What are the contraindications for Glucagon-like peptide-1 (GLP-1) receptor agonists, such as exenatide (Byetta), liraglutide (Victoza), and semaglutide (Ozempic)?

Contraindications for GLP-1 Receptor Agonists

GLP-1 receptor agonists are contraindicated in patients with a personal or family history of medullary thyroid carcinoma, multiple endocrine neoplasia syndrome type 2 (MEN2), history of serious hypersensitivity reaction to the drug, and for specific agents like exenatide and lixisenatide, severe renal impairment or end-stage renal disease. 1, 2

Absolute Contraindications

• Personal or family history of medullary thyroid carcinoma - GLP-1 receptor agonists have been associated with thyroid C-cell tumors in rodent studies, making them unsafe for patients with personal or family history of medullary thyroid cancer 1, 2
• Multiple Endocrine Neoplasia syndrome type 2 (MEN2) - Due to the increased risk of medullary thyroid carcinoma in these patients 1, 2
• History of serious hypersensitivity reaction to the specific GLP-1 receptor agonist - Previous allergic reactions to the medication contraindicate further use 1
• Severe renal impairment or ESRD - Specifically for exenatide and lixisenatide, which are contraindicated in patients with severe kidney dysfunction (eGFR <30 mL/min/1.73m²) 1

Agent-Specific Contraindications

Exenatide:

• Contraindicated in severe renal impairment (eGFR <30 mL/min/1.73m²) or end-stage renal disease 1
• Not recommended for patients on dialysis 1

Lixisenatide:

• Contraindicated in severe renal impairment (eGFR <30 mL/min/1.73m²) 1
• Should be avoided if eGFR <15 mL/min/1.73m² 1

Semaglutide and Liraglutide:

• While not absolutely contraindicated in severe renal impairment, they should be used with caution 1

Cautions and Relative Contraindications

• History of pancreatitis - Use liraglutide with caution in patients with previous pancreatitis 1
• Severe renal impairment - Use liraglutide and semaglutide with caution in patients with severe renal impairment or ESRD 1
• Clinically meaningful gastroparesis - Shorter-acting GLP-1 receptor agonists may delay gastric emptying and are not recommended in patients with significant gastroparesis 1
• Prior gastric surgery - Care should be taken when using these medications in patients with previous gastric surgery 1
• Diabetic retinopathy - Semaglutide has been associated with diabetic retinopathy complications, particularly with rapid glucose reduction 1, 2
• Pregnancy - GLP-1 receptor agonists are contraindicated during pregnancy 1

Important Considerations for Concomitant Medications

• Insulin or insulin secretagogues - Increased risk of hypoglycemia when GLP-1 receptor agonists are used with insulin or sulfonylureas; dose reduction of these agents may be required 1
• Oral medications with narrow therapeutic index - Shorter-acting GLP-1 receptor agonists may affect absorption of concomitantly administered oral medications due to delayed gastric emptying 1

Common Adverse Effects to Monitor

• Gastrointestinal symptoms - Nausea, vomiting, and diarrhea occur in 15-20% of patients, particularly with semaglutide having the highest risk 1, 3
• Pancreatitis - Monitor for signs of acute pancreatitis (persistent severe abdominal pain, sometimes radiating to the back, with or without vomiting) 2, 3
• Increased heart rate - Typically increases by approximately 5 beats per minute 1

Clinical Pearls

• GLP-1 receptor agonists with proven cardiovascular benefit (liraglutide, semaglutide, dulaglutide) are preferred agents for patients with type 2 diabetes and established cardiovascular disease 1, 4
• These medications do not cause hypoglycemia when used alone but may increase risk when combined with insulin or sulfonylureas 1, 5
• Most gastrointestinal side effects tend to occur within the first month of treatment and often improve with time 1, 3
• Dose titration can help minimize gastrointestinal side effects 1

By understanding these contraindications and using appropriate caution in at-risk populations, clinicians can safely prescribe GLP-1 receptor agonists to appropriate patients, maximizing benefits while minimizing risks.