Role of Incretin-Based Therapy for Obesity Management
Incretin-based therapies, particularly GLP-1 receptor agonists such as semaglutide and tirzepatide, are highly effective for obesity management, producing significant weight loss of 6.1-17.4% in non-diabetic individuals, with efficacy comparable to bariatric surgery. 1, 2
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 2
- Delayed gastric emptying, reducing the rate at which glucose appears in circulation postprandially 3
- Glucose-dependent stimulation of insulin secretion and suppression of glucagon secretion 3
- Modulation of β-cell proliferation 4
Clinical Efficacy for Weight Loss
- Semaglutide 2.4mg weekly demonstrates superior weight loss outcomes with a mean total body weight loss of 14.9% at 68 weeks (vs 2.4% with placebo) 1
- Tirzepatide 15mg weekly shows even greater weight loss (20.9%) compared to semaglutide 2.4mg weekly (14.9%) 1
- Liraglutide 3.0mg daily is also effective but with more modest weight reduction compared to newer agents 4, 5
- In a direct comparison study, semaglutide demonstrated significantly greater weight loss than liraglutide (-13.8% to -11.2% vs -7.8%) 5
Cardiovascular and Metabolic Benefits
- Beyond weight loss, GLP-1 receptor agonists provide significant cardiometabolic benefits:
- Reduced risk of cardiovascular events in patients with or without diabetes 1, 2
- The SELECT study demonstrated that semaglutide 2.4mg reduced the composite incidence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (HR 0.80) in patients with cardiovascular disease and BMI ≥27 1
- Improved blood pressure and lipid profiles 2
- Inherent glucoregulatory properties beneficial for patients with comorbid diabetes 4
FDA-Approved Incretin-Based Therapies for Obesity
- Currently FDA-approved incretin-based therapies for obesity management include:
Practical Prescribing Approach
- For patients with BMI ≥30 or BMI ≥27 with weight-related complications:
- Start with lower doses and titrate upward slowly to minimize gastrointestinal side effects 2
- Combine with lifestyle modifications including diet, physical activity, and behavioral interventions 4, 1
- Physical activity (specifically resistance training) should be part of the recommended approach to preserve lean body mass alongside GLP-1 RAs 4
- Monitor for improvement in weight and comorbidities 2
Side Effects and Considerations
Common adverse effects include:
Important considerations:
- Avoid in patients with personal or family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2 1
- Use with caution in patients requiring anesthesia due to delayed gastric emptying 2
- Significant weight regain occurs after cessation (11.6% of lost weight regained after 52 weeks), highlighting the need for long-term use 1
Special Populations
In patients with polycystic ovary syndrome (PCOS):
- Liraglutide shows benefits for anthropometric outcomes but may result in lean body mass loss when used without lifestyle co-interventions 4
- Semaglutide shows promise in small studies for anthropometric measures including visceral body fat 4
- Exenatide twice daily did not confer significant benefits over metformin in PCOS and was associated with more adverse events 4
Weight loss appears to be lower in individuals with type 2 diabetes compared to those without diabetes 1