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 pre-defined inclusion/exclusion criteria, such as being drug-naive (hemoglobin A(1c), 7.0%-11.0% [53-97 mmol/mol]) or being on background glucose-lowering therapy (hemoglobin A(1c), 6.5%-10.5% [48-91 mmol/mol]). Intervention: Of 5,466 consenting individuals with inadequately controlled type 2 diabetes, 3,505 received linagliptin, 5 mg/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 mu mol/L from a baseline value <250 mu mol/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. (C) 2015 The Authors. Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. This is an open access article under the CC BY-NC-ND license.