Background: There are concerns about the cardiovascular safety of dipeptidyl peptidase-4 (DPP-4) inhibitors in patients with type 2 diabetes.
Objectives: To evaluate the effect of DPP-4 inhibitors on cardiovascular effects in patients with type 2 diabetes systematically.
Methods: We searched MEDLINE, Embase, the Cochrane Library and ClinicalTrials.gov from inception to 20 November 2015. We included randomized controlled trials with available data comparing DPP-4 inhibitors with placebo and traditional anti-diabetic drugs in patients with type 2 diabetes, with a minimum 12-week follow-up. The endpoint of interest was a composite of cardiovascular events, which consisted of major adverse cardiovascular events (MACEs) defined by FDA, plus heart failure. MACEs included cardiovascular death, myocardial infarction and stroke. We calculated odds ratios (OR) with 95% confidence intervals (CI) using a random-effects model. We performed network meta-analysis to supplement direct comparisons.
Results: We included 92 trials with 11 treatments, including five DPP-4 inhibitors (alogliptin, linagliptin, saxagliptin, sitagliptin and vildagliptin), placebo and five traditional anti-diabetic drugs (metformin, sulfonylurea, thiazolidinediones, glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter 2). Significant decreased risk of cardiovascular events was detected when vildagliptin was compared with placebo (OR 0.43, 95% CI 0.17 to 0.94), sulfonylurea (OR 0.38, 95% CI 0.14 to 0.76), metformin (OR 0.26, 95% CI 0.06 to 0.95) and sitagliptin (OR 0.42, 95% CI 0.18 to 0.92). The protective effect on cardiovascular events was not detected in other DPP-4 inhibitors. Ranking probability analysis indicated vildagliptin decreased cardiovascular risk most among all 11 treatments with probability of 84%.
Conclusions: Vildagliptin seems associated with decreased risk of cardiovascular events compared with placebo and other anti-diabetic drugs, while other DPP-4 inhibitors do not show any increased risk of cardiovascular events. Further long-term trials and population-based studies are needed to confirm the protective effect on cardiovascular safety of vildagliptin.