Ken Fujioka

Effect of naltrexone plus bupropion on weight loss in overweight and obese adults (COR-I): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

BACKGROUND Despite increasing public health concerns regarding obesity, few safe and effective drug treatments are available. Combination treatment with sustained-release naltrexone and bupropion was developed to produce complementary actions in CNS pathways regulating bodyweight. The Contrave Obesity Research I (COR-I) study assessed the effect of such treatment on bodyweight in overweight and obese participants. METHODS Men and women aged 18-65 years who had a body-mass index (BMI) of 30-45 kg/m(2) and uncomplicated obesity or BMI 27-45 kg/m(2) with dyslipidaemia or hypertension were eligible for enrolment in this randomised, double-blind, placebo-controlled, phase 3 trial undertaken at 34 sites in the USA. Participants were prescribed mild hypocaloric diet and exercise and were randomly assigned in a 1:1:1 ratio to receive sustained-release naltrexone 32 mg per day plus sustained-release bupropion 360 mg per day combined in fixed-dose tablets (also known as NB32), sustained-release naltrexone 16 mg per day plus sustained-release bupropion 360 mg per day combined in fixed-dose tablets (also known as NB16), or matching placebo twice a day, given orally for 56 weeks. The trial included a 3-week dose escalation. Randomisation was done by use of a centralised, computer-generated, web-based system and was stratified by study centre. Co-primary efficacy endpoints at 56 weeks were percentage change in bodyweight and proportion of participants who achieved a decrease in bodyweight of 5% or more. The primary analysis included all randomised participants with a baseline weight measurement and a post-baseline weight measurement while on study drug (last observation carried forward). This study is registered with ClinicalTrials.gov, number NCT00532779. FINDINGS 1742 participants were enrolled and randomised to double-blind treatment (naltrexone 32 mg plus bupropion, n=583; naltrexone 16 mg plus bupropion, n=578; placebo, n=581). 870 (50%) participants completed 56 weeks of treatment (n=296; n=284; n=290, respectively) and 1453 (83%) were included in the primary analysis (n=471; n=471; n=511). Mean change in bodyweight was -1.3% (SE 0.3) in the placebo group, -6.1% (0.3) in the naltrexone 32 mg plus bupropion group (p<0.0001 vs placebo) and -5.0% (0.3) in the naltrexone 16 mg plus bupropion group (p<0.0001 vs placebo). 84 (16%) participants assigned to placebo had a decrease in bodyweight of 5% or more compared with 226 (48%) assigned to naltrexone 32 mg plus bupropion (p<0.0001 vs placebo) and 186 (39%) assigned to naltrexone 16 mg plus bupropion (p<0.0001 vs placebo). The most frequent adverse event in participants assigned to combination treatment was nausea (naltrexone 32 mg plus bupropion, 171 participants [29.8%]; naltrexone 16 mg plus bupropion, 155 [27.2%]; placebo, 30 [5.3%]). Headache, constipation, dizziness, vomiting, and dry mouth were also more frequent in the naltrexone plus bupropion groups than in the placebo group. A transient increase of around 1.5 mm Hg in mean systolic and diastolic blood pressure was followed by a reduction of around 1 mm Hg below baseline in the naltrexone plus bupropion groups. Combination treatment was not associated with increased depression or suicidality events compared with placebo. INTERPRETATION A sustained-release combination of naltrexone plus bupropion could be a useful therapeutic option for treatment of obesity. FUNDING Orexigen Therapeutics.

