A Randomized, Phase 3 Trial of Naltrexone SR/bupropion SR on Weight and Obesity-Related Risk Factors (COR-II)
TL;DR: To examine the effects of naltrexone/bupropion (NB) combination therapy on weight and weight‐related risk factors in overweight and obese participants, a large number of participants were obese or overweight.
Abstract: Objective:
To examine the effects of naltrexone/bupropion (NB) combination therapy on weight and weight-related risk factors in overweight and obese participants.
Design and Methods:
CONTRAVE Obesity Research-II (COR-II) was a double-blind, placebo-controlled study of 1,496 obese (BMI 30-45 kg/m2) or overweight (27-45 kg/m2 with dyslipidemia and/or hypertension) participants randomized 2:1 to combined naltrexone sustained-release (SR) (32 mg/day) plus bupropion SR (360 mg/day) (NB32) or placebo for up to 56 weeks. The co-primary endpoints were percent weight change and proportion achieving ≥5% weight loss at week 28.
Results:
Significantly (P < 0.001) greater weight loss was observed with NB32 versus placebo at week 28 (−6.5% vs. −1.9%) and week 56 (−6.4% vs. −1.2%). More NB32-treated participants (P < 0.001) experienced ≥5% weight loss versus placebo at week 28 (55.6% vs. 17.5%) and week 56 (50.5% vs. 17.1%). NB32 produced greater improvements in various cardiometabolic risk markers, participant-reported weight-related quality of life, and control of eating. The most common adverse event with NB was nausea, which was generally mild to moderate and transient. NB was not associated with increased events of depression or suicidality versus placebo.
Conclusion:
NB represents a novel pharmacological approach to the treatment of obesity, and may become a valuable new therapeutic option.
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TL;DR: It is concluded that physicians have a responsibility to recognise obesity as a disease and help obese patients with appropriate prevention and treatment and focus on realistic goals and lifelong multidisciplinary management.
Abstract: Obesity is a chronic metabolic disease characterised by an increase of body fat stores. It is a gateway to ill health, and it has become one of the leading causes of disability and death, affecting not only adults but also children and adolescents worldwide. In clinical practice, the body fatness is estimated by BMI, and the accumulation of intra-abdominal fat (marker for higher metabolic and cardiovascular disease risk) can be assessed by waist circumference. Complex interactions between biological, behavioural, social and environmental factors are involved in regulation of energy balance and fat stores. A comprehensive history, physical examination and laboratory assessment relevant to the patient's obesity should be obtained. Appropriate goals of weight management emphasise realistic weight loss to achieve a reduction in health risks and should include promotion of weight loss, maintenance and prevention of weight regain. Management of co-morbidities and improving quality of life of obese patients are also included in treatment aims. Balanced hypocaloric diets result in clinically meaningful weight loss regardless of which macronutrients they emphasise. Aerobic training is the optimal mode of exercise for reducing fat mass while a programme including resistance training is needed for increasing lean mass in middle-aged and overweight/obese individuals. Cognitive behavioural therapy directly addresses behaviours that require change for successful weight loss and weight loss maintenance. Pharmacotherapy can help patients to maintain compliance and ameliorate obesity-related health risks. Surgery is the most effective treatment for morbid obesity in terms of long-term weight loss. A comprehensive obesity management can only be accomplished by a multidisciplinary obesity management team. We conclude that physicians have a responsibility to recognise obesity as a disease and help obese patients with appropriate prevention and treatment. Treatment should be based on good clinical care, and evidence-based interventions; should focus on realistic goals and lifelong multidisciplinary management.
1,093 citations
TL;DR: Treatments for obesity include behavioral therapy, pharmacotherapy, and bariatric surgery, and some sequelae of obesity are reversed with weight loss.
Abstract: Obesity is prevalent in the U.S. population and contributes significantly to morbidity and mortality. Treatments include behavioral therapy, pharmacotherapy, and bariatric surgery. Some sequelae of obesity are reversed with weight loss. Maintaining weight loss is a challenge.
1,093 citations
TL;DR: The final recommendations recognize that obesity is a complex, adiposity-based chronic disease, where management targets both weight-related complications and adiposity to improve overall health and quality of life.
978 citations
TL;DR: A systematic review of medications currently approved in the United States for obesity treatment in adults found that medications approved for long-term obesity treatment, when used as an adjunct to lifestyle intervention, lead to greater mean weight loss and an increased likelihood of achieving clinically meaningful 1-year weight loss relative to placebo.
