Abstract
The glucagon-like peptide 1 receptor (GLP-1R) agonist semaglutide is effective for the treatment of obesity and type 2 diabetes mellitus (T2DM). The purpose of this article is to define the therapeutic role of semaglutide for obesity-related heart failure with preserved ejection fraction (HF-pEF). Methods: Critical review of 2 recent randomized trials, the Subjects with Obesity-related Heart Failure with Preserved Ejection Fraction (STEP-HFpEF) and STEP-HFpEF DM. The latter 2 studies had similar design and endpoints that evaluated efficacy and safety of semaglutide 2.4 mg/w in obese subjects without and with T2DM, respectively. The 2 primary endpoints were the change in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS) and the percentage change in body weight. After 52 weeks, placebo-corrected amelioration in the KCCQ-CSS was similar in subjects without and with diabetes, 7.8 points (95% CI, 4.8 to 10.9; P<0.001) and 7.3 points (95% CI, 4.1 to 10.4; P<0.001), respectively. However, placebo-corrected weight loss appeared more marked in subjects without diabetes, -10.7 percentage points (95% CI, -11.9 to -9.4; P<0.001) but -6.4 percentage points (95% CI, -7.6 to -5.2; P<0.001) in patients with diabetes. In both trials, semaglutide improved the 6-minute walking distance (6-MWD) albeit more so in subjects without diabetes with placebo-adjusted difference of 20.3 meters (m) (95% CI, 8.6 to 32.1, P<0.001) and 14.3 m (95% CI, 3.7 to 24.9; P< 0.0001) in subjects without diabetes and with diabetes, respectively. In addition, semaglutide decreased levels of C-reactive protein (CRP) similarly in patients with and without diabetes. In the diabetes trial, the effects of semaglutide on the KCCQ-CSS and weight reduction were attenuated in patients receiving sodium-glucose co-transporter 2 (SGLT2) inhibitors. Subgroup analysis of pooled data from the 2 trials suggested that beneficial effects of semaglutide on the KCCQ-CSS might be more evident in patients with more advanced HFpEF. Adverse effects led to semaglutide discontinuation in 12% of patients compared with 7% with placebo. The most common cause of semaglutide discontinuation was gastrointestinal (GI) disorders. Overall, semaglutide improved physical performance and reduced weight in obese subjects with HF-pEF with and without diabetes. Long-term randomized trials are needed to evaluate the effects of semaglutide on cardiovascular (CV) events and mortality in obesity-related HF-pEF.
Keywords
Heart failure, Preserved ejection fraction, Semaglutide, Obesity, Type 2 diabetes