What weight loss medication options are available for a patient with a body mass index (BMI) of 30 or higher, or a BMI of 27 or higher with at least one weight-related condition, excluding Glucagon-like peptide-1 (GLP-1) and Glucagon-like peptide-2 (GLP-2) medications?

Weight Loss Medications Beyond GLP-1 and GLP-2 Agonists

FDA-Approved Long-Term Weight Loss Medications

For patients with BMI ≥30 kg/m² or BMI ≥27 kg/m² with weight-related comorbidities, several non-GLP-1/GLP-2 medications are FDA-approved for chronic weight management as adjuncts to diet and exercise. 1

Phentermine/Topiramate Extended-Release (Qsymia)

This combination represents the most effective non-incretin weight loss medication currently available, achieving approximately 7% greater weight loss compared to placebo at one year. 2

• Mechanism: Phentermine acts as a sympathomimetic amine suppressing appetite, while topiramate (an antiepileptic) enhances satiety through multiple mechanisms 3, 4
• Dosing: Start at 3.75mg/23mg daily for 14 days, then increase to 7.5mg/46mg daily; can escalate to maximum 15mg/92mg daily based on response 1
• Efficacy: Produces mean weight loss of 7% more than placebo, with higher doses achieving greater results 2, 4
• Major contraindications: Cardiovascular disease, hyperthyroidism, glaucoma, pregnancy, MAO inhibitor use within 14 days 5, 2
• Serious warnings: Metabolic acidosis, increased heart rate, anxiety, insomnia, elevated creatinine, teratogenicity (requires negative pregnancy test and reliable contraception in women of childbearing potential), memory and attention problems 2, 4
• Not approved in Europe due to safety concerns 2

Phentermine Monotherapy

Phentermine is approved only for short-term use (≤12 weeks) and should not be considered for chronic weight management. 1, 5

• Dosing: 15-30mg daily, taken approximately 2 hours after breakfast 5
• Duration limitation: FDA-approved for only "a few weeks" of treatment 1, 5
• Renal dosing: Maximum 15mg daily with severe renal impairment (eGFR 15-29); avoid if eGFR <15 or dialysis 5
• Contraindications: Cardiovascular disease, uncontrolled hypertension, hyperthyroidism, glaucoma, agitated states, drug abuse history, pregnancy, nursing 5
• Avoid in evening: Due to insomnia risk 5

Orlistat (Xenical)

Orlistat is a lipase inhibitor that reduces dietary fat absorption by approximately 30%, producing modest weight loss of 3-5%. 6, 7

• Mechanism: Inhibits pancreatic and gastric lipases, preventing triglyceride breakdown and absorption 6
• Dosing: 120mg three times daily with meals containing fat 6
• Efficacy: Achieves 3-5% weight loss beyond placebo 6
• Side effects: Abdominal pain, diarrhea, fecal urgency, oily spotting, flatulence with discharge (gastrointestinal effects limit tolerability) 6, 7
• Vitamin supplementation required: Reduces absorption of fat-soluble vitamins (A, D, E, K); patients need supplementation taken at least 2 hours apart from orlistat 6
• Advantage: No cardiovascular contraindications, making it suitable for patients with heart disease 6

Naltrexone/Bupropion (Contrave)

This combination produces approximately 3% additional weight loss compared to placebo but carries significant neuropsychiatric risks. 6

• Mechanism: Naltrexone (opioid antagonist) combined with bupropion (antidepressant/smoking cessation agent) acts on hypothalamic appetite centers 6
• Efficacy: Mean weight loss of 3.01% beyond placebo 6
• Major safety concerns: Potentially severe neuropsychiatric disorders, including depression, suicidal ideation, and behavioral changes 6
• Discontinuation rates: 129 more patients per 1000 discontinue due to adverse effects compared to placebo 6
• Contraindications: Uncontrolled hypertension, seizure disorders, eating disorders, opioid use, MAO inhibitor use 6

