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      Letter to the editor: naltrexone sustained-release/bupropion sustained-release for the management of obesity: review of the data to date

      Drug Design, Development and Therapy

      Dove Medical Press

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          Abstract

          Dear editor I read with great interest the systematic review by Caixàs et al1 on the effect of naltrexone sustained-release/bupropion sustained-release (NB) for the management of obesity. By comprehensively appraising five recent clinical trials, the authors concluded that the naltrexone/bupropion combination might represent an important new therapeutic option for the management of obesity, with a weight reduction effect that is similar to other drugs approved for the treatment of obesity. In this respect, it is worth highlighting that shortly after the publication of this systematic review (on September 10, 2014), the United States Food and Drug Administration licensed the NB Contrave® medication as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in obese or overweight patients with at least one weight-related comorbid condition. Together, both pieces of information may represent a remarkable advance in the pharmacological treatment of obesity, since the therapeutic arsenal for obesity is limited, with suboptimal efficacy and safety concerns.2,3 Despite the promising results reported by Caixàs et al1 the accumulated evidence on the efficacy of the NB combination for obesity has some limitations that should be acknowledged. According to the authors’ introduction, lower doses of multiple agents targeting different mechanisms of action often yield better results than strategies that modify one pathway alone, especially when we consider the diabetic population. According to this assertion, NB medication would be expected to work better in the diabetic population. With unfortunate timing, the effect of the NB combination was also investigated exclusively in overweight/obese type 2 diabetes patients (COR-Diabetes Study Group) in another trial,4 which was not included in the systematic review by Caixàs et al.1 In this Phase III trial, 505 overweight and obese patients with type 2 diabetes, using or not using background oral antidiabetes drugs, received a standardized lifestyle intervention and were randomized 2:1 to 32 mg naltrexone sustained-release/360 mg bupropion for 56 weeks in a double-blind, placebo controlled fashion. The treatment protocol and the coprimary outcome were the same as those used by the other three Phase III trials described in detail by Caixàs et al.1 When we analyzed the results in the diabetic population, diabetic patients taking NB had a greater weight reduction (−5.0% versus −1.8%; P<0.001) and a higher proportion of patients achieving ≥5% weight loss (44.5% versus 18.9%; P<0.001).4 To better compare the magnitude of the effect of NB on diabetic patients to nondiabetics patients, I first meta-analyzed the estimates of the effect of NB for the nondiabetic population, while considering the results of the five studies previously included in the systematic review by Caixàs et al.5–9 To do this, I used a random effects model, as well as the absolute mean difference (MD) and risk ratio (RR) as effect sizes for continuous and proportion data, respectively. Further, I did not consider the results of groups of patients assigned to naltrexone or bupropion as monotherapy (when reported by trials with three or more arms); I also considered the results of the groups using more similar Contrave® licensed doses in the longer period of treatment, as assessed by the trial. The studies defined the primary population for the analyses as “modified intention to treat population last observation carried forward” (mITT-LOCF), which included all randomized participants with a baseline measurement of body weight and a ≥1 postbaseline measurement of weight, which was obtained while on the study drug. Additionally, for individual missing data, the authors used the last observation carried forward method, which repeats the last observation data obtained while participants were taking the study drug. The pooled results, totaling 3,063 mITT-LOCF nondiabetic patients, found a reduction of 4.52% (95% confidence interval [CI]: −5.19 to −3.85; I 2=43%) in body weight in the NB group when compared to the placebo group (Figure 1). This percentage of weight loss was greater than that in the COR-Diabetes trial,4 which found a reduction of 3.20% (95% CI: −4.18 to −2.22; a total of 424 patients) in patients taking the NB medication when compared to those in the placebo group. Considering the same primary population (mITT-LOCF; a total of 3,063 patients), patients treated with the NB were 2.54 times (95% CI: 1.84–3.38; I 2=49%) more likely to lose at least 5% of their body weight compared to those on placebo (Figure 2). For the diabetic population, patients treated with the NB were 2.36 times (95% CI: 1.66–3.35) more likely to lose at least 5% of their body weight when compared to those on placebo. These findings are important because the smaller magnitude of the effect of NB in diabetic patients is not expected, and it is not in agreement with the results found in the literature when we consider the use of other antiobesity drugs. The study of Gray et al2 compared orlistat, sibutramine, and other interventions, such rimonabant, in a single-evidence synthesis framework using a systematic review and a mixed treatment comparison approach. In this study, the authors showed that patients with type 2 diabetes treated with antiobesity medications lost more weight in each intervention investigated when compared to those without the disease. According to the authors of the COR-Diabetes trial,4 the somewhat more modest weight loss they observed in patients with diabetes that were taking oral antidiabetes drugs, as compared with patients without diabetes, may be related to the differences in insulin resistance, adipose cell metabolism, and concomitant medications used for the treatment of diabetes and glucose metabolism. Beyond these conflicting findings, the profile of the patients in the COR-Diabetes trial4 differs from that of the other NB studies; the trial included older patients (mean, 54 years versus a range of 40.2–45.9 years in the other trials), a greater proportion of females, and more comorbidities (a greater percentage of patients with dyslipidemia). This finding could suggest a subgroup efficacy effect, which needs to be better investigated. Another important aspect not addressed in the study by Caixàs et al1 was the risk of bias in the trials. Using the Cochrane criteria for the risk of bias of randomized controlled trials,10 there were no important limitations with respect to randomization, allocation concealment, and blinding scheme domains, despite the fact that in the two Phase II trials, the risk of bias for randomization and allocation concealment were unclear. However, there is a high risk of bias due to the “incomplete outcome data” domain, considering that the primary efficacy analyses were done using an mITT-LOCF population with a significant loss to follow-up/withdrawal, especially in the treatment group (which ranged from 18.4% to 29.9%). The studies also showed a high risk of bias due to the presence of conflicts of interest. Despite that Caixàs et al1 reported the more conservative estimates of effect size, showing the results for the intention to treat (ITT) population whenever possible, it is important to demonstrate the impact of this bias on the results. Excluding data from the COR-Diabetes trial,4 which included a very different population profile, I performed a subgroup meta-analysis comparing the data for both the primary efficacy analyses population (modified ITT population [mITT]) and the ITT population, which were reported by three of the five trials as part of a sensitivity analysis.5,7,9 For the percentage change in body weight (Figure 3), there was a significant difference in the subgroup estimates of the effect according to the type of analysis performed. The results for the mITT population showed a greater effect magnitude than those for the ITT population (mITT MD: −4.52% [95% CI: −5.19 to −3.85; I 2=43%] versus ITT MD: −3.33 [95% CI: −3.83 to −2.82; I 2=0%]; P-value for the subgroup =0.003). For the proportion of patients who lost at least 5% of their body weight (Figure 4), the difference according to the type of analysis was not significant between the groups, despite the effect magnitude being greater in the mITT group than in the ITT population (mITT RR: 2.71 [95% CI: 1.84–3.99; I 2=89%] versus ITT RR: 2.02 [95% CI: 1.22–3.35; I 2=93%]; P-value for the subgroup =0.37). Considering that the participants who were not on treatment were not included in the primary analyses, and since the percentage of excluded patients was much greater in the treatment group, these findings may suggest an overestimated effect of the intervention based on a primary efficacy analysis (mITT-LOCF population). Further, in this analysis, the most exacerbated effects came from small Phase II trials, which are known to overestimate the effects of medical interventions.11 Finally, although the profile of adverse reactions to NB was mild, the medication was not well tolerated, since almost three times as many patients discontinued the treatment, according to the pooled estimates of the effect across the trials. Table 1 shows the pooled results for all adverse reactions reported by the six trials. NB significantly increased the risk of all the events reported. Also, it is important to note that the sample included in these analyses was not the same sample included in the efficacy analyses. The safety sample included all randomized participants who took ≥1 pill of the study drug and had ≥1 follow-up visit at any time after the start of the study treatment, which does not necessarily mean that the patients were still on the drug treatment. In this regard, we could not exclude an underestimated effect of NB on the risk of adverse reactions. Conclusion In conclusion, these findings are in accordance with the review’s conclusions, given that the current evidence on the effect of the combination of buproprion plus naltrexone indicates that it has a moderate effect on body weight. The information in this letter provides more precise estimates of the efficacy and safety of the NB medication obtained through a meta-analytic approach, with emphasis on the critical appraisal of the studies through the assessment of the risk of bias and its impact on the results. This complements the information reported by the review’s authors, and hopefully further helps the reader to draw a better and more critical conclusion about the data that have recently become available.

