What are the recommended first-line medication options for weight loss in obese or overweight patients with comorbid conditions?

First-Line Medication Options for Weight Loss in Obese or Overweight Patients with Comorbidities

Semaglutide 2.4 mg is the recommended first-line medication for weight loss in obese or overweight patients with comorbidities due to its superior efficacy with mean weight loss of 14.9-17.4% at 68 weeks compared to other available options. 1

Medication Options Based on Efficacy

The American Gastroenterological Association (AGA) recommends several medications for weight loss, with varying degrees of efficacy:

1. Semaglutide 2.4 mg:

   • Highest efficacy with 14.9-17.4% total body weight loss (TBWL)
   • Should be prioritized over other approved anti-obesity medications for most patients 2
   • Particularly beneficial for patients with type 2 diabetes due to glucoregulatory benefits

2. Liraglutide 3.0 mg:

   • Approximately 5.4% weight loss compared to placebo 3
   • Also approved for treatment of type 2 diabetes
   • Administered as daily subcutaneous injection

3. Phentermine-Topiramate ER:

   • Approximately 6.8% weight loss compared to placebo 3
   • May be preferentially used in patients with comorbid migraines 2
   • Requires gradual dose titration

4. Naltrexone-Bupropion ER:

   • Approximately 4.0% weight loss compared to placebo 3
   • May be considered for patients attempting smoking cessation or with depression 2

5. Phentermine (monotherapy):

   • FDA-approved for short-term use only (12 weeks)
   • Often used off-label for longer periods 2

6. Orlistat:

   • Least effective with approximately 2.9% weight loss compared to placebo 3
   • AGA suggests against its use due to limited efficacy and GI side effects 2

Patient Selection Algorithm

1. First-line for most patients: Semaglutide 2.4 mg weekly injection

   • Particularly for patients with diabetes or prediabetes
   • Contraindicated in patients with personal/family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2 1

2. For patients with migraines: Consider phentermine-topiramate ER

   • Avoid in patients with cardiovascular disease or uncontrolled hypertension
   • Contraindicated in pregnancy (topiramate is teratogenic) 2

3. For patients with depression or attempting smoking cessation: Consider naltrexone-bupropion ER

   • Avoid in patients with seizure disorders
   • Do not use with opioid medications 2, 4

4. For short-term use or when cost is a barrier: Consider phentermine monotherapy

   • Avoid in patients with cardiovascular disease
   • Monitor blood pressure and heart rate regularly 2

Monitoring and Discontinuation

• Evaluate efficacy at 3 months
• If <5% weight loss is achieved, consider discontinuing or switching medications 1
• Continue medication if ≥5% weight loss is achieved 1
• Monitor for medication-specific side effects:
  • GLP-1 RAs (semaglutide/liraglutide): GI symptoms, pancreatitis, gallbladder disease
  • Phentermine/phentermine-topiramate: Blood pressure, heart rate
  • Naltrexone-bupropion: Blood pressure, heart rate, mood changes
  • Orlistat: Fat-soluble vitamin deficiencies 2, 1

Important Considerations and Caveats

• Weight regain is common: Studies show significant weight regain after discontinuation of GLP-1 receptor agonist therapy, with mean weight regain of 11.6% of lost weight within 52 weeks 1

• Medication should not be used alone: All guidelines emphasize that medications should be used as an adjunct to lifestyle modifications including diet and exercise 2

• Cost and insurance coverage: Many weight loss medications are expensive and may not be covered by insurance, which can be a significant barrier to access 2

• Pregnancy considerations: Women of childbearing potential should use effective contraception when taking phentermine-topiramate ER due to teratogenic effects 2

• Cardiovascular safety: Phentermine and phentermine-topiramate ER should be avoided in patients with cardiovascular disease or uncontrolled hypertension 2

• Long-term therapy: Most weight loss medications (except phentermine monotherapy) are approved for long-term use, which may be necessary to maintain weight loss 1

By following this evidence-based approach to medication selection, clinicians can optimize outcomes for patients seeking pharmacological treatment for obesity or overweight with comorbidities.