Abstract: Importance Thirty-six percent of US adults are obese, and many cannot lose sufficient weight to improve health with lifestyle interventions alone. Objective To conduct a systematic review of medications currently approved in the United States for obesity treatment in adults. We also discuss off-label use of medications studied for obesity and provide considerations for obesity medication use in clinical practice. Evidence Review A PubMed search from inception through September 2013 was performed to find meta-analyses, systematic reviews, and randomized, placebo-controlled trials for currently approved obesity medications lasting at least 1 year that had a primary or secondary outcome of body weight change, included at least 50 participants per group, reported at least 50% retention, and reported results on an intention-to-treat basis. Studies of medications approved for other purposes but tested for obesity treatment were also reviewed. Findings Obesity medications approved for long-term use, when prescribed with lifestyle interventions, produce additional weight loss relative to placebo ranging from approximately 3% of initial weight for orlistat and lorcaserin to 9% for top-dose (15/92 mg) phentermine plus topiramate–extended release at 1 year. The proportion of patients achieving clinically meaningful (at least 5%) weight loss ranges from 37% to 47% for lorcaserin, 35% to 73% for orlistat, and 67% to 70% for top-dose phentermine plus topiramate–extended release. All 3 medications produce greater improvements in many cardiometabolic risk factors than placebo, but no obesity medication has been shown to reduce cardiovascular morbidity or mortality. Most prescriptions are for noradrenergic medications, despite their approval only for short-term use and limited data for their long-term safety and efficacy. Conclusions and Relevance Medications approved for long-term obesity treatment, when used as an adjunct to lifestyle intervention, lead to greater mean weight loss and an increased likelihood of achieving clinically meaningful 1-year weight loss relative to placebo. By discontinuing medication in patients who do not respond with weight loss of at least 5%, clinicians can decrease their patients’ exposure to the risks and costs of drug treatment when there is little prospect of long-term benefit.
744 citations
Baylor College of Medicine1, Beth Israel Deaconess Medical Center2, Emory University3, Ochsner Medical Center4, Icahn School of Medicine at Mount Sinai5, Cedars-Sinai Medical Center6, University of Tennessee Health Science Center7, University of Texas Health Science Center at San Antonio8, American Association of Clinical Endocrinologists9, Tulane University10, University of Alabama at Birmingham11, Wayne State University12, The American College of Financial Services13, University of California, San Diego14, University of Washington15, University of Miami16, Washington University in St. Louis17, University of California, Irvine18
TL;DR: This chapter discusses the development and use of eicosapentaenoic acid as a treatment for diabetic ketoacidosis and its applications in conventional and regenerative medicine.
680 citations
Cites background from "A Randomized, Phase 3 Trial of Nalt..."
...Whether achieved through lifestyle therapy, pharmacotherapy, surgery, or some combination thereof, weight loss reduces insulin resistance and can effectively prevent progression to diabetes as well as improve plasma lipid profile and BP (44,48,49,51,53,60,63)....
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...These agents improve BP and lipids, prevent progression to diabetes during trial periods, and improve glycemic control and lipids in patients with T2D (43-60)....
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References
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17 Apr 2003
TL;DR: Comparing the socialist nature of many European counties, there is a requirement that provision be made for patients to be made whole regardless of the outcomes of the trial or if they happened to have been randomized to a control group that did not enjoy the benefits of a successful experimental intervention.
Abstract: Published research in English-language journals are increasingly required to carry a statement that the study has been approved and monitored by an Institutional Review Board in conformance with 45 CFR 46 standards if the study was conducted in the United States. Alternative language attesting conformity with the Helsinki Declaration is often included when the research was conducted in Europe or elsewhere. The Helsinki Declaration was created by the World Medical Association in 1964 (ten years before the Belmont Report) and has been amended several times. The Helsinki Declaration differs from its American version in several respects, the most significant of which is that it was developed by and for physicians. The term "patient" appears in many places where we would expect to see "subject." It is stated in several places that physicians must either conduct or have supervisory control of the research. The dual role of the physician-researcher is acknowledged, but it is made clear that the role of healer takes precedence over that of scientist. In the United States, the federal government developed and enforces regulations on researcher; in the rest of the world, the profession, or a significant part of it, took the initiative in defining and promoting good research practice, and governments in many countries have worked to harmonize their standards along these lines. The Helsinki Declaration is based less on key philosophical principles and more on prescriptive statements. Although there is significant overlap between the Belmont and the Helsinki guidelines, the latter extends much further into research design and publication. Elements in a research protocol, use of placebos, and obligation to enroll trials in public registries (to ensure that negative findings are not buried), and requirements to share findings with the research and professional communities are included in the Helsinki Declaration. As a practical matter, these are often part of the work of American IRBs, but not always as a formal requirement. Reflecting the socialist nature of many European counties, there is a requirement that provision be made for patients to be made whole regardless of the outcomes of the trial or if they happened to have been randomized to a control group that did not enjoy the benefits of a successful experimental intervention.
