Cardiovascular outcomes of semaglutide and tirzepatide in type 2 diabetes mellitus and obesity: a systematic review and meta-analysis

To systematically evaluate cardiovascular outcomes associated with semaglutide and tirzepatide in adults with type 2 diabetes mellitus (T2DM), overweight or obesity. We systematically searched PubMed, Embase, Cochrane Library, Scopus, Web of Science, and ClinicalTrials.gov from inception to November 02, 2024, using standardized search terms for semaglutide and tirzepatide. The review was registered in PROSPERO (CRD420251008819). 47 randomized controlled trials (RCTs) involving 59,352 participants were included. Semaglutide was associated with a reduced risk of major adverse cardiovascular events (MACE) (RR, 0.71; 95% CI [0.60–0.84]; p < 0.001), with reductions in cardiovascular death (RR, 0.81; 95% CI [0.72–0.93]; p = 0.002), myocardial infarction (RR, 0.70; 95% CI [0.61–0.80]; p < 0.001), and heart failure (RR, 0.60; 95% CI [0.41–0.87]; p = 0.007), but not stroke (RR, 0.86; 95% CI [0.73-1.00]; p = 0.056). For tirzepatide, a lower risk of myocardial infarction was observed (RR, 0.63; 95% CI [0.40-1.00]; p = 0.049), whereas the reduction in MACE did not reach statistical significance (RR, 0.79; 95% CI [0.54–1.17]; p = 0.245). Associations with cardiovascular death, heart failure, and stroke were also not statistically significant. Exploratory subgroup analyses suggested variation by treatment duration. Exploratory subgroup analyses suggested variation by treatment duration. Semaglutide showed a more consistent signal of cardiovascular benefit across the included trials, whereas cardiovascular outcome evidence for tirzepatide remained limited and uncertain. Because most available data were derived from separate drug-versus-control trials, the findings should not be interpreted as definitive comparative evidence favoring one agent over the other.