Are off-label weight loss medications (off-label medications) safe and effective for weight loss?

Off-Label Weight Loss Medications: Safety and Efficacy

Off-label weight loss medications have modest efficacy with significant safety concerns and should only be considered for patients with BMI ≥30 kg/m² or BMI ≥27 kg/m² with weight-related comorbidities who have failed lifestyle modifications. 1, 2

Approved vs. Off-Label Medications

FDA-Approved Medications

• FDA-approved medications for long-term weight management include orlistat, phentermine/topiramate, naltrexone/bupropion, liraglutide, and semaglutide 1
• These medications are indicated specifically for patients with BMI ≥30 kg/m² or BMI ≥27 kg/m² with weight-related comorbidities 2
• Short-term FDA-approved medications (≤12 weeks) include phentermine, diethylpropion, benzphetamine, and phendimetrazine 1

Common Off-Label Medications

• Metformin: Associated with approximately 3% weight loss; may be appropriate for patients with prediabetes, polycystic ovary syndrome, or to mitigate weight gain from antipsychotics 1
• GLP-1 receptor agonists approved for diabetes (tirzepatide, semaglutide injection, oral semaglutide, liraglutide injection): Often used off-label for weight loss but insurance coverage may be restricted 1
• Fluoxetine and bupropion: Associated with modest weight loss (3.15 kg at 12 months and 2.8 kg at 6-12 months, respectively) 1

Efficacy of Off-Label Weight Loss Medications

• Weight loss attributable to medications is modest (<5 kg at 1 year) 1
• Metformin: 3% weight loss with 25-50% of patients achieving at least 5% weight loss 1
• Fluoxetine: 3.15 kg weight loss at 12 months 1
• Bupropion: 2.8 kg weight loss at 6-12 months 1
• There is no evidence that one off-label medication is more efficacious than another 1
• Weight regain typically occurs when medications are discontinued, highlighting the need for sustained lifestyle modifications 1, 2

Safety Concerns with Off-Label Use

• Long-term safety data (>12 months) are lacking for most off-label weight loss medications 1
• Potential side effects vary by medication:
  • Metformin: Gastrointestinal effects, vitamin B12 deficiency 1
  • Fluoxetine: Neuropsychiatric effects, sexual dysfunction 1
  • Bupropion: Seizure risk, blood pressure elevation, neuropsychiatric effects 3, 4
• Risk-benefit ratio is unfavorable for patients with normal BMI 2
• Potential drug interactions must be carefully considered, especially in patients with multiple comorbidities 3, 5

Clinical Approach to Weight Management

Initial Assessment

• Determine BMI and presence of weight-related comorbidities 1, 2
• Evaluate for medications that may contribute to weight gain (antipsychotics, certain antidepressants, glucocorticoids, anticonvulsants) 1
• Assess for contraindications to specific medications 1, 5

Treatment Algorithm

1. First-line: Lifestyle modifications

   • Diet, exercise, and behavioral counseling should be recommended for all patients 1, 3
   • Target progressive weight loss of <1 kg/week 3

2. Second-line: Consider FDA-approved medications if BMI ≥30 kg/m² or BMI ≥27 kg/m² with comorbidities and lifestyle modifications have failed 1, 2

3. Third-line: Consider off-label medications only if:

   • Patient meets BMI criteria (≥30 kg/m² or ≥27 kg/m² with comorbidities) 2
   • FDA-approved options are contraindicated, unavailable, or unaffordable 1
   • Patient understands the limited efficacy and potential risks 1

4. Monitoring and follow-up

   • Assess efficacy and safety monthly for the first 3 months 1
   • If weight loss is <5% after 3 months or significant side effects occur, discontinue medication 1
   • For effective treatments (≥5% weight loss), continue monitoring every 3 months 1

Common Pitfalls to Avoid

• Prescribing weight loss medications to patients with normal BMI 2
• Continuing medications despite inadequate response (<5% weight loss after 3 months) 1
• Failing to consider drug interactions with existing medications 3, 5
• Not discussing the temporary nature of medication-induced weight loss 1, 2
• Using medications without concurrent lifestyle modifications 1, 3
• Prescribing sympathomimetic agents (phentermine) to patients with cardiovascular disease 1, 3