BACKGROUND: Obesity and type 2 diabetes are prevalent in patients with heart failure with preserved ejection fraction and are characterized by a high symptom burden. No approved therapies specifically target obesity-related heart failure with preserved ejection fraction in persons with type 2 diabetes.
METHODS: We randomly assigned patients who had heart failure with preserved ejection fraction, a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or more, and type 2 diabetes to receive once-weekly semaglutide (2.4 mg) or placebo for 52 weeks. The primary end points were the change from baseline in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS; scores range from 0 to 100, with higher scores indicating fewer symptoms and physical limitations) and the change in body weight. Confirmatory secondary end points included the change in 6-minute walk distance; a hierarchical composite end point that included death, heart failure events, and differences in the change in the KCCQ-CSS and 6-minute walk distance; and the change in the C-reactive protein (CRP) level.
RESULTS: A total of 616 participants underwent randomization. The mean change in the KCCQ-CSS was 13.7 points with semaglutide and 6.4 points with placebo (estimated difference, 7.3 points; 95% confidence interval [CI], 4.1 to 10.4; P<0.001), and the mean percentage change in body weight was -9.8% with semaglutide and -3.4% with placebo (estimated difference, -6.4 percentage points; 95% CI, -7.6 to -5.2; P<0.001). The results for the confirmatory secondary end points favored semaglutide over placebo (estimated between-group difference in change in 6-minute walk distance, 14.3 m [95% CI, 3.7 to 24.9; P = 0.008]; win ratio for hierarchical composite end point, 1.58 [95% CI, 1.29 to 1.94; P<0.001]; and estimated treatment ratio for change in CRP level, 0.67 [95% CI, 0.55 to 0.80; P<0.001]). Serious adverse events were reported in 55 participants (17.7%) in the semaglutide group and 88 (28.8%) in the placebo group.
CONCLUSIONS: Among patients with obesity-related heart failure with preserved ejection fraction and type 2 diabetes, semaglutide led to larger reductions in heart failure-related symptoms and physical limitations and greater weight loss than placebo at 1 year. (Funded by Novo Nordisk; STEP-HFpEF DM ClinicalTrials.gov number, NCT04916470.).
| Discipline Area | Score |
|---|---|
| Special Interest - Obesity -- Physician |  |
| Endocrine |  |
| Family Medicine (FM)/General Practice (GP) | |
| General Internal Medicine-Primary Care(US) | |
| Internal Medicine | |
| Cardiology | |
| Geriatrics | |
Important study reinforcing the cardiovascular benefits of glucagon-like peptide-1 (GLP-1) receptor agonists.
These are the benefits of this study: 1. semaglutide suggests a statistically significant probability (we rejected a null hypothesis with less than 0.1% probability) group difference over placebo when a change in body weight is considered from baseline to fifty-two weeks; 2. semaglutide also suggested better clinical outcomes with the inflammation biomarker, and the Kansas City Cardiomyopathy Questionnaire over placebo with a statistically significant probability of less than 0.1 % by chance alone. I am motivated to apply other therapeutic modalities that improve the 6-minute walk test and glycated hemoglobin parameters for which neither semaglutide nor placebo were effective.
This randomized trial has a head-to-head comparison of semaglutide and placebo among obesity-related heart failure with preserved ejection fraction and type 2 diabetes. The primary endpoints were stated clearly, the analysis has a low risk of bias, and included a good sample size. The clear benefits in terms of subjective and objective patient improvements and adverse effects are noted in both groups. Overall, this study indicates strong support for using semaglutide in this patient group.
As IM hospitalists, treating DM and obesity is bread and butter for us. Seeing multi-organ comorbdities of formerly untreated severe obesity that is now being treated with newer GLP-1RA and GIP/GLP-1 RA meds are game-changers. We are seeing small but definitive benefits of weight loss on overall health and hope to see more studies on the mortality benefit from weight loss.
