What are the top weight loss (WL) drugs for a patient (pt) with a family history of medullary thyroid carcinoma (MTC)?

Weight Loss Medications for Patients with Family History of Medullary Thyroid Carcinoma

For patients with a family history of medullary thyroid carcinoma (MTC), orlistat is the only recommended weight loss medication as GLP-1 receptor agonists are absolutely contraindicated in this population. 1, 2

Contraindications for GLP-1 Receptor Agonists

• GLP-1 receptor agonists (including semaglutide) are absolutely contraindicated in patients with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2 (MEN2) due to increased risk of thyroid C-cell tumors 1
• This contraindication is based on animal studies and is included in FDA Black Box Warnings for these medications 2
• The risk applies to all GLP-1 receptor agonists including semaglutide (Wegovy), liraglutide (Saxenda), and tirzepatide (Zepbound) 1

Recommended Weight Loss Medications

First-Line Option:

• Orlistat (Xenical 120mg prescription, Alli 60mg OTC) is the safest option for patients with MTC family history 1
  • Mechanism: Inhibits pancreatic and gastric lipases, blocking absorption of about 30% of ingested fat 1
  • Efficacy: Produces modest weight loss of approximately 3.1% at 1 year compared to placebo 1
  • Dosing: 120mg three times daily with meals containing fat 1
  • Side effects: Primarily gastrointestinal (oily spotting, flatus with discharge, fecal urgency, fatty/oily stool) 1

Alternative Options (with caution):

• Phentermine (short-term use only) 3

  • Mechanism: Adrenergic agonist that suppresses appetite through sympathetic nervous system activation 1
  • Efficacy: Approximately 5.1% weight loss at 28 weeks 1
  • Limitations: Only approved for short-term use (≤12 weeks), Schedule IV controlled substance 1, 3
  • Not ideal for long-term management 3

• Naltrexone/bupropion (with careful monitoring) 1

  • Mechanism: Opioid receptor antagonist/dopamine and norepinephrine reuptake inhibitor 1
  • Efficacy: Approximately 4.8% weight loss at 56 weeks 1
  • Side effects: Nausea, constipation, headache, insomnia 1
  • No known direct thyroid concerns but requires monitoring for other side effects 1

Clinical Approach for Patients with Family History of MTC

1. Assess MTC risk level 1

   • Determine if patient has known RET proto-oncogene mutations (associated with hereditary MTC) 1, 4
   • Identify specific mutation if known, as different mutations carry different risk levels 1

2. Screen for MEN2 syndromes 1

   • MEN2A includes MTC, pheochromocytoma, and hyperparathyroidism 1
   • MEN2B includes MTC, pheochromocytoma, and characteristic clinical features 4
   • Familial MTC (FMTC) presents with isolated MTC 4

3. Weight management strategy 1

   • Begin with comprehensive lifestyle interventions (diet, exercise, behavioral therapy) 1
   • If pharmacotherapy needed, use orlistat as first-line medication 1
   • Avoid all GLP-1 receptor agonists regardless of specific formulation 1, 2

Important Considerations

• Patients with family history of MTC should undergo genetic counseling and testing for RET proto-oncogene mutations to determine their personal risk 1
• Regular screening for MTC development is essential in those with confirmed genetic risk 1
• The benefit of weight loss must be balanced against medication risks, particularly in high-risk genetic populations 1, 2
• For patients with severe obesity where medication options are limited, bariatric surgery may be considered as an alternative to pharmacotherapy 1

Common Pitfalls to Avoid

• Never prescribe GLP-1 receptor agonists to patients with family history of MTC, even if the patient has not been genetically tested 1, 2
• Don't assume that oral formulations of GLP-1 receptor agonists are safer - the contraindication applies to all routes of administration 1
• Don't overlook the importance of comprehensive lifestyle interventions, which should be the foundation of any weight management program 1
• Be aware that phentermine is only approved for short-term use and has limited long-term efficacy data 1, 3