linagliptin and Hyperglycemia

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

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

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

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

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

To evaluate the effect of the combination of linagliptin and insulin on metabolic control and prognosis in hospitalized patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and hyperglycemia. A parallel double-blind randomized clinical trial including hospitalized patients with SARS-CoV-2 infection and hyperglycemia, randomized to receive 5 mg linagliptin + insulin (LI group) or insulin alone (I group) was performed. The main outcomes were the need for assisted mechanical ventilation and glucose levels during hospitalization. Subjects were screened for eligibility at hospital admission if they were not with assisted mechanical ventilation and presented hyperglycemia, and a total of 73 patients with SARS-CoV-2 infection and hyperglycemia were randomized to the LI group (n = 35) or I group (n = 38). The average hospital stay was 12 ± 1 vs 10 ± 1 days for the I and LI groups, respectively (p = 0.343). There were no baseline clinical differences between the study groups, but the percentage of males was higher in the LI group (26 vs 18, p = 0.030). The improvements in fasting and postprandial glucose levels were better in the LI group that the I group (122 ± 7 vs 149 ± 10, p = 0.033; and 137 ± 7 vs 173 ± 12, p = 0.017, respectively), and insulin requirements tended to be lower in the LI group than the I group. Three patients in the LI group and 12 in the I group required assisted mechanical ventilation (HR 0.258, CI 95% 0.092-0.719, p = 0.009); 2 patients in the LI group and 6 in the I group died after a follow-up of 30 days (p = 0.139). No major side effects were observed. The combination of linagliptin and insulin in hospitalized patients with SARS-CoV-2 infection and hyperglycemia reduced the relative risk of assisted mechanical ventilation by 74% and improved better pre and postprandial glucose levels with lower insulin requirements, and no higher risk of hypoglycemia.This study is registered at clinicaltrials.gov, number NCT04542213 on 09/03/2020.

Topics: Blood Glucose; COVID-19; Drug Therapy, Combination; Female; Hospitalization; Humans; Hyperglycemia; Insulin; Length of Stay; Linagliptin; Male; Middle Aged; Prognosis; Proportional Hazards Models; Respiration, Artificial; SARS-CoV-2

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

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

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

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

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 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

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

Dipeptidyl peptidase 4 (DPP-4) inhibitors have been shown to have neuroprotective effects in diabetic patients suffering from stroke, but less research has focused on patients with mild hyperglycemia below the threshold for a diagnosis of diabetes. In this investigation, a hyperglycemic mouse model was generated by intraperitoneal injection of streptozotocin and then subjected to focal cerebral ischemia. We demonstrated that the DPP-4 inhibitor linagliptin significantly decreased the infarct volume, reduced neuronal cell death, decreased inflammation, and improved neurological deficit compared with control mice. Linagliptin up-regulated the expression of p-Akt and p-mTOR and regulated the apoptosis factors Bcl-2, Bax, and caspase 9. Taken together, these results suggest that linagliptin exerts a neuroprotective action likely through activation of the Akt/mTOR pathway along with anti-apoptotic and anti-inflammatory mechanisms. Therefore, linagliptin may be considered as a therapeutic treatment for stroke patients with mild hyperglycemia.

Topics: Animals; Apoptosis; Cell Death; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Hyperglycemia; Linagliptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Neuroprotective Agents; Proto-Oncogene Proteins c-akt; Stroke; TOR Serine-Threonine Kinases

Diabetes-induced podocyte apoptosis is considered to play a critical role in the pathogenesis of diabetic kidney disease (DKD). We proposed that hyperglycaemia can induce podocyte apoptosis by inhibiting the action of podocyte survival factors, thus inactivating the cellular effects of insulin signalling. In this study, we aimed to determine the effects of linagliptin on high glucose-induced podocyte apoptosis. Linagliptin reduced the increase in DNA fragmentation as well as the increase in TUNEL-positive cells in podocytes induced by high-glucose condition. Furthermore, linagliptin improved insulin-induced phosphorylation of insulin receptor substrate 1 (IRS1) and Akt, which was inhibited in high-glucose conditions. Adenoviral vector-mediated IRS1 overexpression in podocytes partially normalised DNA fragmentation in high-glucose conditions, while downregulation of IRS1 expression using small interfering RNA increased DNA fragmentation even in low-glucose conditions. Because reactive oxygen species inhibit glomerular insulin signalling in diabetes and Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway is one of the most important intrinsic antioxidative systems, we evaluated whether linagliptin increased Nrf2 in podocytes. High-glucose condition and linagliptin addition increased Nrf2 levels compared to low-glucose conditions. In summary, linagliptin offers protection against DKD by enhancing IRS1/Akt insulin signalling in podocytes and partially via the Keap1/Nrf2 pathway. Our findings suggest that linagliptin may induce protective effects in patients with DKD, and increasing IRS1 levels could be a potential therapeutic target in DKD.