10,704 citations
Journal Article•
8,507 citations
Journal Article•
TL;DR: The Helsinki Declaration on Ethical Principles for Medical Research Involving Human Subjects, adopted by the World Medical Assembly, is presented.
Abstract: WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI Ethical Principles for Medical Research Involving Human Subjects 世界医師会ヘルシンキ宣言 ヒトを対象とした医学研究の倫理原則 ---------------------------------------------------------------------------Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the: 29th WMA General Assembly, Tokyo, Japan, October 1975 35th WMA General Assembly, Venice, Italy, October 1983 41st WMA General Assembly, Hong Kong, September 1989 48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 52nd WMA General Assembly, Edinburgh, Scotland, October 2000 53rd WMA General Assembly, Washington 2002 (Note of Clarification on paragraph 29 added) 55th WMA General Assembly, Tokyo 2004 (Note of Clarification on Paragraph 30 added) 59th WMA General Assembly, Seoul, October 2008 64th WMA General Assembly, Fortaleza, Brazil, October 2013
7,874 citations
TL;DR: A model is described that delineates the roles of individual hormonal and neuropeptide signalling pathways in the control of food intake and the means by which obesity can arise from inherited or acquired defects in their function.
Abstract: New information regarding neuronal circuits that control food intake and their hormonal regulation has extended our understanding of energy homeostasis, the process whereby energy intake is matched to energy expenditure over time. The profound obesity that results in rodents (and in the rare human case as well) from mutation of key signalling molecules involved in this regulatory system highlights its importance to human health. Although each new signalling pathway discovered in the hypothalamus is a potential target for drug development in the treatment of obesity, the growing number of such signalling molecules indicates that food intake is controlled by a highly complex process. To better understand how energy homeostasis can be achieved, we describe a model that delineates the roles of individual hormonal and neuropeptide signalling pathways in the control of food intake and the means by which obesity can arise from inherited or acquired defects in their function.
6,178 citations
TL;DR: The NHANES results indicate continuing disparities by sex and between racial/ethnic groups in the prevalence of overweight and obesity among adults and overweight among children, using the most recent national data of height and weight measurements.
Abstract: ContextThe prevalence of overweight and obesity has increased markedly in the
last 2 decades in the United States.ObjectiveTo update the US prevalence estimates of overweight in children and
obesity in adults, using the most recent national data of height and weight
measurements.Design, Setting, and ParticipantsAs part of the National Health and Nutrition Examination Survey (NHANES),
a complex multistage probability sample of the US noninstitutionalized civilian
population, both height and weight measurements were obtained from 4115 adults
and 4018 children in 1999-2000 and from 4390 adults and 4258 children in 2001-2002.Main Outcome MeasurePrevalence of overweight (body mass index [BMI] ≥95th percentile
of the sex-specific BMI-for-age growth chart) among children and prevalence
of overweight (BMI, 25.0-29.9), obesity (BMI ≥30.0), and extreme obesity
(BMI ≥40.0) among adults by sex, age, and racial/ethnic group.ResultsBetween 1999-2000 and 2001-2002, there were no significant changes among
adults in the prevalence of overweight or obesity (64.5% vs 65.7%), obesity
(30.5% vs 30.6%), or extreme obesity (4.7% vs 5.1%), or among children aged
6 through 19 years in the prevalence of at risk for overweight or overweight
(29.9% vs 31.5%) or overweight (15.0% vs 16.5%). Overall, among adults aged
at least 20 years in 1999-2002, 65.1% were overweight or obese, 30.4% were
obese, and 4.9% were extremely obese. Among children aged 6 through 19 years
in 1999-2002, 31.0% were at risk for overweight or overweight and 16.0% were
overweight. The NHANES results indicate continuing disparities by sex and
between racial/ethnic groups in the prevalence of overweight and obesity.ConclusionsThere is no indication that the prevalence of obesity among adults and
overweight among children is decreasing. The high levels of overweight among
children and obesity among adults remain a major public health concern.
4,559 citations