Screening for Multiple Endocrine Neoplasia Type 2 (MEN2) Before Semaglutide Initiation

Mandatory Pre-Treatment Screening

The American College of Medical Genetics recommends asking every patient about personal history of medullary thyroid carcinoma (MTC) or family history of MTC in any first-degree relatives before prescribing any GLP-1 receptor agonist, as this information is crucial for identifying potential MEN2 cases 1
Screening for family history of pheochromocytoma is also essential, as this raises suspicion for MEN2 even without known thyroid disease 1
Inquiring about oral or ocular neuromas (lips, tongue, sclera, eyelids) and diffuse ganglioneuromatosis or chronic constipation since childhood is necessary, as these symptoms suggest MEN2B 1

The National Comprehensive Cancer Network recommends that any patient with MTC (even apparently sporadic) should undergo RET germline mutation testing, as 25% of unselected MTC cases have a RET mutation 1
Any first-degree relative of a patient with known MEN2 or MTC should also undergo RET germline mutation testing, according to the American Society of Clinical Oncology 2
Any patient with pheochromocytoma, particularly if bilateral, should undergo RET germline mutation testing, as 5% have RET mutations 1

The European Society of Medical Genetics states that RET germline mutation testing detects mutations in 99% of MEN2 cases, with the most common mutations occurring in specific codons with distinct phenotypes 2, 3
The most common mutations occur in specific codons with distinct phenotypes, including MEN2A: Mutations in exons 10, 11 (codons 609, 611, 618, 620, 630) and exon 13, and MEN2B: Codon 918 mutation (M918T) in exon 16 in 95% of cases, or A883F in exon 15 in 2-3% 3

The American Diabetes Association notes that if family history is positive or suspicious, semaglutide should not be prescribed until RET testing is completed, and if RET mutation is confirmed, semaglutide is permanently contraindicated 1
However, remember that 40-50% of MEN2B cases arise from de novo mutations, according to the Endocrine Society 3

Never assume sporadic MTC is truly sporadic—always test for RET mutations as 25% have germline mutations, as recommended by the American Thyroid Association 1
Do not rely solely on family history—up to 50% of MEN2B cases are de novo mutations, according to the European Society of Endocrinology 3

The American College of Cardiology recommends that GLP-1 receptor agonists are absolutely contraindicated in patients with Multiple Endocrine Neoplasia type 2 (MEN 2) due to the risk of thyroid C-cell tumors, but can be used safely in patients with Multiple Endocrine Neoplasia type 1 (MEN 1) 4, 5

The American Heart Association and the American College of Cardiology state that GLP-1 receptor agonists carry an FDA Black Box Warning and are contraindicated in patients with a personal or family history of medullary thyroid carcinoma, or Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) 4, 5, 6, 7, 8
The American College of Cardiology advises that this contraindication applies to all GLP-1 receptor agonists, including liraglutide, semaglutide, dulaglutide, exenatide, and lixisenatide, due to the increased risk of thyroid C-cell tumors 4, 5

The National Comprehensive Cancer Network recommends that patients with Multiple Endocrine Neoplasia type 1 (MEN 1) can safely receive GLP-1 receptor agonists, as MEN 1 does not involve medullary thyroid carcinoma 9, 10, 11, 12

The National Comprehensive Cancer Network suggests that somatostatin analogues, such as octreotide and lanreotide, are not contraindicated and are recommended treatment options for functional neuroendocrine tumors in both MEN 1 and MEN 2 9, 10, 11, 12
The typical dosing for somatostatin analogues includes octreotide 150-250 mcg subcutaneously three times daily or octreotide LAR 20-30 mg intramuscularly every 4 weeks, with dose adjustments based on symptom control 9, 11

The American College of Cardiology warns that GLP-1 receptor agonists should never be prescribed to a patient with known or suspected MEN 2 syndrome, including those with a family history of medullary thyroid carcinoma, or known RET proto-oncogene mutations 4, 5, 6, 7
The American Heart Association advises that screening for family history is crucial before initiating GLP-1 therapy, and to always ask about family history of medullary thyroid cancer or MEN syndromes before prescribing any GLP-1 receptor agonist 4, 5, 7