What are the clinical implications of using semaglutide (Glucagon-like peptide-1 (GLP-1) agonist) for reducing cardiovascular risk in overweight or obese patients without diabetes?

Semaglutide for Cardiovascular Risk Reduction in Overweight/Obese Patients Without Diabetes

Semaglutide 2.4 mg weekly should be prescribed for cardiovascular risk reduction in overweight or obese patients with pre-existing cardiovascular disease, even without diabetes, as it significantly reduces major adverse cardiovascular events by 20% compared to placebo. 1

Clinical Implications of the SELECT Trial

The SELECT trial provides compelling evidence for expanding the use of semaglutide beyond its traditional role in diabetes management:

• Semaglutide 2.4 mg weekly reduced the primary cardiovascular endpoint (cardiovascular death, non-fatal myocardial infarction, or stroke) by 20% in patients with pre-existing cardiovascular disease and BMI ≥27 without diabetes 2, 1
• This cardiovascular benefit was consistent regardless of baseline HbA1c levels or changes in HbA1c, confirming that the cardioprotective effects are independent of glycemic control 3
• The cardiovascular benefits persisted for the entire study duration (mean follow-up of 39.8 months) 1

Mechanisms of Cardiovascular Protection

Semaglutide's cardiovascular benefits are mediated through multiple mechanisms:

• Anti-inflammatory and anti-atherosclerotic effects
• Improved myocardial substrate utilization
• Reduced myocardial ischemia injury
• Lower systemic and pulmonary vascular resistance
• Improved lipid profiles 2
• Significant weight reduction (mean 10.2% at 208 weeks vs 1.5% with placebo) 4
• Improvements in cardiometabolic risk factors including waist circumference, blood pressure, and lipid profiles 5

Weight Management Benefits

Beyond cardiovascular protection, semaglutide offers substantial weight loss benefits:

• Mean weight reduction of 14.9-17.4% in non-diabetic overweight/obese patients at 68 weeks 6, 7
• Weight loss sustained for up to 4 years in the SELECT trial 4
• Clinically meaningful weight loss across all sexes, races, body sizes, and regions 4
• Greater weight loss in non-diabetic patients (14.9-17.4%) compared to those with diabetes (4-6.2%) 2, 6

Practical Prescribing Considerations

Dosing and Titration

• Start at 0.25 mg subcutaneously once weekly for weeks 1-4
• Increase to 0.5 mg weekly for weeks 5-8
• Gradually titrate to maintenance dose of 2.4 mg weekly 6
• Slow titration is crucial to minimize gastrointestinal side effects 6

Monitoring and Expectations

• Assess for 5% weight loss at 12 weeks; consider discontinuation if not achieved 6
• Monitor for improvements in cardiometabolic risk factors including blood pressure and lipids 5
• Benefits are not maintained after treatment discontinuation, emphasizing the need for continued therapy 5

Side Effects Management

Common adverse effects include:

• Gastrointestinal symptoms (nausea, vomiting, diarrhea, constipation)
• Potential cardiac arrhythmias/tachycardia
• Gallbladder disorders 2, 6

Management strategies:

• Start at low dose and titrate slowly
• Reduce meal size
• Avoid high-fat diet, alcohol, and carbonated drinks
• Consider beta blockers if symptomatic tachycardia occurs 2, 6

Caveats and Considerations

• Higher discontinuation rates with semaglutide (16.6%) compared to placebo (8.2%) due to adverse events 1
• Discontinuation rates increase as BMI class decreases 4
• Cost may be a significant barrier for many patients 6
• Not recommended in patients with personal or family history of medullary thyroid cancer, multiple endocrine neoplasia syndrome type 2, or pregnancy 6
• Use with caution in patients with history of pancreatitis or gallbladder disease 6

Conclusion

The SELECT trial represents a paradigm shift in cardiovascular risk management for overweight and obese patients without diabetes. The European Society of Cardiology now recommends considering GLP-1 receptor agonists like semaglutide for weight reduction in patients with chronic coronary syndromes who are overweight or obese 2. This expanded indication offers a powerful new tool for reducing cardiovascular morbidity and mortality in a high-risk population.