At ESC 2025, a pair of presentations highlighted the ongoing debate over cardiovascular risk reduction with semaglutide (Ozempic/Wegovy) and tirzepatide (Mounjaro/Zepbound), yielding conflicting signals that clinicians will need to interpret carefully. In this special edition episode, cohosts Diana Isaacs, PharmD, an endocrine clinical pharmacist, director of Education and Training in Diabetes Technology, and codirector of Endocrine Disorders in Pregnancy at the Cleveland Clinic, and Natalie Bellini, DNP, program director of Diabetes Technology at University Hospitals Diabetes and Metabolic Care Center, explore these studies: SURMOUNT-5 and STEER.

A post hoc analysis of SURMOUNT-5 compared the 10-year predicted CV risk reduction between the 2 agents. Using the Framingham Risk Calculator in 751 patients with obesity, tirzepatide was associated with greater benefit than semaglutide. From baseline risks of ~9%, tirzepatide was projected to lower absolute 10-year CV risk by 2.4% (23% relative reduction) compared with 1.4% (13% relative reduction) for semaglutide. Investigators attributed the advantage largely to greater weight and glycemic reductions.

In contrast, the STEER study, a real-world analysis of more than 21,000 patients with a mean follow-up of 8.5 months, suggested semaglutide was associated with lower rates of major adverse cardiovascular events (MACE) than tirzepatide. Semaglutide users had a 29% risk reduction in nonfatal MI, nonfatal stroke, or CV death compared with tirzepatide. Limitations included short follow-up, relatively few CV events, and the inherent confounding of observational data.

Both Isaacs and Bellini emphasized that while weight and glycemic improvements with tirzepatide appear robust, CV benefits may be molecule-specific. The ongoing SURPASS-CVOT, comparing tirzepatide with dulaglutide, should provide more clarity when full data are released at EASD.

In the interim, the hosts advised prescribing based on labeled indications supported by randomized outcomes data—semaglutide for CV and kidney risk reduction, tirzepatide for obesity and sleep apnea—while awaiting definitive trial results.

References: