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

Hollander, Priscilla; Gupta, Alok; Plodkowski, Raymond A.; Greenway, Frank L.; Bays, Harold; Burns, Colleen; Klassen, Preston S.; Fujioka, Ken

doi:10.2337/dc13-0234

Cited by 387 publications

(331 citation statements)

References 34 publications

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“…37 The COR-Diabetes trial was restricted to patients with T2DM and utilized a low-intensity lifestyle intervention similar to COR-I and COR-II. 38 Bupropion plus naltrexone caused 4% to 5% of body weight more weight loss than placebo in patients without DM and approximately 3% more in patients with DM. The proportion of patients achieving ≥5% weight loss was greater in the treatment group of all 4 trials.…”

Section: Potential Benefits Of Modern Pharmacotherapy For Obesity Phementioning

confidence: 94%

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Modern Obesity Pharmacotherapy: Weighing Cardiovascular Risk and Benefit

Cunningham

Wiviott

2014

Clinical Cardiology

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Obesity is a major correlate of cardiovascular disease. Weight loss improves cardiovascular risk factors and has the potential to improve outcomes. Two drugs, phentermine plus topiramate and lorcaserin, have recently been approved by the US Food and Drug Administration for the indication of obesity; a third, bupropion plus naltrexone, is under consideration for approval. In clinical trials, these drugs cause weight loss and improve glucose tolerance, lipid profile, and, with the exception of bupropion plus naltrexone, blood pressure. However, their effect on cardiovascular outcomes is unknown. In defining appropriate roles for these drugs in preventive cardiology, it is important to remember the checkered history of drugs for obesity. New weight-loss drugs share the serotonergic and sympathomimetic mechanisms that proved harmful in the cases of Fen-Phen and sibutramine, respectively, albeit with significant differences. Given these risks, randomized cardiovascular outcomes trials are needed to establish the safety, and potential benefit, of these drugs. This review will discuss the history of pharmacotherapy for obesity, existing efficacy and safety data for the novel weight-loss drugs, and issues in the design of postapproval clinical trials. IntroductionAdvances in prevention-smoking-cessation campaigns, statin therapy, and tight blood pressure (BP) control, among others-have contributed to decreases in the burden of coronary artery disease over the past several decades. However, the increasing prevalence of obesity and obesityassociated diseases like type 2 diabetes mellitus (T2DM) have tempered these gains. 1 Despite recent data suggesting a plateau, rates of obesity remain substantially higher than a few decades ago. 2 Intensive lifestyle interventions have produced clinically relevant weight loss, 3 but modest interventions that are feasible in the primary-care setting are less successful. 4 Many efforts to develop an effective and safe weight-loss pill have failed. In fact, the history of obesity pharmacotherapy has been notable for cardiovascular side effects, not benefits. In 2012, the US Food and Drug Administration (FDA) approved 2 medications for weight loss, the selective 5-HT 2C agonist lorcaserin and the combination pill phentermine plus topiramate; a third, bupropion plus naltrexone, is under consideration for approval at the time of this writing. 5 The mechanisms of

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Section: Potential Benefits Of Modern Pharmacotherapy For Obesity Phementioning

confidence: 94%

“…35 -38 In patients with DM, bupropion plus naltrexone reduced HbA 1c more than placebo (−0.6% vs −0.2%). 38 …”

Section: Potential Benefits Of Modern Pharmacotherapy For Obesity Phementioning

confidence: 99%

Modern Obesity Pharmacotherapy: Weighing Cardiovascular Risk and Benefit

Cunningham

Wiviott

2014

Clinical Cardiology

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“…[11][12][13][14] In NB-treated clinical trial completers, nausea, constipation and headache were the most frequently reported AEs with greater incidence than placebo.…”

Section: Safetymentioning

confidence: 99%

“…The COR clinical trials were conducted between March 2007 and June 2009 and the data have been published previously. [11][12][13][14] Participants were 18-65 years old with a body mass index (BMI) 30-45 kg m − 2 , or BMI 27-45 kg m − 2 and dyslipidemia and/or controlled hypertension, except for the COR-DM clinical trial, which included participants with type 2 diabetes mellitus (DM, HbA1c from 7-10% and fasting blood glucose o270 mg dl − 1 ), aged 18-70 years, and with a BMI 27-45 kg m − 2 .…”

