Best Weight Loss Medication to Start With
Semaglutide 2.4 mg weekly or tirzepatide should be your first-line choice for most patients due to superior efficacy (15-21% weight loss) and proven cardiovascular benefits. 1, 2
Patient Eligibility Criteria
Before prescribing any weight loss medication, confirm your patient meets these criteria:
- BMI ≥30 kg/m² (obesity), OR 1, 3
- BMI ≥27 kg/m² with weight-related comorbidities such as type 2 diabetes, hypertension, dyslipidemia, or obstructive sleep apnea 1, 3
First-Line Medication Selection Algorithm
Preferred First-Line: GLP-1 Agonists/GIP-GLP-1 Agonists
Start with tirzepatide or semaglutide 2.4 mg weekly as these are the most effective options currently available:
- Tirzepatide (dual GIP/GLP-1 agonist) achieves 21% weight loss at 72 weeks with additional benefits including glycemic control and cardiovascular risk reduction 2
- Semaglutide 2.4 mg weekly achieves 15-17% weight loss at 1 year with proven cardiovascular event reduction in patients with obesity and preexisting cardiovascular disease 2
- Liraglutide 3.0 mg daily (Saxenda) achieves 8-10% weight loss and requires daily subcutaneous injection with dose escalation starting at 0.6 mg daily, increasing by 0.6 mg weekly up to 3.0 mg 4, 2
Alternative First-Line Options When GLP-1s Are Unavailable or Contraindicated
If GLP-1 agonists are contraindicated, unavailable, or unaffordable, consider these alternatives:
Phentermine/Topiramate ER (Qsymia):
- Achieves 6.6-9.8% mean weight loss at 1 year 1, 3
- Fixed-dose combination targeting multiple pathways (sympathomimetic + GABA modulation) 3
- Contraindicated in: cardiovascular disease, pregnancy, glaucoma, and hyperthyroidism 1
- Requires monthly pregnancy testing for women of reproductive age 1
Phentermine monotherapy (off-label):
- Achieves 6.0 kg weight loss at 28 weeks, with 46% of patients achieving ≥5% weight loss 1
- Best for younger patients without active/unstable coronary disease or uncontrolled hypertension 4
- Monitor blood pressure and heart rate regularly 1
- Do not exceed recommended doses when tolerance develops—discontinue instead 4, 1
Orlistat (Xenical 120 mg/Alli 60 mg OTC):
- Achieves 2.9-3.1% mean weight loss at 1 year 2, 3
- Blocks ~30% of dietary fat absorption 4, 1
- Best for patients with: constipation, cardiovascular contraindications to sympathomimetic agents, or limited financial resources 1
- Requires: multivitamin supplementation (fat-soluble vitamins A, D, E, K) taken at bedtime 4, 5
- Common side effects include oily spotting, flatulence, and frequent loose stools 4
Critical Monitoring and Efficacy Assessment
Assess response to medication systematically:
- Monthly for the first 3 months, then quarterly 1, 2
- Discontinue or change medication if <5% weight loss after 3 months at therapeutic dose 1, 3
- Continue medication beyond reaching weight loss goals to maintain benefits, as obesity is a chronic disease requiring indefinite treatment 1, 2
Common Pitfalls to Avoid
Do not combine phentermine with other weight loss medications or exceed recommended doses when tolerance develops 1
Do not use β-blockers as antihypertensives in patients with obesity, as they promote weight gain 1
Review and minimize medications that promote weight gain, including antipsychotics, some antidepressants (paroxetine, mirtazapine, tricyclics), glucocorticoids, and some anticonvulsants (valproic acid, gabapentin, pregabalin) 4, 2
Safety Monitoring for Specific Medications
For phentermine:
- Monitor blood pressure and heart rate regularly 1
- Assess for signs of pulmonary hypertension: dyspnea, angina, syncope, or lower extremity edema 3, 6
- Discontinue immediately if new unexplained symptoms develop 6
For GLP-1 agonists:
- Contraindicated in pregnancy 2
- Common GI side effects (nausea, vomiting) usually improve with dose escalation 2
- Monitor for risk of malnutrition and sarcopenia 2
For orlistat: