Real World Efficacy of Naltrexone/Bupropion for Weight Management in Obesity and After Bariatric Surgery

Real World Efficacy of Naltrexone/Bupropion for Weight Management in Obesity and After Bariatric Surgery | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Real World Efficacy of Naltrexone/Bupropion for Weight Management in Obesity and After Bariatric Surgery Roman Vangoitsenhoven, Marie Yskout, Jarne Hoste, Nele Steenackers, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5357012/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 02 Sep, 2025 Read the published version in International Journal of Obesity → Version 1 posted 11 You are reading this latest preprint version Abstract Background Insufficient weight loss or weight regain after metabolic and bariatric surgery (MBS) is frequent, and the evidence to support the use of pharmacotherapy for weight management is limited. Methods In this single-centre retrospective cohort study, the effectiveness of naltrexone/bupropion (NB) for weight control in surgery-naive and post-MBS patients was evaluated. Data was collected between 2016 and 2022 on all consecutive patients started on NB after multidisciplinary consult. Patients received weekly dose escalation up to 32/360 mg daily per the manufacturer’s protocol, with submaximal doses administered in cases of adverse effects or sufficient therapeutic response. Weight evolution, metabolic status, adherence and adverse events were analysed at 4 and 12 months after NB initiation. Data are presented as median (interquartile range). Results A total of 153 patients initiated NB therapy, including 111 who were surgery-naive, and 42 with prior MBS. The median time after MBS was 7.7 years (4.3, 15.3). Among the post-MBS patients, 18 (42.9%) patients had undergone Roux-en-Y gastric bypass and 11 (26.2%) sleeve gastrectomy. At 4 months after initiation of NB, 46.8% of the surgery-naive patients and 66.7% of the post-MBS patients remained using NB, with a median weight loss of 6.4% (3.0, 10.1) and 6.1% (2.4, 2.0) respectively. At 12-months, 38.5% of surgery-naive patients and 60.7% of post-MBS patients had continued NB, with median weight loss of 8.8% (5.0, 16.7) and 11.1% (4.7, 19.8) respectively. There was no statistically significant difference in weight loss between the surgery-naive and post-MBS group. Weight loss was not significantly influenced by whether the maximal dose was reached in both the surgery-naive patients (p = 0.38) and the post-MBS patients (p = 0.61). Conclusion Real-world data show that NB treatment is equally effective in surgery-naive patients and in patients experiencing weight regain after bariatric surgery, regardless of the maximal dose administered. Health sciences/Endocrinology/Endocrine system and metabolic diseases/Obesity Health sciences/Health care/Weight management Health sciences/Health care/Therapeutics/Surgery/Bariatric surgery Obesity bariatric surgery weight regain naltrexone/bupropion Figures Figure 1 Figure 2 INTRODUCTION Treatment options for obesity have expanded considerably in recent years, with major advancements in pharmacotherapy including the development of medicines like naltrexone/bupropion (NB) and glucagon-like peptide 1 (GLP-1) analogues. Surgical interventions for weight loss have improved greatly, rendering metabolic and bariatric surgery (MBS) a safe, effective and durable treatment for patients with severe obesity [ 1 , 2 ]. According to data from The American Society for Metabolic and Bariatric Surgery, the most common surgical procedures performed in the U.S. in 2021 were laparoscopic sleeve gastrectomy (SG) at 58% and Roux-en-Y Gastric Bypass (RYGB) at 21% [ 3 ]. Despite these advancements, there is still a considerable amount of patients who experience weight regain or insufficient weight loss after MBS [ 4 ]. The prevalence of poor weight loss outcomes ranges between 3.9 to 71% depending on the criteria used and the type of bariatric surgery performed [ 5 ]. While insufficient weight loss has been defined as less than 50% excess weight loss or a BMI above 35 kg/m², there is no consensus on the definition of weight regain [ 6 ]. Both are mitigated by factors such as dietary non-adherence, as well as hormonal and metabolic changes [ 5 , 7 ]. As obesity is a chronic disease, individual variety and sensitivity in postoperative nutrient stimulated hormonal responses may play a role, such as those involving pancreatic peptide YY, ghrelin and glucagon like peptide [ 5 , 7 ]. The optimal way to approach patients with weight regain or insufficient weight loss remains unclear, as limited data has been published on the effectiveness of different multidisciplinary strategies. NB, a combination of naltrexone (an opioid antagonist) and bupropion (a norepinephrine and dopamine reuptake inhibitor), has shown synergistic effect on appetite suppression, especially in patients with addictive overeating and food cravings [ 8 – 12 ]. It’s approved as an anti-obesity drug by the FDA and EMA since 2014 and 2015 under the commercial name Contrave and Mysimba, but treatment with NB is not covered by health insurance in Belgium. A recent systematic review supports the use of NB to reach significant weight loss in primary obesity [ 13 ]. Additionally promising results are reported in patients with genetic obesity, and for the use of NB in combination with other anti-obesity drugs [ 14 , 15 ]. Although numerous studies have shown the effectiveness and safety of NB, initial trials excluded patients with prior surgical interventions for obesity, leaving the effect of NB in these patients not well understood [ 12 , 16 – 18 ]. Several smaller studies have investigated the effectiveness and safety of different anti-obesity drugs in post-MBS patients. Phentermine/topiramate has been reported to prevent and reduce weight regain post-RYGB and gastric banding in retrospective studies, while GLP-1 analogues like liraglutide have demonstrated similar weight loss after SG and RYGB in prospective placebo-controlled trials, regardless of the presence of type 2 diabetes [ 19 – 23 ]. A retrospective study by Hanipah et al. , evaluated the effectiveness of adjuvant weight loss medications, including NB, after MBS [ 24 ]. However, as the number of patients on NB was limited (n = 10) and results on weight evolution were pooled with those of other anti-obesity drugs, definitive conclusions regarding NB’s efficacy in this patient population cannot be made. We aim to provide insight into the real-world efficacy and safety of NB in patients struggling with poor weight loss outcomes after MBS. METHODS This single-centre retrospective cohort study, conducted at the obesity clinic of the University Hospital of Leuven (Belgium), aimed to compare the efficacy of NB initiation in achieving weight loss in adult patients (18 years or older), who were surgery-naive and in patients who had experienced weight regain or insufficient weight loss after MBS (“post-MBS”). Study population Data were retrieved from the electronic medical records of all adult patients prescribed NB, in adjunct to lifestyle advise, between June 2016 and August 2022 at the obesity clinic of the University Hospital of Leuven. Patients underwent a comprehensive multidisciplinary assessment, including evaluation by the endocrinologist, surgeon, dietician and psychologist. Pharmacotherapy was recommended in accordance with international recommendations, specifically for patients with a BMI of ≥ 30 kg/m² or ≥ 27 kg/m² with one or more weight-related comorbidity. Patients receiving other anti-obesity drugs, such as GLP-1 analogues, or those undergoing MBS were not included in the current study. NB-treatment was initiated at a starting dose of 8 mg naltrexone/90 mg bupropion (one tablet) per day. As per leaflet, the dose was increased weekly until reaching the maintenance dose of 32 mg naltrexone/360 mg bupropion per day (two tablets twice daily). Patients who experienced side effects continued the maximal tolerated dose, and patients who reported sufficient subjective effect with a lower dose were allowed to remain at that submaximal dose. Follow-up visits were scheduled at the outpatient clinic 4 and 12 months after treatment initiation. Data management Data from the initial visit, as well as the 4-month and 12-month follow-up appointments, were extracted from a structured electronic medical record system. All data was pseudonymised to ensure patient confidentiality. The research protocols received approval from the local ethics committee (EC UZ Leuven S62590) and adhered to the latest Declaration of Helsinki. Endpoint and assessments For this retrospective analysis, data was collected on the following variables: total body weight before MBS, nadir weight (lowest reported weight after MBS), time from MBS to nadir weight, time from MBS to initiation of NB treatment, body weight prior to the initiation of NB therapy and weight at the 4 and 12-month follow-up. Post MBS-weight loss was calculated as the difference between pre-MBS weight and nadir weight post-surgery. The co-primary endpoints of interest were the percentage change in body weight and the achievement of a reduction in body weight of ≥ 5% from baseline at 4 and 12 months. Additionally, secondary, and exploratory endpoints included changes in BMI (kg/m²), weight change (kg), achievement of a reduction in body weight of more than 0%, 5% or 10%, treatment status, maximal tolerated dose, adherence to therapy, reasons for discontinuation and any adverse effects observed. Statistical analysis Categorical data are presented as counts and percentages, while continuous data are described using median values and interquartile ranges (IQR). Intergroup variances were analysed using Student's t-test for normally distributed data and the Mann-Whitney U test for non-normally distributed data. Statistical analyses were performed using PRISM software, with p-values < 0.05 considered statistically significant. RESULTS Study population A total of 153 patients were started on NB therapy at the UZ Leuven obesity clinic following a multidisciplinary consultation. Of the 153 patients, 111 were treated for primary obesity using NB (surgery-naive group), while 42 patients had sought assistance due to weight regain or insufficient weight loss following MBS (post-MBS group). Baseline characteristics are presented per group in table 1. In the surgery-naive group, the majority of patients was female (77.5%) with a median age of 45.0 years (34.0, 52.0). Similarly, the post-MBS group consisted mostly of females (76.2%) with a median age of 51.0 years (41.0, 59.3). The surgery-naive group had a median body weight of 103.1 kg (90.0, 113.0), with a median BMI of 34.9 kg/m² (32.7, 37.8). The post-MBS group had a median body weight of 102.8 kg (88.0, 129.1) and a median BMI of 35.4 kg/m² (30.9, 45.3). At baseline, 3 (2.7%) patients in the surgery-naive group and 2 (4.8%) patients in the post-MBS group had type 2 diabetes. Details of prior surgery in the post-MBS group are summarized in table 2. The most common type of surgery was RYGB (18 patients, 42.9%), followed by SG (11 patients, 26.2%), gastric banding (3 patients, 7.1%), Mason gastroplasty (1 patient, 2.4%), banded gastric bypass (1 patient, 2.4%) and 8 patients (19.0%) had had secondary MBS. The median total weight loss across all procedures was 41.0 kg (31.5, 48.3), or 33.3% (26.5, 37.9). Overall, the median weight regain for all procedures was 21.0 kg (12.4, 39.5) or 30.1% (16.6, 48.5). The median time between bariatric surgery and the start of NB was 7.7 years (4.3, 15.3). Therapy persistence and dropout Therapy persistence and dropout during 12 months of follow-up are displayed in Fig. 1 . One-hundred and thirty patients attended the 4-month follow-up visit, while 18 patients (16.2%) were lost to follow-up in the surgery-naive group and 5 patients (11.9%) were lost to follow-up in the post-MBS group. For those present, therapy persistence was 46.9% in the surgery-naive group and 66.7% in the post-MBS group. Among the 52 patients in the surgery-naive group still on NB therapy, only 19 (36.5%) were using the maximal daily dose of 32 mg naltrexone/360 mg bupropion while 29 patients (55.8%) were on a submaximal dose. In the post-MBS group, 15 patients (53.6%) were taking the maximal daily dose, and 12 patients (42.9%) were taking a submaximal dose. By the 12-month follow up visit, out of the 52 and 28 patients who had been advised to continue NB at the 4-month visit, 20 patients (38.5%) in the surgery-naive group and 17 patients (60.7%) in the post-MBS group were still on NB. Of those, 8 patients (40.0%) in the surgery-naive group were taking the maximal dose, while 12 patients (60.0%) were taking a submaximal dose. In the post-MBS group, 7 patients (41.2%) were taking the maximal daily dose, and 9 patients (52.9%) were on a submaximal dose. Twenty-one patients had discontinued NB therapy before reaching the 12-month visit in the surgery-naive group, compared to 9 patients in the post-MBS group, with a total of 13 patients lost to follow-up. Change in body weight at 4 months In the surgery-naive group on NB treatment (52 patients), the median weight loss at 4 months was 6.4% (3.0, 10.1). In the post-MBS group (28 patients), the median weight loss was 6.1% (2.4, 12.0). Both groups showed significant reductions in body weight after 4 months. The surgery-naive group decreased from 103.0 kg (88.3, 112.4) to 93.8 kg (82.7, 103.4) (median change: -5.8 kg (-3.0, -9.9); p < 0.0001 ) ). In the post-MBS group, weight decreased from 102.8 kg (88.7, 132.0) to 95.9 kg (79.2, 123.5) (median change: -6.2 kg (-2.4, -11.6); p = 0.0002 ). This corresponded to significant decreases in BMI for both groups: from 34.4 kg/m² (32.4, 37.9) to 32.1 kg/m² (30.1, 35.6) in the surgery-naive group (median change: -2.1 kg/m² (-1.1, -3.4); p < 0.0001 ), and from 37.3 kg/m² (30.1, 45.4) to 32.7 kg/m² (29.1, 41.7) in the post-MBS group (median change: -2.2 kg/m² (-0.88, -3.9); p = 0.0001 ). No statistical difference was observed in the absolute- ( p = 0.51) nor relative (p = 0.85) weight loss in the patients in the surgery-naive group versus the post-MBS group. The majority of patients in both groups achieved weight loss of 5% or more from baseline body weight: 58.5% in the surgery-naive group (Fig. 2 A) and 64.3% in the post-MBS group (Fig. 2 E). Patients at the maximal NB dose experienced a median weight change of -4.9% (-2.3, -10.6) in the surgery-naive group, compared to -9.0% (-0.9, -17.0) in the post-MBS group (Fig. 2 B and F). Patients on a submaximal NB dose experienced median weight changes of -6.7% (-4.2, -10.0; p = 0.46 ) in the surgery-naive group (Fig. 2 C) and − 6.1% (-3.2, -10.0; p = 0.67 ) in the post-MBS group (Fig. 2 G). Forty-one patients (36.9%) in the surgery-naive group, and 9 patients (21.4%) in the post-MBS group, had independently discontinued NB treatment before coming to the 4 month follow up visit, either due to insufficient effect or side effects. Reasons for NB discontinuation are shown in table 3. Their median weight change at 4 months was − 2.4% (-5.0, + 2.4) and − 2.4% (-4.0, + 0.5) respectively. No significant change was observed in median body weight in either group (surgery-naive group; p = 0.22 , post-MBS group; p = 0.09 ). The majority of patients who had prematurely discontinued NB did not achieve weight loss of ≥ 5% or more (76.2% in the surgery-naive group and 88.1% in the post-MBS group) and 38.1% and 33.3% even experienced weight gain respectively. Change in body weight at 12 months In the 20 patients from the surgery-naive group on NB treatment at 12 months (38.4% of the patients who had been advised to continue NB at the 4-month follow op visit), the median weight change was − 8.8% (-5.0, -16.7). A significant decrease in median body weight was observed from 100.2 kg (87.6, 112.0) to 87.7 kg (78.9, 99.3) (median change: -8.5 kg (-5.1, -15.7); p < 0.0001 ). For the post-MBS group (17 patients, 60.7%), the median weight change was − 11.1% (-4.7, -19.8). There was a significant decline in median body weight from 95.0 kg (86.3, 112.1) to 87.0 kg (76.4, 98.7) (median change: -9.0 kg (-5.0, -16.8); p = 0.0024 ). This resulted in a significant decrease in BMI from 33.9 kg/m² (31.8, 35.0) to 30.9 kg/m² (27.8, 32.5) after 12 months of treatment for the surgery-naive group (median difference: -2.9 kg/m² (-1.7, -5.5); p < 0.0001 ). Similarly, for the post-MBS group, there was a significant drop in BMI from 34.4 kg/m² (30.8, 38.5) to 30.4 kg/m² (28.0, 35.3) after 12 months of treatment (median difference: -3.3 kg/m² (-1.7, -5.7); p = 0.0016 ). Weight change in patients treated with NB at 12 months did not differ significantly in the surgery-naive versus the post-MBS group (weight change in kg: p = 0.30 ; weight change in %: p = 0.39 ). Sixteen patients, out of 20 patients who were still taking NB at the 12 months visit in the surgery-naive group (80.0%), achieved a weight loss of 5% or more of their baseline body weight at 12 months, with 8 patients (40.0%) reaching weight loss of 10% or more. In the post-MBS group, 12 out of 17 patients (70.6%) lost 5% or more, and 10 patients (58.8%) achieved weight loss of 10% or more. Patients in the surgery-naive group who used the maximal NB dose experienced a median weight change of -15.5% (-5.9, -17.1), which was not significantly different compared to the median weight change of -8.2% (-2.2, -14.5) observed in patients who were taking a submaximal dose of NB ( p = 0.38 ). Similarly, patients in the post-MBS group who used the maximal dose of NB had a median weight change of -15.5% (-5.9, -21.5), which was not significantly different ( p = 0.61 ) from those taking a submaximal dose, who lost − 9.7% (-3.1, -19.8). Treatment tolerance at 4-month & 12-month follow-up visits The reasons for not achieving the maximal dose, treatment discontinuation or failure to initiate treatment at the 4-month and 12-month visit are outlined in Table 3. At 4 months, the main reason for taking a submaximal dose of NB in both groups was that the patient experienced sufficient benefit (subjectively) from this submaximal dose; 18 patients (62.1%) in the surgery-naive group and 7 patients (58.3%) in the post-MBS group. Gastrointestinal side effects, including nausea, constipation, abdominal pain, vomiting and a dry mouth, were the main reason for early NB discontinuation, and the second most common reason for using a submaximal dose, in both groups. Cardiac and vascular side effects, such as palpitations, hot flashes and hypertension, were reported by 6 patients. Nervous system adverse events including dizziness, syncope and headache were observed in 7 patients in total, leading to NB discontinuation in 5 of them. Among the remaining 41 patients (36.9%) in the surgery-naive group, 2 patients (4.9%) discontinued treatment due to 'other reasons,' defined as difficulty swallowing the tablets. In the post-MBS group, 9 patients (21.4%) stopped NB prematurely, with 1 patient reporting fatigue which was classified as 'other reason'. At the 12-month follow-up, 8 patients (66.7%) in the surgery-naive group and all 9 patients (100.0%) in the post-MBS group reported sufficient benefit from NB at submaximal dose as the reason for not reaching the maximal dose. Gastrointestinal side effects were reported by 3 patients (25.0%) in the surgery-naive group as the reason for not reaching the maximal dose. Additionally, 21 patients (40.4%) in the surgery-naive group and 9 patients (32.1%) in the post-MBS group had discontinued treatment. The most common reason for discontinuation in both groups was inadequate weight loss at the 4-month follow-up, which was the case in 14 patients (63.6%) in the surgery-naive group and 7 patients (77.8%) in the post-MBS group. In the surgery-naive group, ‘other reasons’ for discontinuation included pregnancy (n = 1) and practical issues affecting treatment availability (n = 2). In the post-MBS group the reason for discontinuation was not specified by the patient. DISCUSSION To the best of our knowledge, this study represents the largest cohort to date examining the efficacy of NB treatment for insufficient weight loss or weight regain following MBS. Results indicate that the use of NB in these patients can be as effective as in surgery-naive patients, and can result in significant and