Heart failure (HF) is a major global health concern and can be classified into different phenotypes based on left ventricular ejection fraction (LVEF), including heart failure with preserved ejection fraction (HFpEF), reduced ejection fraction, and mildly reduced ejection fraction. This systematic review aims to determine the effect of semaglutide compared to placebo in obese patients with HFpEF. Following PRISMA 2020 guidelines, relevant studies published from January 2021 to August 2024 were identified through searches in PubMed and Science Direct. Randomized clinical trials (RCTs), cohort studies, and case-control studies were considered; however, only two randomized controlled trials (RCTs) and one retrospective cohort ultimately met the inclusion criteria, encompassing a total of 1463 participants with HFpEF and obesity. The risk of bias was evaluated utilizing the Cochrane risk of bias tool for RCTs and the Newcastle-Ottawa Scale (NOS) for the retrospective cohort. In each study, participants were divided into two groups receiving either semaglutide or placebo. The findings after a 52-week follow-up showed that treatment with semaglutide 2.4 mg once weekly resulted in a significant reduction in biomarkers associated with HF. Specifically, baseline C-reactive protein (CRP) values decreased by 43% and 42% in the RCTs and 37% in the retrospective cohort. NT-proBNP levels declined by 20.90% and 23.20% in the RCTs and 15.80% in the cohort, compared to the placebo group. The reductions in CRP and NT-proBNP are clinically relevant, as elevated levels of these biomarkers are associated with worse outcomes in HFpEF. In addition, participants in the semaglutide group experienced a reduction in body weight ranging from 9% to 13% across the three studies, while those in the placebo group showed weight loss between 2% and 7% across the studies. Functional improvement was also observed, with the Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS) increasing by 13 to 16 points in the semaglutide group compared to the placebo. These results suggest that semaglutide may be a promising treatment for HFpEF in obese patients, offering not only significant weight loss but also improvements in biomarkers and quality of life. Therefore, semaglutide appears to provide potential cardiovascular and metabolic benefits in addition to its established weight-reducing effects, although findings should be interpreted with caution given the limited number of included studies.
