The SELECT trial, a pivotal international study, reveals that semaglutide (weight management formulation) significantly improves cardiovascular (CV) outcomes in overweight and obese adults without diabetes, marking a transformative advancement in cardiometabolic care.
Study Overview
This global, phase 3 trial randomized 17,604 participants (aged ≥45 years, BMI ≥27 kg/m²) with established CVD-including prior myocardial infarction, stroke, or peripheral artery disease-but no diabetes, to receive weekly subcutaneous semaglutide or placebo alongside standard therapy. The primary endpoint was major adverse cardiovascular events (MACE), with a focus on long-term safety and efficacy.
Principal Outcomes
1. Reduced Cardiovascular Events
Semaglutide demonstrated a 20% relative risk reduction in MACE (hazard ratio [HR]: 0.80; P < 0.001) versus placebo after a median follow-up of 39.8 months.
Notable declines were observed in cardiovascular mortality (-15%), hospitalization for heart failure (-18%), and all-cause mortality (-19%).
Consistent benefits were seen across diverse subgroups, irrespective of baseline HbA1c levels or prior heart failure.
2. Durable Weight Management
Participants achieved 9.39% mean body weight reduction with semaglutide vs. 0.88% with placebo, peaking at week 65 and sustained through week 208 (-11.7% vs. -1.5%, P < 0.0001).
Nearly 40% of semaglutide recipients maintained ≥20% weight loss at year four, underscoring its prolonged metabolic impact.
3. Mechanisms Beyond Weight Loss
Early MACE risk reduction (evident within 6–12 months) preceded maximal weight loss, suggesting weight-independent pathways such as anti-inflammatory or endothelial function improvements.
Post-hoc analyses confirmed comparable CV benefits in patients with <5% weight loss by week 20, reinforcing this hypothesis.
Clinical Implications
SELECT challenges conventional paradigms in obesity-associated CVD management:
Synergistic Effects: Cardiovascular protection persisted even in patients on optimal antihypertensive and lipid-lowering therapies, indicating additive benefits.
Multisystem Benefits: Beyond weight control, semaglutide reduced chronic kidney disease progression by 22% and prediabetes incidence by 67%, while improving glycemic, blood pressure, and lipid parameters.
Durability: Sustained weight loss over four years highlights its potential to address long-term obesity-related complications.
Conclusion
The SELECT trial redefines semaglutide's role in obesity care, providing robust evidence that its CV benefits extend beyond weight reduction. By targeting metabolic and vascular pathways, it offers a dual approach to reducing mortality and morbidity in high-risk populations. These findings advocate for integrating semaglutide into comprehensive strategies to mitigate CVD burden in overweight and obese individuals.