GLP-1 receptor agonists: new game changing drugs in patients with heart failure with preserved ejection fraction and obesity

Over the past decade, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have emerged as potent glucose lowering drugs for individuals with type 2 diabetes (T2DM). GLP-1 RAs have exhibited a significant reduction in major adverse cardiac events (MACE), positioning them alongside sodium-glucose co-transporter 2 inhibitors (SGLT2is) as key drugs for the management of T2DM.1–4 People living with obesity have an increased risk of cardiovascular disease and an increased incidence of heart failure (HF), notably HF with preserved ejection fraction (HFpEF). GLP-1 RAs modulate energy intake and facilitate weight loss by attenuating appetite and hunger, as well as promoting satiety. The research study to investigate how well semaglutide works in people living with heart failure and obesity (STEP-HFpEF) trial, an international, double-blind, placebo-controlled study, assessed the impact of once-weekly subcutaneous semaglutide (2.4 mg) in individuals with HFpEF (EF ≥45%) and obesity (BMI >30), specifically excluding those with diabetes or A1c levels ≥6.5.5 At 52 weeks, semaglutide demonstrated significant improvements over placebo in KCCQ-CSS (16.6 vs. 8.7), weight reduction (−13.3 vs.−2.6%), and 6-min walk test (21.5 vs. 1.2 m). In addition, patients randomized to semaglutide had lower HF events (1 vs. 12). Despite limited number of events and the study's non-cardiovascular (CV) outcome nature, the result aligns with previous meta-analyses, suggesting the potential efficacy of GLP-1 RAs’ in reducing the risk of HF. Importantly, semaglutide had fewer serious adverse events, a pivotal finding given the historical safety concerns with developments in weight loss drugs. The upcoming semaglutide effects on heart disease and stroke in patients with overweight or obesity SELECT trial evaluated the effect of semaglutide on harder clinical outcome endpoints, the triple endpoint of CV death, non-fatal myocardial infarction (MI) or non-fatal stroke, in people with established CV disease who were overweighted or obese with no prior history of diabetes. With 1270 MACE events, the SELECT trial demonstrated a statistically significant reduction in MACE of 20% for people treated with semaglutide. All three components of the primary endpoint contributed to the reduction in MACE. While the SELECT trial was not a dedicated HF trial, it should provide further confirmation and additional insights into the existing body of knowledge. A critical question remains: Are the observed benefits primarily a result of weight reduction, or are other pathophysiologic mechanisms at play? Obesity is a metabolic disorder that contribute to the pathophysiology of HFpEF via both direct and indirect molecular and physiological mechanisms. These include modulation of cardiac load, plasma volume, filling pressures, energy expenditure, sympathetic nervous system activity, cardio-renal interactions, and accumulation of fat and lipid. Importantly, the inflammatory cascade serves as a pivotal pathway, triggering endothelial dysfunction, microvascular dysfunction, atrial fibrosis, and insulin resistance, all of which interact synergistically to contribute to the development of coronary artery disease, atrial fibrillation, hypertension, diabetes, chronic kidney disease, and ultimately, HFpEF. Notably, in the STEP-HFpEF trial, the semaglutide group exhibited a significant reduction in C-reactive protein levels when compared to the placebo group (43.5 vs. 7.3%), hinting at semaglutide's potential role in mitigating inflammation (Figure 1). Proposed mechanism of GLP-1 RA on HFpEF with obesity. In summary, GLP-1 RAs, effective glucose-lowering drugs, have now emerged as key agents in managing obesity, and efforts are underway to explore their efficacy in treating HF and cardiometabolic benefits in adolescents. Continued research confirming the broad cardio-protective impact of GLP-1 RAs beyond A1c reduction could enable early, evidence-based interventions for CV risks, thereby addressing public health concerns of obesity and HF while clarifying underlying mechanisms. No new data were generated or analysed in support of this research. Conflict of interest: ETK reports receiving lecture fees from Novo Nordisk, Eli Lilly, and AstraZeneca unrelated to the current work.