linagliptin and Cardiovascular-Diseases

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

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

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

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

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

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

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

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

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

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

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 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

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

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 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

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

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

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

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

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

It remains to be elucidated whether dipeptidylpeptidase-4 (DPP-4) inhibitor can ameliorate cardiovascular injury in salt-sensitive hypertension. The present study was undertaken to test our hypothesis that linagliptin, a DPP-4 inhibitor, administration initiated after onset of hypertension and cardiac hypertrophy can ameliorate cardiovascular injury in Dahl salt-sensitive hypertensive rats (DS rats).. High-salt loaded DS rats with established hypertension and cardiac hypertrophy were divided into two groups, and were orally given (1) vehicle or (2) linagliptin (3 mg/kg/day) once a day for 4 weeks, and cardiovascular protective effects of linagliptin in DS rats were evaluated.. Linagliptin did not significantly affect blood pressure and blood glucose levels in DS rats. Linagliptin significantly lessened cardiac hypertrophy in DS rats, as estimated by cardiac weight and echocardiographic parameters. Linagliptin significantly ameliorated cardiac fibrosis, cardiac macrophage infiltration, and coronary arterial remodeling in DS rats. Furthermore, linagliptin significantly mitigated the impairment of vascular function in DS rats, as shown by the improvement of acetylcholine-induced or sodium nitroprusside-induced vascular relaxation by linagliptin. These cardiovascular protective effects of linagliptin were associated with the attenuation of oxidative stress, NADPH oxidase subunits, p67phox and p22 phox, and angiotensin-converting enzyme (ACE).. Our results provided the experimental evidence that linagliptin treatment initiated after the appearance of hypertension and cardiac hypertrophy protected against cardiovascular injury induced by salt-sensitive hypertension, independently of blood pressure and blood glucose. These beneficial effects of linagliptin seem to be attributed to the reduction of oxidative stress and ACE.

Topics: Animals; Blood Glucose; Blood Pressure; Blood Pressure Determination; Cardiovascular Diseases; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Heart; Hypertension; Linagliptin; Male; Purines; Quinazolines; Rats; Rats, Inbred Dahl; Sodium Chloride, Dietary