Improved Survival With Sodium–Glucose Cotransporter 2 Inhibitors and Glucagon-Like Peptide-1 Receptor Agonists in Patients With Heart Failure With Preserved Ejection Fraction and Metabolic Dysfunction-Associated Steatotic Liver Disease

Background: Adverse metabolic profile manifested as metabolic dysfunction-associated steatotic liver disease (MASLD) and obesity affect the development and prognosis of heart failure (HF). Study Question: Whether treatments targeting metabolic derangements such as sodium–glucose cotransporter 2 inhibitors (SGLT2 inhibitors) and glucagon-like peptide-1 receptor agonists (GLP-1 receptor agonists) are associated with improved outcomes patients with both HF and MASLD or obesity warrants investigation. Study Design: This retrospective study included 7 propensity score matched cohort analyses using deidentified electronic health record data from the TriNetX global health research network. Measures and Outcomes: We evaluated the associations between MASLD, obesity, and the use of SGLT2 inhibitors or GLP-1 receptor agonists with adverse outcomes in patients with HF. Cohorts were defined based on combinations of comorbidities (HF subtype, MASLD, obesity, diabetes status) and medication exposure. Time-to-event outcomes with the Kaplain–Meier method and with Cox proportional hazards models for the calculation of hazard ratios (HRs) and 95% confidence intervals. Results: Among patients with HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction, MASLD was consistently linked to increased risk of nonfatal cardiovascular events, including HF (HR = 1.09, P < 0.001 and HR = 1.23, P < 0.001), myocardial infarction (HR = 1.03, P = 0.07 and HR = 1.08, P < 0.001), and stroke (HR = 1.04, P = 0.08 and HR = 1.07, P = 0.07). Use of SGLT2 inhibitors in HFpEF and MASLD patients with or without diabetes was associated with reduced all-cause mortality (HR = 0.76, P < 0.001 and HR = 0.69, P < 0.001) and major cardiovascular events. GLP-1 receptor agonists demonstrated a significant survival benefit (HR = 0.38, P < 0.001) in obese patients with HFpEF and MASLD without diabetes. Conclusions: In patients with HFpEF, pharmacologic interventions targeting metabolic pathways demonstrate meaningful cardioprotective effects, especially in metabolically vulnerable subgroups.