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

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. 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. 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. 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. 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.