important weight loss. At 4 months, both groups experienced similar mean weight loss percentages; -6.4% the for surgery-naive group and − 6.1% for the post-MBS group (compared to -2.4% for those discontinuing NB prematurely), with 58.5% versus 64.3% reaching ≥ 5% weight loss respectively. At 12 months, the patients in the surgery-naive group still taking NB lost approximately − 8.8% of total body weight while the post-surgery group lost − 11.1% with respectively 80.0 % versus 76.4% of patients losing ≥ 5% and 40.0% versus 58.8% of patients losing ≥ 10% of their initial body weight. Baseline characteristics were similar between cohorts, except that the post-MBS group was older. This cohort resembles well the clinical trial population for weight management using GLP-1 analogues and NB [ 12 , 16 , 17 , 25 – 27 ]. The low incidence of diabetes mellitus is consistent with clinical guidelines, as patients with type 2 diabetes are preferably offered a GLP-1 analogue to target body weight reduction in combination with glycaemic control [ 28 ]. No specific data have been published on the use of NB in patients post-MBS to date. As NB is an extended release tablet, not much is known about the intestinal absorption of this medication. While a Dutch trial is ongoing, no results have been published so far (EudraCT Number: 2021-002145-15). Hanipah et al. included patients on NB after weight regain, but their pooled data prevents specific conclusions regarding NB’s effectiveness [ 24 ]. Our real-world results in surgery-naive patients are however consistent with previous findings for NB in primary obesity. An analysis of pooled, participant-level data from 4 randomized controlled trials, with a total of 3362 patients treated with lifestyle changes plus either NB 32/360 mg total daily dose or placebo, demonstrated that after approximately 4 months of treatment 51% versus 19% of patients reached weight loss of -5% or greater, these patients were called “responders” [ 29 , 30 ]. When these responders continued the treatment for approximately 12 months, 81% of them were able to preserve this 5% weight loss and 57% achieved 10% weight loss. Furthermore, NB continuation was also shown to be associated with a greater likelihood of weight loss maintenance up to 4 years [ 31 ]. The literature suggests that the beneficial effect of NB is dose dependent, as patients who received a lower dose of NB, namely 16/360mg instead of the approved 32/360 mg total daily dose, had significantly less weight loss than those who took the full dose [ 32 ]. However, in this study a notable number of patients chose to remain at a lower dose because they experienced sufficient subjective weight loss with this submaximal dose, suggesting an individual sensitivity and response to NB. We observed comparable outcomes regardless of the used dose, as was shown in Fig. 2 , suggesting that a submaximal dose can be equally effective. Similar observations have been reported for liraglutide [ 33 ]. Given that NB is not reimbursed in many countries, including Belgium, the personal costs for the patients are high. The potential to reach significant weight loss with a lower dose could make NB more accessible and affordable to a larger population of patients. On the other hand, it is possible that these patients who report sufficient subjective benefit from a submaximal dose, if they’d be given the time and motivation to continue slowly up titrating NB, would experience an even greater reduction in their body weight at maximal dosage than can be shown in this study. The observed reasons for discontinuing NB treatment can be divided into three main categories. Firstly, adherence to the 4 month stopping rule, as is advised per label, was applied. This directive is based on the knowledge that (A) 5% weight loss is associated with improved cardiovascular outcomes and (B) patients in which this − 5% weight loss threshold is not reached at 4 months are unlikely to reach this threshold at 12 months [ 30 ]. Thus patients in which − 5% weight loss was not reached at 4 months, were advised to discontinue the therapy. However, a select number of patients did, on their own demand, continue the therapy despite being a non-responder at 4 months. At 12 months they again did not reach this − 5% weight loss threshold, supporting the recommendation to discontinue NB in these patients to prevent unjustified exposure. Secondly, the occurrence of side effects made at least 39 out of 153 patients (25.5%) quit the therapy with NB. No major side effects were reported in this study. Twenty four patients reported gastrointestinal side effects, 6 complained of cardiovascular side effects, 5 of nervous system disorders and 4 reported psychiatric side effects. Notably, a large number of patients reported side effects with the recommended dose (similar side effects to those who discontinued the treatment) but were able to tolerate NB at a lower dose. As was mentioned above, this dose de-escalation was independent of the effect on weight loss at 12 months. Thirdly, as NB is not reimbursed in Belgium it constitutes a relatively high financial burden for the patient. This combined with the perceived cost-benefit analysis, likely led to early discontinuation of the therapy in many patients. Study limitations include that this is a retrospective study and, despite it being the largest cohort to date, still has a limited sample size – especially the subgroups like the group on a submaximal NB dose. A significant number of patients were lost to follow up. Given the large number of patients followed at our outpatient clinic, patients that were doing well were sometimes referred to their general practitioner for further follow up. However, the real world applicability of these results is significant. So far, real-world data on the use of – and thereby also on the persistence with – NB is limited. An evaluation of 26,522 adult patients’ persistence with anti-obesity medications showed that at 6 months persistence with NB was lower than with liraglutide or phentermine/topiramate respectively (18.1% vs. 41.8% and 27.3%) [ 34 , 35 ]. In this retrospective analysis only 37 out of 153 patients (24.2%) were known to continue the therapy at 12 months after initiation. This low adherence and persistence with NB, and other anti-obesity medication for that matter, poses a great challenge in daily clinical practice. The patients included in this study were all, based on their general profile, eating habits and comorbidities, believed to be excellent candidates for NB initiation to reach optimal weight loss. Recent studies have shown the value of adequate patient selection before the initiation of anti-obesity medication, highlighting the need for the development of usable tools to guide clinical practitioners [ 36 ]. This study once again confirms the importance of adequate patient selection. Practitioners should aim to identify specifically those patients who lose up to 10–20% of their body weight after initiation of NB, for they exist both in surgery-naive patients and in patients who previously underwent MBS and experienced poor weight loss outcomes. Conclusion This retrospective analysis includes the largest cohort of patients treated with NB for weight regain or insufficient weight loss after MBS to date. Real-world data demonstrates that NB is as effective and safe in this population as in surgery-naive patients. Additionally, this effect was independent of dose, which could make the therapy more affordable and tolerable for a broader patient population. Further research is warranted to optimize patient selection previous to NB initiation. Declarations Competing interests RV is a clinical investigator for Boehringer Ingelheim, Eli Lilly and Novo Nordisk; he serves or has served on the speakers bureau for Boehringer Ingelheim, Eli Lilly, Goodlife Pharma, Novo Nordisk, Sanofi ; He serves or has served in advisory panels for Eli Lilly, Novo Nordisk, Sanofi; Any financial compensation for these activities has been received by the institution (UZ/KU Leuven). The remaining authors declare that they have no conflicts of interest relevant to this manuscript. Author contributions MY, NS, JH, CS collected data and performed data analyses. MY, JH wrote the first draft of the paper. NS, SP, NM, ED, ML, AM, BVS, RV reviewed the paper and provided critical input. All authors reviewed final manuscript and had access to data. RV is guarantor of this work. Acknowledgements / Data availability statement The data used to support the findings of the study are available from the corresponding author upon reasonable request. 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Effect of combined GLP-1 analogue and bupropion/naltrexone on weight loss: a retrospective cohort study. Int J Obes. 2024;48(8):1118–25. Apovian CM, Aronne L, Rubino D, Still C, Wyatt H, Burns C, Kim D, Dunayevich E. A randomized, phase 3 trial of naltrexone SR/bupropion SR on weight and obesity-related risk factors (COR-II). Obesity. 2013;21(5):935–43. Hollander P, Gupta AK, Plodkowski R, Greenway F, Bays H, Burns C, Klassen P, Fujioka K. Effects of naltrexone sustained-release/bupropion sustained-release combination therapy on body weight and glycemic parameters in overweight and obese patients with type2 diabetes. Diabetes Care. 2013;36(12):4022–9. Wadden TA, Foreyt JP, Foster GD, Hill JO, Klein S, O’Neil PM, Perri MG, Pi-Sunyer FX, Rock CL, Erickson JS, Maier HN, Kim DD, Dunayevich E. Weight loss with naltrexone SR/bupropion SR combination therapy as an adjunct to behavior modification: The COR-BMOD trial. Obesity. 