A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management

BACKGROUND Obesity is a chronic disease with serious health consequences, but weight loss is difficult to maintain through lifestyle intervention alone. Liraglutide, a glucagon-like peptide-1 analogue, has been shown to have potential benefit for weight management at a once-daily dose of 3.0 mg, injected subcutaneously. METHODS We conducted a 56-week, double-blind trial involving 3731 patients who did not have type 2 diabetes and who had a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of at least 30 or a BMI of at least 27 if they had treated or untreated dyslipidemia or hypertension. We randomly assigned patients in a 2:1 ratio to receive once-daily subcutaneous injections of liraglutide at a dose of 3.0 mg (2487 patients) or placebo (1244 patients); both groups received counseling on lifestyle modification. The coprimary end points were the change in body weight and the proportions of patients losing at least 5% and more than 10% of their initial body weight. RESULTS At baseline, the mean (±SD) age of the patients was 45.1±12.0 years, the mean weight was 106.2±21.4 kg, and the mean BMI was 38.3±6.4; a total of 78.5% of the patients were women and 61.2% had prediabetes. At week 56, patients in the liraglutide group had lost a mean of 8.4±7.3 kg of body weight, and those in the placebo group had lost a mean of 2.8±6.5 kg (a difference of -5.6 kg; 95% confidence interval, -6.0 to -5.1; P<0.001, with last-observation-carried-forward imputation). A total of 63.2% of the patients in the liraglutide group as compared with 27.1% in the placebo group lost at least 5% of their body weight (P<0.001), and 33.1% and 10.6%, respectively, lost more than 10% of their body weight (P<0.001). The most frequently reported adverse events with liraglutide were mild or moderate nausea and diarrhea. Serious events occurred in 6.2% of the patients in the liraglutide group and in 5.0% of the patients in the placebo group. CONCLUSIONS In this study, 3.0 mg of liraglutide, as an adjunct to diet and exercise, was associated with reduced body weight and improved metabolic control. (Funded by Novo Nordisk; SCALE Obesity and Prediabetes NN8022-1839 ClinicalTrials.gov number, NCT01272219.).

