What are the contraindications to Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs)?

Contraindications to GLP-1 Receptor Agonists

GLP-1 receptor agonists are contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC), multiple endocrine neoplasia syndrome type 2 (MEN2), or history of serious hypersensitivity reactions to the drug. 1, 2

Absolute Contraindications

1. Thyroid-related contraindications:

   • Personal history of medullary thyroid carcinoma (MTC)
   • Family history of MTC
   • Multiple Endocrine Neoplasia syndrome type 2 (MEN2)
   • The FDA has placed a black box warning on GLP-1 RAs due to the risk of thyroid C-cell tumors observed in rodent studies 2

2. Hypersensitivity:

   • Previous serious hypersensitivity reactions to any GLP-1 receptor agonist
   • History of anaphylactic reactions or angioedema with GLP-1 RAs 2

Relative Contraindications and Cautions

1. Renal impairment:

   • Exenatide and lixisenatide should be avoided in severe renal impairment or end-stage renal disease (ESRD)
   • Other GLP-1 RAs (liraglutide, semaglutide) should be used with caution in severe renal impairment 1

2. Pancreatitis:

   • History of pancreatitis requires caution
   • GLP-1 RAs have been associated with acute pancreatitis in some cases
   • Consider alternative antidiabetic therapies in patients with prior pancreatitis 1, 2

3. Gastrointestinal conditions:

   • Clinically significant gastroparesis (particularly with shorter-acting agents)
   • Prior gastric surgery requires careful consideration due to effects on gastric emptying 1
   • Increased risk of regurgitation and pulmonary aspiration during anesthesia has been reported 3

4. Diabetic retinopathy:

   • Semaglutide has been associated with diabetic retinopathy complications
   • Patients with pre-existing diabetic retinopathy should be monitored closely
   • Rapid glucose reduction may worsen retinopathy 1

5. Pregnancy:

   • GLP-1 RAs are not recommended during pregnancy due to insufficient safety data 1
   • Women of reproductive potential should use reliable contraception methods 3

Special Considerations

1. Hypoglycemia risk:

   • When combining GLP-1 RAs with insulin or insulin secretagogues (e.g., sulfonylureas), there is an increased risk of hypoglycemia
   • Consider reducing doses of insulin or sulfonylureas when initiating GLP-1 RAs 1, 2

2. Monitoring recommendations:

   • Monitor for signs of pancreatitis (persistent severe abdominal pain, sometimes radiating to the back, with or without vomiting)
   • If pancreatitis is suspected, promptly discontinue the GLP-1 RA 2
   • Monitor patients with diabetic retinopathy for disease progression 1

Managing Common Side Effects

The most common adverse effects of GLP-1 RAs are gastrointestinal symptoms:

• Nausea, vomiting, diarrhea, dyspepsia, constipation
• These typically diminish over time with continued treatment
• Management strategies include:
  • Starting at a low dose and titrating slowly
  • Reducing meal size
  • Avoiding high-fat foods, alcohol, and carbonated drinks 3, 4

Recent Evidence on Cancer Risk

Despite initial concerns, recent evidence does not conclusively demonstrate an increased risk of thyroid cancer with GLP-1 RA use in humans:

• A 2024 study found no increased risk of cancer, including pancreatic and medullary thyroid cancers, associated with GLP-1 RA use in patients with type 2 diabetes 5
• A 2024 narrative review concluded there is no conclusive evidence of elevated thyroid cancer risk with GLP-1 RA use 6

However, due to the biological plausibility established in rodent studies, the contraindication for patients with personal or family history of MTC or MEN2 remains in place as a precautionary measure.