2011;19(1):110–20. Redmond IP, Shukla AP, Aronne LJ. Use of Weight Loss Medications in Patients after Bariatric Surgery. Available from: https://doi.org/10.1007/s13679-021-00425-1 Mok J, Adeleke MO, Brown A, Magee CG, Firman C, Makahamadze C, Jassil FC, Marvasti P, Carnemolla A, Devalia K, Fakih N, Elkalaawy M, Pucci A, Jenkinson A, Adamo M, Omar RZ, Batterham RL, Makaronidis J. Safety and Efficacy of Liraglutide, 3.0 mg, Once Daily vs Placebo in Patients with Poor Weight Loss Following Metabolic Surgery: The BARI-OPTIMISE Randomized Clinical Trial. JAMA Surg. 2023;158(10):1003–11. Miras AD, Pérez-Pevida B, Aldhwayan M, Kamocka A, McGlone ER, Al-Najim W, Chahal H, Batterham RL, McGowan B, Khan O, Greener V, Ahmed AR, Petrie A, Scholtz S, Bloom SR, Tan TM. Adjunctive liraglutide treatment in patients with persistent or recurrent type 2 diabetes after metabolic surgery (GRAVITAS): a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2019;7(7):549–59. Schwartz J, Suzo A, Wehr AM, Foreman KS, Mikami DJ, Needleman BJ, Noria SF. Pharmacotherapy in Conjunction with a Diet and Exercise Program for the Treatment of Weight Recidivism or Weight Loss Plateau Post-bariatric Surgery: a Retrospective Review. Obes Surg. 2016;26(2):452–8. Istfan NW, Anderson WA, Hess DT, Yu L, Carmine B, Apovian CM. The Mitigating Effect of Phentermine and Topiramate on Weight Regain After Roux-en-Y Gastric Bypass Surgery. Obesity. 2020;28(6):1023–30. Nor Hanipah Z, Nasr EC, Bucak E, Schauer PR, Aminian A, Brethauer SA, Cetin D. Efficacy of adjuvant weight loss medication after bariatric surgery. Surgery for Obesity and Related Diseases. 2018;14(1):93–8. Wilding JPH, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I, McGowan BM, Rosenstock J, Tran MTD, Wadden TA, Wharton S, Yokote K, Zeuthen N, Kushner RF. Once-Weekly Semaglutide in Adults with Overweight or Obesity. New England Journal of Medicine. 2021;384(11):989–1002. Jastreboff AM, Aronne LJ, Ahmad NN, Wharton S, Connery L, Alves B, Kiyosue A, Zhang S, Liu B, Bunck MC, Stefanski A. Tirzepatide Once Weekly for the Treatment of Obesity. New England Journal of Medicine. 2022;387(3):205–16. Wadden TA, Volger S, Sarwer DB, Vetter ML, Tsai AG, Berkowitz RI, Kumanyika S, Schmitz KH, Diewald LK, Barg R, Chittams J, Moore RH. A Two-Year Randomized Trial of Obesity Treatment in Primary Care Practice. New England Journal of Medicine. 2011;365(21):1969–79. Apovian CM, Aronne LJ, Bessesen DH, McDonnell ME, Murad MH, Pagotto U, Ryan DH, Still CD. Pharmacological management of obesity: An endocrine society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism. 2015;100(2):342–62. Khera R, Murad MH, Chandar AK, Dulai PS, Wang Z, Prokop LJ, Loomba R, Camilleri M, Singh S. Association of pharmacological treatments for obesity withweight loss and adverse events a systematic review and meta-analysis. JAMA - Journal of the American Medical Association. 2016;315(22):2424–34. Fujioka K, Plodkowski R, O’Neil PM, Gilder K, Walsh B, Greenway FL. The relationship between early weight loss and weight loss at 1 year with naltrexone ER/bupropion ER combination therapy. Int J Obes. 2016;40(9):1369–75. Le Roux CW, Ege Fils-Aim N, Camacho F, Gould E, Barakat M. The relationship between early weight loss and weight loss maintenance with naltrexone-bupropion therapy. EClinicalMedicine [Internet]. 2022;49:101436. Available from: https://doi.org/10.1016/j . Onakpoya IJ, Lee JJ, Mahtani KR, Aronson JK, Heneghan CJ. Naltrexone–bupropion (Mysimba) in management of obesity: A systematic review and meta-analysis of unpublished clinical study reports. Vol. 86, British Journal of Clinical Pharmacology. Blackwell Publishing Ltd; 2020. p. 646–67. Trenson L, Trenson S, Van Nes F, Moyson C, Lannoo M, Deleus E, Meulemans A, Matthys C, Mertens A, Van Der Schueren B, Vangoitsenhoven R. Liraglutide for Weight Management in the Real World: Significant Weight Loss even if the Maximal Daily Dose Is Not Achieved. Obes Facts. 2022;15(1):83–9. Ganguly R, Tian Y, Kong SX, Hersloev M, Hobbs T, Smolarz BG, Ramasamy A, Haase CL, Weng W. Persistence of newer anti-obesity medications in a real-world setting. Diabetes Res Clin Pract. 2018;143:348–56. Ahmad NN, Robinson S, Kennedy-Martin T, Poon JL, Kan H. Clinical outcomes associated with anti-obesity medications in real-world practice: A systematic literature review. Vol. 22, Obesity Reviews. John Wiley and Sons Inc; 2021. Acosta A, Camilleri M, Abu Dayyeh B, Calderon G, Gonzalez D, McRae A, Rossini W, Singh S, Burton D, Clark MM. Selection of Antiobesity Medications Based on Phenotypes Enhances Weight Loss: A Pragmatic Trial in an Obesity Clinic. Obesity. 2021;29(4):662–71. Tables Table 1 to 3 are available in the Supplementary Files section. Additional Declarations (Not answered) Supplementary Files Table1Baselinecharacteristics.excel.xlsx Table2Metabolicandbariatricsurgerycharacteristics.excel.xlsx Table3NBdoseandreasonsforsubmaximaldoseortreatmentdiscontinuation.pdf.xlsx Cite Share Download PDF Status: Published Journal Publication published 02 Sep, 2025 Read the published version in International Journal of Obesity → Version 1 posted Editorial decision: revise 04 Mar, 2025 Review # 4 received at journal 25 Feb, 2025 Review # 1 received at journal 20 Feb, 2025 Reviewer # 4 agreed at journal 18 Feb, 2025 Reviewer # 3 agreed at journal 30 Jan, 2025 Reviewer # 2 agreed at journal 14 Nov, 2024 Reviewer # 1 agreed at journal 04 Nov, 2024 Reviewers invited by journal 31 Oct, 2024 Submission checks completed at journal 30 Oct, 2024 Editor assigned by journal 29 Oct, 2024 First submitted to journal 29 Oct, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5357012","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":372568371,"identity":"1a9a3208-04a9-43c8-88ab-9c4c4bde30ec","order_by":0,"name":"Roman Vangoitsenhoven","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0003-3523-669X","institution":"University of Leuven","correspondingAuthor":true,"prefix":"","firstName":"Roman","middleName":"","lastName":"Vangoitsenhoven","suffix":""},{"id":372568372,"identity":"10a0410b-6f87-40fe-9b25-1c9ffb82b97b","order_by":1,"name":"Marie Yskout","email":"","orcid":"","institution":"University of Leuven","correspondingAuthor":false,"prefix":"","firstName":"Marie","middleName":"","lastName":"Yskout","suffix":""},{"id":372568373,"identity":"b238be59-5296-492f-a981-2cf0492778ce","order_by":2,"name":"Jarne Hoste","email":"","orcid":"","institution":"UZ Leuven","correspondingAuthor":false,"prefix":"","firstName":"Jarne","middleName":"","lastName":"Hoste","suffix":""},{"id":372568374,"identity":"ee896b7d-ac81-468b-94a5-fc1c14e22451","order_by":3,"name":"Nele Steenackers","email":"","orcid":"","institution":"University of Leuven","correspondingAuthor":false,"prefix":"","firstName":"Nele","middleName":"","lastName":"Steenackers","suffix":""},{"id":372568375,"identity":"eff33eeb-beda-41a8-8d6d-b20626d8985c","order_by":4,"name":"sofia Pazmino","email":"","orcid":"","institution":"University of Leuven","correspondingAuthor":false,"prefix":"","firstName":"sofia","middleName":"","lastName":"Pazmino","suffix":""},{"id":372568376,"identity":"9a60f0a1-4e28-4855-affb-786af494daa6","order_by":5,"name":"Caroline Simoens","email":"","orcid":"","institution":"University of Leuven","correspondingAuthor":false,"prefix":"","firstName":"Caroline","middleName":"","lastName":"Simoens","suffix":""},{"id":372568377,"identity":"4e32ff18-0560-488d-ace9-f09e27e719cc","order_by":6,"name":"Nele Mattelaer","email":"","orcid":"","institution":"University of Leuven","correspondingAuthor":false,"prefix":"","firstName":"Nele","middleName":"","lastName":"Mattelaer","suffix":""},{"id":372568378,"identity":"9030ded8-ea5a-4f61-9f79-617c4c5705ff","order_by":7,"name":"Ellen Deleus","email":"","orcid":"https://orcid.org/0000-0002-8496-7723","institution":"Department of Abdominal Surgery, UZ Leuven","correspondingAuthor":false,"prefix":"","firstName":"Ellen","middleName":"","lastName":"Deleus","suffix":""},{"id":372568379,"identity":"9910ecbb-6749-4f94-85dc-4eb8ce98be7d","order_by":8,"name":"Matthias Lannoo","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Matthias","middleName":"","lastName":"Lannoo","suffix":""},{"id":372568380,"identity":"ddc4e576-ef3d-4b9d-ac82-eac246899b09","order_by":9,"name":"Ann Mertens","email":"","orcid":"https://orcid.org/0000-0002-1649-4311","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Ann","middleName":"","lastName":"Mertens","suffix":""},{"id":372568381,"identity":"7233893f-d62d-4164-b199-0cd45b320bf5","order_by":10,"name":"Bart Vanderschueren","email":"","orcid":"https://orcid.org/0000-0003-4754-784X","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Bart","middleName":"","lastName":"Vanderschueren","suffix":""}],"badges":[],"createdAt":"2024-10-29 21:35:22","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5357012/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5357012/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41366-025-01870-x","type":"published","date":"2025-09-02T04:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":70211918,"identity":"7331ff73-ed2d-4287-8efd-6e4b45598a8a","added_by":"auto","created_at":"2024-11-29 14:48:52","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":101097,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFlowchart patient population.\u003c/strong\u003e\u003cem\u003e Percentages at the 12 month visit are calculated based on the number of patients that were still on NB at the 4 month follow up visit. Dose UNK (dose unknown): dose was not specified by patient at follow-up visit; LTFU (Lost to follow-up).\u003c/em\u003e\u003c/p\u003e","description":"","filename":"Figure1Flowchartpatientpopulation.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5357012/v1/d5afd05455b3937841464f7e.jpg"},{"id":70211715,"identity":"54bcc28f-66d8-4dc9-bc6a-1f6030b2a3d0","added_by":"auto","created_at":"2024-11-29 14:40:52","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":149224,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eEffect of naltrexone/bupropion on body weight at 4-month and 12-month follow-up visits. \u003c/strong\u003e\u003cem\u003eFigure 2A and 2E: YES = patients (%) who lost the percentage of body weight indicated on the X-axis because of continuation (ON) or discontinuation (OFF) of NB. NO = patients (%) who did not lose the percentage of body weight indicated on the X-axis because of continuation (ON) or discontinuation (OFF) of NB. Figure 2B and 2F: Body Weight Change from Baseline to 4- and 12-Month Follow-Up. Figure 2C and 2D: Body Weight Change from Baseline to 4- and 12-Month Follow-Up per Individual and Dose in Surgery-Naive group. Figure 2G and 2H: Body Weight Change from Baseline to 4- and 12-Month Follow-Up per Individual and Dose in Post-MBS group.