What is the role of incretin-based therapies, specifically GLP-1 (Glucagon-Like Peptide-1) receptor agonists like Liraglutide (generic name) and Semaglutide (generic name), in managing obesity?

Role of Incretin-Based Therapies in Obesity 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 (liraglutide, semaglutide) and dual GIP/GLP-1 receptor agonists (tirzepatide) work through multiple mechanisms to promote weight loss 1:

  • Inhibition of appetite and increased satiety through central actions on the hypothalamus and brainstem nuclei 1
  • Delayed gastric emptying, contributing to prolonged feelings of fullness 2, 3
  • Glucose-dependent insulin secretion and glucagon suppression 2, 3

• These medications mimic the effects of endogenous GLP-1, but have been modified to resist degradation by DPP-IV enzymes, allowing for once-daily (liraglutide) or once-weekly (semaglutide) dosing 2, 3

Clinical Efficacy in Obesity

• FDA-approved GLP-1 receptor agonists for obesity include 1:

  • Liraglutide 3mg daily (approved 2014)
  • Semaglutide 2.4mg weekly (approved 2021)
  • Tirzepatide (dual GIP/GLP-1 agonist)

• Weight loss efficacy in clinical trials 1:

  • Semaglutide: 14.9% mean weight loss at 68 weeks (STEP 1 trial)
  • Liraglutide: 8.0% mean weight loss at 56 weeks
  • Tirzepatide: Up to 20.9% mean weight loss at 72 weeks at highest doses (15mg)

• Weight regain occurs after discontinuation, suggesting long-term therapy is necessary 1

Cardiovascular and Metabolic Benefits

• Beyond weight loss, GLP-1 receptor agonists provide significant cardiometabolic benefits 1:

  • Reduced risk of cardiovascular events in patients with or without diabetes
  • Improved heart failure symptoms in patients with preserved ejection fraction
  • Beneficial effects on blood pressure and lipid profiles

• The SELECT study showed that semaglutide reduced cardiovascular events in non-diabetic patients with obesity and established cardiovascular disease (hazard ratio 0.80) 1

Emerging Applications in Metabolic Liver Disease

• GLP-1 receptor agonists are being investigated for metabolic dysfunction-associated steatotic liver disease (MASLD) 1:
  • Semaglutide demonstrated resolution of steatohepatitis but no fibrosis improvement in clinical trials
  • Substantial weight loss induced by GLP-1RAs may provide hepatic histological benefits
  • Not currently recommended specifically as MASLD-targeted therapies, but safe to use in patients with MASLD for their approved indications 1

Side Effects and Considerations

• Common adverse effects include 1:

  • Nausea and vomiting (most common)
  • Dyspepsia and gastrointestinal reflux
  • Diarrhea or constipation
  • Gallbladder disorders (uncommon)

• Delayed gastric emptying is a significant effect that requires consideration in perioperative settings 1:

  • Increased risk of pulmonary aspiration during anesthesia
  • Conflicting recommendations exist regarding perioperative management
  • Some guidelines suggest stopping daily doses the day before procedures and weekly doses a week before 1

Practical Prescribing Approach

• For patients with BMI ≥30 or BMI ≥27 with weight-related complications 1:

  1. Start with lower doses and titrate upward slowly to minimize gastrointestinal side effects
  2. Combine with lifestyle modifications (reduced-calorie diet and physical activity)
  3. Monitor for improvement in weight and comorbidities
  4. Plan for long-term therapy as weight regain occurs with discontinuation

• Special considerations:

  • Avoid in patients with gastroparesis 1
  • Use with caution in patients requiring anesthesia due to delayed gastric emptying 1
  • Consider cardiovascular benefits when selecting therapy for patients with obesity and cardiovascular risk factors 1

Future Directions

• Newer incretin-based therapies under development include 1:

  • Dual GLP-1/glucagon receptor agonists (cotadutide, survodutide)
  • Triple GLP-1/GIP/glucagon agonists (retatrutide)
  • Combinations of semaglutide with lipogenesis inhibitors

• These newer agents may provide even greater weight loss efficacy and additional metabolic benefits 1