What are the contraindications to starting Glucagon-like peptide-1 (GLP-1) receptor agonist therapy?

Contraindications to Starting GLP-1 Receptor Agonists

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

Absolute Contraindications

• Personal or family history of medullary thyroid carcinoma (MTC)
• Multiple endocrine neoplasia syndrome type 2 (MEN2)
• History of serious hypersensitivity reaction to the specific GLP-1 RA
• For specific agents only:
  • Exenatide and lixisenatide: Severe renal impairment (eGFR <30 mL/min/1.73 m²) or end-stage renal disease (ESRD) 1

Relative Contraindications/Use with Caution

Gastrointestinal Conditions

• History of pancreatitis: Use liraglutide with caution 1
• Clinically meaningful gastroparesis: Shorter-acting GLP-1 RAs may delay gastric emptying 1
• Prior gastric surgery: Exercise caution 1

Renal Considerations

• Severe renal impairment or ESRD: Use liraglutide and semaglutide with caution 1
• For exenatide: Caution when initiating or escalating doses if eGFR 30-50 mL/min/1.73 m² 1
• For lixisenatide: Clinical experience limited with eGFR 15-29 mL/min/1.73 m²; monitor for side effects and changes in kidney function 1

Ophthalmologic Considerations

• Diabetic retinopathy: Semaglutide has been associated with diabetic retinopathy complications, particularly with rapid and marked glucose reductions 1

Medication Interactions

• Insulin and insulin secretagogues: Increased hypoglycemia risk; consider lower doses of these agents when used with GLP-1 RAs 1

Monitoring Recommendations

1. Before initiating therapy:

   • Screen for personal and family history of MTC and MEN2
   • Assess baseline renal function
   • Consider comprehensive diabetic retinopathy evaluation, especially if planning rapid glucose control with semaglutide

2. During therapy:

   • Monitor for symptoms of pancreatitis (persistent severe abdominal pain)
   • Monitor renal function when initiating or escalating doses, particularly in patients with adverse gastrointestinal reactions 1
   • Watch for thyroid-related symptoms (thyroid nodules, dysphagia, persistent hoarseness) 2

Special Considerations

• Hypoglycemia risk: GLP-1 RAs alone have low risk of hypoglycemia, but risk increases when combined with insulin or insulin secretagogues 1, 3
• Gastrointestinal side effects: Common, especially during initiation and titration; typically transient 4, 5
• Cardiovascular benefits: Despite contraindications, GLP-1 RAs have demonstrated cardiovascular benefits in patients with established cardiovascular disease 1, 4

Algorithm for Patient Selection

1. Rule out absolute contraindications

   • No personal/family history of MTC or MEN2
   • No history of serious hypersensitivity to the specific GLP-1 RA
   • For exenatide/lixisenatide: eGFR ≥30 mL/min/1.73 m²

2. Assess relative contraindications

   • History of pancreatitis → Consider alternative agent or use liraglutide with caution
   • Significant gastroparesis → Consider longer-acting GLP-1 RA
   • Advanced diabetic retinopathy → Consider slower titration, especially with semaglutide

3. Consider specific agent based on patient characteristics

   • Renal impairment: Dulaglutide, semaglutide, or liraglutide preferred over exenatide/lixisenatide
   • Cardiovascular disease: Prefer agents with proven cardiovascular benefits (liraglutide, semaglutide, dulaglutide)

By carefully screening for contraindications and using appropriate caution in specific patient populations, GLP-1 receptor agonists can be safely and effectively used in the management of type 2 diabetes and obesity.