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"Figure2Effectofonbodyweightat4and12months.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5357012/v1/a8ba88896f9c44b78ac19033.jpg"},{"id":90384617,"identity":"555a0cb0-756f-4fd4-b10c-61b42d8ac3ce","added_by":"auto","created_at":"2025-09-02 07:10:55","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":877460,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5357012/v1/7172c113-572c-477e-81d5-94ca63914a62.pdf"},{"id":70211713,"identity":"09662f6a-266c-4a89-9037-7d834189b2fd","added_by":"auto","created_at":"2024-11-29 14:40:52","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":11366,"visible":true,"origin":"","legend":"","description":"","filename":"Table1Baselinecharacteristics.excel.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-5357012/v1/bfb064dbdd17d153fb6246e7.xlsx"},{"id":70211711,"identity":"a41fa2d1-aa78-486a-8bd8-17f58e7becfc","added_by":"auto","created_at":"2024-11-29 14:40:52","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":12500,"visible":true,"origin":"","legend":"","description":"","filename":"Table2Metabolicandbariatricsurgerycharacteristics.excel.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-5357012/v1/bc1a9eec33f5f209e1f779a1.xlsx"},{"id":70213534,"identity":"572a1b86-f76f-4e7f-96f3-224dec3766dc","added_by":"auto","created_at":"2024-11-29 14:56:52","extension":"xlsx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":12026,"visible":true,"origin":"","legend":"","description":"","filename":"Table3NBdoseandreasonsforsubmaximaldoseortreatmentdiscontinuation.pdf.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-5357012/v1/66d43b9690f87e5e1127cb5c.xlsx"}],"financialInterests":"(Not answered)","formattedTitle":"Real World Efficacy of Naltrexone/Bupropion for Weight Management in Obesity and After Bariatric Surgery","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eTreatment options for obesity have expanded considerably in recent years, with major advancements in pharmacotherapy including the development of medicines like naltrexone/bupropion (NB) and glucagon-like peptide 1 (GLP-1) analogues. Surgical interventions for weight loss have improved greatly, rendering metabolic and bariatric surgery (MBS) a safe, effective and durable treatment for patients with severe obesity [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. According to data from The American Society for Metabolic and Bariatric Surgery, the most common surgical procedures performed in the U.S. in 2021 were laparoscopic sleeve gastrectomy (SG) at 58% and Roux-en-Y Gastric Bypass (RYGB) at 21% [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDespite these advancements, there is still a considerable amount of patients who experience weight regain or insufficient weight loss after MBS [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. The prevalence of poor weight loss outcomes ranges between 3.9 to 71% depending on the criteria used and the type of bariatric surgery performed [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. While insufficient weight loss has been defined as less than 50% excess weight loss or a BMI above 35 kg/m\u0026sup2;, there is no consensus on the definition of weight regain [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Both are mitigated by factors such as dietary non-adherence, as well as hormonal and metabolic changes [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. As obesity is a chronic disease, individual variety and sensitivity in postoperative nutrient stimulated hormonal responses may play a role, such as those involving pancreatic peptide YY, ghrelin and glucagon like peptide [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. The optimal way to approach patients with weight regain or insufficient weight loss remains unclear, as limited data has been published on the effectiveness of different multidisciplinary strategies.\u003c/p\u003e \u003cp\u003eNB, a combination of naltrexone (an opioid antagonist) and bupropion (a norepinephrine and dopamine reuptake inhibitor), has shown synergistic effect on appetite suppression, especially in patients with addictive overeating and food cravings [\u003cspan additionalcitationids=\"CR9 CR10 CR11\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. It\u0026rsquo;s approved as an anti-obesity drug by the FDA and EMA since 2014 and 2015 under the commercial name Contrave and Mysimba, but treatment with NB is not covered by health insurance in Belgium. A recent systematic review supports the use of NB to reach significant weight loss in primary obesity [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Additionally promising results are reported in patients with genetic obesity, and for the use of NB in combination with other anti-obesity drugs [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Although numerous studies have shown the effectiveness and safety of NB, initial trials excluded patients with prior surgical interventions for obesity, leaving the effect of NB in these patients not well understood [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSeveral smaller studies have investigated the effectiveness and safety of different anti-obesity drugs in post-MBS patients. Phentermine/topiramate has been reported to prevent and reduce weight regain post-RYGB and gastric banding in retrospective studies, while GLP-1 analogues like liraglutide have demonstrated similar weight loss after SG and RYGB in prospective placebo-controlled trials, regardless of the presence of type 2 diabetes [\u003cspan additionalcitationids=\"CR20 CR21 CR22\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. A retrospective study by Hanipah \u003cem\u003eet al.\u003c/em\u003e, evaluated the effectiveness of adjuvant weight loss medications, including NB, after MBS [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. However, as the number of patients on NB was limited (n\u0026thinsp;=\u0026thinsp;10) and results on weight evolution were pooled with those of other anti-obesity drugs, definitive conclusions regarding NB\u0026rsquo;s efficacy in this patient population cannot be made. We aim to provide insight into the real-world efficacy and safety of NB in patients struggling with poor weight loss outcomes after MBS.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003eThis single-centre retrospective cohort study, conducted at the obesity clinic of the University Hospital of Leuven (Belgium), aimed to compare the efficacy of NB initiation in achieving weight loss in adult patients (18 years or older), who were surgery-naive and in patients who had experienced weight regain or insufficient weight loss after MBS (\u0026ldquo;post-MBS\u0026rdquo;).\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy population\u003c/h2\u003e \u003cp\u003eData were retrieved from the electronic medical records of all adult patients prescribed NB, in adjunct to lifestyle advise, between June 2016 and August 2022 at the obesity clinic of the University Hospital of Leuven. Patients underwent a comprehensive multidisciplinary assessment, including evaluation by the endocrinologist, surgeon, dietician and psychologist. Pharmacotherapy was recommended in accordance with international recommendations, specifically for patients with a BMI of \u0026ge;\u0026thinsp;30 kg/m\u0026sup2; or \u0026ge;\u0026thinsp;27 kg/m\u0026sup2; with one or more weight-related comorbidity. Patients receiving other anti-obesity drugs, such as GLP-1 analogues, or those undergoing MBS were not included in the current study.\u003c/p\u003e \u003cp\u003eNB-treatment was initiated at a starting dose of 8 mg naltrexone/90 mg bupropion (one tablet) per day. As per leaflet, the dose was increased weekly until reaching the maintenance dose of 32 mg naltrexone/360 mg bupropion per day (two tablets twice daily). Patients who experienced side effects continued the maximal tolerated dose, and patients who reported sufficient subjective effect with a lower dose were allowed to remain at that submaximal dose. Follow-up visits were scheduled at the outpatient clinic 4 and 12 months after treatment initiation.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eData management\u003c/h3\u003e\n\u003cp\u003eData from the initial visit, as well as the 4-month and 12-month follow-up appointments, were extracted from a structured electronic medical record system. All data was pseudonymised to ensure patient confidentiality. The research protocols received approval from the local ethics committee (EC UZ Leuven S62590) and adhered to the latest Declaration of Helsinki.\u003c/p\u003e\n\u003ch3\u003eEndpoint and assessments\u003c/h3\u003e\n\u003cp\u003eFor this retrospective analysis, data was collected on the following variables: total body weight before MBS, nadir weight (lowest reported weight after MBS), time from MBS to nadir weight, time from MBS to initiation of NB treatment, body weight prior to the initiation of NB therapy and weight at the 4 and 12-month follow-up. Post MBS-weight loss was calculated as the difference between pre-MBS weight and nadir weight post-surgery.\u003c/p\u003e \u003cp\u003eThe co-primary endpoints of interest were the percentage change in body weight and the achievement of a reduction in body weight of \u0026ge;\u0026thinsp;5% from baseline at 4 and 12 months. Additionally, secondary, and exploratory endpoints included changes in BMI (kg/m\u0026sup2;), weight change (kg), achievement of a reduction in body weight of more than 0%, 5% or 10%, treatment status, maximal tolerated dose, adherence to therapy, reasons for discontinuation and any adverse effects observed.