What are GLP-1 Receptor Agonists?
GLP-1 (Glucagon-Like Peptide-1) receptor agonists are injectable or oral medications that mimic a naturally occurring incretin hormone to lower blood glucose, promote weight loss, and reduce cardiovascular risk in patients with type 2 diabetes. 1, 2
Mechanism of Action
GLP-1 receptor agonists work through multiple complementary pathways:
Pancreatic Effects:
- Enhance glucose-dependent insulin secretion from pancreatic beta-cells, meaning they only stimulate insulin release when blood glucose is elevated 1, 3
- Suppress inappropriate glucagon secretion from alpha-cells, preventing excessive hepatic glucose production 1, 4
- Stimulate beta-cell proliferation and differentiation while decreasing apoptosis, potentially preserving pancreatic function over time 1, 5
Gastrointestinal Effects:
- Delay gastric emptying by inhibiting gastric peristalsis and increasing pyloric tone, which slows nutrient absorption and prolongs satiety 6, 4
- Much of the glucose-lowering effect comes from delayed gastric emptying rather than pancreatic effects alone 6
Central Nervous System Effects:
- Activate GLP-1 receptors in the hypothalamus and brainstem to suppress appetite and promote satiety 2, 3
- Reduce caloric intake through central appetite regulation 5, 2
Cardiovascular and Metabolic Effects:
- Improve myocardial substrate utilization and provide anti-inflammatory and anti-atherosclerotic effects 5
- Reduce systemic and pulmonary vascular resistance 5
- Improve lipid profiles 5
FDA-Approved Indications
For Type 2 Diabetes:
- Adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older 7, 8, 7
- Reduce the risk of major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) in adults with type 2 diabetes and established cardiovascular disease 8, 7
For Obesity Management:
- Chronic weight management in adults with BMI ≥30 kg/m² or BMI ≥27 kg/m² with at least one weight-related comorbidity 5
- Must be used as adjunct to reduced-calorie diet and increased physical activity 5
Available Formulations
Short-Acting Agents (administered once or twice daily):
- Exenatide twice daily 3, 9
- Lixisenatide once daily 9
- Liraglutide once daily (Victoza 1.8mg for diabetes, Saxenda 3.0mg for obesity) 7, 3, 9
Long-Acting Agents (administered once weekly):
- Exenatide once weekly 3, 9
- Dulaglutide 3, 9
- Albiglutide 3, 9
- Semaglutide subcutaneous (Ozempic 1mg for diabetes, Wegovy 2.4mg for obesity) 8, 9
Oral Formulation:
- Oral semaglutide (Rybelsus) is the only oral GLP-1 receptor agonist, FDA-approved for type 2 diabetes but not for obesity management 5, 10, 9
Dual GIP/GLP-1 Receptor Agonist:
- Tirzepatide (Mounjaro for diabetes, Zepbound for obesity) activates both GLP-1 and GIP receptors, achieving superior weight loss of 20.9% compared to semaglutide's 14.9% 5
Clinical Efficacy
Glycemic Control:
- GLP-1 receptor agonists reduce HbA1c by approximately 1.4-1.5% from baseline 5, 2
- Long-acting agents have more profound effects on fasting plasma glucose compared to short-acting agents 9
Weight Loss:
- Liraglutide 3.0mg achieves 5.2-6.1% weight loss 5
- Semaglutide 2.4mg achieves 14.9% weight loss at 68 weeks 5
- Tirzepatide 15mg achieves 20.9% weight loss at 72 weeks 5
Cardiovascular Benefits:
- Semaglutide reduces major adverse cardiovascular events by 26% (HR 0.74,95% CI 0.58-0.95) in patients with established cardiovascular disease 5
- Liraglutide demonstrates similar cardiovascular risk reduction 5
Safety Profile and Contraindications
Absolute Contraindications:
- Personal or family history of medullary thyroid carcinoma 7, 8, 7
- Multiple Endocrine Neoplasia syndrome type 2 (MEN2) 7, 8, 7
- Serious hypersensitivity reaction to the medication 7
Common Adverse Effects:
- Gastrointestinal effects (nausea, vomiting, diarrhea, constipation) are the most frequent, occurring in a dose-dependent manner 5, 3
- These effects are typically mild-to-moderate, transient, and decrease over time 5
- Short-acting agents cause more gastrointestinal effects than long-acting agents 5
Serious but Rare Risks:
- Pancreatitis (causality not definitively established) 5, 7
- Gallbladder disease including cholelithiasis and cholecystitis 5, 7
- Acute kidney injury, usually associated with dehydration from gastrointestinal effects 7
Perioperative Concern:
- Delayed gastric emptying persists even with extended fasting periods, creating aspiration risk during anesthesia 6
- For elective surgery, discontinue semaglutide/tirzepatide for at least 3 weeks (three half-lives) before procedures requiring anesthesia 6, 5
Hypoglycemia Risk
GLP-1 receptor agonists have minimal intrinsic risk for hypoglycemia when used as monotherapy because their insulin-stimulating and glucagon-suppressing effects are glucose-dependent 5, 3. However, when combined with insulin or insulin secretagogues (sulfonylureas), hypoglycemia risk increases and dose reduction of these agents is necessary 7.
Clinical Positioning
GLP-1 receptor agonists are recommended as preferred first injectable therapy for type 2 diabetes, even before insulin treatment, due to superior HbA1c reduction with additional weight loss and no intrinsic hypoglycemia risk 9. They are particularly recommended for patients with established atherosclerotic cardiovascular disease 6, 9.