Cardiometabolic and RAAS-Targeted Therapy in Thoracic Aortic Aneurysm: Propensity-Matched Associations with Survival and Major Cardiovascular Events

Background: Thoracic aortic aneurysm (TAA) remains a high-risk vascular condition despite major advances in imaging surveillance, operative repair, and endovascular therapy. Medical management still relies largely on blood pressure control and global cardiovascular risk reduction. Renin–angiotensin–aldosterone system (RAAS) inhibitors are frequently used in TAA, but contemporary data evaluating survival and cardiovascular outcomes in broad TAA populations are limited. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2 inhibitors) have established cardiometabolic benefits, yet their role in TAA has not been well defined. Methods: We performed a retrospective multicenter cohort study of adults with imaging-confirmed TAA diagnosed between 1 January 2018 and 1 January 2026 using a Mayo Clinic electronic data platform encompassing more than 15 million patient records. Primary exposures were documented use of RAAS inhibitors, GLP-1 RAs, and SGLT2 inhibitors, evaluated individually and in prespecified combination-therapy analyses. Propensity score matching was used to balance demographics, comorbidities, aortic procedural history, and concomitant cardiovascular medications. Primary outcomes were all-cause mortality and major adverse cardiovascular events (MACE) through 60 months. Results: The study included 162,126 patients with TAA. After matching, RAAS inhibitor use was associated with higher 60-month overall survival (88.3% vs. 85.5%; hazard ratio [HR], 0.79; 95% CI, 0.76–0.83; p < 0.001) and MACE-free survival (86.1% vs. 84.2%; HR, 0.87; 95% CI, 0.83–0.91; p < 0.001). GLP-1 RA therapy was associated with higher overall survival (97.5% vs. 92.5%; HR, 0.32; 95% CI, 0.27–0.38; p < 0.001) and MACE-free survival (93.2% vs. 89.3%; HR, 0.62; 95% CI, 0.56–0.70; p < 0.001). SGLT2 inhibitor therapy was similarly associated with higher overall survival (89.8% vs. 81.5%; HR, 0.51; 95% CI, 0.47–0.54; p < 0.001) and MACE-free survival (86.3% vs. 79.1%; HR, 0.62; 95% CI, 0.58–0.66; p < 0.001). Combination therapy with RAAS inhibitors plus either GLP-1 RAs or SGLT2 inhibitors was associated with incremental improvements in overall survival and MACE-free survival compared with GLP-1 RA or SGLT2 inhibitor monotherapy. Conclusions: In this large propensity-matched TAA cohort, RAAS inhibitors, GLP-1 RAs, and SGLT2 inhibitors were each associated with improved survival and fewer major cardiovascular events, with additional benefit observed for RAAS-based combination therapy. These findings support further prospective investigation of integrated cardiometabolic and vascular-targeted therapy in TAA, while underscoring that observational associations should not be interpreted as proof of aneurysm-specific disease modification.