GLP-1 Receptor Agonists and Cardiorenal Outcomes in Non-Obese, Non- Diabetic MASLD: A Propensity Score-Matched Study

Abstract Purpose Non-obese individuals account for up to 30% of metabolic dysfunction-associated steatotic liver disease (MASLD) cases yet are routinely excluded from glucagon-like peptide-1 receptor agonist (GLP-1 RA) outcome trials. Because MASLD is increasingly recognized as the hepatic component of a systemic cardiometabolic disorder, we evaluated the association between sustained GLP-1 RA use and cardiovascular, renal and hepatic outcomes in non-obese, non-diabetic adults with MASLD. Methods Using the TriNetX federated health research network, we identified non-obese (body mass index ≤ 27 kg/m²), non-diabetic adults with MASLD and at least one cardiometabolic risk factor. Sustained GLP-1 RA users, defined by a second prescription within three months of an initial prescription started within three months of diagnosis, were matched 1:1 to non-users on 38 demographic, comorbidity, medication and laboratory covariates. Cox models estimated five-year hazard ratios (HR) for major adverse cardiovascular events (MACE), heart failure, major liver outcomes (MALO), acute kidney injury (AKI), and atrial fibrillation/flutter (Afib). Sensitivity analyses excluded baseline metformin, substance use, and tirzepatide. Results Among 1,261 matched pairs, sustained GLP-1 RA use was associated with lower rates of MACE (HR 0.54, 95% CI 0.33–0.87), heart failure (0.34, 0.19–0.59), AKI (0.46, 0.26–0.81) and Afib (0.64, 0.42–0.97). MALO did not differ (1.16, 0.59–2.28). Associations persisted after excluding baseline metformin use and were directionally consistent after excluding tirzepatide. Conclusion In non-obese, non-diabetic MASLD, sustained GLP-1 RA use was associated with lower cardiovascular and renal event rates but not with hepatic events. These findings support prospective evaluation of GLP-1 RA therapy in this understudied phenotype.