Abstract
The prevalence of obesity is growing rapidly worldwide, and therefore there is a need for effective treatment strategies. The rationale of combination therapy in treating chronic diseases, such as obesity, is the potential additive or synergistic effects. This review considers the results of phase III clinical trials with naltrexone sustained-release (SR) + bupropion SR combination therapy in obese patients with or without type 2 diabetes mellitus. We also discuss the potential therapeutic applications of this weight-reducing treatment option. Recent clinical trials have shown that the administration of naltrexone SR + bupropion SR resulted in effective weight loss. Furthermore, this treatment was associated with improvement in cardiometabolic variables. Depression and suicidal ideation were more frequently reported in the placebo compared with the combination groups. However, significantly more patients on naltrexone SR + bupropion SR experienced adverse events, mainly nausea, and discontinued treatment compared with placebo. Increases in blood pressure and pulse rate were observed only in the combination groups. Further investigation is needed to clarify the clinical significance of this weight-reducing therapeutic option.
| Abbreviations | ||
| BMI | = | body mass index |
| BMOD | = | behaviour modification |
| COEQ | = | Control of Eating Questionnaire |
| COR | = | Contrave Obesity Research |
| CV | = | cardiovascular |
| DBP | = | diastolic blood pressure |
| FCI | = | Food Craving Inventory |
| FDA | = | Food and Drug Administration |
| HbA1c | = | glycosylated haemoglobin A1c |
| HDL-C | = | high-density lipoprotein cholesterol |
| HOMA-IR | = | homeostasis model assessment of insulin resistance |
| hsCRP | = | high-sensitivity C-reactive protein |
| IWQOL-Lite | = | Impact of Weight on Quality of Life-Lite |
| LDL-C | = | low-density lipoprotein cholesterol |
| NAFLD | = | non-alcoholic fatty liver disease |
| NNHs | = | numbers needed to harm |
| NNTs | = | numbers needed to treat |
| POMC | = | pro-opiomelanocortin |
| SBP | = | systolic blood pressure |
| SR | = | sustained-release |
| T2DM | = | type 2 diabetes mellitus |
| TG | = | triglycerides |
Key messages
In four phase III clinical studies involving obese patients (with or without type 2 diabetes mellitus), naltrexone sustained-release (SR) + bupropion SR combination treatment achieved significantly greater weight reductions compared with placebo.
Patients on naltrexone SR + bupropion SR showed better improvement in cardiometabolic parameters (e.g. waist circumference, lipids, high-sensitivity C-reactive protein, fasting glucose, and insulin sensitivity) than placebo.
Naltrexone SR + bupropion SR was not associated with increased reports of depression or suicidal ideation, although more patients on combination therapy experienced adverse events (mainly nausea) and discontinued treatment.
Introduction
Obesity is associated with heart disease, hypertension, dyslipidaemia, type 2 diabetes mellitus (T2DM), cancer, non-alcoholic fatty liver disease (NAFLD), osteoarthritis, sleep apnoea, and psychological disorders (Citation1). Furthermore, it has been estimated that non-smoking overweight (body mass index (BMI) = 25–29.9 kg/m2) 40-year-old women and men lose a mean of 3.3 and 3.1 years of life, respectively, compared with normal-weight individuals (Citation2). In turn, obese (BMI ≥ 30 kg/m2) women and men lose about 7.1 and 5.8 years of life, respectively (Citation2).
Loss of 5%–10% of initial weight is associated with decreased risk of obesity-related co-morbidities (e.g. hypertension and risk of developing T2DM) (Citation3). Management of weight reduction includes lifestyle interventions (i.e. diet, physical exercise, and behavioural modification), drug therapy, and bariatric surgery. Lifestyle modification remains the first-line option. Pharmacotherapy is recommended when lifestyle measures fail in patients with BMI > 27 kg/m2 in the presence of obesity-related risk factors, or BMI > 30 kg/m2 even without these factors (Citation4). Criteria for bariatric surgery include a BMI ≥ 40 kg/m2 or a BMI ≥ 35 kg/m2 in a patient with a high-risk condition such as severe sleep apnoea, obesity-related cardiomyopathy, or DM (Citation5).