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          Most cited references 6

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          Rational design of a combination medication for the treatment of obesity.

          Existing obesity therapies are limited by safety concerns and modest efficacy reflecting a weight loss plateau. Here, we explore combination therapy with bupropion (BUP), a putative stimulator of melanocortin pathways, and an opioid antagonist, naltrexone (NAL), to antagonize an inhibitory feedback loop that limits sustained weight reduction. In vitro electrophysiologic experiments were conducted to determine the extent to which BUP+NAL stimulated hypothalamic pro-opiomelanocortin (POMC) neurons in mouse brain. A subsequent study further characterized the effect of combination BUP+NAL treatment on food intake in lean and obese mice. Finally, a randomized, blinded, placebo-controlled trial in obese adult subjects was conducted. Randomization included: BUP (300 mg) + NAL (50 mg), BUP (300 mg) + placebo (P), NAL (50 mg) + P or P+P for up to 24 weeks. BUP+NAL stimulated murine POMC neurons in vitro and caused a greater reduction in acute food intake than either monotherapy, an effect consistent with synergism. Combined BUP+NAL provided sustained weight loss without evidence of an efficacy plateau through 24 weeks of treatment. BUP+NAL completers diverged from NAL+P (P < 0.01) and P+P (P < 0.001) at week 16 and from BUP+P by week 24 (P < 0.05). The combination was also well tolerated. Translational studies indicated that BUP+NAL therapy produced synergistic weight loss which exceeded either BUP or NAL alone. These results supported the hypothesis that NAL, through blockade of beta-endorphin mediated POMC autoinhibition, prevents the classic weight loss plateau observed with monotherapies such as BUP. This novel treatment approach (BUP+NAL) holds promise for the treatment of obesity.\
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            Effects of Naltrexone Sustained- Release/Bupropion Sustained-Release Combination Therapy on Body Weight and Glycemic Parameters in Overweight and Obese Patients With Type 2 Diabetes

