Recommended Weight Loss Medications for Obese or Overweight Patients with Comorbidities
Semaglutide 2.4 mg is the 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. 1
Medication Selection Algorithm
First-line Options:
- Semaglutide 2.4 mg weekly (subcutaneous injection)
- Superior efficacy compared to other medications
- Particularly beneficial for patients with type 2 diabetes due to glucoregulatory benefits
- Administered via subcutaneous injection in the abdomen, thigh, or upper arm
- Requires dose titration over 16 weeks to reach maintenance dose
Second-line Options (based on patient-specific factors):
Phentermine-topiramate ER
- Approximately 6.8% weight loss compared to placebo
- Preferred for patients with comorbid migraines
- Requires gradual dose titration
- Avoid in patients with cardiovascular disease or uncontrolled hypertension
- Contraindicated in pregnancy due to teratogenic effects
Naltrexone-bupropion ER
- Approximately 4.0% weight loss compared to placebo
- Consider for patients attempting smoking cessation or with depression
- Avoid in patients with seizure disorders
- Do not use with opioid medications
Phentermine (monotherapy)
- FDA-approved for short-term use only (12 weeks)
- Often used off-label for longer periods
- Avoid in patients with cardiovascular disease
- Contraindicated in patients with history of cardiovascular disease, hyperthyroidism, glaucoma, agitated states, or history of drug abuse 2
Orlistat
- Least effective option (approximately 2.9% weight loss compared to placebo)
- Suggested against by the American Gastroenterological Association due to limited efficacy and GI side effects
- Requires taking a multivitamin once daily at bedtime to prevent fat-soluble vitamin deficiencies 3
Eligibility Criteria
Weight loss medications should be considered for individuals who:
- Have a BMI ≥30 kg/m², or
- Have a BMI ≥27 kg/m² with weight-related comorbidities
- Have failed to achieve adequate weight loss with lifestyle interventions alone 4
Medication Administration and Monitoring
Semaglutide Dose Titration:
| Week | Dose |
|---|---|
| 1-4 | 0.25 mg weekly |
| 5-8 | 0.5 mg weekly |
| 9-12 | 1.0 mg weekly |
| 13-16 | 1.7 mg weekly |
| 17+ | 2.4 mg weekly (maintenance) |
Monitoring Requirements:
- For all medications: Regular assessment of efficacy (weight loss)
- For GLP-1 RAs (semaglutide/liraglutide): Monitor for GI symptoms, pancreatitis, gallbladder disease, and lipid profile
- For phentermine/phentermine-topiramate: Monitor blood pressure and heart rate
- For naltrexone-bupropion: Monitor blood pressure, heart rate, and mood changes
- For orlistat: Monitor for fat-soluble vitamin deficiencies
Evaluation of Treatment Response
- Evaluate weight loss at 3 months
- Consider discontinuing or switching medications if <5% weight loss is achieved
- Continue medication if ≥5% weight loss is achieved
Important Considerations and Contraindications
- Pregnancy: Phentermine-topiramate ER is contraindicated; women of childbearing potential should use effective contraception
- Cardiovascular disease: Avoid phentermine and phentermine-topiramate ER
- Seizure disorders: Avoid naltrexone-bupropion
- GLP-1 RAs contraindications: Personal/family history of medullary thyroid carcinoma, multiple endocrine neoplasia type 2, and pregnancy
Common Side Effects
- Semaglutide: Primarily gastrointestinal (nausea, vomiting, diarrhea, constipation)
- Phentermine: Insomnia, dry mouth, constipation, increased heart rate
- Naltrexone-bupropion: Nausea, headache, constipation
- Orlistat: Oily spotting, flatulence with discharge, fecal urgency
Clinical Pearls
- Weight loss medications should always be used as an adjunct to lifestyle modifications (diet and exercise)
- Long-term medication use may be necessary as weight regain is common after discontinuation without maintained lifestyle interventions
- Consider medication-induced weight gain from other treatments (antidiabetics, antihypertensives, antidepressants) when managing obesity 4
- In real-world settings, liraglutide has shown greater effectiveness in weight loss compared to orlistat (-7.7 kg vs -3.3 kg) 5