GLP-1 Receptor Agonist in Nonobese Patients with Type 2 Diabetes Mellitus and Heart Failure with Preserved Ejection Fraction

Background: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) promote weight loss and improve heart failure-related symptoms, quality of life, and functional capacity in patients with obesity and heart failure with preserved ejection fraction (HFpEF). However, their clinical effectiveness in nonobese patients with diabetes and HFpEF is understudied. Methods: The TriNetX research network was used to identify adult patients (≥18 years) with type 2 diabetes mellitus (T2DM), heart failure with preserved ejection fraction (left ventricular ejection fraction ≥45%), elevated brain natriuretic peptide (≥ 150 pg/mL) or N-terminal pro-B-type natriuretic peptide(≥ 450 pg/mL) and a body mass index (BMI) <30 kg/m2 on or before August 31, 2022. Patients were divided into two groups based on GLP-1RA use. After propensity score matching, Cox proportional hazard ratios (HRs) were used to compare outcomes over a 12-month follow-up period. Results: The study included 84,990 patients (n= 42,495 per group, mean age 64 years, 49% females, 65% white). Patients on GLP-1RAs were associated with lower incidence of heart failure exacerbation events (HR 0.60, 95% CI 0.58-0.62, p<0.001) and all-cause emergency room visits or hospitalizations (HR, 0.67, 95% CI 0.66–0.69; P < .001) compared with those not on GLP-1RAs. Other outcomes, including acute myocardial infarction, atrial fibrillation, ischemic stroke, pulmonary hypertension, C-reactive protein ≥ 5 mg/L, acute kidney injury, and the need for renal replacement therapy, were also significantly less frequent in the GLP-1RA group. These associated benefits persisted even among patients on a sodium-glucose cotransporter-2 inhibitor (SGLT2i). Conclusion: GLP-1RA use is associated with improved cardiovascular outcomes in nonobese patients with T2DM and HFpEF and has an associated incremental benefit even among patients on SGLT2i.