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.
Keywords: Dipeptidyl peptidase 4 (DPP-4) inhibition; albuminuria; glucose control; glucose-lowering therapy; hyperglycemia; kidney disease end points; linagliptin; pooled analysis; renal function; renal risk; type 2 diabetes mellitus (T2DM).
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.