Tirzepatide and risk of newly diagnosed aortic stenosis in patients with obesity: a multi-institutional real-world cohort study.

BACKGROUND: Obesity is a major risk factor for the development of degenerative aortic stenosis (AS), yet no pharmacologic therapy has been proven to prevent AS onset. Tirzepatide, a dual GIP/GLP-1 receptor agonist, provides greater metabolic and anti-inflammatory benefits than conventional GLP-1 receptor agonists (GLP-1 RAs). Whether tirzepatide reduces the risk of incident AS remains unknown. OBJECTIVES: To evaluate the association between tirzepatide use and the risk of newly diagnosed AS or aortic valve replacement (AVR) compared with GLP-1 receptor agonists in adults with obesity. METHODS: This retrospective cohort study used the TriNetX global federated database. Adults ≥ 18 years with obesity who initiated tirzepatide or GLP-1 RAs between 2022 and 2025 were identified. An active-comparator, new-user design with 1:1 propensity score matching (PSM) was applied. The primary endpoint was a composite of newly diagnosed AS or AVR. Secondary outcomes included individual AS, AVR, and all-cause mortality. Cox proportional hazards models estimated hazard ratios (HRs) with 95% confidence intervals (CIs). Robustness was assessed using negative-control outcomes and E-values. RESULTS: After PSM, 584,236 patients were included. During follow-up, tirzepatide users had a significantly lower risk of AS or AVR compared with GLP-1 RA users (0.2% vs. 0.6%; HR 0.90, 95% CI 0.81-0.98; P = 0.022). Tirzepatide was also associated with reduced risk of newly diagnosed AS (HR 0.90, 95% CI 0.81-0.99; P = 0.025) and lower all-cause mortality (HR 0.88, 95% CI 0.81-0.95; P = 0.001). No association was observed for the negative-control outcome of skin cancer. Subgroup findings were generally consistent, with stronger protective associations observed in women and adults ≥ 65 years. In a sensitivity analysis using a no-treatment comparator, tirzepatide was also associated with lower risks of AS/AVR, AS, AVR, and all-cause mortality; however, the mortality association was interpreted cautiously because of potential healthy-user and treatment-selection biases. CONCLUSIONS: Among adults with obesity, tirzepatide use was associated with a significantly lower incidence of newly diagnosed AS or AVR compared with GLP-1 RAs during follow-up, suggesting a potential association between tirzepatide use and a lower rate of newly diagnosed AS/AVR. Because AS may remain asymptomatic for years and echocardiographic progression data were unavailable, these findings should be interpreted as hypothesis-generating. Prospective studies are needed to confirm causality and elucidate underlying mechanisms.