Oral semaglutide significantly lowered all-cause mortality, MACE, and non-fatal MI in high-risk T2DM patients with coexisting CVD or CKD. The meta-analysis, published in Circulation, evaluated cardiovascular outcomes in adults aged over 50 years with T2DM and established CVD or CKD. A total of 19,663 patients were included, with 9,831 receiving oral semaglutide and 9,832 receiving placebo across four randomized controlled trials. The primary outcomes were all-cause mortality, MACE, non-fatal MI, cardiovascular death, and non-fatal stroke. Secondary outcomes included serious adverse events of interest such as malignant neoplasms and acute pancreatitis.

Pooled data demonstrated reductions in all-cause mortality (hazard ratio [HR]: 0.87; 95% confidence interval [CI]: 0.78–0.95; p = 0.004), MACE (HR: 0.81; 95% CI: 0.75–0.88; p < 0.00001), and non-fatal MI (HR: 0.79; 95% CI: 0.67–0.93; p = 0.005) with oral semaglutide compared to placebo. No significant differences were observed for cardiovascular death (HR: 0.80; 95% CI: 0.64–1.01), non-fatal stroke (HR: 0.88; 95% CI: 0.67–1.15), or HF hospitalization (HR: 0.91; 95% CI: 0.76–1.09). Adverse-event rates, including malignant neoplasms (risk ratio [RR]: 1.08; p = 0.17) and acute pancreatitis (RR: 0.89; p = 0.60), did not differ from placebo.

These findings indicate that oral semaglutide offers meaningful cardiovascular benefit in high-risk T2DM patients without increasing serious safety concerns. The evidence supports its broader consideration within cardiovascular risk reduction strategies for patients with coexisting CVD or CKD.