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

GLP-1 (Glucagon-Like Peptide-1) Receptor Agonists

GLP-1 receptor agonists are a class of medications that mimic the action of the endogenous incretin hormone GLP-1, primarily used to treat type 2 diabetes and obesity by enhancing insulin secretion, suppressing glucagon release, delaying gastric emptying, and increasing satiety. 1, 2

Mechanism of Action

GLP-1 receptor agonists work through multiple mechanisms:

• Pancreatic effects:

  • Increase glucose-dependent insulin secretion from β-cells
  • Suppress glucagon secretion from α-cells in a glucose-dependent manner
  • May promote β-cell proliferation and protect against apoptosis 1, 2

• Gastrointestinal effects:

  • Delay gastric emptying by inhibiting gastric peristalsis and increasing pyloric tone
  • Reduce gastric acid secretion
  • Increase fasting and postprandial gastric volumes 1

• Central nervous system effects:

  • Act on receptors in the hypothalamus and brainstem to regulate appetite and satiety
  • Reduce caloric intake and promote weight loss 1, 3

• Cardiovascular effects:

  • Improve myocardial substrate utilization
  • Provide anti-inflammatory and anti-atherosclerotic effects
  • Reduce myocardial ischemia injury
  • Lower systemic and pulmonary vascular resistance
  • Improve lipid profiles 1

Types of GLP-1 Receptor Agonists

GLP-1 receptor agonists can be categorized based on their duration of action:

Short-acting (daily administration)

• Exenatide: Synthetic peptide with 50% homology to human GLP-1, administered twice daily 3, 4
• Liraglutide: Acylated human GLP-1 receptor agonist with 97% amino acid sequence homology to endogenous human GLP-1, administered once daily 2, 4

Long-acting (weekly administration)

• Semaglutide: Liraglutide analogue with greater albumin affinity 3, 5
• Dulaglutide: Conjugated with fragment crystallizable region of immunoglobulin G 3
• Albiglutide: Non-covalently conjugated with albumin 3, 4
• Tirzepatide: Dual GLP-1/GIP receptor agonist 3

Clinical Applications

Type 2 Diabetes Management

• Effective in lowering fasting plasma glucose and HbA1c
• Low risk of hypoglycemia when used as monotherapy
• Recommended as second-line therapy in combination with metformin, sulfonylureas, thiazolidinediones, or basal insulin 3, 5

Weight Management

• Promote significant weight loss (6.1-17.4% in non-diabetic patients, 4-6.2% in diabetic patients)
• Tirzepatide (dual GIP/GLP-1 receptor agonist) can achieve up to 20.9% weight loss at higher doses 1, 3

Cardiovascular Benefits

• Reduce major adverse cardiovascular events in patients with established cardiovascular disease
• The LEADER trial showed a 13% relative risk reduction in cardiovascular death, non-fatal myocardial infarction, or stroke with liraglutide 1, 5

Common Adverse Effects

The most common adverse effects are gastrointestinal:

• Nausea and vomiting
• Dyspepsia
• Diarrhea
• Gastrointestinal reflux
• Constipation 1, 5

Other potential adverse effects include:

• Gallbladder disorders
• Cardiac arrhythmia/tachycardia (usually mild)
• Risk of thyroid C-cell tumors (observed in rodents, human relevance uncertain) 1, 5

Special Considerations

• Peri-operative management: Consider withholding GLP-1 receptor agonists for at least three half-lives before elective surgical procedures due to delayed gastric emptying and potential risk of aspiration 1

• Contraindications:

  • Personal or family history of medullary thyroid carcinoma
  • Multiple Endocrine Neoplasia syndrome type 2
  • Known hypersensitivity to the medication or its components 5

• Use with caution in:

  • Patients with history of pancreatitis
  • Patients with diabetic retinopathy
  • Patients with kidney disease (risk of acute kidney injury) 3, 5

GLP-1 receptor agonists represent a significant advancement in the treatment of type 2 diabetes and obesity, offering benefits beyond glycemic control including weight loss and cardiovascular protection, with a favorable safety profile when used appropriately.