Enhanced weight loss outcomes with GLP-1 analogues and bupropion/naltrexone combination

In a recent study published in the International Journal of Obesity, researchers investigated the effects of combined glucagon-like peptide 1 (GLP-1) analog and bupropion/naltrexone treatment on weight loss.

Clinical Research: Effect of combined GLP-1 analogue and bupropion/naltrexone on weight loss: a retrospective cohort study. Image Credit: MillaF / Shutterstock

Obesity is associated with several complications, such as hypertension, diabetes, osteoarthritis, cancer, cardiovascular death, and premature death. Optimized diet and exercise are integral to obesity treatment; however, changes in health behavior alone are usually unsustainable or insufficient, necessitating pharmacological therapy. Several effective and safe pharmacological therapies promoting weight loss and weight plateau have been introduced.

GLP-1 inhibits agouti-related peptide and hypothalamic neuropeptide Y for homeostatic appetite regulation, reducing hunger, and increasing satiety. A trial reported that a 1-mg weekly dose of semaglutide (a GLP-1 analog) was associated with 6 kg weight loss in diabetes patients. Bupropion inhibits noradrenaline and dopamine reuptake, whereas naltrexone is an opioid antagonist of the mesolimbic reward pathway, reducing rewards/pleasure-based or hedonic hunger.

A study showed that naltrexone and bupropion treatment was associated with a total body weight loss (TBWL) of 5.2%. Combining these therapies that target mesolimbic hedonic hunger and hypothalamic appetite regulation may synergistically affect weight loss. Nevertheless, the putative effects of the combined GLP-1 analog and bupropion/naltrexone treatment on weight loss are undefined.

About the study

In the present study, researchers determined the effects of a combined GLP-1 analog and bupropion/naltrexone treatment on weight loss in obese patients. Adults aged ≥ 19 with a body mass index (BMI) ≥ 30 kg/m2 attending a clinic in Vancouver were included if they were prescribed a GLP-1 analog for obesity and had a follow-up visit at six months.

Individuals who received bupropion/naltrexone before GLP-1 analog therapy and those with surgical treatment for obesity before or during the study were excluded. Participants received lifestyle recommendations through counseling sessions or educational materials. Data on the use and dosage of GLP-1 analogs, bupropion, and naltrexone were collected.

Further, data on other weight loss-related medications, such as sodium-glucose cotransporter-2 inhibitors, diuretics, and orlistat, were obtained. Information on age, sex, hypertension, diabetes, dyslipidemia, smoking, alcohol intake, depression, anxiety, and sedentariness was collected at baseline. Baseline characteristics were compared by the pharmacotherapy, i.e., GLP-1 analog therapy alone or combined with bupropion/naltrexone.

For GLP-1 analog monotherapy patients, the percent TBWL was computed from baseline to six and 12 months. In contrast, for combination therapy patients, it was estimated from the start of the bupropion/naltrexone add-on treatment to six and 12 months. Responders were those with ≥ 5% TBWL to GLP-1 analogs; non-responders were those with less than 5% TBWL. A linear regression model examined associations between the use of combined treatment and percent TBWL relative to monotherapy; analysis was repeated after adjusting for baseline BMI, age, and sex differences.


Overall, 415 participants were included for analysis. Over three-fourths of subjects were female; most individuals had a BMI ≥ 40 kg/m2. Participants were followed up for approximately 511 days, on average. All subjects were started on GLP-1 analog monotherapy, and 22.9% were initiated on the add-on treatment (bupropion/naltrexone). Comorbidities were similar between patients on GLP-1 analog monotherapy and combination therapy.

However, combination therapy patients were less likely to have diabetes and more likely to have polycystic ovarian syndrome. On average, monotherapy and combination therapy patients had 7.7 and 6.1 physician visits, respectively, within the first year. The add-on treatment was started 150.4 and 293.6 days after GLP-1 analog monotherapy initiation among responders and non-responders, respectively.

At one year, GLP-1 analog monotherapy recipients had a mean weight loss of 11.42 kg, whereas combination treatment patients had an average weight loss of 5.51 kg. The mean percent TBWL was 4.3% at six months and 5.3% at 12 months among responders after add-on initiation. The corresponding estimates among non-responders were 3.7% and 4%, respectively.

No significant differences were observed in the percent TBWL between monotherapy and combination therapy patients. Nevertheless, a significant difference was evident when stratified by GLP-1 analog response; the combination therapy was significantly associated with a higher percent TBWL in responders and non-responders than GLP-1 analog monotherapy alone. These differences remained following age, sex, and BMI adjustments.


In sum, the findings illustrate that adding bupropion/naltrexone therapy to GLP-1 analog monotherapy results in additional weight loss, even in those with an initially poor response to the monotherapy. The additional weight loss with bupropion/naltrexone was 4% to 5%. However, these results require confirmation in randomized controlled trials.

Journal reference:

  • Naude J, Zentner A, Suresh P, Bittman J, Khan NA. Effect of combined GLP-1 analogue and bupropion/naltrexone on weight loss: a retrospective cohort study. Int J Obes, 2024, DOI: 10.1038/s41366-024-01526-2, https://www.nature.com/articles/s41366-024-01526-2

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