As the prevalence of obesity is rapidly increasing worldwide (Citation6), there is a need for effective treatment strategies. This review considers the results of phase III clinical trials with naltrexone sustained-release (SR) + bupropion SR combination therapy in obese patients with or without T2DM. We also discuss the potential therapeutic applications of this weight-reducing therapeutic option.
The role of pharmacotherapy in the treatment of obesity
Although lifestyle interventions may result in significant weight loss (up to 8.6% of initial weight after 1 year) (Citation7), long-term adherence to structured diets and specific physical activity programmes are difficult to maintain. On the other hand, bariatric surgery is associated with low rates of early and late overall mortality, although perioperative complications may occur, especially in centres without considerable experience with this type of surgery (Citation8–10). However, bariatric surgery is restricted to those patients that meet the recommended criteria described above (Citation5).
Pharmacotherapy can be applied to a broader range of overweight/obese patients filling the gap between lifestyle measures and surgery. Several antiobesity drugs that exert either peripheral or central actions were developed. These agents reduce appetite, increase energy consumption, or decrease intestinal caloric uptake (Citation11). The advantages of drug therapy include weight loss and prevention of weight regain, along with improvement of cardiometabolic risk factors and obesity-related disorders (Citation12–16). A few of these drugs were approved by the Food and Drug Administration (FDA) (Citation4,Citation17) and/or the European Medicines Agency (Citation17,Citation18). However, psychiatric and cardiovascular (CV) side-effects led to the withdrawal of rimonabant (a selective cannabinoid CB1 receptor antagonist (Citation19)) in 2008 (Citation20) and sibutramine (a selective inhibitor of central neuronal reuptake of serotonin and noradrenaline) in 2010 (Citation21), respectively.
Orlistat, an inhibitor of gastrointestinal lipases, is another antiobesity agent. Although the safety and efficacy of orlistat treatment has been established (Citation15–17,Citation22), adverse effects and drug interactions may lead to discontinuation, limiting its efficacy (Citation23). Clearly, new weight-reducing drugs that are both effective and safe are needed.
Naltrexone SR + bupropion SR combination for the treatment of obesity
The rationale of combination therapy in treating chronic diseases, such as T2DM, hypertension and obesity, is the potential additive or synergistic effects (Citation24). The efficacy and safety of weight-reducing combination treatment has been previously investigated with conflicting results. For example, when combined, fenfluramine and phentermine exerted synergistic effects on weight loss (Citation25,Citation26). On the other hand, adding orlistat to sibutramine does not induce further weight reduction, whereas the addition of sibutramine to orlistat results in a significant greater weight loss compared with orlistat monotherapy (Citation27–29). It has been suggested that the absence of an additive weight loss effect when orlistat is added to sibutramine treatment may be attributed to their mode of action since sibutramine-induced suppression of appetite leads to decreased food intake and therefore reduced faecal fat loss, the mechanism of action for orlistat (Citation30).
Several drugs approved for purposes other than weight loss have been documented to reduce weight (e.g. naltrexone SR and bupropion SR) (Citation17,Citation31). Naltrexone, an opioid receptor antagonist primarily used for the treatment of opioid addiction and alcohol dependence, was associated with minimal or no weight loss in obese patients when administered alone (Citation31,Citation32). On the other hand, bupropion, a norepinephrine and dopamine reuptake inhibitor approved for the treatment of depression and smoking cessation, was consistently related to significant weight reductions in obese patients with or without depression compared with placebo (Citation32). Furthermore, bupropion was shown to diminish the weight gain associated with smoking cessation (Citation33). This weight-lowering effect of bupropion has been attributed to the activation of anorexigenic neurons (pro-opiomelanocortin (POMC)) in the hypothalamic arcuate nucleus; this outcome, however, is modest and reaches a plateau after 6 months of therapy probably due to the autoinhibition of POMC neurons by the endogenous opioid β-endorphin (Citation24). Therefore, it was suggested that naltrexone could prolong the action of bupropion by maintaining POMC stimulation, subsequently leading to further weight loss, a suggestion that was confirmed in both animal and human studies (Citation24,Citation34).
