What are the examples of Glucagon-like peptide-1 (GLP-1) receptor agonist medications?

GLP-1 Receptor Agonist Medications

GLP-1 receptor agonists include exenatide, liraglutide, dulaglutide, semaglutide, lixisenatide, albiglutide, and tirzepatide (a dual GLP-1/GIP receptor agonist). 1, 2

Classification of GLP-1 Receptor Agonists

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

Short-Acting GLP-1 Receptor Agonists

• Exenatide twice daily - First FDA-approved GLP-1 receptor agonist (2005) 1
• Lixisenatide once daily - Primarily affects postprandial glucose 3, 4

Long-Acting GLP-1 Receptor Agonists

• Liraglutide once daily - Modified to have greater albumin affinity 1, 5
• Exenatide once weekly - Encapsulated in microspheres for gradual release 1
• Dulaglutide once weekly - Conjugated with immunoglobulin G for prolonged action 1, 6
• Albiglutide once weekly - Non-covalent conjugation with albumin 1, 3
• Semaglutide once weekly (injectable) - Higher potency than other GLP-1 RAs 7, 3
• Semaglutide once daily (oral) - First oral GLP-1 receptor agonist 7

Dual Receptor Agonist

• Tirzepatide once weekly - Acts on both GLP-1 and GIP receptors 1

Mechanism of Action

GLP-1 receptor agonists work through multiple mechanisms:

1. Pancreatic effects:

   • Stimulate glucose-dependent insulin secretion from β-cells
   • Inhibit glucagon secretion in hyperglycemic and euglycemic states
   • Promote β-cell proliferation and protection against apoptosis 1, 2

2. Gastrointestinal effects:

   • Delay gastric emptying (more pronounced with short-acting agents)
   • Reduce gastrointestinal motility and secretions 1, 2

3. Central nervous system effects:

   • Increase satiety and reduce appetite through hypothalamic and brainstem receptors
   • Promote weight loss 2

Pharmacokinetic Properties

GLP-1 receptor agonists have been molecularly modified to prevent rapid degradation by dipeptidyl peptidase-4 (DPP-4), which breaks down native GLP-1 within 1-2 minutes 1, 2:

• Exenatide: Synthetic peptide with 50% homology to human GLP-1, resistant to DPP-4 cleavage 1
• Liraglutide: Modified with fatty acid side chain (palmitic acid) for albumin binding 5
• Dulaglutide: Conjugated with fragment crystallizable region of immunoglobulin G 1, 6
• Semaglutide: Liraglutide analogue with greater albumin affinity 1
• Albiglutide: Non-covalent conjugation with albumin 1

Clinical Differences Between Short-Acting and Long-Acting GLP-1 RAs

Short-Acting GLP-1 RAs (exenatide twice daily, lixisenatide)

• More pronounced effect on delaying gastric emptying
• Greater reduction in postprandial glucose excursions
• Less effect on fasting plasma glucose
• Maintain effect on gastric emptying during long-term treatment 1, 4

Long-Acting GLP-1 RAs (liraglutide, dulaglutide, exenatide weekly, semaglutide, albiglutide)

• More profound effects on fasting plasma glucose and HbA1c
• Greater weight reduction effects, particularly with semaglutide
• Develop tachyphylaxis to the gastric emptying effect over time
• More convenient dosing schedules (once daily or once weekly) 1, 7, 4

Cardiovascular and Renal Benefits

Several GLP-1 receptor agonists have demonstrated cardiovascular benefits:

• Reduced major adverse cardiovascular events (non-fatal myocardial infarction, stroke, cardiovascular death)
• Liraglutide has shown reduction in cardiovascular and all-cause mortality 2, 3
• May help prevent renal complications of type 2 diabetes 7

Common Adverse Effects

• Gastrointestinal effects: Nausea, vomiting, diarrhea (more common with short-acting agents) 6, 8
• Injection site reactions 6, 8
• Risk of hypoglycemia: Low when used as monotherapy or with metformin, but increased when combined with sulfonylureas or insulin 1, 8
• Delayed gastric emptying: Potential concern in perioperative settings 1

Important Considerations

• GLP-1 receptor agonists are now recommended as preferred first injectable glucose-lowering therapy for type 2 diabetes, even before insulin treatment 1, 7
• These medications can be combined with basal insulin for enhanced glycemic control 1, 7
• Semaglutide appears to have greater efficacy for both glucose lowering and weight reduction compared to other GLP-1 RAs 7, 3
• Tirzepatide (dual GLP-1/GIP receptor agonist) has shown greater reductions in HbA1c and body weight compared to semaglutide and dulaglutide 1

GLP-1 receptor agonists represent a diverse class of medications with significant benefits for glycemic control, weight management, and cardiovascular risk reduction in patients with type 2 diabetes.