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

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Perkovic, Vlado
Toto, Robert
Cooper, Mark E
Mann, Johannes FE
Rosenstock, Julio
McGuire, Darren K
Kahn, Steven E
Marx, Nikolaus
Alexander, John H
Zinman, Bernard

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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.


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.


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.





CARMELINA investigators, Kidney, Cardiovascular System, Humans, Diabetic Nephropathies, Kidney Failure, Chronic, Cardiovascular Diseases, Diabetes Mellitus, Type 2, Hypoglycemic Agents, Glomerular Filtration Rate, Prognosis, Treatment Outcome, Incidence, Mortality, Retrospective Studies, Aged, Middle Aged, Female, Male, Renal Insufficiency, Chronic, Dipeptidyl-Peptidase IV Inhibitors, Linagliptin


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Publication Info

Perkovic, Vlado, Robert Toto, Mark E Cooper, Johannes FE Mann, Julio Rosenstock, Darren K McGuire, Steven E Kahn, Nikolaus Marx, et al. (2020). 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, 43(8). pp. 1803–1812. 10.2337/dc20-0279 Retrieved from https://hdl.handle.net/10161/22866.

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John Hunter Peel Alexander

Professor of Medicine

John H. Alexander, MD, MHS is a cardiologist and Professor of Medicine in the Department of Medicine, Division of Cardiology at Duke University School of Medicine, as well as the Vice Chief, Clinical Research in the Division of Cardiology. He is the Director of Cardiovascular Research at the Duke Clinical Research Institute where he oversees a large group of clinical research faculty and a broad portfolio of cardiovascular clinical trials and observational clinical research programs. He is a member of the American Society of Clinical Investigation.

Dr. Alexander’s clinical interests are in acute and general cardiovascular disease, valvular heart disease, and echocardiology. His research is focused on the translation of novel therapeutic concepts into clinical data through clinical trials, specifically on the therapeutics of acute coronary syndromes, chronic coronary artery disease, and cardiac surgery and on novel methodological approaches to clinical trials. He was on the Executive Committee of the ARISTOTLE trial of apixaban in patients with atrial fibrillation and was the Principal Investigator of the APPRAISE-2 trial of apixaban in patients with acute coronary syndromes.

Dr. Alexander has published extensively and has served as the principal investigator of numerous multicenter clinical trials. He currently serves as the co-chair of the Clinical Trial Transformation Initiative (CTTI).

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