Abstract Body (Do not enter title and authors here): Background: While injectable GLP-1 receptor agonists like semaglutide have demonstrated clear cardiovascular benefits in type 2 diabetes, the role of oral incretin-based therapies, including oral semaglutide and DPP-4 inhibitors—remains less well defined. Comprehensive evaluation of their cardiovascular efficacy is warranted.
Research Question: What are the cardiovascular outcomes associated with oral incretin-based therapies, specifically oral semaglutide and DPP-4 inhibitors, in patients with type 2 diabetes compared to placebo or standard care?
Methods: We searched electronic databases for randomized controlled trials (RCTs). Meta-analysis was conducted in R version 4.4.3 using the “meta” and “metasens” packages. A restricted maximum likelihood random-effects model with Hartung-Knapp adjustment was used to calculate risk ratios (RRs) with 95% confidence intervals (CIs).
Results: A total of 11 RCTs comprising 62,821 patients were included, of which two evaluated oral semaglutide and the remaining nine assessed DPP-4 inhibitors. There was no statistically significant difference between oral incretin therapies and control in the risk of major adverse cardiovascular events (RR: 0.95; 95% CI: 0.87–1.03), cardiovascular death (RR: 0.97; 95% CI: 0.87–1.09), myocardial infarction (RR: 0.90; 95% CI: 0.67–1.21), non-fatal myocardial infarction (RR: 0.95; 95% CI: 0.76–1.18), unstable angina (RR: 0.99; 95% CI: 0.82–1.20), stroke (RR: 0.96; 95% CI: 0.83–1.11), hospitalization for heart failure (RR: 0.99; 95% CI: 0.70–1.38), and all-cause mortality (RR: 0.99; 95% CI: 0.70–1.38). However, oral incretin therapies were associated with a modest but statistically significant reduction in the risk of non-fatal stroke (RR: 0.88; 95% CI: 0.79–0.99). There were no significant differences in the risk of serious adverse events (RR: 0.96; 95% CI: 0.87–1.05) or discontinuation due to serious adverse events (RR: 1.08; 95% CI: 0.53–2.21). Sensitivity analyses were conducted due to significant heterogeneity in key outcomes. While omitting certain studies reduced heterogeneity, the overall results remained consistent.
Conclusion: Oral incretin-based therapies did not significantly impact major cardiovascular outcomes or mortality in patients with type 2 diabetes, but were associated with a modest reduction in non-fatal stroke risk. Further trials should be conducted including oral GLP-1 RAs to establish conclusive evidence.