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:

  • - 5% or greater weight loss: 53% versus 21% (number needed to treat [NNT]=4).

  • - 10% or more weight loss: 29% versus 9% (NNT=5).

  • - Mean weight loss (2 RCTs reporting): about 6 kg versus about 1 kg.

  • - Withdrawals due to adverse effects: 25% versus 13% (number needed to harm [NNH]=8).

  • - 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:

  • - 5% or greater weight loss: 38% versus 17%, NNT=5.

  • - 10% or greater weight loss: 22% versus 8%, NNT=8.

  • - Mean weight loss: about 4.5 kg versus 2 kg.

  • - Withdrawals due to adverse events: 23% versus 12%, NNH=10.

  • - 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