This column highlights clinical trial data and landmark trials. Information for obtaining trial data and the references to the published articles are provided to facilitate discussion with your patients/colleagues. The trial is identified by the acronym and the National Clinical Trials Identifier. Primary outcome results are summarized.
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Study title: Effect of Linagliptin on Cardiovascular Events in Type 2 Diabetes Mellitus with High Cardiovascular and Renal Risk
Study title acronym: CARMELINA
ClinicalTrials.gov identifier: NCT01897532
1. Rosenstock J, Perkovic V, Johansen OE, et al. Effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes (T2D) and high cardiovascular and renal risk: The CARMELINA randomized clinical trial. JAMA. 2019;321(1):69-79. doi:10.1001/jama.2018.18269.
Sponsor: Boehringer Ingelheim
Study design: Randomized, placebo-controlled, multicenter, non-inferiority trial in adults with type 2 diabetes (T2D) and cardiovascular or renal risk factors. Cardiovascular and renal risk factors were history of vascular disease, reduced estimated glomerular filtration rate and micro- or macroalbuminuria. Patients with end-stage renal disease were excluded. Patients in the trial had a hemoglobin A1c (A1C) between 6.5 and 10%. Patients were randomized to receive linagliptin 5 mg daily or placebo added to usual care, which could include other glucose-lowering medications or insulin.
Primary outcome: First occurrence of the composite of cardiovascular death, nonfatal myocardial infarction or nonfatal stroke.
Other outcome: Time to first occurrence of adjudicated death due to renal failure, end-stage renal disease or a sustained 40% or more decrease in estimated glomerular filtration rate.
Results: A total of 6,991 patients were enrolled in the study. During a mean follow-up of 2.2 years, the composite cardiovascular outcome occurred in 12.4% of the linagliptin group and 12.1% of the placebo group. The composite renal outcome occurred in 9.4% of the linagliptin group and 8.8% of the placebo group. The absolute incidence rate differences for both the primary and secondary outcomes showed that linagliptin is non-inferior to placebo in terms of cardiovascular and renal risk. Adverse events were reported in 77.2% of patients on linagliptin and 78.1% of patients on placebo. Some 0.3% of patients on linagliptin had confirmed pancreatitis versus 0.1% of patients in the placebo arm.
Summary: Linagliptin and other dipeptidyl peptidase-4 agents are commonly used medications for T2D. These medications are administered orally and have a very favorable side effect profile. This trial demonstrates that these medications are not associated with an increase in cardiovascular or renal events. However, this trial was not designed to show whether linagliptin use results in a decrease in cardiovascular or renal endpoints.
About our experts: Kathryn Thrailkill, MD, Professor of Pediatrics, Division of Pediatric Endocrinology, Barnstable Brown Endowed Chair in Pediatric Diabetes Research, Barnstable Brown Diabetes Center, University of Kentucky, Lexington, Kentucky
Derick Adams, DO, Assistant professor, internal medicine, Division of Endocrinology, Endocrinology Fellowship associate program director, Barnstable Brown Diabetes Center, University of Kentucky, Lexington, Kentucky