What are the contraindications for the use of Glucagon-Like Peptide-1 (GLP-1) receptor agonists, such as liraglutide (Victoza), in patients with type 2 diabetes mellitus (T2DM)?

Contraindications for GLP-1 Receptor Agonists

GLP-1 receptor agonists are absolutely contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC) or Multiple Endocrine Neoplasia syndrome type 2 (MEN 2), and in those with known hypersensitivity to the specific agent. 1, 2, 3

Absolute Contraindications

Thyroid C-Cell Tumor Risk

• Personal or family history of medullary thyroid carcinoma (MTC) is an absolute contraindication due to rodent studies showing dose-dependent thyroid C-cell tumors, though human relevance remains uncertain 1, 2, 3
• Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) is an absolute contraindication for all GLP-1 receptor agonists 1, 2, 3
• The FDA mandates a Black Box Warning for thyroid C-cell tumor risk based on animal data, despite lack of conclusive human evidence 4, 5

Hypersensitivity

• Known serious hypersensitivity reactions (anaphylaxis or angioedema) to the specific GLP-1 receptor agonist contraindicate its use 1, 3

Pregnancy and Breastfeeding

• Pregnancy is an absolute contraindication for all GLP-1 receptor agonists 4, 1
• Breastfeeding is contraindicated as safety has not been established 4

Severe Renal Impairment (Agent-Specific)

• Exenatide and lixisenatide are absolutely contraindicated in severe renal impairment (eGFR <30 mL/min/1.73 m²) or end-stage renal disease 4, 1
• Semaglutide and liraglutide can be used with caution in severe renal impairment but require close monitoring 4, 1

Important Clinical Cautions (Not Absolute Contraindications)

Pancreatitis History

• Use with extreme caution in patients with prior pancreatitis history, as acute pancreatitis has been reported with GLP-1 receptor agonists 4, 1, 2, 3
• If pancreatitis is suspected (persistent severe abdominal pain radiating to back), discontinue immediately and do not restart if confirmed 2, 3
• Consider alternative antidiabetic therapies in patients with documented pancreatitis history 3

Gastroparesis

• Do not use in patients with clinically meaningful gastroparesis, as GLP-1 receptor agonists delay gastric emptying and will worsen symptoms 4, 1
• Exercise caution in patients with prior gastric surgery, including bariatric procedures 4, 1

Diabetic Retinopathy

• Monitor closely for retinopathy progression in patients with pre-existing diabetic retinopathy, particularly with semaglutide 4, 1, 2
• Rapid glucose improvement can temporarily worsen diabetic retinopathy; risk is higher in those with baseline retinopathy (8.2% vs 0.7% without history) 4, 2

Renal Impairment Monitoring

• For liraglutide and semaglutide in severe renal impairment: monitor renal function closely when initiating or escalating doses, especially with severe GI symptoms that could cause dehydration 4, 1
• Risk of acute kidney injury from dehydration secondary to GI side effects 4

Hypoglycemia Risk with Concomitant Medications

• Reduce doses of insulin or insulin secretagogues (sulfonylureas, glinides) when initiating GLP-1 receptor agonists to prevent hypoglycemia 4, 1, 2, 3
• GLP-1 receptor agonists alone have minimal intrinsic hypoglycemia risk due to glucose-dependent mechanism 1

Gallbladder Disease

• Monitor for cholelithiasis and cholecystitis, as GLP-1 receptor agonists increase risk of gallbladder disease 4

Perioperative Considerations

• Delayed gastric emptying increases aspiration risk during general anesthesia or deep sedation 1

Critical Monitoring Parameters

• Screen for personal or family history of MTC or MEN 2 before initiating therapy 1, 2, 3
• If serum calcitonin is measured and >50 ng/L, further evaluate for MTC 2, 3
• Monitor renal function, particularly with severe GI symptoms 4
• Assess for signs of pancreatitis (persistent severe abdominal pain) 2, 3
• Monitor for gallbladder disease periodically 4
• In patients with diabetic retinopathy, monitor for progression 4, 2

Special Drug Interaction Considerations

• For oral contraceptive users: switch to non-oral method or add barrier method for 4 weeks after initiation and each dose escalation due to delayed gastric emptying affecting absorption 4
• May delay absorption of concomitantly administered oral medications, particularly those with narrow therapeutic index (e.g., warfarin) 4