A new pooled analysis published in The Lancet indicates that semaglutide significantly reduces the risk of combined cardiovascular (CV) death or worsening heart failure (HF) events in patients with heart failure with mildly reduced or preserved ejection fraction (HFpEF). The analysis, which combined data from the SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM trials, suggests a potential new treatment avenue for this challenging condition.
The study, a post hoc participant-level analysis of 3,743 patients, examined the effects of once-weekly semaglutide (2.4 mg in SELECT, STEP-HFpEF, STEP-HFpEF DM; 1.0 mg in FLOW) on HF events. The primary endpoint was a composite of time to first CV death or worsening HF event (hospitalizations or urgent visits due to HF).
Key Findings
The analysis revealed a 31% reduced risk of combined CV death or worsening HF events with semaglutide, with an incidence of 5.4% in the semaglutide group versus 7.5% in the placebo group (HR 0.69; 95% CI 0.53-0.89; P=0.0045). Semaglutide also led to a 41% lower risk of worsening HF (2.8% versus 4.7% with placebo; HR 0.59 (95% CI 0.41-0.82), P=0.0019). However, there was no significant effect on the incidence of CV death alone (3.1% with semaglutide versus 3.7% with placebo; HR 0.82 (95% CI 0.57-1.16), P=0.25).
Expert Commentary
"Due in part to the obesity epidemic, HFpEF has emerged as the most common type of heart failure. Patients with obesity-related HFpEF are at high risk for serious complications including hospitalizations and death, and have limited treatment options," said Dr. Mikhail Kosiborod, lead study author and cardiologist at Saint Luke's Mid America Heart Institute. "Collectively, this new analysis is the most comprehensive evaluation of semaglutide to date that assesses clinically relevant HF events, such as CV death and hospitalization."
Obesity and Heart Failure
Obesity is considered a key driver in the development of HFpEF, with approximately 80% of people with HFpEF living with overweight or obesity. Type 2 diabetes is also highly prevalent in people with HFpEF, exacerbating symptom burden and impairing quality of life.
Trial Details
The STEP-HFpEF Program enrolled participants with obesity-related HFpEF, while SELECT included participants with atherosclerotic cardiovascular (CV) disease and overweight/obesity, and FLOW included participants with type 2 diabetes and chronic kidney disease. HFpEF classification was investigator-reported.
Safety Profile
Adverse events leading to treatment discontinuation occurred in 21% of patients in the semaglutide group and 13.9% of patients in the placebo group. Gastrointestinal disorders leading to treatment discontinuation occurred in 11.1% of patients in the semaglutide group and 2.7% of patients in the placebo group. Fewer semaglutide versus placebo-treated patients experienced serious adverse events across the four trial populations.
About Semaglutide
Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist. It is currently approved for the treatment of type 2 diabetes and for weight management in adults with obesity or overweight with at least one weight-related condition. Semaglutide is not approved in the US to reduce heart failure outcomes.
Future Implications
This pooled analysis provides further evidence supporting the potential of semaglutide in managing heart failure, particularly in patients with HFpEF and comorbidities like obesity and type 2 diabetes. Further research is warranted to fully elucidate the mechanisms of action and long-term benefits of semaglutide in this patient population.