Effects of Sibutramine Treatment in Obese Adolescents: A Randomized Trial

Context Few trials have evaluated drugs for obesity in adolescents. Contribution This 12-month randomized, double-blind trial evaluated behavioral therapy plus either sibutramine or placebo in 498 very obese adolescents who were 12 to 16 years of age. Sibutramine reduced mean body mass index (between-group difference, 2.9 kg/m2) and mean weight (between-group difference, 8.4 kg) more than placebo. Sibutramine also improved some lipid and glycemic measures and was associated with tachycardia. Cautions Only 76% and 62% of the sibutramine and placebo recipients, respectively, completed the trial. Implications Sibutramine plus behavioral therapy for 1 year can reduce weight and improve metabolic risk factors in some very obese adolescents. The Editors Adolescent obesity is a major public health problem, with 15.5% of U.S. adolescents 12 to 19 years of age defined as overweight (>95th percentile for age- and sex-specific measures for body mass index [BMI]) (1, 2). Overweight often leads to serious health consequences during childhood, such as hypertension, depression, and social exclusion (3). Recently, the incidence of type 2 diabetes, typically an adult disease, has dramatically increased in the pediatric population (46). Cardiovascular risk factors, such as dyslipidemia, insulin sensitivity, and hypertension, are also more prevalent in adolescents with a BMI greater than the 95th percentile than in those with a BMI less than the 85th percentile (7). Management of adult obesity relies on a range of options, including diet, physical activity, behavior modification, pharmacotherapy, and surgery (8, 9). The serotonin and norepinephrine reuptake inhibitor sibutramine facilitates weight loss and weight maintenance in obese adults with commensurate improvements in metabolic variables for up to 2 years of treatment (1012). Prevention is the optimal approach; however, effective treatment in children with a BMI greater than the 95th percentile is needed. Comprehensive behavioral methods have shown weight loss benefit in younger children (13). In most studies, adolescents typically remain overweight after therapy (14). In an earlier single-center, 6-month controlled trial, sibutramine and a comprehensive behavioral program induced statistically significantly more weight loss in obese adolescents than the behavioral program alone (15). Overall, sibutramine is well tolerated; however, increases in mean blood pressure and pulse rate have been reported in some adults (10, 16) and adolescents (15). Our large multicenter study examined the longer-term effects on weight loss by adding sibutramine to behavior therapy in obese adolescents. Methods Design Overview The protocol-designated objective of our 12-month, double-blind study was to evaluate the efficacy and safety of sibutramine in addition to behavior therapy in obese adolescents. At baseline, we randomly assigned participants (3:1 randomization ratio) to sibutramine or placebo (Figure 1). The randomization schedule was stratified by center and baseline BMI (37 kg/m2 or >37 kg/m2) and was computer-generated in blocks of 4 by the sponsor. Each site was responsible for assigning sequential treatments within each stratum. The sponsor kept allocation codes sealed and secure until the database was locked before analysis. Participants, their parents, and study personnel were blinded to treatment. All participants received a behavior therapy program that included lifestyle modification instructions to improve nutrition and increase physical activity. We conducted the study from July 2000 to February 2002 at 33 U.S. weight loss clinics. Individual sites were responsible for recruitment, and we selected eligible participants from the sites clinical database or from responses to advertisements of the study. We obtained approval from individual institutional review boards. Figure 1. Study flow diagram. P P P Participants We included adolescents 12 to 16 years of age with a BMI (calculated as weight [kg] divided by height [m2]) that was at least 2 units more than the U.S. weighted mean of the 95th percentile based on age and sex (17) and was not more than 44 kg/m2. Contraindications included cardiovascular disease (including arrhythmias), type 1 or 2 diabetes mellitus, major psychiatric disorders, pregnancy, use of a weight loss medication or participation in structured weight loss programs for more than 2 weeks, medication use promoting weight gain or contraindicated with sibutramine (16), or cigarette smoking. We excluded candidates with systolic blood pressure greater than 130 mm Hg, diastolic blood pressure greater than 85 mm Hg, or pulse rate greater than 95 beats/min. We included candidates with stable hypertension who were receiving therapy. Participants completed behavioral assessments conducted by a staff psychologist or psychiatrist. We obtained written, informed consent from the parent and assent from the adolescent. Interventions Behavioral Protocol Participants received instruction in a center-specific behavior therapy program. Individual centers implemented flexible lifestyle modification approaches that were specific to the participants needs. This included self-monitoring of eating habits and physical activity, stress management, stimulus control, problem solving, contingency management, cognitive restructuring, and social support. Counseling at each visit promoted increased physical activity and reduced sedentary behavior. Nutritional counseling encouraged development of healthy eating habits and promoted dietary consumption based on a 500-kcal/d deficit. Medication Protocol At baseline, we randomly assigned participants (3:1 randomization ratio) to receive 10 mg of sibutramine or placebo daily. At month 6, doses of all participants who had not lost more than 10% of their initial BMI were uptitrated (blinded) to 15 mg of sibutramine or placebo. Abbott (previously Knoll Pharmaceuticals) manufactured and provided all capsules. Placebo and sibutramine capsules appeared identical and were dispensed similarly. We discontinued therapy for or closely monitored the participants with systolic blood pressure, diastolic blood pressure, or pulse rate that increased at a single visit to more than 150 mm Hg or by more than 20 mm Hg, to 95 mm Hg or by more than 15 mm Hg, or to 110 beats/min or by more than 20 beats/min, respectively, until acceptable values returned. We used a protocol-driven algorithm for repeating visits or withdrawing participants whose values did not return to specified limits. In the case of intolerance, participants were to be withdrawn from the study. Measurements and Follow-up Procedures The primary efficacy measure was absolute change from baseline in BMI. Secondary outcomes included percentage change in BMI, proportion of patients achieving reductions in BMI of 5% or more or 10% or more, absolute and percentage changes in body weight and lipid and glycemic variables, and absolute change in waist circumference. Participants had weekly visits for the first 2 weeks, visits every 2 weeks until week 12, and monthly visits thereafter. At each visit, we recorded weight to the nearest 0.1 kg, with the participant in light clothing and without shoes, and height to the nearest 0.5 cm. We measured waist circumference monthly. We evaluated medication adherence by capsule count. We assessed growth by using a pediatric growth chart (18) and performed full physical examinations at screening and at months 3, 6, and 12 (or at discontinuation). We assessed sexual maturation by self-reported changes in Tanner staging (19). We determined fasting lipid and glycemic variables at major assessments (Clinical Reference Laboratory, Lenexa, Kansas). We performed electrocardiography before treatment and at month 12 or at discontinuation. We obtained blood pressure (manually) and pulse rate (by palpation of the radial or brachial artery) at all visits. We withheld study medication until blood samples were obtained for laboratory assessments at months 3, 6, and 12. The investigator recorded all adverse events, both observed and volunteered, on the appropriate case report form, as well as in the participants clinic, office, or hospital chart. For each event, the investigator provided information on severity, start and stop dates, relationship to study drug, actions taken, and outcome. The investigator also recorded adverse events resulting from concomitant illnesses, reactions to concomitant medications, or progression of disease states. Statistical Analysis The planned sample size was approximately 400 participants with a 3:1 randomization ratio of sibutramine to placebo. On the basis of previous 12-month adult trials, we determined that 300 participants in the sibutramine group would be adequate to assess safety and exposure, allowing an overall dropout rate of approximately 50% and a probability that approximately 50% of participants receiving 10 mg of sibutramine would lose 10% or more of initial BMI at 6 months. The inflated sample size ensured enough participants with echocardiograms, ambulatory blood pressure monitoring, and dual-energy x-ray absorptiometry measurements (minimum of 120, 80, and 100 participants, respectively, at baseline) since these assessments would be performed in subsets. Although the protocol did not document a formal sample size calculation for efficacy, approximately 132 adolescents (99 in the sibutramine group and 33 in the placebo group) would allow a between-group difference in BMI of 2 kg/m2, with 90% power (2-sided level of 0.05) to be statistically significant, assuming a common SD of 3 kg/m2. We documented the prespecified statistical analysis methods while all study and sponsor personnel, including the statistician, were blinded to treatment. The primary efficacy variable was the absolute change from baseline in BMI. Secondary efficacy variables determined from baseline included percentage change in BMI, proportions of participants achieving 5%