\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eCategorical data are presented as counts and percentages, while continuous data are described using median values and interquartile ranges (IQR). Intergroup variances were analysed using Student's t-test for normally distributed data and the Mann-Whitney U test for non-normally distributed data. Statistical analyses were performed using PRISM software, with p-values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStudy population\u003c/h2\u003e \u003cp\u003eA total of 153 patients were started on NB therapy at the UZ Leuven obesity clinic following a multidisciplinary consultation. Of the 153 patients, 111 were treated for primary obesity using NB (surgery-naive group), while 42 patients had sought assistance due to weight regain or insufficient weight loss following MBS (post-MBS group). Baseline characteristics are presented per group in table 1. In the surgery-naive group, the majority of patients was female (77.5%) with a median age of 45.0 years (34.0, 52.0). Similarly, the post-MBS group consisted mostly of females (76.2%) with a median age of 51.0 years (41.0, 59.3). The surgery-naive group had a median body weight of 103.1 kg (90.0, 113.0), with a median BMI of 34.9 kg/m\u0026sup2; (32.7, 37.8). The post-MBS group had a median body weight of 102.8 kg (88.0, 129.1) and a median BMI of 35.4 kg/m\u0026sup2; (30.9, 45.3). At baseline, 3 (2.7%) patients in the surgery-naive group and 2 (4.8%) patients in the post-MBS group had type 2 diabetes.\u003c/p\u003e \u003cp\u003eDetails of prior surgery in the post-MBS group are summarized in table 2. The most common type of surgery was RYGB (18 patients, 42.9%), followed by SG (11 patients, 26.2%), gastric banding (3 patients, 7.1%), Mason gastroplasty (1 patient, 2.4%), banded gastric bypass (1 patient, 2.4%) and 8 patients (19.0%) had had secondary MBS. The median total weight loss across all procedures was 41.0 kg (31.5, 48.3), or 33.3% (26.5, 37.9). Overall, the median weight regain for all procedures was 21.0 kg (12.4, 39.5) or 30.1% (16.6, 48.5). The median time between bariatric surgery and the start of NB was 7.7 years (4.3, 15.3).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eTherapy persistence and dropout\u003c/h3\u003e\n\u003cp\u003eTherapy persistence and dropout during 12 months of follow-up are displayed in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. One-hundred and thirty patients attended the 4-month follow-up visit, while 18 patients (16.2%) were lost to follow-up in the surgery-naive group and 5 patients (11.9%) were lost to follow-up in the post-MBS group. For those present, therapy persistence was 46.9% in the surgery-naive group and 66.7% in the post-MBS group.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAmong the 52 patients in the surgery-naive group still on NB therapy, only 19 (36.5%) were using the maximal daily dose of 32 mg naltrexone/360 mg bupropion while 29 patients (55.8%) were on a submaximal dose. In the post-MBS group, 15 patients (53.6%) were taking the maximal daily dose, and 12 patients (42.9%) were taking a submaximal dose.\u003c/p\u003e \u003cp\u003eBy the 12-month follow up visit, out of the 52 and 28 patients who had been advised to continue NB at the 4-month visit, 20 patients (38.5%) in the surgery-naive group and 17 patients (60.7%) in the post-MBS group were still on NB. Of those, 8 patients (40.0%) in the surgery-naive group were taking the maximal dose, while 12 patients (60.0%) were taking a submaximal dose. In the post-MBS group, 7 patients (41.2%) were taking the maximal daily dose, and 9 patients (52.9%) were on a submaximal dose. Twenty-one patients had discontinued NB therapy before reaching the 12-month visit in the surgery-naive group, compared to 9 patients in the post-MBS group, with a total of 13 patients lost to follow-up.\u003c/p\u003e\n\u003ch3\u003eChange in body weight at 4 months\u003c/h3\u003e\n\u003cp\u003eIn the surgery-naive group on NB treatment (52 patients), the median weight loss at 4 months was 6.4% (3.0, 10.1). In the post-MBS group (28 patients), the median weight loss was 6.1% (2.4, 12.0). Both groups showed significant reductions in body weight after 4 months. The surgery-naive group decreased from 103.0 kg (88.3, 112.4) to 93.8 kg (82.7, 103.4) (median change: -5.8 kg (-3.0, -9.9); \u003cem\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.0001\u003c/em\u003e) ). In the post-MBS group, weight decreased from 102.8 kg (88.7, 132.0) to 95.9 kg (79.2, 123.5) (median change: -6.2 kg (-2.4, -11.6); \u003cem\u003ep\u0026thinsp;=\u0026thinsp;0.0002\u003c/em\u003e). This corresponded to significant decreases in BMI for both groups: from 34.4 kg/m\u0026sup2; (32.4, 37.9) to 32.1 kg/m\u0026sup2; (30.1, 35.6) in the surgery-naive group (median change: -2.1 kg/m\u0026sup2; (-1.1, -3.4); \u003cem\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.0001\u003c/em\u003e), and from 37.3 kg/m\u0026sup2; (30.1, 45.4) to 32.7 kg/m\u0026sup2; (29.1, 41.7) in the post-MBS group (median change: -2.2 kg/m\u0026sup2; (-0.88, -3.9); \u003cem\u003ep\u0026thinsp;=\u0026thinsp;0.0001\u003c/em\u003e). No statistical difference was observed in the absolute- (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.51) nor relative (p\u0026thinsp;=\u0026thinsp;0.85) weight loss in the patients in the surgery-naive group versus the post-MBS group.\u003c/p\u003e \u003cp\u003eThe majority of patients in both groups achieved weight loss of 5% or more from baseline body weight: 58.5% in the surgery-naive group (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA) and 64.3% in the post-MBS group (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eE). Patients at the maximal NB dose experienced a median weight change of -4.9% (-2.3, -10.6) in the surgery-naive group, compared to -9.0% (-0.9, -17.0) in the post-MBS group (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB and F). Patients on a submaximal NB dose experienced median weight changes of -6.7% (-4.2, -10.0; \u003cem\u003ep\u0026thinsp;=\u0026thinsp;0.46\u003c/em\u003e) in the surgery-naive group (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC) and \u0026minus;\u0026thinsp;6.1% (-3.2, -10.0; \u003cem\u003ep\u0026thinsp;=\u0026thinsp;0.67\u003c/em\u003e) in the post-MBS group (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eG).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eForty-one patients (36.9%) in the surgery-naive group, and 9 patients (21.4%) in the post-MBS group, had independently discontinued NB treatment before coming to the 4 month follow up visit, either due to insufficient effect or side effects. Reasons for NB discontinuation are shown in table 3. Their median weight change at 4 months was \u0026minus;\u0026thinsp;2.4% (-5.0, +\u0026thinsp;2.4) and \u0026minus;\u0026thinsp;2.4% (-4.0, +\u0026thinsp;0.5) respectively. No significant change was observed in median body weight in either group (surgery-naive group; \u003cem\u003ep\u0026thinsp;=\u0026thinsp;0.22\u003c/em\u003e, post-MBS group; \u003cem\u003ep\u0026thinsp;=\u0026thinsp;0.09\u003c/em\u003e). The majority of patients who had prematurely discontinued NB did not achieve weight loss of \u0026ge;\u0026thinsp;5% or more (76.2% in the surgery-naive group and 88.1% in the post-MBS group) and 38.1% and 33.3% even experienced weight gain respectively.\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eChange in body weight at 12 months\u003c/h2\u003e \u003cp\u003eIn the 20 patients from the surgery-naive group on NB treatment at 12 months (38.4% of the patients who had been advised to continue NB at the 4-month follow op visit), the median weight change was \u0026minus;\u0026thinsp;8.8% (-5.0, -16.7). A significant decrease in median body weight was observed from 100.2 kg (87.6, 112.0) to 87.7 kg (78.9, 99.3) (median change: -8.5 kg (-5.1, -15.7); \u003cem\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.0001\u003c/em\u003e). For the post-MBS group (17 patients, 60.7%), the median weight change was \u0026minus;\u0026thinsp;11.1% (-4.7, -19.8). There was a significant decline in median body weight from 95.0 kg (86.3, 112.1) to 87.0 kg (76.4, 98.7) (median change: -9.0 kg (-5.0, -16.8); \u003cem\u003ep\u0026thinsp;=\u0026thinsp;0.0024\u003c/em\u003e).\u003c/p\u003e \u003cp\u003eThis resulted in a significant decrease in BMI from 33.9 kg/m\u0026sup2; (31.8, 35.0) to 30.9 kg/m\u0026sup2; (27.8, 32.5) after 12 months of treatment for the surgery-naive group (median difference: -2.9 kg/m\u0026sup2; (-1.7, -5.5); \u003cem\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.0001\u003c/em\u003e). Similarly, for the post-MBS group, there was a significant drop in BMI from 34.4 kg/m\u0026sup2; (30.8, 38.5) to 30.4 kg/m\u0026sup2; (28.0, 35.3) after 12 months of treatment (median difference: -3.3 kg/m\u0026sup2; (-1.7, -5.7); \u003cem\u003ep\u0026thinsp;=\u0026thinsp;0.0016\u003c/em\u003e). Weight change in patients treated with NB at 12 months did not differ significantly in the surgery-naive versus the post-MBS group (weight change in kg: \u003cem\u003ep\u0026thinsp;=\u0026thinsp;0.30\u003c/em\u003e; weight change in %: \u003cem\u003ep\u0026thinsp;=\u0026thinsp;0.39\u003c/em\u003e).\u003c/p\u003e \u003cp\u003eSixteen patients, out of 20 patients who were still taking NB at the 12 months visit in the surgery-naive group (80.0%), achieved a weight loss of 5% or more of their baseline body weight at 12 months, with 8 patients (40.0%) reaching weight loss of 10% or more. In the post-MBS group, 12 out of 17 patients (70.6%) lost 5% or more, and 10 patients (58.8%) achieved weight loss of 10% or more.\u003c/p\u003e \u003cp\u003ePatients in the surgery-naive group who used the maximal NB dose experienced a median weight change of -15.5% (-5.9, -17.1), which was not significantly different compared to the median weight change of -8.2% (-2.2, -14.5) observed in patients who were taking a submaximal dose of NB (\u003cem\u003ep\u0026thinsp;=\u0026thinsp;0.38\u003c/em\u003e). Similarly, patients in the post-MBS group who used the maximal dose of NB had a median weight change of -15.5% (-5.9, -21.5), which was not significantly different (\u003cem\u003ep\u0026thinsp;=\u0026thinsp;0.61\u003c/em\u003e) from those taking a submaximal dose, who lost \u0026minus;\u0026thinsp;9.7% (-3.1, -19.8).