Cardiovascular Safety of Empagliflozin Versus Dipeptidyl Peptidase-4 (DPP-4) Inhibitors in Type 2 Diabetes: Systematic Literature Review and Indirect Comparisons

Introduction: Clinical trials conducted in patients with type 2 diabetes (T2DM) treated with glucose-lowering drugs and examining cardiovascular-related outcomes have yielded mixed results. In this work, we aimed to assess the relative treatment effects of empagliflozin versus sitagliptin and saxagliptin (dipeptidyl peptidase-4 (DPP-4) inhibitors) on cardiovascular- related outcomes in patients with T2DM. Methods: We conducted a systematic literature review to identify clinical trials assessing cardiovascular- related outcomes for sitagliptin-, saxagliptin-, and empagliflozin-treated patients with T2DM. A network meta-analysis of indirect treatment comparisons was conducted in a Bayesian framework. Hazard ratios (HR) and 95% credible intervals (CrI) were computed for six cardiovascular-related outcomes to estimate the relative efficacies of these agents. Results: Empagliflozin showed a statistically significant superiority over saxagliptin (HR 0.60; 95% CrI 0.46-0.80) and sitagliptin (HR 0.60; 95% CrI 0.46-0.79) to reduce the risk for cardiovascular-related mortality. For all-cause mortality, empagliflozin showed a statistically significant risk reduction compared to saxagliptin (HR 0.61; 95% CrI 0.49-0.76) and sitagliptin (HR 0.67; 95% CrI 0.54-0.83). A similar pattern was observed in the risk reduction for hospitalization due to heart failure, where empagliflozin was found to be statistically significantly superior to saxagliptin (HR 0.51; 95% CrI 0.37-0.70) and sitagliptin (HR 0.65; 95% CrI 0.47-0.90). Empagliflozin was not statistically significantly different to sitagliptin and saxagliptin with regard to the risk of a composite endpoint composed of death, stroke or myocardial infarction. Conclusion: In this indirect comparison to the DPP-4 inhibitors saxagliptin and sitagliptin, empagliflozin significantly lowered the risk of cardiovascular-related mortality, all-cause mortality and hospitalizations due to heart failure. Funding: Boehringer Ingelheim GmbH.