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Obesity rates are continuing to increase in the USA and in many other westernised countries across the globe. Currently 1/3 of Americans are overweight (body mass index (BMI) >25 kg/m2) and another 1/3 are obese (BMI>25 kg/m2). The upward trends in the incidence and prevalence continue unabated. Obesity leads to a myriad of health problems ranging from an increased rate of conversion to diabetes, hypertension and other cardiovascular diseases, orthopaedic problems and even cancer. In addition to these medical complications and the resulting associated medical and lost productivity, obesity is associated with reduced quality of life. Bias and discrimination in the workplace and social stigmatisation are real issues and together take a toll on patients with obesity. In contrast to the epidemic, current treatments for obesity are limited. Diet and lifestyle interventions are effective but weight regain is the norm rather than the rule. Bariatric (metabolic) surgery is effective; however, safety concerns continue and many patients do not choose surgery as an option in spite of solid data showing reduced mortality over the long term. Between these two options is a huge gap: only one medication is approved by the Food and Drug Administration (FDA) for long-term use – orlistat. The medical and economic case for safe and effective drugs is clear but the development pathways have been difficult because of safety issues. The purpose of this study was to test a novel combination drug therapy for body weight regulation in obesity and overweight patients with co-morbidities.
This multi-centre trial enrolled patients aged 18–65 years with uncomplicated obesity (BMI>30 kg/m2) or patients with complicated obesity (defined as a BMI>25 kg/m2 with controlled hypertension or dyslipidaemia or both). Patients were enrolled at 34 centres in the USA. Subjects with endocrine causes of obesity, diabetes, cerebrovascular, hepatic, renal or cardiovascular diseases were excluded. Prior surgical obesity was also exclusionary as was recent weight change greater than 4 kg in the 3 months prior to randomisation. Finally, patients with prior treatment with one or more of the study drugs, a history of seizures or serious psychiatric illness were also excluded. Patients were randomised in a 1:1:1 ratio to receive sustained release naltrexone (8 mg) plus buproprion (90 mg) two tablets twice daily (NB32); sustained release naltrexone (4 mg) plus buproprion (90 mg) two tablets twice daily (NB16); or matching placebo in a double blind fashion. The study included a 3-week dose escalation starting at 1/4 of the final dose and ending with a full dose at week 4. In addition to the drug, a lifestyle intervention program was initiated at the start of the study. The program included a 500 kcal deficit hypocaloric diet and advice on lifestyle modification including instructions to increase physical activity. The lifestyle intervention was given at baseline and every 12 weeks thereafter. The co-primary efficacy variables were the percentage change in body weight and the proportion of participants with a decrease in body weight of 5% or more from baseline at week 56. Body weight and vital signs were measured at each study visit. Subjects who stopped the study drug were encouraged to return for body weight and waist circumference measurements at week 56. The mean BMI was about 100 kg; 85% were women and the mean age was 44. About 20% of patients had hypertension and approximately 1/2 had dyslipidaemia.
Fifty percent of patients completed the 1 year study. Over the 56-week treatment period, the placebo group (n=277) lost 1.3±0.3% of their starting body weight. In contrast, NB16- and NB32-treated patients lost 5.0±0.3% and 6.1±0.3% of their body weight (n=273 and 284, respectively). Sixteen per cent of placebo-treated patients and 39/48% of NB16- and NB32-treated patients lost 5% or more of body weight. Waist circumference was reduced by NB relative to control. Cardiovascular and diabetes risk factors including blood pressure, high-density lipoprotein-cholesterol, high-sensitivity c-reactive protein, insulin, glucose and homeostatic model assessment of insulin resistance improved with NB as compared with placebo. Approximately 20% of NB-treated patients experienced an adverse event that led to discontinuation versus 9.8% of placebo-treated patients. The most common adverse events in NB-treated patients were nausea, dizziness, constipation, dry mouth and headache. The fall in blood pressure seen with weight reduction in the NB groups was attenuated as compared to placebo.
The paper by Greenway and colleagues demonstrates that naltrexone–buproprionproduces meaningful weight loss in obese and overweight patients on a background of lifestyle intervention. The improvements in intermediate cardiovascular and diabetes risk factors were generally in line with the expected positive effects of weight loss. The transient rise in blood pressure followed by a fall in blood pressure with weight loss should be carefully examined in light of the recent withdrawal of Sibutramine from the marketplace due to concerns over cardiovascular safety. One limitation of the study is the lack of a detailed analysis of the patient-to-patient variation in blood pressure response. Additional studies in high risk populations may be needed to identify patient populations that will receive the most benefit while minimising risk. The overall safety profile, tolerability and the degree of weight loss are encouraging. Should the FDA approve this medication, it would fill a large unmet medical need for medical therapy in obesity. In addition, this degree of weight loss, about 5% above the placebo group, prevented diabetes in the National Institutes of Health Diabetes Prevention program; if the NB combination was to perform similarly, then clinical practice for the pre-diabetes patient might change radically with a reorientation towards pharmacotherapy when diet and lifestyle have failed.
Competing interests SRS has been reimbursed as a consultant ore received research support from by Arena, Amylin, BMS, Jenrin Discoveries Zafgen, Takeda. SRS has also conducted research for, and served as a consultant to, Orexigen pharmaceuticals who sponsored the reviewed paper.
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