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eTreatment tolerance at 4-month \u0026amp; 12-month follow-up visits\u003c/h2\u003e \u003cp\u003eThe reasons for not achieving the maximal dose, treatment discontinuation or failure to initiate treatment at the 4-month and 12-month visit are outlined in Table\u0026nbsp;3. At 4 months, the main reason for taking a submaximal dose of NB in both groups was that the patient experienced sufficient benefit (subjectively) from this submaximal dose; 18 patients (62.1%) in the surgery-naive group and 7 patients (58.3%) in the post-MBS group. Gastrointestinal side effects, including nausea, constipation, abdominal pain, vomiting and a dry mouth, were the main reason for early NB discontinuation, and the second most common reason for using a submaximal dose, in both groups. Cardiac and vascular side effects, such as palpitations, hot flashes and hypertension, were reported by 6 patients. Nervous system adverse events including dizziness, syncope and headache were observed in 7 patients in total, leading to NB discontinuation in 5 of them. Among the remaining 41 patients (36.9%) in the surgery-naive group, 2 patients (4.9%) discontinued treatment due to 'other reasons,' defined as difficulty swallowing the tablets. In the post-MBS group, 9 patients (21.4%) stopped NB prematurely, with 1 patient reporting fatigue which was classified as 'other reason'.\u003c/p\u003e \u003cp\u003eAt the 12-month follow-up, 8 patients (66.7%) in the surgery-naive group and all 9 patients (100.0%) in the post-MBS group reported sufficient benefit from NB at submaximal dose as the reason for not reaching the maximal dose. Gastrointestinal side effects were reported by 3 patients (25.0%) in the surgery-naive group as the reason for not reaching the maximal dose. Additionally, 21 patients (40.4%) in the surgery-naive group and 9 patients (32.1%) in the post-MBS group had discontinued treatment. The most common reason for discontinuation in both groups was inadequate weight loss at the 4-month follow-up, which was the case in 14 patients (63.6%) in the surgery-naive group and 7 patients (77.8%) in the post-MBS group. In the surgery-naive group, \u0026lsquo;other reasons\u0026rsquo; for discontinuation included pregnancy (n\u0026thinsp;=\u0026thinsp;1) and practical issues affecting treatment availability (n\u0026thinsp;=\u0026thinsp;2). In the post-MBS group the reason for discontinuation was not specified by the patient.\u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eTo the best of our knowledge, this study represents the largest cohort to date examining the efficacy of NB treatment for insufficient weight loss or weight regain following MBS. Results indicate that the use of NB in these patients can be as effective as in surgery-naive patients, and can result in significant and important weight loss. At 4 months, both groups experienced similar mean weight loss percentages; -6.4% the for surgery-naive group and \u0026minus;\u0026thinsp;6.1% for the post-MBS group (compared to -2.4% for those discontinuing NB prematurely), with 58.5% versus 64.3% reaching\u0026thinsp;\u0026ge;\u0026thinsp;5% weight loss respectively. At 12 months, the patients in the surgery-naive group still taking NB lost approximately \u0026minus;\u0026thinsp;8.8% of total body weight while the post-surgery group lost \u0026minus;\u0026thinsp;11.1% with respectively 80.0\u003cb\u003e%\u003c/b\u003e versus 76.4% of patients losing\u0026thinsp;\u0026ge;\u0026thinsp;5% and 40.0% versus 58.8% of patients losing\u0026thinsp;\u0026ge;\u0026thinsp;10% of their initial body weight.\u003c/p\u003e \u003cp\u003eBaseline characteristics were similar between cohorts, except that the post-MBS group was older. This cohort resembles well the clinical trial population for weight management using GLP-1 analogues and NB [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan additionalcitationids=\"CR26\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. The low incidence of diabetes mellitus is consistent with clinical guidelines, as patients with type 2 diabetes are preferably offered a GLP-1 analogue to target body weight reduction in combination with glycaemic control [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eNo specific data have been published on the use of NB in patients post-MBS to date. As NB is an extended release tablet, not much is known about the intestinal absorption of this medication. While a Dutch trial is ongoing, no results have been published so far (EudraCT Number: 2021-002145-15). Hanipah \u003cem\u003eet al.\u003c/em\u003e included patients on NB after weight regain, but their pooled data prevents specific conclusions regarding NB\u0026rsquo;s effectiveness [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Our real-world results in surgery-naive patients are however consistent with previous findings for NB in primary obesity. An analysis of pooled, participant-level data from 4 randomized controlled trials, with a total of 3362 patients treated with lifestyle changes plus either NB 32/360 mg total daily dose or placebo, demonstrated that after approximately 4 months of treatment 51% versus 19% of patients reached weight loss of -5% or greater, these patients were called \u0026ldquo;responders\u0026rdquo; [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. When these responders continued the treatment for approximately 12 months, 81% of them were able to preserve this 5% weight loss and 57% achieved 10% weight loss. Furthermore, NB continuation was also shown to be associated with a greater likelihood of weight loss maintenance up to 4 years [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe literature suggests that the beneficial effect of NB is dose dependent, as patients who received a lower dose of NB, namely 16/360mg instead of the approved 32/360 mg total daily dose, had significantly less weight loss than those who took the full dose [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. However, in this study a notable number of patients chose to remain at a lower dose because they experienced sufficient subjective weight loss with this submaximal dose, suggesting an individual sensitivity and response to NB. We observed comparable outcomes regardless of the used dose, as was shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, suggesting that a submaximal dose can be equally effective. Similar observations have been reported for liraglutide [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eGiven that NB is not reimbursed in many countries, including Belgium, the personal costs for the patients are high. The potential to reach significant weight loss with a lower dose could make NB more accessible and affordable to a larger population of patients. On the other hand, it is possible that these patients who report sufficient subjective benefit from a submaximal dose, if they\u0026rsquo;d be given the time and motivation to continue slowly up titrating NB, would experience an even greater reduction in their body weight at maximal dosage than can be shown in this study.\u003c/p\u003e \u003cp\u003eThe observed reasons for discontinuing NB treatment can be divided into three main categories. Firstly, adherence to the 4 month stopping rule, as is advised per label, was applied. This directive is based on the knowledge that (A) 5% weight loss is associated with improved cardiovascular outcomes and (B) patients in which this \u0026minus;\u0026thinsp;5% weight loss threshold is not reached at 4 months are unlikely to reach this threshold at 12 months [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Thus patients in which \u0026minus;\u0026thinsp;5% weight loss was not reached at 4 months, were advised to discontinue the therapy. However, a select number of patients did, on their own demand, continue the therapy despite being a non-responder at 4 months. At 12 months they again did not reach this \u0026minus;\u0026thinsp;5% weight loss threshold, supporting the recommendation to discontinue NB in these patients to prevent unjustified exposure.\u003c/p\u003e \u003cp\u003eSecondly, the occurrence of side effects made at least 39 out of 153 patients (25.5%) quit the therapy with NB. No major side effects were reported in this study. Twenty four patients reported gastrointestinal side effects, 6 complained of cardiovascular side effects, 5 of nervous system disorders and 4 reported psychiatric side effects. Notably, a large number of patients reported side effects with the recommended dose (similar side effects to those who discontinued the treatment) but were able to tolerate NB at a lower dose. As was mentioned above, this dose de-escalation was independent of the effect on weight loss at 12 months.\u003c/p\u003e \u003cp\u003eThirdly, as NB is not reimbursed in Belgium it constitutes a relatively high financial burden for the patient. This combined with the perceived cost-benefit analysis, likely led to early discontinuation of the therapy in many patients.\u003c/p\u003e \u003cp\u003eStudy limitations include that this is a retrospective study and, despite it being the largest cohort to date, still has a limited sample size \u0026ndash; especially the subgroups like the group on a submaximal NB dose. A significant number of patients were lost to follow up. Given the large number of patients followed at our outpatient clinic, patients that were doing well were sometimes referred to their general practitioner for further follow up. However, the real world applicability of these results is significant. So far, real-world data on the use of \u0026ndash; and thereby also on the persistence with \u0026ndash; NB is limited. An evaluation of 26,522 adult patients\u0026rsquo; persistence with anti-obesity medications showed that at 6 months persistence with NB was lower than with liraglutide or phentermine/topiramate respectively (18.1% vs. 41.8% and 27.3%) [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. In this retrospective analysis only 37 out of 153 patients (24.2%) were known to continue the therapy at 12 months after initiation. This low adherence and persistence with NB, and other anti-obesity medication for that matter, poses a great challenge in daily clinical practice.