Based on these observations, naltrexone SR + bupropion SR combination therapy (ContraveR, Orexigen Therapeutics Inc.) is under development as an antiobesity therapeutic option (Citation32,Citation35).
Phase III clinical trials with naltrexone SR + bupropion SR combination therapy
The Contrave Obesity Research (COR) programme consists of four randomized, double-blind, placebo-controlled, phase III clinical studies of 56-week duration (COR-I (Citation36), COR-II (Citation37), COR-BMOD (COR–Behaviour MODification) (Citation38), and COR-Diabetes (Citation37)) assessing the efficacy, safety, and tolerability of naltrexone SR+ bupropion SR combination therapy in obese patients with or without T2DM. The results of the COR-I (Citation36) and COR-BMOD trials (Citation38) have been recently published. Preliminary data from the COR-II and COR-Diabetes studies have been presented at the 27th Annual Scientific Meeting of the Obesity Society (2009) and the 70th Scientific Sessions of the American Diabetes Association (2010), respectively (Citation37).
COR-I trial
In this trial, 1,742 obese patients (1,482 women) were randomly assigned in a 1:1:1 ratio to a fixed oral dose of 32 mg naltrexone SR + 360 mg bupropion SR (8 + 90 mg in each tablet, two tablets taken twice a day; mean BMI = 36.1 ± 4.4 kg/m2), 16 mg naltrexone SR + 360 mg bupropion SR (4 + 90 mg in each tablet, two tablets taken twice a day; mean BMI = 36.2 ± 4.3 kg/m2), or matching placebo (mean BMI = 36.2 ± 4.0 kg/m2) for 56 weeks (Citation36). Altogether 1,453 participants had a base-line and a post base-line weight measurement and were included in the primary analysis, whereas 870 participants completed the 56-week study and were analysed separately. Weight loss was significantly greater in the combination treatment groups compared with placebo (P < 0.0001 for all comparisons) in both analyses (primary analysis: −6.1%, −5.0%, and −1.3% in the naltrexone SR 32 mg + bupropion SR, naltrexone SR 16 mg + bupropion SR, and placebo groups, respectively; in the study population that completed 56 weeks of treatment: −8.1%, −6.7%, and −1.8% in the naltrexone SR 32 mg + bupropion SR, naltrexone SR 16 mg + bupropion SR, and placebo groups, respectively) (Citation36). Maximum weight reduction in the combination treatment groups was achieved between 28 and 36 weeks.
In both analyses, significantly more participants achieved a weight reduction of ≥ 5%, ≥ 10%, and ≥ 15% in the naltrexone SR + bupropion SR groups than in the placebo group (P < 0.0001 for all comparisons) (). In the primary analysis population, both mean changes in body weight (%) and the proportion of participants with weight loss of ≥ 5% were significantly higher in the naltrexone SR 32 mg + bupropion SR group compared with the naltrexone SR 16 mg + bupropion SR group (P = 0.0079 and P = 0.0099, respectively) (Citation36).
Table I. Percentages of participants achieving different degrees of weight loss in the (Contrave Obesity Research) COR-I trial.
Waist circumference, triglycerides (TG), high-sensitivity C-reactive protein (hsCRP), and homeostasis model assessment of insulin resistance (HOMA-IR) were significantly more reduced, and high-density lipoprotein cholesterol (HDL-C) levels were significantly more increased, in the combination treatment groups compared with placebo (P = 0.0461 to < 0.0001) () (Citation36). Low-density lipoprotein cholesterol (LDL-C) levels were similarly reduced between study groups. Decreases in fasting glucose and insulin levels differed significantly only between naltrexone SR 32 mg + bupropion SR and placebo groups (fasting glucose change: −0.18 and −0.07 mmol/L in naltrexone SR 32 mg + bupropion SR and placebo group, respectively(P = 0.0104); percentage change in fasting insulin: −17.1% and −4.6% in naltrexone SR 32 mg + bupropion SR and placebo group, respectively (P = 0.0007)).
