What is the role of Glucagon-like peptide-1 (GLP-1) receptor agonists, such as liraglutide (Saxenda) (liraglutide) or semaglutide (Wegovy) (semaglutide), in weight loss management?

GLP-1 Receptor Agonists for Weight Loss Management

GLP-1 receptor agonists are highly effective for obesity management, producing significant weight loss of 6.1-17.4% in non-diabetic individuals, with semaglutide and tirzepatide showing the greatest efficacy comparable to bariatric surgery. 1

Mechanism of Action

• GLP-1 receptor agonists work through multiple mechanisms to promote weight loss, including inhibition of appetite and increased satiety through central actions on the hypothalamus and brainstem nuclei 1
• Semaglutide is a GLP-1 analogue with 94% sequence homology to human GLP-1 that selectively binds to and activates the GLP-1 receptor 2
• These medications delay gastric emptying, suppress appetite, and improve insulin secretion in a glucose-dependent manner 3
• GLP-1 receptors are expressed in multiple organs, including pancreas, gastrointestinal tract, heart, brain, kidney, lung, and thyroid, explaining their pleiotropic benefits 3

Efficacy for Weight Loss

• Semaglutide 2.4mg weekly demonstrates superior weight loss outcomes with a mean total body weight loss of 14.9% over 68 weeks (vs 2.4% with placebo) 3
• Tirzepatide 15mg weekly shows even greater weight loss (20.9%) compared to semaglutide 2.4mg weekly (14.9%) 3
• Weight loss appears to be greater in those without diabetes (mean weight loss 6.1–17.4%) compared with patients with diabetes (4–6.2%) 4
• Liraglutide 3.0mg daily was the first GLP-1 receptor agonist approved for obesity management, though it produces less weight loss than newer agents 5

Cardiovascular and Metabolic Benefits

• Beyond weight loss, GLP-1 receptor agonists provide significant cardiometabolic benefits, including reduced risk of cardiovascular events 1
• Semaglutide has demonstrated cardiovascular benefits in the SELECT study, reducing the composite incidence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (HR 0.80) in patients with cardiovascular disease and BMI ≥27 3
• In the SUSTAIN 6 trial, semaglutide reduced cardiovascular death, non-fatal myocardial infarction or stroke (6.6% vs 8.9% with placebo; RR 0.74,95% CI 0.58–0.95) 4
• These medications improve lipid profiles, blood pressure, and have anti-inflammatory and anti-atherosclerotic effects 4

FDA-Approved Options

• Liraglutide 3.0mg daily (Saxenda) was the first GLP-1 receptor agonist approved for obesity management 5
• Semaglutide 2.4mg weekly (Wegovy) is FDA-approved for obesity treatment with superior efficacy 3
• Tirzepatide (a dual GLP-1/GIP receptor agonist) was approved in November 2023 for obesity treatment 3
• These medications are approved for patients with BMI ≥30 kg/m² or ≥27 kg/m² with one or more obesity-associated comorbid conditions 3

Side Effects and Considerations

• Common adverse effects include nausea, vomiting, dyspepsia, diarrhea or constipation, and gastrointestinal reflux 4, 1
• Management strategies include:
  • Starting at low doses and titrating upward slowly 1
  • Reducing meal size 4
  • Limiting alcohol and carbonated drinks 4
  • Avoiding high-fat diets 4
• These medications are contraindicated in patients with personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2 3
• Gallbladder disorders and pancreatitis have been reported, requiring monitoring 1, 3
• Delayed gastric emptying may increase risk of pulmonary aspiration during anesthesia 1

Long-Term Considerations

• After cessation of semaglutide, significant weight regain occurs (11.6% of lost weight regained after 52 weeks), highlighting the need for long-term use 3
• These medications should be used in conjunction with lifestyle changes and may need to be used lifelong for sustained benefit 3
• Physical activity, specifically resistance training, should be incorporated to preserve lean body mass 3

Clinical Decision Algorithm

1. For patients with BMI ≥30 or BMI ≥27 with weight-related complications, consider GLP-1 receptor agonists 1
2. Choose agent based on efficacy and patient factors:
   • For maximum weight loss: Tirzepatide > Semaglutide > Liraglutide 3
   • For patients with cardiovascular disease: Semaglutide has proven cardiovascular benefits 3
   • For patients with type 2 diabetes: All options provide dual benefits of weight loss and improved glycemic control 3
3. Start with lower doses and titrate upward slowly to minimize gastrointestinal side effects 1
4. Monitor for improvement in weight and comorbidities, as well as potential adverse effects 1
5. Counsel patients that these medications must be used long-term to maintain weight loss 3