Topics: Animals; Apoptosis; Cells, Cultured; Cytoprotection; Glucose; Hyperglycemia; Hypoglycemic Agents; Insulin Receptor Substrate Proteins; Linagliptin; Male; Podocytes; Protective Agents; Proto-Oncogene Proteins c-akt; Rats, Sprague-Dawley; Signal Transduction

Post-renal-transplanted patients frequently present hyperglycemia immediately after the procedure. The goal of this work was to evaluate the effect of linagliptin + insulin in post-renal-transplanted patients with hyperglycemia.. Retrospective comparative study in post-renal transplanted patients with hyperglycemia after transplantation who were treated with linagliptin 5 mg daily plus insulin vs insulin alone for 5 days after renal transplantation with hyperglycemia. Main outcomes were glucose levels, insulin dose and severity of hypoglycemia.. There were 14 patients treated with linagliptin + insulin and 14 patients treated only with insulin. Glucose levels and insulin doses were lower in the linagliptin + insulin group in comparison with the insulin alone group, 131.0 ± 15.1 vs 191.1 ± 22.5 mg/dl (7.27 ± 0.84 vs 10.61 ± 1.25 mmol/l) and 37.5 ± 6.3 vs 24.2 ± 6.6 U, respectively (p < 0.05). Hypoglycemia was less severe in the linagliptin + insulin group, 65.1 ± 2.2 vs 54.2 ± 3.3 mg/dl (3.61 ± 0.12 vs 3.00 ± 3.3 ± 0.18 mmol/l), p 0.036.. The combination of linagliptin + insulin provided better glycemic control with a lower insulin dose and less severe hypoglycemia in comparison to insulin alone in patients with hyperglycemia immediately after renal transplantation.

Topics: Drug Therapy, Combination; Female; Humans; Hyperglycemia; Hypoglycemic Agents; Insulin; Kidney Transplantation; Linagliptin; Male; Middle Aged; Retrospective Studies

Vascular risk factors, such as type 2 diabetes mellitus (T2DM), are associated with the increased risk of Alzheimer's disease. One of the common T2DM medications, dipeptidyl peptidase (DPP)-4 inhibitors, have a minimum risk for hypoglycemia and have recently been suggested to ameliorate β-amyloid pathology. However, conflicting results have been reported regarding the effects of DPP-4 inhibition on cognitive function and tau pathology. Thus, we investigated whether inhibiting DPP-4 affects tau pathology and cognition in a mouse model of tauopathy with hyperglycemia. Male mice overexpressing the P301S mutant human microtubule-associated protein tau gene (PS19) were fed either a low or high-fat diet. PS19 mice were then administered either linagliptin, a DPP-4 inhibitor, or vehicle, from 6 weeks to 8 months of age. Linagliptin-treated mice exhibited higher levels of glucagon-like peptide-1 and decreased fasting blood glucose, compared with the vehicle-treated mice at 8 months. Linagliptin treatment significantly restored spatial reference memory and increased cerebral blood flow without affecting phosphorylation levels of tau or endothelial nitric oxide synthase (eNOS) in the brain. Linagliptin may ameliorate HFD-induced cognitive worsening in tauopathy, at least partially, by increasing cerebral perfusion via the eNOS-independent pathway.

Topics: Animals; Cognitive Dysfunction; Diet, High-Fat; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Humans; Hyperglycemia; Hypoglycemic Agents; Linagliptin; Male; Mice; Mice, Inbred C57BL; Tauopathies

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 herein report a case of hemichorea-hemiballism in an 85-year-old man diagnosed with diabetes at 76 years of age. After a one-year interruption in treatment, he was treated with a low-calorie diet, linagliptin, and nateglinide. Over 51 days, his HbA1c level decreased from 15.8% to 7.7%. After a prompt improvement in his hyperglycemia, he began experiencing involuntary movements in the right upper and lower extremities. T1-weighted magnetic resonance imaging showed a high signal intensity in the left lens nucleus. The patient was diagnosed with diabetic hemichorea-hemiballism and received haloperidol (1 mg/day) as treatment.

Topics: Chorea; Cyclohexanes; Diabetes Complications; Dyskinesias; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Linagliptin; Lower Extremity; Magnetic Resonance Imaging; Male; Middle Aged; Nateglinide; Phenylalanine