What are GLP-1 Receptor Agonists?
GLP-1 (Glucagon-Like Peptide-1) receptor agonists are a class of injectable medications that mimic the action of the naturally occurring incretin hormone GLP-1 to lower blood glucose, promote weight loss, and provide cardiovascular protection in patients with type 2 diabetes and obesity. 1
Physiological Basis and Mechanism
GLP-1 is an incretin hormone released by L-enteroendocrine cells in the terminal ileum and proximal colon in response to glucose and triglycerides 1, 2. Natural GLP-1 has an extremely short half-life of approximately 1.5-2 minutes due to rapid degradation by dipeptidyl peptidase-4 (DPP-4) enzyme 2, 3. This rapid breakdown necessitated the development of synthetic GLP-1 receptor agonists that resist enzymatic degradation and maintain therapeutic levels for extended periods 1.
Primary Mechanisms of Action
Pancreatic Effects:
- GLP-1 receptor agonists bind to G-protein coupled receptors on pancreatic β-cells, increasing intracellular calcium and triggering glucose-dependent insulin secretion 2, 3
- The glucose-dependent nature means insulin secretion subsides as blood glucose approaches normal levels, explaining the low intrinsic hypoglycemia risk 2, 3
- These agents suppress glucagon secretion from pancreatic α-cells in a glucose-dependent manner, reducing hepatic glucose production 2, 3
- GLP-1 receptor agonists may promote β-cell proliferation and protect against apoptosis, potentially preserving pancreatic function 4, 2
Gastrointestinal Effects:
- GLP-1 receptor activation delays gastric emptying by inhibiting gastric peristalsis while increasing pyloric tone, mediated through vagal pathways 1, 2, 3
- This delayed gastric emptying reduces the rate at which postprandial glucose appears in circulation and prolongs satiety 1, 2
- The effect on gastric emptying shows tachyphylaxis (diminishing response) with continuous exposure, though weight loss benefits persist through multiple mechanisms 2
Central Nervous System Effects:
- GLP-1 receptors in the hypothalamus and brainstem nuclei mediate appetite suppression, satiety, and energy expenditure 2, 5
- These central effects contribute significantly to the weight loss observed with GLP-1 receptor agonist therapy 4, 2
Available Medications
Currently FDA-approved GLP-1 receptor agonists include: 1, 6, 7
Short-acting agents (daily dosing):
Long-acting agents (weekly dosing):
- Semaglutide (Ozempic for diabetes, Wegovy for obesity) 1, 4
- Dulaglutide (Trulicity) 1, 8, 6
- Exenatide extended-release 1, 6
Dual GIP/GLP-1 receptor agonist:
- Tirzepatide (Mounjaro for diabetes, Zepbound for obesity) represents a distinct class that activates both GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptors, producing superior weight loss and glycemic control compared to selective GLP-1 agonists 1, 4, 2
Oral formulation:
- Oral semaglutide (Rybelsus) is FDA-approved only for type 2 diabetes treatment, not obesity management 4
Clinical Applications
Type 2 Diabetes Management:
- GLP-1 receptor agonists achieve HbA1c reductions of approximately 1.4-2.59% depending on the agent and dose 4, 6, 7
- These medications are recommended as second-line therapy in combination with metformin or as alternatives when metformin is contraindicated 4, 7
- No dose adjustment is required across all stages of chronic kidney disease for semaglutide, liraglutide, and dulaglutide 4
Obesity Management:
- Injectable semaglutide 2.4mg weekly achieves 14.9% total body weight loss at 68 weeks 4
- Tirzepatide 15mg weekly demonstrates superior efficacy with 20.9% weight loss at 72 weeks 4
- Liraglutide 3.0mg daily produces 5.2-6.1% weight loss 4
- FDA approval requires BMI ≥30 kg/m² or BMI ≥27 kg/m² with at least one weight-related comorbidity 4
Cardiovascular Protection:
- Semaglutide reduces cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke by 20-26% in patients with established cardiovascular disease 4
- Cardioprotective effects are mediated through improved myocardial substrate utilization, anti-inflammatory and anti-atherosclerotic effects, reduced myocardial ischemia injury, and improved lipid profiles 4
Safety Profile and Adverse Effects
Common gastrointestinal effects include: 1, 4, 7
- Nausea (17-44% of patients, typically mild-to-moderate and transient)
- Diarrhea (12-32%)
- Vomiting (7-25%)
- Constipation (10-23%)
- Slow titration with gradual dose escalation every 4 weeks minimizes these effects 4
Serious but rare risks include: 1, 4
- Pancreatitis (causality not definitively established)
- Gallbladder disease (cholelithiasis, cholecystitis)
- Acute kidney injury in the setting of severe dehydration
Absolute contraindications: 1, 4
- Personal or family history of medullary thyroid cancer
- Multiple endocrine neoplasia syndrome type 2 (MEN2)
- Based on animal studies showing thyroid C-cell tumors
Critical Perioperative Consideration
GLP-1 receptor agonists create significant aspiration risk during anesthesia due to delayed gastric emptying that persists even after extended fasting periods. 1, 4 Retained gastric contents are documented in 24.2% of semaglutide users versus 5.1% of controls despite 10-14 day discontinuation and 12-hour fasting 4. For non-diabetic patients taking these medications for weight management, discontinuation for at least 3 half-lives (3 weeks for semaglutide/tirzepatide, 3 days for liraglutide) before elective surgery is recommended 1, 4. For diabetic patients, consultation with endocrinology is necessary to weigh risks and benefits of holding medication 1, 4.
Long-Term Treatment Considerations
GLP-1 receptor agonists typically require lifelong use to maintain benefits. 4 Sudden discontinuation results in regain of one-half to two-thirds of lost weight within 1 year 4. These medications must be combined with lifestyle modifications including a reduced-calorie diet (500-kcal deficit) and minimum 150 minutes per week of physical activity 4. The average wholesale price ranges from $1,272-$1,619 per 30-day supply, creating significant cost barriers to long-term adherence 4.