Core Viewpoint - Semaglutide can improve health and slow the aging process, significantly reducing the risk of major adverse cardiovascular events (MACE) in overweight or obese patients with cardiovascular disease but without diabetes [2][4][5]. Group 1: Introduction and Background - GLP-1 receptor agonists (GLP-1RAs) were initially used for blood glucose control in type 2 diabetes, showing weight loss and cardiovascular risk improvement in non-diabetic populations [4][5]. - Obesity is a major risk factor for cardiovascular morbidity and mortality, affecting through hemodynamic, metabolic, and inflammatory pathways [4]. - Prior cardiovascular outcome trials of GLP-1RAs were primarily conducted in type 2 diabetes patients, complicating the interpretation of cardiovascular benefits due to diabetes-related effects [5]. Group 2: Study Design and Methods - The SELECT trial recruited patients aged at least 45 years with a BMI ≥ 27 kg/m², randomly assigning them to receive either 2.4 mg semaglutide weekly or a placebo [7][13]. - The primary endpoint was the time to the first occurrence of MACE, including cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke [7][8]. Group 3: Results - In 17,604 patients, semaglutide significantly reduced the incidence of MACE across all baseline weight and waist circumference categories [9]. - A linear trend analysis indicated that a 5 kg weight reduction was associated with a 4% average decrease in MACE risk (HR 0.96 [95% CI 0.94–0.99]; p=0.001) [9]. - Waist circumference reduction was correlated with decreased MACE risk, with approximately 33% of the observed MACE benefit mediated through waist circumference changes [9][10]. Group 4: New Insights and Implications - The cardiovascular protective effects of semaglutide are independent of baseline fat measurements and weight changes, suggesting mechanisms beyond fat reduction [10][11]. - The findings indicate that semaglutide and other GLP-1RAs should be redefined as disease-modifying treatments rather than solely for blood glucose control or weight loss [11]. - Prescribing restrictions based on BMI thresholds or weight loss targets may not be applicable to overweight or obese patients, as they may benefit regardless of weight loss response [11].