Table II. Changes in cardiometabolic parameters in the primary analysis population of the (Contrave Obesity Research) COR-I trial.
COR-I investigators (Citation36) also reported greater improvements in quality of life, eating behaviour, and food craving in participants on naltrexone SR + bupropion SR compared with placebo. These differences were significant when assessed by the Impact of Weight on Quality of Life-Lite (IWQOL-Lite) total and subscale scores (Citation39) and the Control of Eating Questionnaire (COEQ) (Citation40). In contrast, the Food Craving Inventory (FCI) did not differ significantly (Citation36). Of note, as presented at the 28th Annual Scientific Meeting of the Obesity Society (October 2010), subjects with base-line IWQOL-Lite scores in the severely impaired range showed greater improvements (P < 0.05) in total score, and physical function, self-esteem, and sexual life subscales, when treated with naltrexone SR 32 mg + bupropion SR versus placebo (http://www.obesity.org/obesity2010/abstracts.asp).
Changes in mean systolic blood pressure (SBP) significantly differed between combination treatment groups and placebo (−0.1, +0.3, and −1.9 mmHg in the naltrexone SR 32 mg + bupropion SR, naltrexone SR 16 mg + bupropion SR, and placebo groups, respectively; P = 0.0008 for the naltrexone SR 32 mg + bupropion SR and P < 0.0001 for naltrexone SR 16 mg + bupropion SR versus placebo) (Citation36). In particular, a transient increase in SBP of about 1.5 mmHg was observed during the first 8 weeks of the study in the combination groups, followed by decreases of approximately 1 mmHg, whereas in the placebo group SBP was continuously decreasing during the study. A similar trend was seen for diastolic blood pressure (DBP): mean DBP was reduced in the placebo group, whereas it was increased or unchanged in the combination treatment groups (+0.0, +0.1, and −0.9 mmHg in the naltrexone SR 32 mg + bupropion SR, naltrexone SR 16 mg + bupropion SR, and placebo group, respectively; P = 0.0217 for naltrexone SR 32 mg + bupropion SR and P = 0.0150 for naltrexone SR 16 mg + bupropion SR versus placebo). Pulse rate was increased (ranging from 1.5 to 2.5 beats/min higher than base-line value) in the combination treatment groups, whereas it remained unchanged in the placebo group (Citation36).
The percentage of participants reporting any adverse event was significantly higher in the combination treatment groups compared with placebo (83.1%, 80%, and 68.5% in the naltrexone SR 32 mg + bupropion SR, naltrexone SR 16 mg + bupropion SR, and placebo groups, respectively; P < 0.05 for naltrexone SR + bupropion SR groups versus placebo) (Citation36). These adverse events were mostly mild to moderate in severity and transient, usually occurring during the titration phase. The most frequent side-effect was nausea (29.8%, 27.2%, and 5.3% in the naltrexone SR 32 mg + bupropion SR, naltrexone SR 16 mg + bupropion SR, and placebo groups, respectively; P < 0.05 for naltrexone SR + bupropion SR groups versus placebo). Of note, the rates of both nausea, which is associated with naltrexone therapy, and insomnia and dry mouth, which are associated with bupropion treatment, were at or below previously reported rates (Citation34,Citation41). No differences were observed in depression and suicidality frequencies between combination treatment groups and placebo (Citation36).
Significantly more participants in the combination treatment groups discontinued due to adverse events compared with placebo (19.5%, 21.4%, and 9.8% in the naltrexone SR 32 mg + bupropion SR, naltrexone SR 16 mg + bupropion SR, and placebo groups, respectively; P < 0.0001 for both combination groups versus placebo) (Citation36).
