AHA Scientific Sessions 2026 Abstract · Nov 2, 2026
Beyond Glycemic Control: Primary Prevention of Heart Failure with Preserved Ejection Fraction with Sodium-Glucose Cotransporter-2 Inhibitors and Glucagon-Like Peptide-1 Receptor Agonists
By Tetteh E, Acheampong IA, Blankson GA et al.
Background: Heart Failure with preserved Ejection Fraction (HFpEF) is the predominant heart failure phenotype among patients with obesity and type 2 diabetes mellitus (T2DM) and is increasingly recognized as a cardiometabolic syndrome driven by systemic inflammation, endothelial dysfunction, and adverse myocardial remodeling. Although sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) improve cardiovascular outcomes in T2DM and obesity, their comparative effectiveness for preventing incident HFpEF remains poorly defined. Methods: We conducted a retrospective new-user active-comparator cohort study using the TriNetX Research Network comprising 107 U.S. healthcare organizations. Adults with obesity and T2DM initiating SGLT2i or GLP-1RA therapy without prior exposure to the comparator drug were identified. The primary outcome was incident diastolic heart failure/HFpEF surrogate defined by ICD-10-CM I50.3. Secondary outcomes included acute-on-chronic diastolic heart failure, systolic heart failure, any heart failure, atrial fibrillation, acute myocardial infarction, ischemic stroke, and all-cause mortality. Propensity score matching (1:1 nearest neighbor) was performed using 85 covariates including demographics, cardiometabolic comorbidities, outpatient healthcare utilization, medications, renal disease, and laboratory variables. Outcomes were assessed from 30 days through 5 years following therapy initiation. Results: Among 889,624 eligible patients, 370,559 initiated SGLT2i and 519,065 initiated GLP-1RA therapy. After matching, 260,639 patients remained in each cohort. Compared with GLP-1RA therapy, SGLT2i therapy was associated with lower risk of incident diastolic HF/HFpEF surrogate (HR 0.842, 95% CI 0.818–0.867; p<0.001), acute-on-chronic diastolic HF (HR 0.828, 95% CI 0.795–0.863; p<0.001), systolic HF (HR 0.660, 95% CI 0.638–0.681; p<0.001), and any HF (HR 0.925, 95% CI 0.905–0.945; p<0.001). Conversely, GLP-1RA therapy was associated with lower risk of acute myocardial infarction (HR 1.234, 95% CI 1.192–1.276; p<0.001), ischemic stroke (HR 1.083, 95% CI 1.045–1.122; p<0.001), atrial fibrillation (HR 1.070, 95% CI 1.040–1.101; p<0.001), and all-cause mortality (HR 1.117, 95% CI 1.092–1.142; p<0.001). Conclusions: In this large real-world propensity-matched analysis of patients with obesity and T2DM, SGLT2i therapy was associated with lower risk of HFpEF-related and overall HF outcomes compared with GLP-1RA therapy, whereas GLP-1RA therapy demonstrated greater protection against atherosclerotic cardiovascular events and mortality. These findings suggest distinct cardiometabolic risk-reduction profiles and support preferential consideration of SGLT2i when heart failure prevention is the dominant therapeutic priority.