Semaglutide consistently reduced MACE, CV death, MI, and heart failure; tirzepatide's CV benefits uncertain.

Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality in individuals with type 2 diabetes mellitus (T2DM) and obesity. Traditional treatments often fail to adequately address both glycemic control and cardiovascular risk reduction, leaving a significant therapeutic gap. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor co-agonists have emerged as promising agents due to their pleiotropic effects beyond glucose lowering, including weight loss and potential cardiovascular benefits. Understanding the comparative cardiovascular outcomes of these newer agents is crucial for optimizing patient care and improving long-term prognosis in these high-risk populations.

This systematic review and meta-analysis synthesized data from 47 randomized controlled trials (RCTs) involving 59,352 participants with type 2 diabetes mellitus, overweight, or obesity. Researchers systematically searched PubMed, Embase, Cochrane Library, Scopus, Web of Science, and ClinicalTrials.gov from inception to November 02, 2024. The primary endpoint was major adverse cardiovascular events (MACE), with secondary endpoints including cardiovascular death, myocardial infarction (MI), heart failure (HF), and stroke. Data for semaglutide and tirzepatide were analyzed separately against control arms.

Semaglutide demonstrated a consistent and significant reduction in major adverse cardiovascular events (MACE), with a relative risk (RR) of 0.71 (95% CI [0.60-0.84]; p < 0.001).

This included substantial 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). However, semaglutide did not show a statistically significant reduction in stroke risk (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), but the reduction in MACE did not reach statistical significance (RR, 0.79; 95% CI [0.54-1.17]; p = 0.245). Associations between tirzepatide and cardiovascular death, heart failure, and stroke were also not statistically significant. Exploratory subgroup analyses suggested variation in outcomes by treatment duration for both agents.