Uwe Hehnke

Kidney Disease End Points in a Pooled Analysis of Individual Patient–Level Data From a Large Clinical Trials Program of the Dipeptidyl Peptidase 4 Inhibitor Linagliptin in Type 2 Diabetes

BACKGROUND 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. STUDY DESIGN 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. SETTING & PARTICIPANTS 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]). INTERVENTION Of 5,466 consenting individuals with inadequately controlled type 2 diabetes, 3,505 received linagliptin, 5mg/d, and 1,961 received placebo. OUTCOMES 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. MEASUREMENTS Albuminuria was assessed using ACR. GFR was estimated using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation. RESULTS 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). LIMITATIONS Retrospective and hypothesis-generating study involving short- to midterm clinical trials. CONCLUSIONS 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.

Cardiovascular Outcomes and Safety of Empagliflozin in Patients With Type 2 Diabetes Mellitus and Peripheral Artery Disease: A Subanalysis of EMPA-REG OUTCOME

Peripheral artery disease (PAD) is one of the most common cardiovascular complications in patients with type 2 diabetes mellitus (T2DM) 1 and is a predictor of cardiovascular death. 2 Interventions that reduce cardiovascular complications in this patient population are urgently required. In the EMPA-REG OUTCOME trial, the sodium glucose cotransporter 2 inhibitor empagliflozin reduced the risk of cardiovascular death by 38% (hazard ratio [HR], 0.62; 95% confidence interval [CI] 0.49-0.77]) and hospitalization for heart failure (HHF) by 35% (HR, 0.65; 95% CI, 0.50-0.85) versus placebo when given in addition to standard of care. 3 We report analyses of the effects of empagliflozin on cardiovascular outcomes, mortality, and renal outcomes in patients with and without PAD at baseline in the EMPA-REG OUTCOME trial.

Treatment With the Dipeptidyl Peptidase-4 Inhibitor Linagliptin or Placebo Followed by Glimepiride in Patients With Type 2 Diabetes With Moderate to Severe Renal Impairment: A 52-Week, Randomized, Double-Blind Clinical Trial

Chronic kidney disease (CKD) is frequently comorbid with type 2 diabetes, and glucose-lowering treatment options are limited for such patients (1). We investigated the efficacy and safety of linagliptin, a dipeptidyl peptidase-4 inhibitor, in type 2 diabetic patients with moderate to severe renal impairment and insufficient glycemic control. This randomized, double-blind, parallel-group clinical trial comprised a 12-week, placebo-controlled phase followed by a 40-week, active-controlled extension. The study was conducted between 17 March 2010 and 18 June 2012 at 52 outpatient clinics in nine countries (ClinicalTrials.gov, NCT01087502). Patients with type 2 diabetes, HbA1c 7.0–10.0% (53–86 mmol/mol), and estimated glomerular filtration rate (eGFR) 110 mg/dL. The primary end point was change in HbA1c from baseline to week 12 in the full-analysis set (FAS; all randomized patients who received ≥1 dose of study drug and had a baseline and ≥1 postbaseline measurement of HbA1c); missing data were imputed using last observation carried forward. Secondary end points included change in HbA1c from baseline over time. The incidence of adverse events (AEs) was evaluated for the treated set (TS; all randomized patients who received ≥1 dose …

Safety and efficacy of the dipeptidyl peptidase-4 inhibitor linagliptin in elderly patients with type 2 diabetes: a comprehensive analysis of data from 1331 individuals aged ≥ 65 years

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).

Improved glucose control with reduced hypoglycaemic risk when linagliptin is added to basal insulin in elderly patients with type 2 diabetes.

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.

Regardless of the degree of glycaemic control, linagliptin has lower hypoglycaemia risk than all doses of glimepiride, at all time points, over the course of a 2-year trial.

To evaluate the risk of documented hypoglycaemia with glimepiride versus linagliptin.

The dipeptidyl peptidase-4 inhibitor linagliptin lowers postprandial glucose and improves measures of β-cell function in type 2 diabetes†

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.

Efficacy and safety of linagliptin as add-on therapy to basal insulin and metformin in people with Type 2 diabetes

To evaluate the efficacy and safety of linagliptin in people with Type 2 diabetes inadequately controlled on basal insulin and metformin.

Impact of empagliflozin on blood pressure in dipper and non-dipper patients with type 2 diabetes mellitus and hypertension

In the EMPA‐REG BP trial, empagliflozin significantly reduced systolic and diastolic blood pressure (SBP and DBP) compared with placebo at week 12 in patients with type 2 diabetes mellitus (T2DM) and hypertension. In a post‐hoc analysis, we assessed the effect of empagliflozin on SBP and DBP using 24‐hour ambulatory BP monitoring in patients categorized as dippers (sleep‐time mean SBP ≤ 90% of awake‐time mean; n = 417) or non‐dippers (sleep‐time mean SBP > 90% of awake‐time mean; n = 350). In dippers, adjusted mean (SE) changes from baseline in mean 24‐hour SBP (mm Hg) at week 12 were −0.2 (0.7) with placebo vs −3.8 (0.6) and −3.9 (0.7) with empagliflozin 10 and 25 mg, respectively (both P  < .001 vs placebo). In non‐dippers, these changes were 1.0 (0.7) with placebo vs −1.6 (0.7) with empagliflozin 10 mg ( P  = .013 vs placebo) and −3.8 (0.7) with empagliflozin 25 mg ( P  < .001 vs placebo). In both dippers and non‐dippers, SBP and DBP patterns over 24 hours were maintained. There were no clinically relevant changes in heart rate with empagliflozin. In conclusion, empagliflozin significantly reduced mean 24‐hour SBP compared with placebo in dippers and non‐dippers.

Safety and efficacy of linagliptin in patients with type 2 diabetes mellitus and coronary artery disease: Analysis of pooled events from 19 clinical trials

AIMS To examine the safety and efficacy of linagliptin in patients with type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD) using pooled data from the global clinical trials program. METHODS Patient-level data were pooled from randomized, placebo-controlled clinical trials of linagliptin (5mg, monotherapy or combination therapy). Safety/efficacy analyses were conducted for patients with CAD and ≥12 and ≥24weeks of treatment, respectively. RESULTS The safety analysis included 19 trials (linagliptin, n=451; placebo, n=272) and the efficacy analysis, 12 trials (linagliptin, n=328; placebo, n=198); mean (± standard deviation) exposure to study treatment was 212 (144) days linagliptin and 245 (171) days placebo. Occurrence of cardiac adverse events (AEs) was similar for linagliptin- and placebo-treated patients (9.1% and 9.2%, respectively); exposure-adjusted incidence rates (per 100 patient-years) were 16.6 and 14.0, respectively. Overall incidence of AEs was numerically lower with linagliptin than placebo. After 24weeks, mean adjusted change (standard error) from baseline glycosylated hemoglobin was -0.64% (0.04) with linagliptin vs. -0.08% (0.05) with placebo (P<.001). CONCLUSIONS This comprehensive pooled analysis showed that addition of linagliptin to treatment regimens of patients with T2DM and CAD was not associated with an increased incidence of cardiac AEs, was well tolerated, and was effective.