1. Mechanism of Action
Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by intestinal L-cells in response to food intake. GLP-1 receptor agonists (GLP-1 RAs) mimic this hormone’s physiological effects through several metabolic pathways:
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Appetite Suppression and Delayed Gastric Emptying
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Act on the hypothalamic satiety centers (especially POMC/CART neurons), reducing hunger.
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Slow gastric emptying, prolonging the feeling of fullness.
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Enhanced Insulin Secretion and Reduced Glucagon Release
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Stimulate pancreatic β-cells to secrete insulin in a glucose-dependent manner.
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Suppress glucagon secretion, improving both fasting and postprandial glucose levels.
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Improved Energy Metabolism
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Increase insulin sensitivity and promote fat oxidation.
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Reduce hepatic fat synthesis and improve lipid metabolism.
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2. Key GLP-1–Based Weight Loss Agents
| Drug | Main Indication | Administration | Average Weight Loss |
|---|---|---|---|
| Liraglutide | Type 2 diabetes, obesity | Daily injection | 5–8% |
| Semaglutide | Type 2 diabetes, obesity | Weekly injection / oral | 10–15% |
| Tirzepatide | Type 2 diabetes, obesity | Weekly injection | 15–22% |
| Retatrutide (in trials) | Obesity (non-diabetic) | Weekly injection | Up to 24% |
Trend: Drug evolution is progressing from single GLP-1 receptor agonists → dual GIP/GLP-1 agonists → triple agonists (GIP/GLP-1/GCGR).
3. Major Clinical Trials and Results
Semaglutide – STEP Trials
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STEP 1 (NEJM, 2021)
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Participants: Adults with obesity, without diabetes
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Dose: 2.4 mg weekly (subcutaneous)
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Results: Mean body-weight reduction of 14.9% at 68 weeks vs. 2.4% with placebo
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~33% of participants achieved ≥20% weight loss.
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STEP 5 (2022)
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Demonstrated sustained weight loss over 2 years and improvements in cardiometabolic risk factors.
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Tirzepatide – SURMOUNT & SURPASS Programs
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SURMOUNT-1 (NEJM, 2022)
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Participants: Adults with obesity, without diabetes
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Dose: 5 mg, 10 mg, 15 mg weekly
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Results: Mean weight loss of 15–21% after 72 weeks (dose-dependent)
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Nearly 40% achieved ≥25% weight reduction.
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SURPASS Trials (Diabetic population)
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HbA1c reduction: up to 2.2%
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Concurrent average weight loss of 10–15%.
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4. Additional Health and Metabolic Benefits
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Reduction in blood pressure, LDL-cholesterol, and triglycerides
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Decreased visceral and hepatic fat (improvement in NAFLD)
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Lower risk of cardiovascular events (e.g., MI, stroke)
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Delayed progression from prediabetes to type 2 diabetes
5. Safety Profile and Considerations
Common side effects (usually mild to moderate):
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Nausea, vomiting, bloating, constipation
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Appetite loss
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Transient gastrointestinal discomfort
Cautions / contraindications:
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History of pancreatitis or medullary thyroid carcinoma
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Pregnancy and breastfeeding
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Gradual dose titration recommended to improve tolerability
6. Future Research Directions
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Next-generation multi-agonists:
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Triple agonists targeting GIP/GLP-1/GCGR (e.g., Retatrutide)
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Oral GLP-1 formulations:
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High-dose oral semaglutide (up to 50 mg) under evaluation
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Combination therapies:
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GLP-1 + insulin or SGLT2 inhibitors
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Broader metabolic indications:
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Non-alcoholic fatty liver disease (NAFLD), polycystic ovary syndrome (PCOS), sleep apnea, cardiovascular prevention
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7. Conclusion
GLP-1–based drugs represent a paradigm shift from diabetes control to comprehensive metabolic and weight management.
With agents like Semaglutide and Tirzepatide, non-surgical weight loss exceeding 20% has become achievable.
Future multi-receptor agonists are expected to further enhance efficacy, durability, and cardiometabolic benefits.
Post time: Oct-11-2025