Real-World Cardiovascular Outcomes of Obesity Treatment With Tirzepatide Versus Semaglutide in Non-Diabetic Adults.
This retrospective cohort study used the TriNetX global federated electronic health record (EHR) database to compare real-world cardiovascular outcomes between tirzepatide (a dual GIP/GLP-1 receptor agonist) and semaglutide (a GLP-1 receptor agonist) in non-diabetic adults treated for obesity. Patients who initiated either medication between November 2023 and August 2024 were included, with individuals having recent atherosclerotic events, prior heart failure, or treatment crossovers excluded. After 1:1 propensity score matching yielding 35,336 pairs, the study found that tirzepatide was associated with a statistically significantly lower incidence of the composite primary endpoint — all-cause death, acute coronary syndrome, stroke, or new-onset heart failure — at 12 months (1.90% vs. 2.18%; HR 0.86). This difference was primarily driven by a reduction in new-onset heart failure (both reduced and preserved ejection fraction). No significant differences were observed for all-cause mortality, acute coronary syndrome, or stroke individually. Tirzepatide also produced greater mean weight loss. Limitations include the retrospective observational design, reliance on EHR coding accuracy, inability to confirm medication adherence, short follow-up duration, and potential for residual confounding despite propensity matching.
Why this grade: Large propensity-matched real-world cohort (35,336 pairs) in humans provides moderate evidence, but the retrospective observational design with EHR data limits causal inference due to potential residual confounding and coding inaccuracies.
Aims Treatment of obesity with glucagon-like peptide-1 (GLP-1) receptor agonists improves cardiovascular outcomes. Tirzepatide, a dual glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist, achieves greater weight loss than GLP-1 receptor agonists alone; however, direct real-world comparisons of clinical outcomes are limited. Materials and methods We conducted a retrospective, active-comparator, new-user cohort study using the TriNetX global federated electronic health record database. Adults (≥ 18 years) without diabetes who initiated tirzepatide or semaglutide for the treatment of obesity between November 2023 and August 2024 were included. Patients with recent atherosclerotic events, prior heart failure (HF), or crossovers to the comparator were excluded. The primary outcome was major cardiovascular events including all-cause death, acute coronary syndrome, stroke, or new-onset HF at 12 months. Results One-to-one propensity score matching yielded 35 336 pairs. Tirzepatide was associated with a lower incidence of the composite outcome compared with semaglutide (1.90% vs. 2.18%; hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.77-0.97; p = 0.01), driven by reduced new-onset HF (1.04% vs. 1.29%; HR, 0.79; 95% CI, 0.68-0.92; p = 0.002), including both HF with reduced and preserved ejection fraction. No significant differences were observed in all-cause mortality, acute coronary syndrome, or stroke. Mean weight loss was greater with tirzepatide (-9.8 kg vs. -8.0 kg; p Conclusions In obese individuals without diabetes, tirzepatide was associated with a lower risk of cardiovascular events, especially incident HF, compared with semaglutide, with a similar safety profile.
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