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Semaglutide in Patients With Obesity-Related Heart Failure and Type 2 Diabetes
abstract
This abstract is available on the publisher's site.
Access this abstract nowBACKGROUND
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.).
Additional Info
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Semaglutide in Patients with Obesity-Related Heart Failure and Type 2 Diabetes
N. Engl. J. Med 2024 Mar 28;390(15)1394-1407, MN Kosiborod, MC Petrie, BA Borlaug, J Butler, MJ Davies, GK Hovingh, DW Kitzman, DV Møller, MB Treppendahl, S Verma, TJ Jensen, K Liisberg, ML Lindegaard, W Abhayaratna, FZ Ahmed, T Ben-Gal, V Chopra, JA Ezekowitz, M Fu, H Ito, M Lelonek, V Melenovský, B Merkely, J Núñez, E Perna, M Schou, M Senni, K Sharma, P van der Meer, D Von Lewinski, D Wolf, SJ ShahFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Obesity and diabetes are common risk factors for heart failure with preserved ejection fraction (HFpEF). Patients with obesity, diabetes, and HFpEF have significantly impaired quality of life and high symptom burdens. The STEP-HFpEF DM trial tested whether semaglutide, a GLP-1 receptor agonist, could promote intentional weight loss and improve symptoms and physical limitations in individuals with HFpEF, obesity, and type 2 diabetes (T2DM). After 52 weeks, patients randomized to once-weekly semaglutide 2.4 mg lost 9.8% of their body weight (vs 3.4% with placebo) and had a 13.7-point improvement in KCCQ-CSS (vs 6.4 points with placebo), with significant improvements in 6-minute walk distance, NT-proBNP, and CRP.
These results build upon the findings of STEP-HFpEF, which also enrolled patients with obesity and HFpEF, but required that they not have T2DM.1 In both trials, patients randomized to semaglutide lost significantly more weight and had larger improvements in KCCQ-CSS and 6-minute walk distance compared with placebo. Importantly, patients randomized to semaglutide also had significant decreases in NT-proBNP, a biomarker associated with cardiac stress and heart failure events. Since NT-proBNP is known to have an inverse correlation with body weight, the decrease in NT-proBNP despite weight reduction supports a HF disease-modifying effect. Although patients with T2DM lost relatively less weight than those without T2DM (9.8% vs 13.3% among those randomized to semaglutide in STEP HFpEF DM vs STEP HFpEF), both groups had similar improvements in HF functional status and exercise capacity, suggesting benefits with semaglutide beyond weight loss. Of note, the effects were consistent in patients who received concurrent SGLT2 inhibitors.
Taken together, the use of semaglutide in patients with obesity and HFpEF both with and without T2DM leads to symptomatic and functional improvements. Whether this translates to reduced HF clinical events (hospitalizations and deaths) remains to be determined.
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