Abstract
Heart failure with preserved ejection fraction (HFpEF) poses a growing public health challenge, characterized by limited therapeutic options and a high burden of comorbid obesity and type 2 diabetes (T2D). Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), has shown promise in addressing these comorbidities, offering potential benefits in obesity-related HFpEF. We analyzed key clinical trials, including SUSTAIN 6, PIONEER 6, STEP HFpEF, STEP HFpEF DM, and supportive studies on glucagon-like peptide receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter 2 (SGLT2) inhibitors, alongside mechanistic insights into semaglutide's metabolic, anti-inflammatory, and decongestive effects. Data were drawn from randomized controlled trials, cohort studies, and pathophysiological reviews. Semaglutide significantly improves HFpEF outcomes in obese patients, with STEP HFpEF (n = 529) and STEP HFpEF DM (n = 616) demonstrating Kansas City Cardiomyopathy Questionnaire Clinical Summary Score increases of 16.6 and 13.7 points (vs. 8.7 and 6.4 with placebo, P < 0.001), weight reductions of 13.3% and 9.8% (P < 0.001), and 43.5% C-reactive protein reductions (P < 0.001), all of which are clinically relevant in HFpEF management. SUSTAIN 6 and PIONEER 6 highlight cardiovascular safety in T2D, reducing stroke and mortality, while combination with SGLT2 inhibitors lowers HF exacerbations (HR 0.62). However, these findings are primarily derived from trials enrolling patients with obesity and relatively well-preserved renal and cardiac function, limiting applicability to the broader, heterogeneous HFpEF population. The included trials differed substantially in design: STEP trials focused on short-term, functional outcomes over 52 weeks; SUSTAIN 6 and PIONEER 6 assessed cardiovascular safety in T2D populations with varied HF status. Follow-up durations, primary endpoints, and inclusion criteria also varied across studies. This heterogeneity complicates direct comparison and limits the ability to draw firm conclusions about semaglutide's effects on hard clinical endpoints such as hospitalization or mortality. Semaglutide improves HFpEF symptoms by reducing visceral adiposity, systemic inflammation, and filling pressures, thereby enhancing exercise tolerance. These effects are primarily seen in obese patients with preserved renal and cardiac function and may not generalize to all HFpEF phenotypes. Semaglutide offers a novel therapeutic avenue for obese HFpEF patients, improving symptoms, function, and quality of life compared with existing therapies such as SGLT2 inhibitors, MRAs, and ARNIs. While cardiovascular benefits were established in T2D patients, cost-effectiveness remains a potential barrier to access and adherence, especially in lower-resource settings. Long-term trials, cost-effectiveness studies, and comparative analyses are needed to solidify its role in clinical practice, particularly across diverse HFpEF subgroups.