DPP-4 inhibitor non-inferior to placebo in preventing CV outcomes
Effect of Linagliptin vs Placebo on Major Cardiovascular Events in Adults With Type 2 Diabetes and High Cardiovascular and Renal Risk
Introduction and methods
Linagliptin is a selective, once-daily, dipeptidyl peptidase 4 (DPP-4) inhibitor, indicated for glucose-lowering in patients with type 2 diabetes (T2DM), and it has been hypothesized that linagliptin therapy may also provide cardiovascular (CV) and renal protection to T2DM patients [1,2]. The Cardiovascular and Renal Microvascular Outcome Study With Linagliptin (CARMELINA)  tested this hypothesis by evaluating the CV and renal safety of linagliptin in adult T2DM patients at high cardiorenal risk. Participants with end-stage renal disease (ESRD), defined as an eGFR <15 mL/min/1.73 m2 or requiring maintenance dialysis, were excluded.
CARMELINA, a randomized, double-blind, placebo-controlled clinical trial, randomized eligible individuals 1:1 to receive either oral linagliptin (5 mg/day) or placebo, on top of standard of care. The primary endpoint was the time to first occurrence of CV death, non-fatal myocardial infarction (MI), or non-fatal stroke (3-point major adverse CV event [MACE]). The secondary endpoint was the time to first occurrence of a composite of ESRD, death due to renal failure, or a sustained decrease of at least 40% in eGFR from baseline.
- Between 2013 and 2016, 6,979 patients were randomized, and received study drug for a median of 1.9 years. The median observation time was 2.2 years.
- The primary composite 3-point MACE outcome occurred in 12.4% of patients in the linagliptin group (5.77 per 100 person-years) and in 12.1% of patients in the placebo group (5.63 per 100 person-years).
- The respective absolute incidence rate difference was 0.13 (95%CI: −0.63 to 0.90) per 100 person-years and the HR for non-inferiority was 1.02 (95%CI: 0.89-1.17; P <0.001 for non-inferiority).
- The risk of the secondary endpoint was not significantly different between the 2 groups (linagliptin: 9.4%; 4.89 per 100 person-years; placebo: 8.8%; 4.66 per 100 person-years; absolute incidence rate difference: 0.22; 95%CI: −0.52 to 0.97 per 100 person-years; HR: 1.04; 95%CI: 0.89-1.22; P=0.62).
- Adverse events occurred in 77.2% of patients in the linagliptin group and in 78.1% of patients in the placebo group, serious adverse events occurred in 37.0% vs. 38.5%, and adverse events leading to study drug discontinuation occurred in 10.3% vs. 11.5%
In adult T2DM patients at high cardiorenal risk, linagliptin on top of standard of care was non-inferior compared with placebo, with regard to the risk of CV outcomes, during a median observation time of 2.2 years. Renal outcomes were slightly more in the linagliptin group, however, this difference between groups was not statistically significant.