            OBJECTIVE To assess the efficacy and safety of 32 mg naltrexone sustained-release (SR)/360 mg bupropion SR (NB) in overweight/obese individuals with type 2 diabetes with or without background oral antidiabetes drugs. RESEARCH DESIGN AND METHODS This was a 56-week, double-blind, placebo-controlled study in which 505 patients received standardized lifestyle intervention and were randomized 2:1 to NB or placebo. Coprimary end points were percent weight change and achievement of ≥5% weight loss. Secondary end points included achievement of HbA1c <7% (53 mmol/mol), achievement of weight loss ≥10%, and change in HbA1c, waist circumference, fasting blood glucose, and lipids. RESULTS In the modified intent-to-treat population (54% female, 80% Caucasian, and mean age 54 years, weight 106 kg, BMI 37 kg/m2, and HbA1c 8.0% [64 mmol/mol]), NB resulted in significantly greater weight reduction (−5.0 vs. −1.8%; P < 0.001) and proportion of patients achieving ≥5% weight loss (44.5 vs. 18.9%, P < 0.001) compared with placebo. NB also resulted in significantly greater HbA1c reduction (−0.6 vs. −0.1% [6.6 vs. 1.1 mmol/mol]; P < 0.001), percent of patients achieving HbA1c <7% (53 mmol/mol) (44.1 vs. 26.3%; P < 0.001), and improvement in triglycerides and HDL cholesterol compared with placebo. NB was associated with higher incidence of nausea (42.3 vs. 7.1%), constipation (17.7 vs. 7.1%), and vomiting (18.3 vs. 3.6%). No difference was observed between groups in the incidence of depression, suicidal ideation, or hypoglycemia. CONCLUSIONS NB therapy in overweight/obese patients with type 2 diabetes induced weight loss, which was associated with improvements in glycemic control and select cardiovascular risk factors and was generally well tolerated with a safety profile similar to that in patients without diabetes.
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              Comparison of combined bupropion and naltrexone therapy for obesity with monotherapy and placebo.

              The efficacy of current centrally acting obesity pharmacotherapies is limited by compensatory mechanisms that mitigate weight loss. Our objective was to determine whether opioid receptor antagonism (naltrexone) plus pro-opiomelanocortin activation (bupropion) causes greater weight loss than placebo or monotherapy. A randomized, placebo- and monotherapy-controlled, double-blind, dose-finding trial was conducted from August 2005 to December 2006 in seven U.S. outpatient clinics. A total of 419 patients with uncomplicated obesity participated. Interventions included 24 wk of sustained-release bupropion (400 mg/d), immediate-release naltrexone (48 mg/d), placebo, and three combination therapy [naltrexone/bupropion (NB)] groups consisting of immediate-release naltrexone, 16, 32, or 48 mg/d, plus sustained-release bupropion (400 mg/d) with a 24-wk extension. A minimal diet and exercise component was also included. Percent weight change from baseline at wk 24 in the intent-to-treat population for NB48 vs. placebo and monotherapy was assessed. Other measurements included body mass index, waist circumference, fasting lipids, glycemic variables, safety, and tolerability. At wk 24, placebo-subtracted weight loss was -4.62% [95% confidence interval (CI) -6.24 to -2.99; P < 0.001] for NB16, -4.65% (95% CI -6.20 to -3.09; P < 0.001) for NB32, and -3.53% (95% CI -5.15 to -1.90; P < 0.001) for NB48. Weight loss was statistically significant vs. monotherapy for all three NB combinations with the exception of NB48 vs. bupropion. Weight loss with NB continued after wk 24. The most common treatment-emergent adverse event was mild transient nausea. NB caused gradual sustained weight loss over 48 wk; NB32 and NB16 demonstrated greater weight loss in the intent-to-treat population due to lower attrition rates. Further study is needed to demonstrate long-term efficacy and safety of NB.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2015
                08 January 2015
                : 9
                : 419-423
                Affiliations
                Hospital Alemao Oswaldo Cruz, Institute of Health Education and Sciences, Sao Paulo, Brazil
                Author notes
                Correspondence: Anna M Buehler, Hospital Alemao Oswaldo Cruz, Institute of Health Education and Sciences, Rua João Juliao, 245, First floor, 01323-903, Sao Paulo, SP, Brazil, Tel +55 11 354 905 82, Email abuehler@ 123456haoc.com.br
                Article
                dddt-9-419
                10.2147/DDDT.S77881
                4293294
                © 2015 Buehler. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Letter

                Pharmacology & Pharmaceutical medicine

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