Weight loss with sibutramine improves glycaemic control and other metabolic parameters in obese patients with type 2 diabetes mellitus

Aim: To determine the efficacy and tolerability of sibutramine hydrochloride in obese patients whose type 2 diabetes was poorly controlled on diet alone or with an oral antidiabetic agent

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 β‐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.

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.

Pre‐ and Postsurgery Behavioral Compliance, Patient Health, and Postbariatric Surgical Weight Loss

This study investigated the relationship between weight loss from gastric bypass surgery, patient characteristics, and compliance with physician instructions before and after surgery. A chart review of psychiatric and medical files was conducted for an initial cohort of 172 patients in a postsurgical management program. A total of 112 patients (primarily women (85%), white (79%), and well educated) from this cohort had presurgical data. Of these 112 subjects, 67 (60%) had postsurgical compliance information and BMI at 24 months postsurgery. The relationships between weight loss and a number of demographic, psychiatric, comorbid, and behavioral compliance factors were examined for these 67 patients. Missed appointments and noncompliance with exercise and weight loss plan instructions were high before and after surgery (65% vs. 72% for missed appointments, 39% vs. 51% for exercise, 42% vs. 57% for weight loss instructions). Although poor food choices were not frequently a problem before surgery (11%), they increased significantly after surgery: 37%, χ2(1) = 25.00, P < 0.001. Participants who lost the least weight at 2 years postsurgery were more likely to be nonwhite (r = 0.27, P = 0.039), have a lower socioeconomic status (SES) (r = 0.285, P = 0.02), and have a diagnosis of binge eating before surgery (r = 0.25, P = 0.039). Having more contact with patients and requiring adherence to behavioral changes, especially with respect to exercise and dietary restrictions, may improve the long‐term outcomes for bariatric procedures. In addition, those patients who are depressed and suffer from binge eating may need special attention from physicians during long‐term postoperative follow‐up.