COR-II trial
Preliminary results from the COR-II trial were presented at the 27th Annual Scientific Meeting of the Obesity Society (2009). Inclusion criteria included alanine and aspartate aminotransferase (ALT and AST, respectively) activities within 2.5× upper limit of normal and a fasting glucose < 126 mg/dL (6.9 mmol/L) on no hypoglycaemic agents (www.clinicaltrials.gov). The percentage of participants achieving weight loss of ≥ 10% was significantly higher in the naltrexone SR 32 mg + bupropion SR 360 mg group (n = 702) compared with the placebo group (n = 456) (32.9% versus 5.7%, respectively; P < 0.05) as was the proportion of those achieving weight loss of ≥ 15% (15.7% versus 2.4% in the naltrexone SR + bupropion SR (32 + 360 mg) group versus placebo; P < 0.05) (Citation37). Furthermore, reductions in waist circumference, TG, LDL-C, and hsCRP were significantly greater in the naltrexone SR 32 mg + bupropion SR group compared with the placebo group as were the increases in HDL-C levels (P < 0.05 for all comparisons) (). The most frequently reported side-effects were nausea, constipation, and headache.
Table III. Preliminary results from the (Contrave Obesity Research) COR-II trial regarding changes in markers of cardiometabolic risk.
A recent (28th Annual Scientific Meeting of the Obesity Society, October 2010) pooled analysis of COR-I and COR-II trials including 1,173 overweight/obese individuals on naltrexone SR 32 mg + bupropion SR 360 mg and 967 matched controls on placebo showed a greater BP reduction with greater weight loss in both groups (P < 0.001) (http://www.obesity.org/obesity2010/abstracts.asp). Furthermore, in those with increased cardiometabolic risk (i.e. waist circumference > 88 cm women, > 102 cm men; HDL-C < 50 mg/dL women, < 40 mg/dL men; TG ≥ 150 mg/dL; and hsCRP > 3 mg/dL) at base-line, the combination treatment group showed greater improvements versus placebo (P < 0.001).
COR-BMOD trial
In this trial, 793 obese patients (713 women, mean BMI = 36.5 ± 4.2 kg/m2) were randomly assigned in a 3:1 ratio to a fixed oral dose of naltrexone SR 32 mg + bupropion SR 360 mg (8 + 90 mg in each tablet, two tablets taken twice a day) or placebo (Citation38). All participants were on an energy-reduced diet and attended group BMOD sessions. At week 56 (n = 407 participants), a significantly greater weight loss was observed in the naltrexone SR + bupropion SR group compared with placebo (−1.5% versus −7.3%, respectively; P < 0.001). Similarly, in a modified intent-to-treat population analysis including patients with ≥ 1 post base-line weight measurement on study drug (n = 675 participants), weight reduction was significantly greater in the combination treatment group compared with placebo (−9.3% versus −5.1%, respectively; P < 0.001) (Citation38). This difference remained significant on a sensitivity analysis of all randomized participants (−7.8% versus −4.9% for the two groups, respectively; P < 0.001).
In all analyses, the percentages of patients achieving ≥ 5%, ≥ 10%, and ≥ 15% reductions of initial weight were higher in the naltrexone SR + bupropion SR group compared with placebo (P ≤ 0.001 for all comparisons) () (Citation38). The highest percentages of weight loss were observed in the patients who completed the study.
Participants in both groups attended a similar number of BMOD sessions (Citation38); the more sessions attended, the higher the percentage of weight reduction (P < 0.0001).
Table IV. Percentages of participants achieving different degrees of weight loss in the Contrave Obesity Research-Behaviour MODification (COR-BMOD) trial.
At week 56, patients in the naltrexone SR + bupropion SR group achieved greater reductions in waist circumference, TG, fasting insulin levels, and HOMA-IR compared with placebo (waist circumference: −9.1% versus −6.1%, respectively (P < 0.001); TG: −16.6% versus −8.5%, respectively (P = 0.004); fasting insulin: −28% versus −15.5%, respectively (P = 0.003); HOMA-IR: −29.9 versus −16.6%, respectively (P = 0.003)) (Citation38). Furthermore, increases in HDL-C levels were significantly higher in the combination treatment group compared with placebo (+9.4% versus +2.8%, respectively; P < 0.001). Of note, similar increases in LDL-C and decreases in hsCRP levels were observed in the two study groups.
