Association of GLP-1 receptor agonist therapy with cardiovascular outcomes in patients with MASLD: A translational study

Patients with metabolic dysfunction–associated steatotic liver disease (MASLD) and type 2 diabetes (T2D) are at increased risk of adverse cardiovascular outcomes, potentially involving systemic metabolic dysfunction and cardiac remodeling. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) improve metabolic dysfunction in MASLD; however, their associations with cardiovascular outcomes and effects on MASLD-associated cardiac remodeling remain incompletely understood. In this translational study, we integrated a real-world TriNetX cohort of patients with MASLD and T2D with complementary experimental studies in a mouse model of MASLD. Following propensity score matching, 42,910 patients were included in each treatment group. GLP-1 RA therapy was associated with a lower risk of the primary composite cardiovascular outcome compared with sulfonylurea therapy (hazard ratio 0.87, 95% confidence interval 0.84–0.91; P < 0.001), although this association was not statistically significant in 90-day and 180-day landmark analyses. In Western diet-fed mice, GLP-1 RA treatment improved selected indices of cardiac function and attenuated cardiomyocyte hypertrophy. Although myocardial fibrosis was numerically reduced, the difference compared with vehicle-treated mice was not statistically significant (P = 0.28). Molecular analyses showed reduced expression of fibrosis- and extracellular matrix remodeling–related markers, including CTGF, TGF-β1, and vimentin. Collectively, GLP-1 RA therapy was associated with lower cardiovascular risk in the primary observational analysis, although this finding was not consistently supported by sensitivity analyses. Complementary experimental findings suggest improvements in selected cardiac functional indices and changes in fibrosis-associated molecular remodeling, warranting further investigation.