title: 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.
abstract: 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.
  
  
  METHODS
  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.
  
  
  METHODS
  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]).
  
  
  METHODS
  Of 5,466 consenting individuals with inadequately controlled type 2 diabetes, 3,505 received linagliptin, 5mg/d, and 1,961 received placebo.
  
  
  RESULTS
  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.
  
  
  METHODS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia. Electronic address: mark.cooper@bakeridi.edu.au.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Cooper
authors.affiliation: George Institute for Global Health, University of Sydney, New South Wales, Australia.
authors.forename: Vlado
authors.initials: V
authors.lastname: Perkovic
authors.affiliation: Washington University in St Louis, St Louis, MO.
authors.forename: Janet B
authors.initials: JB
authors.lastname: McGill
authors.affiliation: Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia; Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland; Division of Nephrology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Per-Henrik
authors.initials: PH
authors.lastname: Groop
authors.affiliation: University of Würzburg, Würzburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Wanner
authors.affiliation: Dallas Diabetes and Endocrine Center at Medical City, Dallas, TX.
authors.forename: Julio
authors.initials: J
authors.lastname: Rosenstock
authors.affiliation: Boehringer Ingelheim, Ingelheim, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Hehnke
authors.affiliation: Boehringer Ingelheim, Ingelheim, Germany.
authors.forename: Hans-Juergen
authors.initials: HJ
authors.lastname: Woerle
authors.affiliation: Boehringer Ingelheim, Ingelheim, Germany.
authors.forename: Maximilian
authors.initials: M
authors.lastname: von Eynatten
mesh_terms: D000368:Aged; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D003928:Diabetic Nephropathies / Q000453:epidemiology* / Q000517:prevention & control; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D000069476:Linagliptin; D008297:Male; D008875:Middle Aged; D011687:Purines / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D011687:Purines; D011799:Quinazolines; D000069476:Linagliptin
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)