Semaglutide in heart failure and atherosclerotic cardiovascular disease: the current state-of-the-art.

Cardiovascular disease mortality rates, which had steadily declined over decades, are now plateauing or reversing due to the global rise in type 2 diabetes mellitus (T2DM) and obesity. These cardiometabolic conditions contribute significantly to atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), and chronic kidney disease. Among emerging pharmacological treatments, glucagon-like peptide-1 receptor agonists, particularly semaglutide, have shown benefits beyond diabetes and obesity management, including cardioprotective and renoprotective effects. This state-of-the-art review comprehensively analyzes current evidence from clinical trials, identifies critical insights, and outlines research directions regarding semaglutide use in HF, ASCVD, and diabetic nephropathy. In ASCVD, semaglutide has demonstrated significant reductions in major adverse cardiovascular events, supported by findings from meta-analyses of trials in patients with T2DM and the SELECT trial for patients without T2DM. In a prespecified analysis of the SELECT trial, semaglutide demonstrated significant reductions in cardiovascular mortality and HF hospitalizations for patients with HF and ASCVD. In HF with preserved ejection fraction and mildly reduced ejection fraction, semaglutide improved symptoms, physical function, natriuretic peptide levels, echocardiographic parameters, and HF hospitalizations, as shown in the STEP-HFpEF program and a pooled analysis of trials. Furthermore, evidence from the FLOW trial underscores semaglutide's renal and cardiovascular benefits in diabetic nephropathy, irrespective of body mass index. While these findings suggest semaglutide's efficacy in cardiorenal diseases, gaps in evidence remain, including the need for event-driven trials in HF populations without ASCVD and irrespective of obesity. Future research should address these gaps, which could potentially update guideline recommendations.