How GLP-1 Causes Weight Loss
GLP-1 receptor agonists cause weight loss primarily by diminishing appetite, delaying gastric emptying, and increasing satiety through central nervous system effects, resulting in reduced caloric intake. 1, 2
Mechanisms of Action
Central Nervous System Effects
- GLP-1 receptor agonists activate GLP-1 receptors in the hypothalamus and brainstem to suppress appetite and increase satiety 1
- These medications regulate energy balance by influencing hunger-satiety mechanisms in the brain 1
- GLP-1 works in concert with other satiety hormones like PYY and CCK to control food intake 2
Gastrointestinal Effects
- Delayed gastric emptying leads to prolonged feelings of fullness after meals 1, 3
- This slowed gastric emptying reduces the rate at which postprandial glucose appears in circulation 3
- The combined effect is early satiation and reduced food consumption 2
Metabolic Effects
- GLP-1 increases insulin secretion in a glucose-dependent manner, improving glycemic control 3
- It simultaneously decreases glucagon secretion, further contributing to metabolic improvements 3
- These metabolic improvements may indirectly support weight loss efforts 1
Efficacy for Weight Loss
Expected Weight Loss
- Semaglutide (2.4 mg weekly) demonstrates superior efficacy with mean weight loss of 14.9% from baseline in non-diabetic patients with obesity 1
- Liraglutide (3.0 mg daily) produces approximately 4-6% weight loss at 6 months 1
- Tirzepatide, a dual GIP/GLP-1 receptor agonist, shows even greater efficacy with weight loss of 15-20.9% at higher doses 1, 2
Factors Affecting Response
- Patients with diabetes typically experience less weight loss (4-6.2%) compared to non-diabetic patients (6.1-17.4%) 1
- Weight regain occurs after discontinuation of therapy, suggesting long-term use is necessary for sustained weight loss 1, 4
- Gastrointestinal side effects may limit adherence and affect overall weight loss outcomes 1, 5
Physiological Impact
Hormonal Regulation
- GLP-1 is part of a complex enteroendocrine system that regulates food intake through central nervous system interactions 2
- It works in conjunction with other satiety hormones like PYY, CCK, and amylin to control appetite 2
- GLP-1 helps maintain free leptin levels during weight loss, which may prevent weight regain 4
Additional Benefits
- Beyond weight loss, GLP-1 receptor agonists improve cardiovascular outcomes in high-risk patients 1
- They reduce HbA1c levels and improve lipid profiles 1
- Potential benefits for non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) have been observed 1
Clinical Considerations
Dosing and Administration
- Higher doses are typically required for weight loss compared to diabetes management (liraglutide 3.0 mg vs 1.8 mg; semaglutide 2.4 mg vs 1.0 mg) 1
- Dosing should start low and titrate upward slowly to minimize gastrointestinal side effects 1
- Regular monitoring is essential to assess response and adjust treatment as needed 1
Common Adverse Effects
- Gastrointestinal symptoms (nausea, vomiting, diarrhea, dyspepsia) are the most common side effects 1, 5
- These side effects can affect adherence and potentially limit weight loss outcomes 5
- Slow titration can help minimize these adverse effects 1
Contraindications
- GLP-1 receptor agonists carry a boxed warning for people with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2 5
- They should be used with caution in patients with a history of pancreatitis 5
- Recent heart failure decompensation may be a contraindication for some GLP-1 receptor agonists 2
By targeting multiple pathways involved in appetite regulation and energy balance, GLP-1 receptor agonists effectively promote weight loss through reduced caloric intake while offering additional metabolic benefits.