In a study of people with obesity but no diabetes, weekly injections of tirzepatide (10‑15 mg) cut the predicted 10‑year heart disease risk more than semaglutide (1.7‑2.4 mg). The drop in risk was about 2.4% versus 1.4% for semaglutide, which could translate to roughly 2 million fewer heart events in the U.S. over a decade.

Approximately two-thirds of obesity-related mortality is attributable to cardiovascular disease (CVD). The aim of this analysis is to examine predicted CVD risk reduction following weight loss in persons with obesity for primary prevention between tirzepatide and semaglutide, and projected CVD events that could be potentially prevented in the USA. SURMOUNT-5 was a Phase 3b, open-label, randomized trial conducted in participants with obesity and without Type-2 diabetes, comparing tirzepatide (10 or 15&#x2005;mg) with semaglutide (1.7 or 2.4&#x2005;mg) and administered via weekly subcutaneous injection. Predicted 10-year CVD risks were compared between treatments at baseline and up to 72 weeks post-treatment among participants without prior CVD. The impact of cardiovascular risk reduction was estimated as the projected preventable CVD events over 10 years for tirzepatide and semaglutide in the USA. The average predicted 10-year CVD risk score before treatment was 9.3%. Treatment with tirzepatide was associated with significantly greater reduction in predicted 10-year CVD risk compared with semaglutide (absolute reduction from baseline of 2.4% and 1.4%, respectively, <i>P</i> &lt; 0.001). Translating risk reduction to the US population who met treatment eligibility criteria and without prior CVD (&#x223c;85 million), an estimated 2 million CVD events could be potentially prevented over 10 years after 72 weeks of tirzepatide treatment, vs. 1.15 million with semaglutide. In SURMOUNT-5, treatment with tirzepatide was associated with greater predicted 10-year CVD risk reduction compared with semaglutide. This <i>post hoc</i> analysis suggests tirzepatide treatment may provide greater benefit in primary prevention of CVD than semaglutide in people with obesity and overweight. ClinicalTrials.gov: NCT05822830.