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) [3] 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.
Main results
- 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%
Conclusion
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.
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