Quality of life, as assessed by the IWQOL-Lite total score and subscales, was improved significantly more in the naltrexone SR + bupropion SR group compared with placebo (P < 0.001). Both groups had similar changes in total score and subscales of the FCI and the COEQ, assessing aspects of eating behaviour, food craving, and mood (Citation38).
At week 56, reductions in mean SBP were greater in the placebo group compared with the combination treatment group (−3.9 ± 0.7 versus −1.3 ± 0.5 mmHg, respectively; P = 0.002). A similar difference was observed for DBP (−2.8 ± 0.5 versus −1.4 ± 0.3 mmHg, respectively; P = 0.017). Pulse rate was slightly increased in patients treated with naltrexone SR + bupropion SR (+1.1 ± 0.4 beats/min), whereas it remained unchanged in the placebo group (Citation38).
Significantly more participants in the combination treatment group reported adverse events compared with placebo (nausea: 34.1% versus 10.5%; constipation: 24.1% versus 14%; dizziness: 14.6% versus 4.5%; dry mouth: 8% versus 3%; tremor: 5.8% versus 1%; upper abdominal pain: 5.5% versus 1.5%; and tinnitus: 5.3% versus 0.5%, respectively; P 0.017 to < 0.001 for all comparisons) (Citation38). These adverse events were mostly mild to moderate in severity and occurred during the first weeks of the study. Depression was more frequent in the placebo group compared with the naltrexone SR + bupropion SR group (2.5% versus 0.3%; P = 0.014). Suicidal ideation was reported by two participants in the placebo group and none in the combination treatment group (Citation38). However, there were two serious cases of cholecystitis (followed by successful surgery) in patients on naltrexone SR + bupropion SR who achieved weight loss > 15 kg.
More participants in the combination treatment group discontinued compared with placebo, mainly due to nausea (4.6% versus 0%, respectively; P < 0.001) (Citation38). The second most common cause for discontinuation was urticaria, with similar rates observed between the two study groups (1.7% and 0.5% for naltrexone SR + bupropion SR group and placebo, respectively; P > 0.05).
COR-Diabetes trial
Preliminary results from the COR-Diabetes trial were presented at the 70th Scientific Sessions of the American Diabetes Association (2010). In this study, 505 overweight or obese T2DM patients with glycosylated haemoglobin A1c (HbA1c) between 7% and 10% (mean HbA1c = 8.0%) and on several oral hypoglycaemic drugs were randomized in a 2:1 ratio to either naltrexone SR 32 mg + bupropion SR 360 mg or placebo (Citation37). More patients on combination treatment lost ≥ 5% of their initial weight compared with placebo group (44.5% versus 18.9%, respectively; P not provided). Furthermore, reductions in mean HbA1c values were greater in the naltrexone SR + bupropion SR group compared with placebo (−0.6% versus −0.1%, respectively; P not provided), leading to a higher proportion of T2DM patients achieving HbA1c target levels of < 7% in the combination treatment group compared with placebo (44% versus 26%, respectively; P < 0.001) (Citation37). Of note, in T2DM patients with a base-line HbA1c > 8%, even greater reductions in HbA1c levels were observed in the naltrexone SR + bupropion SR group compared with placebo (−1.1% versus −0.5%, respectively; P < 0.01).
T2DM patients on naltrexone SR + bupropion SR showed significantly greater improvements in various cardiometabolic risk factors compared with placebo (waist circumference: −5 versus −2.9 cm (P < 0.01); TG: −11.2% versus −0.8% (P < 0.01); HDL-C: +3% versus −0.3% (P < 0.001)) (Citation37). Mean reductions in LDL-C, fasting glucose, insulin, HOMA-IR, and hsCRP levels were also greater in the combination group compared with placebo, although they did not reach significance.
The most frequently reported adverse events were nausea, vomiting, constipation, and dizziness. Discontinuation usually occurred due to nausea (Citation37). No data regarding changes in SBP, DBP, and pulse rate were reported.