Critical Treatment Principles

Medication Selection Algorithm

When GLP-1/GLP-2 agonists are not options, prioritize medications based on cardiovascular risk profile and comorbidities:

1. For patients WITH cardiovascular disease: Choose orlistat (no CV contraindications) 6
2. For patients WITHOUT cardiovascular disease seeking maximum efficacy: Choose phentermine/topiramate (highest weight loss) 2, 4
3. For patients with psychiatric contraindications: Avoid naltrexone/bupropion and phentermine/topiramate 6, 2
4. For patients needing short-term therapy only: Phentermine monotherapy for ≤12 weeks 1, 5

Mandatory Lifestyle Interventions

All FDA-approved weight loss medications require concurrent implementation of reduced-calorie diet (500-kcal deficit) and minimum 150 minutes weekly of physical activity. 1, 6

• Medications as monotherapy without lifestyle modification do not meet FDA approval criteria and produce suboptimal results 6
• Resistance training should be incorporated to preserve lean body mass 6

Efficacy Assessment and Discontinuation Criteria

Discontinue medication if weight loss is <5% after 3 months at therapeutic dose, as this predicts poor long-term response. 1

• Assess efficacy and safety monthly for first 3 months, then at least quarterly 1
• Early responders (≥5% weight loss at 3 months) should continue long-term treatment 1
• Discontinue immediately for any safety or tolerability issues 1

Concomitant Medication Management

Minimize medications that promote weight gain whenever possible. 1

• Weight-promoting medications to consider alternatives for: Antipsychotics (clozapine, olanzapine, risperidone), tricyclic antidepressants, some SSRIs, MAO inhibitors, glucocorticoids, injectable progestins, anticonvulsants (gabapentin, pregabalin), sedating antihistamines 1
• For diabetes patients: Prioritize glucose-lowering medications with weight loss or weight-neutral effects (metformin, SGLT2 inhibitors); avoid or minimize insulin secretagogues, thiazolidinediones, and insulin when possible 1, 7

Special Populations and Contraindications

Women of Childbearing Potential

Phentermine/topiramate is teratogenic and absolutely contraindicated in pregnancy. 2, 4

• Requires negative pregnancy test before initiation 1, 4
• Mandates reliable contraception throughout treatment 1, 2, 4
• All weight loss medications should prompt counseling about contraception 1

Renal Impairment

Phentermine requires dose reduction with severe renal impairment and is contraindicated with ESRD. 5

• Maximum 15mg daily if eGFR 15-29 mL/min/1.73m² 5
• Avoid completely if eGFR <15 or dialysis-dependent 5

Cardiovascular Disease

Phentermine and phentermine/topiramate are absolutely contraindicated with cardiovascular disease history. 5, 2

• Contraindications include: coronary artery disease, stroke, arrhythmias, congestive heart failure, uncontrolled hypertension 5
• Orlistat remains the safest option for patients with established cardiovascular disease 6

Critical Pitfalls to Avoid

• Never prescribe phentermine for chronic weight management – it is FDA-approved only for short-term use (≤12 weeks) 1, 5
• Never use weight loss medications as monotherapy – they must be combined with lifestyle modifications to meet FDA criteria 6
• Never continue ineffective treatment beyond 3 months – if <5% weight loss achieved, switch to alternative approach 1
• Never prescribe phentermine/topiramate without pregnancy prevention counseling in women of childbearing age 2, 4
• Never ignore cardiovascular contraindications – phentermine-containing products are absolutely contraindicated with CV disease 5, 2

Metabolic Surgery Consideration

For patients with BMI ≥40 kg/m² (≥37.5 kg/m² in Asian Americans) or BMI 35-39.9 kg/m² (32.5-37.4 kg/m² in Asian Americans) who fail to achieve durable weight loss with medications, metabolic surgery should be recommended. 1

• Surgery may be considered for BMI 30-34.9 kg/m² (27.5-32.4 kg/m² in Asian Americans) if medical management fails 1
• Should be performed in high-volume centers with multidisciplinary teams 1