The global prevalence of obesity has nearly tripled since 1975, significantly increasing the burden of cardiovascular disease and other chronic conditions. Excess body fat, particularly visceral and ectopic fat, is a major driver of these health problems. Achieving and maintaining significant weight loss is crucial for mitigating these risks. While lifestyle interventions alone often prove challenging, weight-management medications, especially glucagon-like peptide-1 receptor agonists (GLP-1 RAs), have shown promise in promoting sustained weight loss. Semaglutide, a GLP-1 RA, has demonstrated efficacy in weight management and type 2 diabetes treatment. The SELECT (Semaglutide Effects on Heart Disease and Stroke in Patients with Overweight or Obesity) trial investigated the effects of semaglutide on cardiovascular outcomes in patients with established CVD, overweight or obesity, but without diabetes. This prespecified analysis of the SELECT trial focuses on the long-term effects of semaglutide on weight loss and anthropometric measurements in this population.

The introduction adequately cites previous research establishing the link between obesity, excess body fat (particularly visceral and ectopic fat), and the increased risk of cardiovascular disease and other chronic illnesses. The role of lifestyle interventions and the increasing efficacy of weight-management medications, especially GLP-1 RAs like semaglutide, in achieving and sustaining clinically meaningful weight loss are also reviewed. Studies such as STEP 1, demonstrating significant weight loss with semaglutide in individuals without diabetes, are referenced to contextualize the current research. The inclusion of the SELECT trial's primary focus on cardiovascular events, and the current analysis's focus on weight loss as a secondary outcome, clarifies the study's design and scope.

The SELECT trial was a randomized, double-blind, placebo-controlled study enrolling 17,604 patients (72.3% male) with established CVD and overweight or obesity (BMI ≥27 kg/m²) but without diabetes. Patients were randomly assigned (1:1 ratio) to receive once-weekly subcutaneous semaglutide 2.4 mg or placebo. The starting dose of semaglutide was 0.24 mg, escalating to 2.4 mg over 16 weeks. Standard-of-care recommendations for secondary CVD prevention were followed, but lifestyle counseling was not specifically targeted at weight loss. Key endpoints included changes in body weight (percentage and categorical), waist circumference (WC), waist-to-height ratio (WHtR), and BMI category changes. Statistical analyses used analysis of covariance models for continuous endpoints and logistic regression for binary endpoints. Multiple imputation was used to handle missing data. Subgroup analyses were conducted for various demographic and clinical characteristics. A first-on-treatment analysis was also performed to assess the effect of drug exposure.

At 208 weeks, semaglutide was associated with a significantly greater mean weight loss (-10.2%) compared to placebo (-1.5%). This weight loss was sustained throughout the four-year study period. The first-on-treatment analysis showed an even greater mean weight loss (-11.7%) with semaglutide. At week 104, a substantially higher proportion of patients in the semaglutide group achieved clinically meaningful weight loss (≥5%, ≥10%, ≥15%, ≥20%, and ≥25%). Semaglutide also led to significant improvements in WC and WHtR. A greater proportion of patients in the semaglutide group achieved improvements in BMI category and fell below sex- and race-specific WC cutoff points for increased metabolic risk. Women experienced greater weight loss than men. While Asian patients showed slightly less weight loss, clinically meaningful results were still observed across all races and regions. Semaglutide was associated with a lower rate of serious adverse events (SAEs) across all BMI categories, but a higher rate of trial product discontinuation, especially in lower BMI categories.

The findings demonstrate the long-term efficacy and safety of semaglutide 2.4 mg for weight loss in a diverse population of patients with established CVD, overweight or obesity, but without diabetes. The sustained weight loss over four years is a significant achievement and has important implications for managing the comorbidities associated with obesity. The observed variations in weight loss response across subgroups highlight the need for personalized approaches to weight management. The higher discontinuation rates with semaglutide in lower BMI categories warrant further investigation, potentially exploring factors such as higher drug exposure or individual differences in motivation and cultural perspectives on body size. The study’s focus on cardiovascular outcomes, rather than targeted weight loss, provides valuable insights into the broader health benefits of weight loss in this population.

This analysis of the SELECT trial confirms the significant and sustained weight loss achieved with once-weekly subcutaneous semaglutide 2.4 mg in patients with established CVD and overweight or obesity without diabetes. The benefits were observed across various subgroups, highlighting its potential for broad application. Further research is needed to optimize treatment strategies and address the higher discontinuation rates observed in lower BMI categories. Exploring the relationship between weight loss, BMI, and the reduction of ectopic and visceral fat could further refine our understanding of weight-loss physiology and its impact on cardiometabolic health.

The study was designed primarily to assess cardiovascular outcomes, with weight loss as a secondary endpoint. The lack of detailed body composition data beyond anthropometric measurements limits a complete understanding of the effects on fat distribution. The higher discontinuation rates with semaglutide in lower BMI categories require further exploration to determine the underlying causes. The results may not be fully generalizable to populations with different baseline characteristics or those without preexisting CVD.