Discussion
Combination therapy with naltrexone SR 32 mg + bupropion SR 360 mg has been recently proposed as an option for the treatment of obesity. Four randomized, double-blind, placebo-controlled, phase III clinical studies (COR-I (Citation36), COR-II (Citation37), COR-BMOD (Citation38), and COR-Diabetes (Citation37)) assessed the efficacy, safety, and tolerability of the naltrexone SR + bupropion SR combination in obese patients with or without T2DM. In these studies, significantly greater weight reductions and higher proportions of patients achieving losses ≥ 5% of initial weight were observed in the naltrexone SR + bupropion SR groups compared with placebo. Of note, when combined with BMOD, patients on combination treatment achieved greater weight reductions compared with those not on BMOD.
Weight loss is associated with decreases in inflammatory markers (Citation42) and CV risk reduction (Citation3). In this context, patients on naltrexone SR + bupropion SR showed better improvement in cardiometabolic parameters such as waist circumference, lipids, hsCRP, fasting glucose, insulin, and HOMA-IR compared with placebo. In the COR-Diabetes study, significantly more T2DM patients on naltrexone SR + bupropion SR achieved good glycaemic control (HbA1c < 7%) compared with those on placebo (Citation37).
Bupropion is used for smoking cessation which, in turn, is associated with weight increase (Citation33). Therefore, it is not surprising that the effects of combination therapy were also evaluated in smokers (Citation43,Citation44). Normal-weight patients on naltrexone 25 mg + bupropion SR 300 mg gained less weight compared with those on bupropion monotherapy (P not significant) (Citation43,Citation44). In greater detail, the weight gain among abstainers was 47% less in the combination group compared with those on bupropion monotherapy. Similarly, the post-quit weight increase in the entire sample was 78% less in smokers on naltrexone 25 mg + bupropion SR 300 mg compared with those on bupropion 300 mg alone. Although these differences are numerically impressive, they are not significant possibly due to the small numbers in each treatment group (n = 20). Furthermore, in another study involving overweight/obese smokers, naltrexone SR 32 mg + bupropion SR 360 mg combination therapy was associated with reduced nicotine intake, fewer withdrawal symptoms, and a non-significant increase in weight (Citation44). These findings suggest that more research is needed in the field of weight gain following smoking cessation.
Combination treatment exerts several beneficial metabolic actions, and therefore it could be beneficial in high-risk patients (e.g. those with metabolic syndrome, NAFLD, impaired fasting glucose, or impaired glucose tolerance). In particular, the observed consistent rise in HDL-C levels may prove useful in terms of CV risk reduction (Citation45). Clinical trials evaluating the effectiveness and safety of naltrexone SR + bupropion SR therapy in such populations should be conducted, as multifactorial treatment aiming at several targets may be effective (Citation46,Citation47).
Certain negative effects may limit the use of combination treatment and need to be addressed. In general, reductions in mean SBP and DBP were greater in the placebo group compared with the combination treatment group. Furthermore, pulse rate was slightly increased in patients treated with naltrexone SR + bupropion SR, whereas it remained unchanged in the placebo group. Of note, elevated heart rate is associated with coronary atherosclerosis (Citation48). Where details are available (COR-I (Citation36) and COR-BMOD trials (Citation38)), the results described above were observed in patients with mean base-line SBP < 120 mmHg and DBP < 80 mmHg. Furthermore, patients with mild untreated hypertension (SBP = 140–159 mmHg and/or DBP = 90–99 mmHg) showed significantly smaller decreases in SBP when on bupropion SR 300 mg/day compared with placebo, whereas heart rate was increased only in those on bupropion SR 400 mg/day (Citation49). It follows that the effects of combination treatment on SBP and DBP warrants further investigation in hypertensive patients. This issue is relevant since sibutramine, also acting on the central nervous system, was associated with increases in BP and resting heart rate (Citation21) and was finally withdrawn from several markets due to unfavourable CV outcomes (Citation50). Interestingly, combination of sibutramine with antihypertensive therapy resulted in greater reductions in both SBP and DBP compared with antihypertensive therapy alone, although this difference was significant only for DBP (Citation51). Such an effect should also be assessed for naltrexone SR + bupropion SR therapy.
