Semaglutide 2.4 mg Significantly Reduces HF Symptom Burden, Body Weight in Adults with HFpEF and Obesity

Mikhail Kosiborod, MD

In patients with heart failure with preserved ejection fraction (HFpEF) and comorbid obesity, once-weekly subcutaneous semaglutide 2.4 mg (Wegovy; Novo Nordisk) was associated with greater improvements in HF-related physical symptoms and functional status as well as superior weight loss compared with placebo.¹

The findings, from the phase 3 STEP-HFpEF (Effect of Semaglutide 2.4 mg Once Weekly on Function and Symptoms in Subjects with Obesity-related Heart Failure with Preserved Ejection Fraction) clinical trial were presented today at the European Society of Cardiology (ESC) Congress 2023 and simultaneously published in the New England Journal of Medicine.¹

These results, when combined with data published less than one month ago from the SELECT cardiovascular outcomes trial,² suggest broad potential for the glucagon-like peptide-1 (GLP-1) receptor agonist in cardiovascular risk reduction.

“To our knowledge, this is the first trial of a pharmacologic agent to specifically target obesity as a treatment strategy for HFpEF, and the magnitude of the benefits we observed is the largest seen with any agent in HFpEF,” said principal investigator Mikhail Kosiborod, MD, a cardiologist at St Luke’s Mid America Heart Institute and vice president of Research for Saint Luke’s Health System, in an ESC statement.³

“This will likely have a significant impact on clinical practice, especially since there is a dearth of efficacious therapies in this vulnerable patient group. We believe that these findings should also change the nature of the conversation about the role of obesity in HFpEF, as the STEP-HFpEF results clearly indicate that obesity is not simply a comorbidity in patients with HFpEF but a root cause and a target for therapeutic intervention.”³

Semaglutide 2.4 mg was approved by the US Food and Drug Administration with an indication for chronic weight management in persons with overweight or obesity in June 2021, becoming the first drug to win such an approval since 2014.⁴ Across all studies in the STEP clinical trial program, the weekly subcutaneous incretin mimetic was associated with an average weight loss of 17-18% that was sustained over 68 weeks.⁴

Kosiborod and colleagues mounted STEP-HFpEF to test the hypothesis that treatment with the potent GLP-1 receptor agonist could substantially improve symptoms, physical limitations, and exercise function, in addition to promoting weight loss, in patients with HFpEF and obesity.¹

STEP-HFpEF

The study was a randomized, double-blind, placebo-controlled trial conducted at 96 sites in 13 countries in Asia, Europe, and North and South America.¹

For study inclusion participants were required to have HFpEF (LVEF ≥45%), body mass index (BMI) ≥30 kg/m², heart failure symptoms and functional limitations (New York Heart Association functional class II–IV and Kansas City Cardiomyopathy Questionnaire Clinical Summary Score [KCCQ-CSS] <90 points). Potential participants were excluded for a self-reported change in body weight of >5 kg within 90 days of screening or a history of diabetes.¹

Participants were assigned randomly in a 1:1 ratio to receive treatment with semaglutide 2.4 mg or placebo for 52 weeks. Investigators defined dual primary endpoints: change from baseline to week 52 in KCCQ-CSS (range, 0 to 100) and change in body weight. Kosiborod et al also were interested in a range of confirmatory secondary endpoints: change in the 6-minute walk distance (6MWD), change in level of C-reactive protein (CRP), and a hierarchical composite end point that included death, heart failure events, and differences in the change in the KCCQ-CSS and 6MWD.¹

Cohort baseline characteristics

The final cohort numbered 529 participants; 263 were randomly assigned to receive semaglutide 2.4 mg and 266 to receive placebo. Median age of the participants was 69 years, approximately half were women (56.1%) and the majority was White (95.8%), according to the study. The median baseline body weight was recorded as 105.1 kg and median BMI as 37 kg/m². Of particular note, two-thirds (66%) of the cohort had a BMI ≥35 kg/m².¹

The researchers found that baseline HF symptom burden was high: 66.2% were NYHA class II and 33.8% were NYHA class III–IV; the median KCCQ-CSS was 58.9 points; and the median 6MWD was 320 meters. Median baseline LVEF was 57.0%; CRP level, 3.8 mg/dL.

FINDINGS¹

STEP-HFpEF met both primary endpoints and all confirmatory secondary endpoints, according to the published study. The mean change in KCCQ-CSS from baseline to week 52 was 16.6 points with semaglutide versus 8.7 points with placebo (estimated treatment difference [ETD], 7.8 points; 95% CI, 4.8 to 10.9; P<.001). The observed mean change in bodyweight was also statistically significant, recorded from baseline to week 52 at -13.3% with semaglutide vs -2.6% with placebo (ETD, -10.7%; 95% CI -11.9% to -9.4%; P<.001).

The analysis of secondary endpoints found a mean change of 21.5 meters for semaglutide in the 6MWD test compared with 1.2 meters with placebo (ETD, 20.3 meters; 95% CI, 8.6 to 32.1; P<.001).1 For the hierarchical composite end point, the study drug produced more wins vs placebo (win ratio, 1.72; 95% CI, 1.37 to 2.15; P < .001). The team also reported a mean percentage change in CRP level of −43.5% with semaglutide 2.4 mg and −7.3% with placebo (estimated treatment ratio, 0.61; 95% CI, 0.51 to 0.72; P<.001).

Only 1 adjudicated heart failure event occurred among the semaglutide 2.4 mg group compared to 12 among the placebo group (hazard ratio, 0.08; 95% CI, 0.00 to 0.42).1 Serious adverse events were observed in 35 (13.3%) and 71 (26.7%) participants with semaglutide and placebo, respectively (P<.001).

“Today’s news heralds a possible fundamental paradigm shift in how cardiologists approach HFpEF in people with obesity. It’s gratifying to be able to share important evidence that has a potential to change the future clinical management of this vulnerable patient population,” Kosiborod concluded.³

References

1. Kosiborod MN, Abildstrøm SZ, Borlaug BA, et al. Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity. The New England Journal of Medicine. Published online August 25, 2023. doi:10.1056/NEJMoa2306963
2. Halsey G. Semaglutide 2.4 mg Could Reduce US Obesity by Half, Prevent 1.5 million CVD Events. Patient Care Online. August 22, 2023. Accessed August 25, 2023. https://www.patientcareonline.com/ view/antiobesity-medication-semaglutide-2-4-mg-reduced-risk-of-mace-by-20-topline-results-from-landmark-select-trial
3. Weight loss medication benefits patients with heart failure and obesity. European Society of Cardiology. Press release. August 25, 2023. Accessed August 25, 2023. https://www.escardio.org/The-ESC/Press-Office/Press-releases/Weight-loss-medication-benefits-patients-with-heart-failure-and-obesity
4. Halsey G. FDA approves semaglutide 2.4 mg for chronic weight management in obesity, overweight. Patient Care. June 5, 2021. Accessed August 25, 2023. https://www.patientcareonline.com/ view/fda-approves-semaglutide-2-4-mg-for-chronic-weight-management-in-obesity-overweight