suggested that saturable binding of BI 1356 to DPP-4 in the body also influenced elimination.. High affinity, but readily saturable binding of BI 1356 to its target DPP-4 accounted primarily for the concentration-dependent plasma protein binding at therapeutic plasma concentrations of BI 1356.

Topics: Algorithms; Animals; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Kinetics; Linagliptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Structure; Protein Binding; Purines; Quinazolines; Rats; Rats, Inbred F344

Linagliptin (BI 1356) is a novel dipeptidyl peptidase-4 (DPP-4) inhibitor in clinical development for the treatment of type 2 diabetes. It exhibits non-linear pharmacokinetics and shows concentration-dependent plasma protein binding to its target, DPP-4. The aim of this study was to investigate the impact of saturable binding of linagliptin to plasma and tissue DPP-4 by comparing the pharmacokinetics of linagliptin in wildtype and DPP-4 deficient Fischer rats using non-compartmental and model-based data analysis. The non-compartmental analysis revealed a significantly reduced AUC in DPP-4 deficient rats compared with wildtype rats when single intravenous doses

Topics: Animals; Binding Sites; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Linagliptin; Purines; Quinazolines; Rats; Rats, Inbred F344

BI 1356 [proposed trade name ONDERO; (R)-8-(3-amino-piperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione] is a novel dipeptidyl peptidase (DPP)-4 inhibitor under clinical development for the treatment of type 2 diabetes. In this study, we investigated the potency, selectivity, mechanism, and duration of action of BI 1356 in vitro and in vivo and compared it with other DPP-4 inhibitors. BI 1356 inhibited DPP-4 activity in vitro with an IC(50) of approximately 1 nM, compared with sitagliptin (19 nM), alogliptin (24 nM), saxagliptin (50 nM), and vildagliptin (62 nM). BI 1356 was a competitive inhibitor, with a K(i) of 1 nM. The calculated k(off) rate for BI 1356 was 3.0 x 10(-5)/s (versus 2.1 x 10(-4)/s for vildagliptin). BI 1356 was >/=10,000-fold more selective for DPP-4 than DPP-8, DPP-9, amino-peptidases N and P, prolyloligopeptidase, trypsin, plasmin, and thrombin and was 90-fold more selective than for fibroblast activation protein in vitro. In HanWistar rats, the DPP-4 inhibition 24 h after administration of BI 1356 was more profound than with any of the other DPP-4 inhibitors. In C57BL/6J mice and Zucker fatty (fa/fa) rats, the duration of action on glucose tolerance decreased in the order BI 1356 > (sitagliptin/saxagliptin) > vildagliptin. These effects were mediated through control of glucagon-like peptide-1 and insulin. In conclusion, BI 1356 inhibited DPP-4 more effectively than vildagliptin, sitagliptin, saxagliptin, and alogliptin and has the potential to become the first truly once-a-day DPP-4 inhibitor for the treatment of type 2 diabetes.

Topics: Animals; Antigens, Neoplasm; Biomarkers, Tumor; Caco-2 Cells; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Endopeptidases; Gelatinases; Humans; Hypoglycemic Agents; Inhibitory Concentration 50; Linagliptin; Male; Membrane Proteins; Mice; Protease Inhibitors; Purines; Quinazolines; Rats; Rats, Wistar; Rats, Zucker; Serine Endopeptidases; Xanthines

A new chemical class of potent DPP-4 inhibitors structurally derived from the xanthine scaffold for the treatment of type 2 diabetes has been discovered and evaluated. Systematic structural variations have led to 1 (BI 1356), a highly potent, selective, long-acting, and orally active DPP-4 inhibitor that shows considerable blood glucose lowering in different animal species. 1 is currently undergoing clinical phase IIb trials and holds the potential for once-daily treatment of type 2 diabetics.

Topics: Administration, Oral; Animals; Caco-2 Cells; Crystallography, X-Ray; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Dogs; Humans; Hypoglycemic Agents; Linagliptin; Macaca fascicularis; Macaca mulatta; Male; Models, Molecular; Piperidines; Purines; Quinazolines; Rats; Rats, Wistar; Stereoisomerism; Structure-Activity Relationship