Section: The Phase 3 (Cor) Programmentioning

confidence: 99%

“…10 In four randomized, controlled, phase 3 clinical trials, participants taking NB were approximately three to five times more likely to achieve clinically meaningful weight loss at Week 56 as participants taking placebo. [11][12][13][14] As with other recently approved weight loss medications, 8,9 the prescribing information for NB includes an evaluation of weight loss after treatment with the maintenance dose (32 mg naltrexone ER/ 360 mg bupropion ER) for 12 weeks, which, in conjunction with a 4-week dose-escalation period, means the assessment should occur approximately 16 weeks after initiation of treatment. 10 The purpose of this investigation was to evaluate early weight loss with NB as a predictor of clinically meaningful long-term weight loss.…”

Section: Introductionmentioning

confidence: 99%

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The relationship between early weight loss and weight loss at 1 year with naltrexone ER/bupropion ER combination therapy

et al. 2016

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BACKGROUND/OBJECTIVES: Weight management medications increase the likelihood that patients will achieve clinically meaningful improvements in cardiovascular, metabolic and other weight-related measures of health. However, the weight loss achieved with any weight management intervention can vary widely among individuals, and patients who do not respond to pharmacotherapy by achieving clinically meaningful weight loss should discontinue therapy. We characterized 1-year weight loss in the phase 3 clinical trial program of the weight management medication, naltrexone/bupropion 32/360 mg (NB), as well as the relationship between early weight loss and long-term weight loss, particularly with respect to participants who achieved the clinically recommended threshold of ⩾ 5% weight loss by Week 16. PARTICIPANTS/METHODS: Data from participants from each of the four phase 3, randomized, placebo-controlled, 56-week clinical trials with NB were pooled (modified intent-to-treat population; NB N = 2043, Placebo N = 1319). This exploratory analysis examined the relationship between participant achievement of various weight loss thresholds early in treatment (at Week 8, 12 or 16) and the associated weight loss at Week 56 (Completers population; NB N = 1310, Placebo N = 763). RESULTS: In the NB participants who completed 1 year of treatment, weight loss of at least 5% at Week 16 (n = 873) was associated with least-squares mean weight loss of 11.7% at Week 56 and 85% of these participants had Week 56 weight loss of ⩾ 5%. Eighty percent (95% confidence interval: 78-82%) of the participants who would, and would not, achieve ⩾ 5% weight loss at Week 56 were correctly identified using the clinically recommended threshold of ⩾ 5% at Week 16. Safety and tolerability of NB was similar to previously published reports. CONCLUSIONS: Participants who meet the Week 16 threshold of ⩾ 5% weight loss are likely to maintain clinically significant weight loss after 1 year of treatment. Further evaluations are required to evaluate improvements in measures of cardiovascular and metabolic risk.

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Naltrexone Extended-Release Plus Bupropion Extended-Release for Treatment of Obesity

Yanovski

2015

JAMA

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a proprietary formulation of naltrexone-extended release plus bupropion -extended release (NB) (brand name, Contrave) was approved by the US Food and Drug Administration (FDA), 1 becoming the fourth medication approved for long-term weight management in patients with obesity. 2 Liraglutide (brand name, Saxenda), a glucagon-like peptide 1 receptor agonist, was also approved for obesity treatment in December 2014. Both naltrexone and bupropion are FDA-approved for other indications as monotherapies: bupropion, a dopamine/norepinephrine reuptake inhibitor, is approved to treat depression and to aid smoking cessation. Naltrexone, an opioid receptor antagonist, is approved to treat alcohol and opioid dependence.Bupropion was investigated, but never FDA-approved, as monotherapy for obesity; studies found ~2.8kg placebo-subtracted weight loss at 6-12 months. 3 Among its effects, bupropion is thought to stimulate secretion of anorexigenic α-melanocyte stimulating hormone (αMSH) from pro-opiomelanocortin-producing hypothalamic cells, but may also simultaneously induce secretion of the endogenous opioid products of pro-opiomelanocortin that might inhibit αMSH secretion, limiting bupropion's effectiveness. Naltrexone monotherapy has little efficacy for weight management. However, because naltrexone might specifically counteract the autoinhibitory actions of bupropion-stimulated endogenous opioids, NB combination therapy was investigated for obesity treatment.NB is FDA-approved for adults with BMI ≥30kg/m 2 or with BMI ≥27kg/m 2 plus obesityrelated comorbidities. Treatment is initiated with one 8mg naltrexone/90mg bupropion

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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

Cited by 387 publications

References 34 publications

Modern Obesity Pharmacotherapy: Weighing Cardiovascular Risk and Benefit

Modern Obesity Pharmacotherapy: Weighing Cardiovascular Risk and Benefit

The relationship between early weight loss and weight loss at 1 year with naltrexone ER/bupropion ER combination therapy

Naltrexone Extended-Release Plus Bupropion Extended-Release for Treatment of Obesity

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