The vast majority of the participants in the four phase III clinical trials of the COR programme were women. The effects of combination therapy on both weight and cardiometabolic parameters also need to be evaluated in males since other treatments (e.g. statins) may produce different results in men and women (Citation52). Furthermore, women on naltrexone gained less weight after quitting smoking compared with placebo (P = 0.04), whereas these effects were not significant in men (Citation53).
Although naltrexone SR + bupropion SR treatment was not associated with increased reports of depression or suicidal ideation compared with placebo, significantly more patients on combination therapy experienced adverse events (mainly nausea, dizziness, headache, and constipation). These were mostly of mild to moderate severity and transient. However, discontinuation rates, usually due to nausea, were higher in patients on naltrexone SR + bupropion SR compared with placebo. In the COR-BMOD and COR-I trials the difference in reports of nausea between the combination and the placebo groups was up to 3- and 6-fold, respectively (Citation36,Citation38). In a combined analysis of 3,239 patients on all doses of the combination treatment (naltrexone + bupropion SR) and 1,515 controls on placebo (http://www.obesity.org/obesity2010/abstracts.asp), no difference in depression-related psychiatric adverse events (PAEs) (relative risk (RR) 0.72 (95% CI 0.48–1.07)) or suicidal ideation (RR 0.16 (0.02–1.42)) was found. However, combination-treated subjects experienced more anxiety and sleep disorder-related PAEs versus placebo (RR 1.62 (1.18–2.22) and RR 1.63 (1.33–2.00), respectively). Depression-, anxiety-, and sleep-disorder-related PAEs were mild, transient, and tended to occur early in the trial. PAE-induced discontinuations were similar between groups.
Interestingly, in a recent report the numbers needed to treat (NNTs) and the numbers needed to harm (NNHs) for patients in COR-I trial were calculated (Citation54). The NNTs for losses ≥ 5% of initial weight were 4 for naltrexone SR 32 mg + bupropion SR versus placebo and 5 for naltrexone SR 16 mg + bupropion SR versus placebo; for weight reduction ≥ 10%, the NNTs were 6 and 8, respectively (Citation54). On the other hand, the NNHs for nausea were 5 for naltrexone SR 32 mg + bupropion SR versus placebo and 5 for naltrexone SR 16 mg + bupropion SR versus placebo, whereas for discontinuation they were 11 and 9, respectively. Furthermore, it was calculated that there was a three times higher likelihood for a patient on naltrexone SR 32 mg + bupropion SR to lose ≥ 5% of initial weight than to discontinue (Citation54).
In the COR-BMOD trial (Citation38), there were two serious cases of cholecystitis in patients on naltrexone SR + bupropion SR who achieved weight loss > 15 kg. This may be attributed to rapid weight loss (Citation55).
Patients on combination treatment received two tablets (4 mg naltrexone SR + 90 mg bupropion SR in each tablet) twice a day. Therefore, there is a risk of long-term non-compliance due to the increased number of tablets required. This may be an even greater disadvantage for patients already on several drugs.
Finally, the effects of combination therapy on weight and cardiometabolic parameters should also be compared with other available antiobesity therapeutic options, such as diet, lifestyle measures, and orlistat, and not only with placebo.
In conclusion, the results from the COR programme trials suggest that combination therapy with naltrexone SR + bupropion SR is effective in weight loss. Furthermore, this treatment was associated with improvements in cardiometabolic parameters. Depression and suicidal ideation were more frequently reported in the placebo group compared with the combination group. However, more patients on naltrexone SR + bupropion SR experienced adverse events, mainly nausea, and discontinued than placebo. Certain issues such as the increases in SBP, DBP, and pulse rate observed in the combination groups should be addressed in future trials. Clearly, further investigation is needed to clarify the clinical significance of this emerging weight-reducing combination treatment.
Declaration of interest: This study was conducted independently; no company or institution supported it financially. Some of the authors have given talks, attended conferences and participated in trials and advisory boards sponsored by MSD, AstraZeneca, Genzyme, Pfizer, Alapis, Eli Lilly, and Bayer.
Dr N. Katsiki MD, FRSPH, is supported by a grant from the Hellenic Atherosclerosis Society.
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