What are the contraindications for Glucagon-like peptide-1 (GLP-1) receptor agonists in patients with a history of thyroid cancer, pancreatitis, or severe gastrointestinal disease?

GLP-1 Receptor Agonist Contraindications

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 are not recommended in patients with severe gastroparesis, pregnancy, or breastfeeding. 1

Absolute Contraindications

Thyroid C-Cell Tumor Risk

• Personal or family history of medullary thyroid carcinoma (MTC) is an absolute contraindication due to FDA black box warnings based on rodent studies showing thyroid C-cell tumors, though human relevance remains uncertain. 1
• Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) is an absolute contraindication for all GLP-1 receptor agonists. 1, 2

Pregnancy and Breastfeeding

• Pregnancy and breastfeeding are absolute contraindications as safety has not been established in these populations. 2

Serious Hypersensitivity

• Prior serious hypersensitivity reaction to any GLP-1 receptor agonist or its components is an absolute contraindication. 1

Strong Relative Contraindications (Not Recommended)

Gastrointestinal Disease

• Severe gastroparesis is a strong relative contraindication because GLP-1 receptor agonists delay gastric emptying and will worsen symptoms. 1, 2
• Severe gastrointestinal disease of any type warrants avoidance of these agents. 1

Pancreatitis History

• History of pancreatitis requires consideration of alternative therapies, as GLP-1 receptor agonists have not been studied in this population and theoretical risk exists based on preclinical models. 3, 1
• History of pancreatic cancer is a relative contraindication based on theoretical risks from preclinical models. 3

Conditions Requiring Caution and Close Monitoring

Renal Impairment

• Severe renal impairment (eGFR <30 mL/min/1.73 m²) requires careful monitoring but is not a contraindication, as GLP-1 receptor agonists have been studied down to eGFR 15 mL/min/1.73 m². 3
• Monitor closely for gastrointestinal side effects that could lead to dehydration and acute kidney injury, particularly during dose initiation and escalation. 2, 4

Diabetic Retinopathy

• Patients with diabetic retinopathy require close monitoring for progression when using semaglutide specifically, due to increased risk of diabetic retinopathy complications observed in trials. 2

Gallbladder Disease Risk

• Monitor for cholelithiasis and cholecystitis as GLP-1 receptor agonists increase risk of gallbladder disease, though this is not a contraindication. 2, 4

Prior Gastric Surgery

• Patients with prior gastric surgery, including bariatric surgery, require extreme caution due to altered gastric anatomy and potential for worsened symptoms from delayed gastric emptying. 2

Drug Interaction Considerations

Hypoglycemia Risk

• When combined with insulin or insulin secretagogues (sulfonylureas, glinides), dose reduction of these medications is necessary to prevent hypoglycemia, though GLP-1 receptor agonists themselves do not cause hypoglycemia. 3, 2

Oral Contraceptives

• For patients using oral hormonal contraceptives, switch to non-oral contraception or add barrier method for 4 weeks after initiation and each dose escalation due to delayed gastric emptying affecting absorption. 2

Narrow Therapeutic Index Medications

• Medications with narrow therapeutic index (e.g., warfarin) require closer monitoring due to delayed gastric emptying affecting absorption. 2

Common Pitfalls to Avoid

• Never start at maximum dose—always begin with the lowest dose (0.25 mg weekly for semaglutide, 0.75 mg weekly for dulaglutide) and titrate slowly over at least 4 weeks at each dose level to minimize gastrointestinal side effects. 2, 1
• Do not confuse MTC risk with differentiated thyroid cancer (DTC)—the black box warning applies only to MTC and MEN 2, while evidence for DTC risk remains inconclusive and inconsistent. 5, 6, 7
• Recognize that theoretical pancreatic cancer risk is not supported by cardiovascular outcome trials, though follow-up duration may be insufficient for definitive conclusions. 2
• Ensure adequate hydration during initiation to prevent dehydration-related acute kidney injury from gastrointestinal side effects. 2, 4