What are GLP-1 (Glucagon-Like Peptide-1) receptor agonists?

What Are GLP-1 Receptor Agonists?

GLP-1 receptor agonists are a class of injectable medications that mimic the action of the naturally occurring incretin hormone glucagon-like peptide-1, used primarily to treat type 2 diabetes mellitus and obesity by enhancing glucose-dependent insulin secretion, suppressing glucagon release, delaying gastric emptying, and reducing appetite. 1, 2

Mechanism of Action

GLP-1 receptor agonists work through multiple complementary pathways:

Pancreatic Effects

• These drugs bind to GLP-1 receptors on pancreatic beta cells, stimulating insulin secretion only when blood glucose levels are elevated, which explains their low risk of causing hypoglycemia 3, 2, 4
• They simultaneously suppress glucagon secretion from pancreatic alpha cells in a glucose-dependent manner, reducing hepatic glucose production 3, 2
• The glucose-dependent nature of both insulin stimulation and glucagon suppression means these effects diminish as blood glucose approaches normal levels 2

Gastrointestinal Effects

• GLP-1 receptor agonists delay gastric emptying by inhibiting gastric peristalsis while increasing pyloric tone, which slows the rate at which postprandial glucose enters the circulation 5, 3, 2
• This delayed gastric emptying reduces gastric contractions, decreases gastric acid secretion, and increases both fasting and postprandial gastric volumes 5
• The effect on gastric emptying is more pronounced with short-acting formulations (like exenatide and liraglutide) compared to long-acting versions 5

Central Nervous System Effects

• GLP-1 receptors in the hypothalamus and brainstem nuclei mediate appetite suppression, increased satiety, and effects on energy intake and expenditure 3
• These central effects contribute significantly to the weight loss observed with these medications 1

Clinical Indications

Type 2 Diabetes Mellitus

• GLP-1 receptor agonists are indicated as adjunct therapy to diet and exercise to improve glycemic control in adults with type 2 diabetes 4
• They are particularly appropriate for early treatment of type 2 diabetes, especially in patients with obesity and/or those at high risk for atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease 1
• These drugs effectively lower fasting plasma glucose and glycated hemoglobin (HbA1c) 1

Cardiovascular Risk Reduction

• GLP-1 receptor agonists are indicated to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes and established cardiovascular disease 4

Weight Management

• These medications have demonstrated efficacy for weight loss by delaying gastric emptying and increasing satiety in patients both with and without diabetes 1

Available Agents and Formulations

Short-Acting Formulations

• Exenatide (twice daily) and liraglutide (once daily) primarily target postprandial glucose through more pronounced effects on gastric emptying 6, 7

Long-Acting Formulations

• Exenatide extended-release, dulaglutide, albiglutide, and semaglutide (all once weekly) affect both fasting and postprandial glucose through enhanced glucose-dependent insulin secretion and reduced glucagon secretion 6, 7
• Long-acting formulations have improved gastrointestinal tolerability profiles with smaller fluctuations in plasma drug concentrations 6

Pharmacokinetics

• Natural GLP-1 has an extremely short half-life of approximately 1.5-2 minutes due to rapid degradation by dipeptidyl peptidase-4 (DPP-IV) and neutral endopeptidases 3, 2
• GLP-1 receptor agonists are engineered to resist metabolic degradation, with liraglutide having a plasma half-life of 13 hours after subcutaneous administration 2
• The extended half-life results from self-association that delays absorption, plasma protein binding, and stability against enzymatic degradation 2

Safety Profile and Adverse Effects

Common Adverse Effects

• The most common adverse reactions (occurring in ≥5% of patients) are gastrointestinal: nausea, vomiting, diarrhea, abdominal pain, and constipation 4
• These gastrointestinal adverse events typically abate over time with continued treatment and are less frequent with long-acting formulations 8, 6

Hypoglycemia Risk

• GLP-1 receptor agonists have a low intrinsic risk of hypoglycemia due to their glucose-dependent mechanism of action 1, 3
• Hypoglycemia incidence increases when these drugs are used in combination with insulin secretagogues or insulin 8, 7

Serious Warnings

• GLP-1 receptor agonists are contraindicated in patients with a personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia syndrome type 2 4
• Pancreatitis has been reported in clinical trials; these drugs have not been studied in patients with a history of pancreatitis 4
• Diabetic retinopathy complications have been reported and patients with a history of diabetic retinopathy should be monitored 4

Critical Perioperative Considerations

Aspiration Risk

• There is emerging concern that GLP-1 receptor agonists are associated with increased risk of bronchopulmonary aspiration due to retained gastric contents in the perioperative period 1
• Case reports have documented regurgitation or aspiration during general anesthesia, and gastric ultrasonography has shown retained solids in patients taking these medications 1

Preoperative Management

• For patients taking GLP-1 receptor agonists for weight management, withhold these drugs for at least three half-lives before elective surgical procedures 1, 5
• For patients with type 2 diabetes, prolonged cessation before surgery may have detrimental effects on perioperative glycemic control, and discussion with an endocrinologist is advised 1, 5
• There is currently insufficient evidence to establish definitive guidance on the ideal cessation period before elective surgery 1

Drug Interactions

• GLP-1 receptor agonists delay gastric emptying, which may impact the absorption of concomitantly administered oral medications 4

Special Populations

• Discontinue GLP-1 receptor agonists in women at least 2 months before a planned pregnancy due to the long washout period for semaglutide 4