Cardiovascular efficacy and safety of dipeptidyl peptidase-4 inhibitors: A meta-analysis of cardiovascular outcome trials

BACKGROUND: Dipeptidyl peptidase-4 (DPP-4) inhibitors are a generally safe and well tolerated antidiabetic drug class with proven efficacy in type 2 diabetes mellitus (T2DM). Recently, a series of large, randomized controlled trials (RCTs) addressing cardiovascular outcomes with DPP-4 inhibitors have been published. AIM: To pool data from the aforementioned trials concerning the impact of DPP-4 inhibitors on surrogate cardiovascular efficacy outcomes and on major cardiac arrhythmias. METHODS: We searched PubMed and grey literature sources for all published RCTs assessing cardiovascular outcomes with DPP-4 inhibitors compared to placebo until October 2020. We extracted data concerning the following “hard” efficacy outcomes: fatal and non-fatal myocardial infarction, fatal and non-fatal stroke, hospitalization for heart failure, hospitalization for unstable angina, hospitalization for coronary revascularization and cardiovascular death. We also extracted data regarding the risk for major cardiac arrhythmias, such as atrial fibrillation, atrial flutter, ventricular fibrillation and ventricular tachycardia. RESULTS: We pooled data from 6 trials in a total of 52520 patients with T2DM assigned either to DPP-4 inhibitor or placebo. DPP-4 inhibitors compared to placebo led to a non-significant increase in the risk for fatal and non-fatal myocardial infarction [risk ratio (RR) = 1.02, 95%CI: 0.94-1.11, I(2 )= 0%], hospitalization for heart failure (RR = 1.09, 95%CI: 0.92-1.29, I(2 )= 65%) and cardiovascular death (RR = 1.02, 95%CI: 0.93-1.11, I(2 )= 0%). DPP-4 inhibitors resulted in a non-significant decrease in the risk for fatal and non-fatal stroke (RR = 0.96, 95%CI: 0.85-1.08, I(2 )= 0%) and coronary revascularization (RR = 0.99, 95%CI: 0.90-1.09, I(2 )= 0%), Finally, DPP-4 inhibitors demonstrated a neutral effect on the risk for hospitalization due to unstable angina (RR = 1.00, 95%CI: 0.85-1.18, I(2 )= 0%). As far as cardiac arrhythmias are concerned, DPP-4 inhibitors did not significantly affect the risk for atrial fibrillation (RR = 0.95, 95%CI: 0.78-1.17, I(2 )= 0%), while they were associated with a significant increase in the risk for atrial flutter, equal to 52% (RR = 1.52, 95%CI: 1.03-2.24, I(2 )= 0%). DPP-4 inhibitors did not have a significant impact on the risk for any of the rest assessed cardiac arrhythmias. CONCLUSION: DPP-4 inhibitors do not seem to confer any significant cardiovascular benefit for patients with T2DM, while they do not seem to be associated with a significant risk for any major cardiac arrhythmias, except for atrial flutter. Therefore, this drug class should not be the treatment of choice for patients with established cardiovascular disease or multiple risk factors, except for those cases when newer antidiabetics (glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter-2 inhibitors) are not tolerated, contraindicated or not affordable for the patient.