\u003c/p\u003e \u003cp\u003eThe patients included in this study were all, based on their general profile, eating habits and comorbidities, believed to be excellent candidates for NB initiation to reach optimal weight loss. Recent studies have shown the value of adequate patient selection before the initiation of anti-obesity medication, highlighting the need for the development of usable tools to guide clinical practitioners [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. This study once again confirms the importance of adequate patient selection. Practitioners should aim to identify specifically those patients who lose up to 10\u0026ndash;20% of their body weight after initiation of NB, for they exist both in surgery-naive patients and in patients who previously underwent MBS and experienced poor weight loss outcomes.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis retrospective analysis includes the largest cohort of patients treated with NB for weight regain or insufficient weight loss after MBS to date. Real-world data demonstrates that NB is as effective and safe in this population as in surgery-naive patients. Additionally, this effect was independent of dose, which could make the therapy more affordable and tolerable for a broader patient population. Further research is warranted to optimize patient selection previous to NB initiation.\u003c/p\u003e"},{"header":"Declarations","content":" \u003ch2\u003eCompeting interests\u003c/h2\u003e \u003cp\u003eRV is a clinical investigator for Boehringer Ingelheim, Eli Lilly and Novo Nordisk; he serves or has served on the speakers bureau for Boehringer Ingelheim, Eli Lilly, Goodlife Pharma, Novo Nordisk, Sanofi ; He serves or has served in advisory panels for Eli Lilly, Novo Nordisk, Sanofi; Any financial compensation for these activities has been received by the institution (UZ/KU Leuven). The remaining authors declare that they have no conflicts of interest relevant to this manuscript.\u003c/p\u003e \u003ch2\u003eAuthor contributions\u003c/h2\u003e \u003cp\u003eMY, NS, JH, CS collected data and performed data analyses. MY, JH wrote the first draft of the paper. NS, SP, NM, ED, ML, AM, BVS, RV reviewed the paper and provided critical input. All authors reviewed final manuscript and had access to data. RV is guarantor of this work.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e \u003cp\u003e/\u003c/p\u003e\u003ch2\u003eData availability statement\u003c/h2\u003e \u003cp\u003eThe data used to support the findings of the study are available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eThe Longitudinal Assessment of Bariatric Surgery (LABS) Consortium. Perioperative Safety in the Longitudinal Assessment of Bariatric Surgery. N Engl J Med. 2009;361(5):445\u0026ndash;54.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThe American Society for metabolic and bariatric surgery. Metabolic \u0026amp; Bariatric Surgery fact sheet 2021. 2021.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eThe American Society for Metabolic and Bariatric Surgery. 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The relationship between early weight loss and weight loss maintenance with naltrexone-bupropion therapy. EClinicalMedicine [Internet]. 2022;49:101436. Available from: https://doi.org/10.1016/j\u003c/div\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOnakpoya IJ, Lee JJ, Mahtani KR, Aronson JK, Heneghan CJ. Naltrexone\u0026ndash;bupropion (Mysimba) in management of obesity: A systematic review and meta-analysis of unpublished clinical study reports. Vol. 86, British Journal of Clinical Pharmacology. Blackwell Publishing Ltd; 2020. p. 646\u0026ndash;67.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTrenson L, Trenson S, Van Nes F, Moyson C, Lannoo M, Deleus E, Meulemans A, Matthys C, Mertens A, Van Der Schueren B, Vangoitsenhoven R. Liraglutide for Weight Management in the Real World: Significant Weight Loss even if the Maximal Daily Dose Is Not Achieved. Obes Facts. 2022;15(1):83\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGanguly R, Tian Y, Kong SX, Hersloev M, Hobbs T, Smolarz BG, Ramasamy A, Haase CL, Weng W. Persistence of newer anti-obesity medications in a real-world setting. Diabetes Res Clin Pract. 2018;143:348\u0026ndash;56.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAhmad NN, Robinson S, Kennedy-Martin T, Poon JL, Kan H. Clinical outcomes associated with anti-obesity medications in real-world practice: A systematic literature review. Vol. 22, Obesity Reviews. John Wiley and Sons Inc; 2021.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAcosta A, Camilleri M, Abu Dayyeh B, Calderon G, Gonzalez D, McRae A, Rossini W, Singh S, Burton D, Clark MM. Selection of Antiobesity Medications Based on Phenotypes Enhances Weight Loss: A Pragmatic Trial in an Obesity Clinic. Obesity. 2021;29(4):662\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 to 3 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-obesity","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"ijo","sideBox":"Learn more about [International Journal of Obesity](http://www.nature.com/ijo/)","snPcode":"41366","submissionUrl":"https://mts-ijo.nature.com/cgi-bin/main.plex","title":"International Journal of Obesity","twitterHandle":"@intjobesity","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Obesity, bariatric surgery, weight regain, naltrexone/bupropion","lastPublishedDoi":"10.21203/rs.3.rs-5357012/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5357012/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eInsufficient weight loss or weight regain after metabolic and bariatric surgery (MBS) is frequent, and the evidence to support the use of pharmacotherapy for weight management is limited.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eIn this single-centre retrospective cohort study, the effectiveness of naltrexone/bupropion (NB) for weight control in surgery-naive and post-MBS patients was evaluated. Data was collected between 2016 and 2022 on all consecutive patients started on NB after multidisciplinary consult. Patients received weekly dose escalation up to 32/360 mg daily per the manufacturer\u0026rsquo;s protocol, with submaximal doses administered in cases of adverse effects or sufficient therapeutic response. Weight evolution, metabolic status, adherence and adverse events were analysed at 4 and 12 months after NB initiation. Data are presented as median (interquartile range).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eA total of 153 patients initiated NB therapy, including 111 who were surgery-naive, and 42 with prior MBS. The median time after MBS was 7.7 years (4.3, 15.3). Among the post-MBS patients, 18 (42.9%) patients had undergone Roux-en-Y gastric bypass and 11 (26.2%) sleeve gastrectomy. At 4 months after initiation of NB, 46.8% of the surgery-naive patients and 66.7% of the post-MBS patients remained using NB, with a median weight loss of 6.4% (3.0, 10.1) and 6.1% (2.4, 2.0) respectively. At 12-months, 38.5% of surgery-naive patients and 60.7% of post-MBS patients had continued NB, with median weight loss of 8.8% (5.0, 16.7) and 11.1% (4.7, 19.8) respectively. There was no statistically significant difference in weight loss between the surgery-naive and post-MBS group. Weight loss was not significantly influenced by whether the maximal dose was reached in both the surgery-naive patients (p\u0026thinsp;=\u0026thinsp;0.38) and the post-MBS patients (p\u0026thinsp;=\u0026thinsp;0.61).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eReal-world data show that NB treatment is equally effective in surgery-naive patients and in patients experiencing weight regain after bariatric surgery, regardless of the maximal dose administered.\u003c/p\u003e","manuscriptTitle":"Real World Efficacy of Naltrexone/Bupropion for Weight Management in Obesity and After Bariatric Surgery","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-11-29 14:40:47","doi":"10.21203/rs.3.rs-5357012/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2025-03-04T16:14:37+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"This content is not available.","date":"2025-02-25T16:03:40+00:00","index":4,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2025-02-20T15:18:17+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2025-02-18T10:49:06+00:00","index":4,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2025-01-30T14:28:44+00:00","index":3,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-11-14T17:57:31+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-11-04T14:07:18+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2024-10-31T09:34:37+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-10-30T13:46:52+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-10-29T21:33:09+00:00","index":"","fulltext":""},{"type":"submitted","content":"International Journal of Obesity","date":"2024-10-29T21:33:08+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-obesity","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"ijo","sideBox":"Learn more about [International Journal of Obesity](http://www.nature.com/ijo/)","snPcode":"41366","submissionUrl":"https://mts-ijo.nature.com/cgi-bin/main.plex","title":"International Journal of Obesity","twitterHandle":"@intjobesity","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"0fbca8df-03f2-4020-8967-c561352c1835","owner":[],"postedDate":"November 29th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":39655911,"name":"Health sciences/Endocrinology/Endocrine system and metabolic diseases/Obesity"},{"id":39655912,"name":"Health sciences/Health care/Weight management"},{"id":39655913,"name":"Health sciences/Health care/Therapeutics/Surgery/Bariatric surgery"}],"tags":[],"updatedAt":"2025-09-02T07:10:50+00:00","versionOfRecord":{"articleIdentity":"rs-5357012","link":"https://doi.org/10.1038/s41366-025-01870-x","journal":{"identity":"international-journal-of-obesity","isVorOnly":false,"title":"International Journal of Obesity"},"publishedOn":"2025-09-02 04:00:00","publishedOnDateReadable":"September 2nd, 2025"},"versionCreatedAt":"2024-11-29 14:40:47","video":"","vorDoi":"10.1038/s41366-025-01870-x","vorDoiUrl":"https://doi.org/10.1038/s41366-025-01870-x","workflowStages":[]},"version":"v1","identity":"rs-5357012","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5357012","identity":"rs-5357012","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}