Semaglutide reduced the risk of combined cardiovascular death or worsening heart failure events, and worsening heart failure events alone, a new analysis finds. 

Summary: A new analysis published in The Lancet reveals that semaglutide reduces the risk of combined cardiovascular death or worsening heart failure in patients with heart failure with mildly reduced or preserved ejection fraction (HFpEF). The pooled data from four randomized trials (SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM) show semaglutide lowers the risk of worsening heart failure events by 41% and combined cardiovascular death or worsening heart failure by 31% compared to placebo. The study highlights semaglutide’s potential impact on patients with obesity-related HFpEF, a population at high risk for serious complications.

Three Key Takeaways:

  1. Risk Reduction in Heart Failure Events: Semaglutide led to a 31% reduced risk of combined cardiovascular death or worsening heart failure, and a 41% reduction in worsening heart failure events alone, in patients with HFpEF.
  2. No Significant Effect on Cardiovascular Death: While semaglutide lowered heart failure events, the drug did not have a statistically significant impact on cardiovascular death rates.
  3. Obesity’s Role in HFpEF: With approximately 80% of HFpEF patients living with obesity, researchers say the study underscores the importance of addressing this condition in heart failure management, particularly in vulnerable populations.

Semaglutide is associated with a reduced risk of combined cardiovascular death or worsening heart failure in patients with mildly reduced or preserved ejection fraction (HFpEF), according to a new analysis of randomized trials published in The Lancet.

According to the analysis of four randomized, placebo-controlled trials (SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM), semaglutide led to a 31% reduced risk of combined cardiovascular death or worsening heart failure events, based on an incidence of 5.4% in patients assigned to semaglutide versus 7.5% in those assigned to placebo. 

Semaglutide, an antidiabetic medication used for the treatment of type 2 diabetes and an anti-obesity medication used for long-term weight management, also led to a 41% lower risk of worsening heart failure (2.8% versus 4.7% with placebo). There was no significant effect on the incidence of cardiovascular death (3.1% with semaglutide versus 3.7% with placebo). Statistical analyses were not adjusted for multiplicity, and hazard ratios should not be used to infer definitive treatment effects. Semaglutide is not approved in the United States to reduce heart failure outcomes.

Pooled Analysis of Four RCTs

The study was a pooled, post hoc participant-level analysis of 3,743 patients with a history of HFpEF from four randomized trials to examine the effects of once-weekly semaglutide (2.4 mg in SELECT, STEP-HFpEF, STEP-HFpEF DM; 1.0 mg in FLOW) on heart failure events. 

The STEP-HFpEF program enrolled participants with obesity-related HFpEF; in SELECT (participants with atherosclerotic cardiovascular disease and overweight/obesity) and FLOW (participants with type 2 diabetes and chronic kidney disease), HFpEF classification was investigator-reported. 

The main endpoint for this pooled analysis was a composite of time to first cardiovascular death or worsening heart failure event (hospitalizations or urgent visits due to heart failure). Additional endpoints included components of the composite: time to first heart failure event and time to cardiovascular death.

Obesity’s Role in HFpEF

Obesity is considered a key driver in the development of HFpEF, with approximately 80% of people with HFpEF living with overweight or obesity. In addition, type 2 diabetes is also highly prevalent in people with HFpEF and is associated with greater symptom burden, worse functional capacity, and more severely impaired quality of life.

“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,” says Mikhail Kosiborod, MD, lead study author and cardiologist at Saint Luke’s Mid America Heart Institute, in a release. “Collectively, this new analysis is the most comprehensive evaluation of semaglutide to date that assesses clinically relevant [heart failure] events, such as [cardiovascular] death and hospitalization.”

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.

“Combining the HFpEF participant populations across the SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM trials allowed us to take a closer look at how semaglutide impacted patients living with this debilitating and often progressive condition,” says Michelle Skinner, PharmD, vice president medical affairs at Novo Nordisk, which funded the study, in a release. “It is encouraging to have this additional analysis that examines the effect of semaglutide in this vulnerable patient population.” 

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