What are the contraindications for Glucagon-like peptide-1 (GLP-1) agonists?

GLP-1 Agonist Contraindications

GLP-1 receptor agonists are contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC) and in patients with multiple endocrine neoplasia syndrome type 2 (MEN2). 1

Absolute Contraindications

1. Thyroid C-cell tumors

   • Personal history of medullary thyroid carcinoma
   • Family history of medullary thyroid carcinoma
   • Multiple endocrine neoplasia syndrome type 2 (MEN2)
   • This contraindication is based on FDA Black Box Warning due to increased risk of thyroid C-cell tumors observed in rodent studies 1

2. Hypersensitivity

   • History of serious hypersensitivity reaction to the specific GLP-1 receptor agonist
   • Previous anaphylaxis or angioedema with GLP-1 receptor agonists 2

Relative Contraindications and Cautions

1. Renal Function Considerations

   • Exenatide: Not recommended if eGFR <30 ml/min/1.73m²
   • Lixisenatide: Use with caution if eGFR <30 ml/min/1.73m²
   • Other GLP-1 agonists can be used with dose adjustment in renal impairment 1

2. Gastrointestinal Disorders

   • Clinically meaningful gastroparesis (particularly for shorter-acting agents)
   • History of pancreatitis (use with caution)
   • Severe gastrointestinal disease 1

3. Heart Failure

   • Recent heart failure decompensation (avoid GLP-1 receptor agonists) 1

4. Diabetic Retinopathy

   • History of diabetic retinopathy requires careful monitoring
   • Rapid improvement in glucose control with GLP-1 agonists may temporarily worsen diabetic retinopathy 2

5. Other Cautions

   • Prior gastric surgery (use with caution) 1
   • Concurrent use with insulin secretagogues or insulin (increased hypoglycemia risk; may require dose reduction of these agents) 2
   • Pregnancy and lactation (limited data on safety)

Clinical Pearls and Pitfalls

• Thyroid monitoring: While the risk of thyroid cancer in humans remains controversial, the FDA Black Box Warning for thyroid C-cell tumors is based on rodent studies. Recent evidence suggests this may be a rodent-specific effect 3, 4, 5.

• Pancreatitis risk: Monitor for signs of pancreatitis (persistent severe abdominal pain, sometimes radiating to the back, with or without vomiting). If pancreatitis is confirmed, GLP-1 receptor agonists should not be restarted 2.

• Renal function: Acute kidney injury has been reported with GLP-1 receptor agonists, particularly in patients experiencing severe gastrointestinal adverse effects leading to dehydration. Monitor renal function when initiating or escalating doses 2.

• Medication interactions: GLP-1 agonists may delay gastric emptying, potentially affecting absorption of concomitantly administered oral medications. This effect is usually more pronounced with shorter-acting agents 1.

• Cardiovascular effects: While GLP-1 receptor agonists have demonstrated cardiovascular benefits in patients with type 2 diabetes and established cardiovascular disease, they can increase heart rate by approximately 5 bpm 1.

By carefully screening for these contraindications and using appropriate caution in at-risk populations, GLP-1 receptor agonists can be safely used to improve glycemic control, reduce cardiovascular risk, and promote weight loss in appropriate patients.