Naltrexone-bupropion for weight loss

Clinical question

Is combination naltrexone-bupropion effective for weight loss?

Bottom line

Over 28 to 56 weeks about 50% of patients (at best) taking naltrexone-bupropion achieved a 5% or greater loss in body weight, compared with about 20% in the placebo group. Naltrexone-bupropion adverse events (eg, nausea, constipation) led to withdrawal in 23% of the study group versus 12% in the placebo group.

Evidence

Evidence is mostly systematic reviews with meta-analysis of RCTs. Results are statistically significant unless noted.

• In a systematic review of 4 RCTs of 3955 patients who received at least 1 dose, median baseline weight was 100 kg.¹ Both arms included lifestyle changes. Naltrexone-bupropion was titrated to 16 mg and 180 mg twice daily versus placebo. Outcomes at 56 weeks for naltrexone-bupropion and placebo, respectively, were as follows:

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    5% or greater weight loss: 53% versus 21% (number needed to treat [NNT]=4).
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    10% or more weight loss: 29% versus 9% (NNT=5).
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    Mean weight loss (2 RCTs reporting): about 6 kg versus about 1 kg.
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    Withdrawals due to adverse effects: 25% versus 13% (number needed to harm [NNH]=8).
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    Other systematic reviews had similar findings.^2,3
• A systematic review of the same 4 RCTs included the lower-dosage arm (16 mg and 360 mg daily) and all randomized participants (N=4536).⁴ The following outcomes were seen at 28 to 56 weeks for naltrexone-bupropion and placebo, respectively:

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    5% or greater weight loss: 38% versus 17%, NNT=5.
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    10% or greater weight loss: 22% versus 8%, NNT=8.
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    Mean weight loss: about 4.5 kg versus 2 kg.
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    Withdrawals due to adverse events: 23% versus 12%, NNH=10.
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    Most common adverse events were nausea (31% vs 7%) and constipation (18% vs 7%).

• Limitations: All RCTs were industry funded, had high dropout rates (about 45%), and had inconsistent magnitudes of effect across RCTs but all showed benefit.

Context

• A trial of cardiovascular safety stopped early due to a data breach; however, a systematic review of 5 RCTs found no association with cardiovascular events.⁵

• Weight regain after stopping medication is unknown.

• Cost (1 month) is about $360 (generally not covered; personal communication with Summerside Pharmacy, Edmonton, Alta; July 4, 2023). Off-label prescribing of individual components at lower doses is about $90.

• Other weight-loss medications (followed by mean weight loss) are orlistat (about 2.6 kg)¹ and glucagonlike peptide-1 agonists such as semaglutide (10-15 kg)⁶ and liraglutide (about 5 kg).⁷ Baseline weight was 101 to 106 kg.

Implementation

While glucagonlike peptide-1 agonists appear to be more effective and better tolerated, naltrexone-bupropion is an option for patients averse to injections.^6,7 Naltrexone-bupropion is started at 8 mg and 90 mg once daily and increased over 4 weeks to a daily maximum of 32 mg and 360 mg (2 tablets of 8 mg and 90 mg each, twice daily).⁸ It is contraindicated in patients with seizure disorders and uncontrolled hypertension.⁸ Mild to moderate nausea is typically reported in the first week and is common during dose escalation.⁹ Duration of nausea ranges from 9 to 14 days and about 10% of patients complain of nausea beyond week 4.⁹ Weight loss occurs independently of patient nausea.⁹

Tools for Practice articles in CFP are adapted from peer-reviewed articles at http://www.toolsforpractice.ca and summarize practice-changing medical evidence for primary care. Coordinated by Dr G. Michael Allan and Dr Adrienne J. Lindblad, articles are developed by the Patients, Experience, Evidence, Research (PEER) team and supported by the College of Family Physicians of Canada and its Alberta, Ontario, and Saskatchewan Chapters. Feedback is welcome at toolsforpractice@cfpc.ca.