Effects of Linagliptin on Cardiovascular and Kidney Outcomes in People With Normal and Reduced Kidney Function: Secondary Analysis of the CARMELINA Randomized Trial

Diabetes Care. 2020 Aug;43(8):1803-1812. doi: 10.2337/dc20-0279. Epub 2020 May 22.


Objective: Type 2 diabetes is a leading cause of kidney failure, but few outcome trials proactively enrolled individuals with chronic kidney disease (CKD). We performed secondary analyses of cardiovascular (CV) and kidney outcomes across baseline estimated glomerular filtration rate (eGFR) categories (≥60, 45 to <60, 30 to <45, and <30 mL/min/1.73 m2) in Cardiovascular and Renal Microvascular Outcome Study With Linagliptin (CARMELINA), a cardiorenal placebo-controlled outcome trial of the dipeptidyl peptidase 4 inhibitor linagliptin (NCT01897532).

Research design and methods: Participants with CV disease and/or CKD were included. The primary outcome was time to first occurrence of CV death, nonfatal myocardial infarction, or nonfatal stroke (three-point major adverse CV event [3P-MACE]), with a secondary outcome of renal death, end-stage kidney disease, or sustained ≥40% decrease in eGFR from baseline. Other end points included progression of albuminuria, change in HbA1c, and adverse events (AEs) including hypoglycemia.

Results: A total of 6,979 subjects (mean age 65.9 years; eGFR 54.6 mL/min/1.73 m2; 80.1% albuminuria) were followed for 2.2 years. Across eGFR categories, linagliptin as compared with placebo did not affect the risk for 3P-MACE (hazard ratio 1.02 [95% CI 0.89, 1.17]) or the secondary kidney outcome (1.04 [0.89, 1.22]) (interaction P values >0.05). Regardless of eGFR, albuminuria progression was reduced with linagliptin, as was HbA1c, without increasing risk for hypoglycemia. AEs were balanced among groups overall and across eGFR categories.

Conclusions: Across all GFR categories, in participants with type 2 diabetes and CKD and/or CV disease, there was no difference in risk for linagliptin versus placebo on CV and kidney events. Significant reductions in risk for albuminuria progression and HbA1c and no difference in AEs were observed.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Cardiovascular Diseases / epidemiology*
  • Cardiovascular Diseases / etiology
  • Cardiovascular Diseases / prevention & control
  • Cardiovascular System / drug effects*
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / diagnosis
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / epidemiology
  • Diabetic Nephropathies / drug therapy
  • Diabetic Nephropathies / epidemiology
  • Dipeptidyl-Peptidase IV Inhibitors / pharmacology
  • Dipeptidyl-Peptidase IV Inhibitors / therapeutic use
  • Female
  • Glomerular Filtration Rate / drug effects
  • Humans
  • Hypoglycemic Agents / pharmacology
  • Hypoglycemic Agents / therapeutic use
  • Incidence
  • Kidney / drug effects*
  • Kidney Failure, Chronic / complications
  • Kidney Failure, Chronic / epidemiology*
  • Kidney Failure, Chronic / physiopathology
  • Kidney Failure, Chronic / prevention & control
  • Linagliptin / pharmacology*
  • Linagliptin / therapeutic use
  • Male
  • Middle Aged
  • Mortality
  • Prognosis
  • Renal Insufficiency, Chronic / complications
  • Renal Insufficiency, Chronic / drug therapy
  • Renal Insufficiency, Chronic / epidemiology
  • Renal Insufficiency, Chronic / physiopathology
  • Retrospective Studies
  • Treatment Outcome


  • Dipeptidyl-Peptidase IV Inhibitors
  • Hypoglycemic Agents
  • Linagliptin

Associated data

  • ClinicalTrials.gov/NCT01897532
  • figshare/10.2337/figshare.12129993