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, parallelgroup 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) ,60 mL/min/1.73 m were randomized 1:1 to double-blind treatment with linagliptin 5 mg/day or placebo for 12 weeks; placebo patients were then switched to glimepiride 1–4 mg/day, with double blinding maintained using a doubledummy design, and treatments continued until week 52. Glimepiride could be uptitrated in 1-mg increments from a 1-mg starting dose to a maximum of 4 mg at 4-week intervals during the first 12 weeks of the extension if patients’ self-monitored fasting blood glucose values were.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 of study drug). A total of 235 patients were randomized to linagliptin (n 5 113) or placebo (n 5 122), constituting the TS. The FAS comprised 113 and 120 linagliptin and placebo patients, respectively. Baseline demographic and clinical characteristics were similar between treatment groups. Overall, participants had a mean 6 SD age of 66.6 6 9.3 years and HbA1c of 8.1 6 0.9% (65 6 10 mmol/mol); 63.4% were male, 70.2% were white, 86% were receiving insulin, and the mean eGFR was 37.2 mL/min/1.73 m. After 12 weeks, the adjusted mean 6 SE change from baseline in HbA1c was –0.53 6 0.11% (–5.8 6 1.2 mmol/mol) with linagliptin and –0.11 6 0.11% (–1.3 6 1.2 mmol/mol) with placebo, a placebo-corrected change with linagliptin of –0.42% (95% CI –0.60 to –0.24 [–4.6 mmol/mol, 95% CI –6.5 to –2.6]; P , 0.0001). After 52 weeks, adjusted mean change from baseline in HbA1c was –0.64% (–7.0 mmol/mol) and –0.50% (–5.5 mmol/mol) in the linagliptin and placebo/glimepiride groups, respectively (Fig. 1A). During the placebo-controlled 12 weeks, AEs occurred in approximately three-quarters of both treatment groups (linagliptin, 76.1%; placebo, 73.8%) but were drug-related in fewer than one-quarter (linagliptin, 23.9%; placebo, 24.6%). Fewer than 10% of linagliptin and placebo patients reported serious AEs (7.1% and 8.2%, respectively) or AEs leading to discontinuation of study drug (3.5 vs. 4.9%). During the extension, fewer linagliptin than glimepiride patients reported any AE (90.7 vs.