Dipeptidyl Peptidase-4 Inhibitors and Cardiovascular Outcomes: Meta-Analysis of Randomized Clinical Trials with 55,141 Participants

Aims: The association between glucose lowering in diabetes mellitus and major cardiovascular (CV) outcomes is weak; indeed, some oral hypoglycemic agents are associated with increased CV events. Dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors) are a new class of oral hypoglycemic agent that may have beneficial CV effects. We undertook a systematic review and meta-analysis to appraise the CV safety and efficacy of DPP-4 inhibitors. Methods: Comprehensive search for prospective trials involving DPP-4 inhibitors. Trials included reported at least one of the outcomes examined, recruited minimum 100 patients and minimum follow-up 24 weeks. The risk ratio (RR) was calculated using the Mantel-Haenszel random-effects model for mortality and major cardiovascular (CV) outcomes. Results: Fifty trials enrolling 55,141 participants were included. Mean follow-up 45.3 weeks. DPP-4 inhibitors compared with all comparators (placebo and active) showed no difference in all-cause mortality (n = 50,982, RR = 1.01, 95% CI 0.91-1.13, P = 0.83), CV mortality (n = 48,151, RR = 0.97, 95% CI 0.85-1.11, P = 0.70), acute coronary syndrome (ACS) (n = 53,034 RR = 0.97, 95% CI 0.87-1.08, P = 0.59), or stroke (n = 42,737, RR = 0.98, 95% CI 0.81-1.18, P = 0.80), and a statistically significant increase in heart failure outcomes (n = 39,953, RR = 1.16, 95% CI 1.01-1.33, P = 0.04). Discussion: Treatment with DPP-4 inhibitors compared with placebo shows no increase in risk with regards to all-cause mortality, CV mortality, ACS, or stroke, but a statistically significant trend toward increased risk of HF outcomes. Conclusion: These findings suggest no cardiovascular harm (or benefit) with DPP-4 inhibitors; further large-scale CV outcome studies will resolve the issue of excess HF risk.