Effect of Medications for Type 2 Diabetes on Cardiovascular Events and Mortality: A Comprehensive Pairwise and Network Meta-Analysis

Aim: To assess the effect of all the approved classes of medications for type 2 diabetes on Major Adverse Cardiovascular events (MACE) and all-cause mortality. Methods: We performed a pairwise and network meta-analysis, including randomised controlled trials with a duration of at least 40 weeks, comparing medications versus placebo or an active comparator, in which MACE and deaths were adjudicated. Results: We included 93 studies. In pairwise meta-analyses, versus all comparators, GLP-1 receptor agonists (GLP1RA), SGLT-2 inhibitors (SGLT2i), metformin and pioglitazone were associated with a significant reduction of MACE and sulfonylureas with increased MACE. Furthermore, tirzepatide, SGLT2i and GLP1RA were associated with a significantly reduced all-cause mortality. In the principal (frequentist) network meta-analysis, metformin (OR 0.69, 95% CI 0.53–0.89), SGLT2i (0.82, 0.75–0.90), GLP1RA (0.87, 0.83–0.92) and tirzepatide (0.82, 0.72–0.93) were associated with a significant reduction of MACE versus placebo; no effect was observed for insulin, DPP4 inhibitors (DPP4i) or sulfonylureas. Tirzepatide (0.72, 0.64–0.82), SGLT2i (0.85, 0.80–0.91) and GLP1RA (0.85, 0.80–0.91) were associated with a significantly reduced mortality versus placebo; no effect was detected for other drugs. The sensitivity (Bayesian) analysis did not confirm the significance of results for pioglitazone on MACE. The certainty of evidence was moderate-to-high for GLP1RA, SGLT2i, Tirzepatide, DPP4i; low for metformin; low-to-moderate for other drugs. Conclusion: SGLT2i, GLP1RA, tirzepatide and (with lower quality of evidence) pioglitazone and metformin are associated with a reduced incidence of cardiovascular events; tirzepatide, SGLT2i and GLP1RA are also associated with a reduced all-cause mortality.