Comparison of Combined Bupropion and Naltrexone Therapy for Obesity with Monotherapy and Placebo

CONTEXT The efficacy of current centrally acting obesity pharmacotherapies is limited by compensatory mechanisms that mitigate weight loss. OBJECTIVE Our objective was to determine whether opioid receptor antagonism (naltrexone) plus pro-opiomelanocortin activation (bupropion) causes greater weight loss than placebo or monotherapy. DESIGN/SETTING 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. PARTICIPANTS A total of 419 patients with uncomplicated obesity participated. INTERVENTIONS 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. MAIN OUTCOME MEASURES 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. RESULTS 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. CONCLUSIONS 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.

Effect of Reversible Intermittent Intra-abdominal Vagal Nerve Blockade on Morbid Obesity The ReCharge Randomized Clinical Trial

IMPORTANCE Although conventional bariatric surgery results in weight loss, it does so with potential short-term and long-term morbidity. OBJECTIVE To evaluate the effectiveness and safety of intermittent, reversible vagal nerve blockade therapy for obesity treatment. DESIGN, SETTING, AND PARTICIPANTS A randomized, double-blind, sham-controlled clinical trial involving 239 participants who had a body mass index of 40 to 45 or 35 to 40 and 1 or more obesity-related condition was conducted at 10 sites in the United States and Australia between May and December 2011. The 12-month blinded portion of the 5-year study was completed in January 2013. INTERVENTIONS One hundred sixty-two patients received an active vagal nerve block device and 77 received a sham device. All participants received weight management education. MAIN OUTCOMES AND MEASURES The coprimary efficacy objectives were to determine whether the vagal nerve block was superior in mean percentage excess weight loss to sham by a 10-point margin with at least 55% of patients in the vagal block group achieving a 20% loss and 45% achieving a 25% loss. The primary safety objective was to determine whether the rate of serious adverse events related to device, procedure, or therapy in the vagal block group was less than 15%. RESULTS In the intent-to-treat analysis, the vagal nerve block group had a mean 24.4% excess weight loss (9.2% of their initial body weight loss) vs 15.9% excess weight loss (6.0% initial body weight loss) in the sham group. The mean difference in the percentage of the excess weight loss between groups was 8.5 percentage points (95% CI, 3.1-13.9), which did not meet the 10-point target (P = .71), although weight loss was statistically greater in the vagal nerve block group (P = .002 for treatment difference in a post hoc analysis). At 12 months, 52% of patients in the vagal nerve block group achieved 20% or more excess weight loss and 38% achieved 25% or more excess weight loss vs 32% in the sham group who achieved 20% or more loss and 23% who achieved 25% or more loss. The device, procedure, or therapy-related serious adverse event rate in the vagal nerve block group was 3.7% (95% CI, 1.4%-7.9%), significantly lower than the 15% goal. The adverse events more frequent in the vagal nerve block group were heartburn or dyspepsia and abdominal pain attributed to therapy; all were reported as mild or moderate in severity. CONCLUSION AND RELEVANCE Among patients with morbid obesity, the use of vagal nerve block therapy compared with a sham control device did not meet either of the prespecified coprimary efficacy objectives, although weight loss in the vagal block group was statistically greater than in the sham device group. The treatment was well tolerated, having met the primary safety objective. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01327976.

Nutrition Therapy of the Severely Obese, Critically Ill Patient: Summation of Conclusions and Recommendations

This report compiles the conclusions and recommendations for nutrition therapy of the obese, critically ill patient derived by the group of experts participating in this workshop on obesity in critical care nutrition. The recommendations are based on consensus opinions of the group after review of the current literature. Obesity clearly adds to the complexity of nutrition therapy in the intensive care unit (ICU). Obesity alters the incidence and severity of comorbidities, tolerance of the prescribed regimen, and ultimately patient outcome through the course of hospitalization. Although the basic principles of critical care nutrition apply to the obese ICU patient, a high-protein, hypocaloric regimen should be provided to reduce the fat mass, improve insulin sensitivity, and preserve lean body mass. The ideal enteral formula should have a low nonprotein calorie to nitrogen ratio and have a variety of pharmaconutrient agents added to modulate immune responses and reduce inflammation.