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

Contraindications for Starting 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

• Personal or family history of medullary thyroid carcinoma (MTC)

  • GLP-1 receptor agonists have been associated with thyroid C-cell tumors in rodents
  • Human relevance has not been definitively established, but caution is warranted
  • FDA black box warning exists for this risk 2

• Multiple endocrine neoplasia syndrome type 2 (MEN2)

  • Genetic syndrome with high risk of developing MTC
  • GLP-1 receptor agonists may potentially increase this risk 1, 2

• History of serious hypersensitivity reaction to the specific GLP-1 receptor agonist

  • Includes anaphylaxis and severe injection site reactions 1, 3

Medication-Specific Contraindications

• Severe renal impairment or end-stage renal disease (ESRD)
  • Specifically for exenatide and lixisenatide 1
  • Other GLP-1 receptor agonists (liraglutide, semaglutide) should be used with caution in severe renal impairment 1

Cautions and Relative Contraindications

1. History of pancreatitis

   • Use liraglutide with caution in patients with prior pancreatitis 1
   • Acute pancreatitis has been reported with GLP-1 receptor agonist use 4, 5
   • Risk may be dose-dependent 5

2. Clinically meaningful gastroparesis

   • Shorter-acting GLP-1 receptor agonists delay gastric emptying 1
   • Not recommended in patients with significant gastroparesis

3. Prior gastric surgery

   • Requires careful consideration due to effects on gastric emptying 1

4. Diabetic retinopathy

   • Semaglutide has been associated with diabetic retinopathy complications
   • Particularly with rapid and marked glucose reductions 1, 2
   • Patients with history of diabetic retinopathy should be monitored closely

5. Pregnancy or potential for pregnancy

   • Not recommended during pregnancy due to insufficient safety data 6

Risk Mitigation When Using GLP-1 Receptor Agonists

1. When combining with insulin or insulin secretagogues:

   • Increased risk of hypoglycemia
   • Consider reducing doses of insulin or sulfonylureas 1, 7

2. Monitoring recommendations:

   • Assess for history of pancreatitis before initiation
   • Monitor for signs of pancreatitis during treatment (persistent severe abdominal pain, sometimes radiating to the back, with or without vomiting) 2
   • Monitor patients with diabetic retinopathy for disease progression 2

3. Managing common side effects:

   • Gastrointestinal symptoms (nausea, vomiting, diarrhea) are most common
   • These typically diminish over time with continued treatment 1, 7
   • Consider reducing meal size and limiting alcohol and high-fat foods to minimize GI effects 6

Clinical Decision Algorithm

1. Screen for absolute contraindications:

   • MTC history (personal or family)
   • MEN2 diagnosis
   • Previous serious hypersensitivity to GLP-1 receptor agonists

2. Assess renal function:

   • If eGFR < 30 ml/min/1.73m²: Avoid exenatide and lixisenatide
   • Use liraglutide or semaglutide with caution in severe renal impairment

3. Review medical history for cautions:

   • History of pancreatitis
   • Gastroparesis
   • Prior gastric surgery
   • Diabetic retinopathy
   • Pregnancy status

4. If no absolute contraindications exist but cautions are present:

   • Consider risk-benefit ratio
   • Select appropriate GLP-1 receptor agonist based on specific patient factors
   • Implement appropriate monitoring

By carefully screening for these contraindications and using appropriate caution in at-risk populations, the benefits of GLP-1 receptor agonists for glycemic control and cardiovascular risk reduction can be maximized while minimizing potential risks.