The global prevalence of obesity has nearly tripled since 1975, posing a significant public health challenge. Obesity, characterized by excess body fat accumulation, is a major risk factor for cardiovascular disease (CVD), type 2 diabetes, and other chronic conditions. Achieving and maintaining clinically meaningful weight loss (≥10%) through lifestyle interventions alone is often difficult. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), such as semaglutide, have emerged as effective weight-management medications. Prior studies have shown the efficacy of semaglutide in reducing cardiovascular events in patients with type 2 diabetes. The SELECT trial investigated the cardiovascular and weight-loss effects of semaglutide in a large population of adults with established CVD, overweight or obesity, but without diabetes. This prespecified analysis focuses on the long-term weight loss effects of semaglutide within this population, examining its efficacy across various subgroups and assessing its safety and tolerability profile.

The literature extensively documents the adverse health consequences associated with obesity, highlighting its strong correlation with CVD, type 2 diabetes, and other chronic diseases. While lifestyle interventions are crucial, their effectiveness in achieving and sustaining significant weight loss is often limited. The development of weight-management medications, particularly GLP-1 RAs, has provided new avenues for addressing this challenge. Previous research has demonstrated the efficacy of semaglutide in managing type 2 diabetes and reducing cardiovascular events in high-risk patients. However, more research was needed to determine its long-term weight-loss effects and safety profile in a diverse population of adults with established CVD, overweight or obesity, but without diabetes. This study builds on existing knowledge of semaglutide’s efficacy, specifically focusing on its long-term impact on weight and anthropometric measures in a broader patient population.

The SELECT trial (NCT03574597) was a randomized, double-blind, placebo-controlled trial involving 17,604 patients (72.3% male) aged ≥45 years with a BMI of ≥27 kg/m² and established CVD (myocardial infarction, stroke, or peripheral artery disease). Patients were randomly assigned to receive once-weekly subcutaneous semaglutide 2.4 mg or placebo. The primary outcome was the reduction of major adverse cardiovascular events (MACE). This prespecified secondary analysis focused on weight loss, anthropometric changes (waist circumference, waist-to-height ratio), and safety and tolerability outcomes across various baseline BMI categories. Weight and anthropometric measurements were collected at baseline and at various time points throughout the 4-year study period. Data were analyzed using analysis of covariance models for continuous outcomes and logistic regression for binary outcomes. Subgroup analyses were conducted to assess the effects of semaglutide across different demographic and clinical characteristics. Safety and tolerability were assessed by monitoring adverse events (AEs), serious adverse events (SAEs), and treatment discontinuations.

Over the 4-year study period, semaglutide demonstrated significantly greater weight loss compared to placebo (-10.2% vs. -1.5%, p<0.0001). This weight loss was sustained through week 208. Similar improvements were observed in waist circumference (-7.7 cm vs. -1.3 cm, p<0.0001) and waist-to-height ratio (-6.9% vs. -1.0%, p<0.0001). At week 104, a substantial proportion of patients treated with semaglutide achieved clinically meaningful weight loss (≥5%, ≥10%, ≥15%, ≥20%, and ≥25%). These benefits were observed across various subgroups based on sex, race, age, BMI category, region, and other clinical characteristics. While semaglutide was associated with a lower rate of SAEs compared to placebo across all BMI categories, there was a higher rate of treatment discontinuation with semaglutide, particularly in lower BMI categories. The subgroup analysis revealed that women experienced a greater treatment difference in weight loss compared to men (-11.1% vs. -7.5% respectively, p<0.0001), and those of Asian race experienced slightly less weight loss compared to other racial groups.

This study provides strong evidence supporting the long-term efficacy and safety of semaglutide for weight management in adults with established CVD, overweight or obesity, and without diabetes. The sustained weight loss observed with semaglutide, coupled with improvements in key anthropometric measures, has significant implications for the management of obesity-related comorbidities, particularly CVD. The consistent benefit across various demographic and clinical subgroups highlights the broad applicability of semaglutide. The increased discontinuation rates observed with semaglutide warrant further investigation, potentially exploring factors such as higher drug exposure in lower BMI categories or differences in patient motivation. The study's limitations include the focus on secondary CVD prevention and lack of detailed body composition assessment.

The SELECT trial demonstrates the significant and sustained weight loss achieved with semaglutide in a diverse population of adults with established CVD, overweight or obesity, and without diabetes. The findings support the use of semaglutide as a valuable tool for weight management in this patient population. Future research should focus on exploring the underlying mechanisms of the observed variations in weight-loss response among subgroups and investigate potential strategies to improve treatment adherence.

The SELECT trial was primarily designed to evaluate cardiovascular outcomes, so while weight loss was a secondary outcome, it wasn't the primary focus of the study design or patient recruitment. The study population, while diverse, may not fully represent the global population of individuals with overweight or obesity. Furthermore, the lack of detailed body composition data (beyond anthropometric measures) limits our understanding of the precise effects of semaglutide on fat mass and lean mass. The higher discontinuation rates observed with semaglutide, particularly in lower BMI classes, warrant further investigation into potential causes.