Effect of Naltrexone-Bupropion on Major Adverse Cardiovascular Events in Overweight and Obese Patients With Cardiovascular Risk Factors: A Randomized Clinical Trial
Open accessAbstract
IMPORTANCE: Few cardiovascular outcomes trials have been conducted for obesity treatments. Withdrawal of 2 marketed drugs has resulted in controversy about the cardiovascular safety of obesity agents. OBJECTIVE: To determine whether the combination of naltrexone and bupropion increases major adverse cardiovascular events (MACE, defined as cardiovascular death, nonfatal stroke, or nonfatal myocardial infarction) compared with placebo in overweight and obese patients. DESIGN, SETTING, AND PARTICIPANTS: Randomized, multicenter, placebo-controlled, double-blind noninferiority trial enrolling 8910 overweight or obese patients at increased cardiovascular risk from June 13, 2012, to January 21, 2013, at 266 US centers. After public release of confidential interim data by the sponsor, the academic leadership of the study recommended termination of the trial and the sponsor agreed. INTERVENTIONS: An Internet-based weight management program was provided to all participants. Participants were randomized to receive placebo (n=4454) or naltrexone, 32 mg/d, and bupropion, 360 mg/d (n=4456). MAIN OUTCOMES AND MEASURES: Time from randomization to first confirmed occurrence of a MACE. The primary analysis planned to assess a noninferiority hazard ratio (HR) of 1.4 after 378 expected events, with a confidential interim analysis after approximately 87 events (25% interim analysis) to assess a noninferiority HR of 2.0 for consideration of regulatory approval. RESULTS: Among the 8910 participants randomized, mean age was 61.0 years (SD, 7.3 years), 54.5% were female, 32.1% had a history of cardiovascular disease, and 85.2% had diabetes, with a median body mass index of 36.6 (interquartile range, 33.1-40.9). For the 25% interim analysis, MACE occurred in 59 placebo-treated patients (1.3%) and 35 naltrexone-bupropion-treated patients (0.8%; HR, 0.59; 95% CI, 0.39-0.90). After 50% of planned events, MACE occurred in 102 patients (2.3%) in the placebo group and 90 patients (2.0%) in the naltrexone-bupropion group (HR, 0.88; adjusted 99.7% CI, 0.57-1.34). Adverse effects were more common in the naltrexone-bupropion group, including gastrointestinal events in 14.2% vs 1.9% (P < .001) and central nervous system symptoms in 5.1% vs 1.2% (P < .001). CONCLUSIONS AND RELEVANCE: Among overweight or obese patients at increased cardiovascular risk, based on the interim analyses performed after 25% and 50% of planned events, the upper limit of the 95% CI of the HR for MACE for naltrexone-bupropion treatment, compared with placebo, did not exceed 2.0. However, because of the unanticipated early termination of the trial, it is not possible to assess noninferiority for the prespecified upper limit of 1.4. Accordingly, the cardiovascular safety of this treatment remains uncertain and will require evaluation in a new adequately powered outcome trial. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01601704.
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Weight loss with phentermine/topiramate-extended release was accompanied by improvements in lipids, blood pressure, and cardiovascular disease risk biomarkers, which were significantly greater than with lifestyle intervention alone and occurred despite greater reductions in the need for conventional diabetes drugs.
“Weight loss was accompanied by improvements in lipids, BP, and CVD risk biomarkers. Importantly, these improvements were significantly greater than the lifestyle intervention alone and occurred despite greater reductions in the need for conventional DM drugs.”
From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [749]
Split into 2 atoms — 0 confirmed, 0 partially supported, 1 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.
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Experimental — accuracy not yet measuredThe LIGHT trial was terminated early, limiting long-term conclusions, but no oncogenic signals were observed during follow-up.
“The LIGHT trial was terminated early, limiting long-term conclusions, but no oncogenic signals were observed during follow-up [15].”
From Precision obesity medicine: A phenotype-guided framework for pharmacologic therapy across the lifespan (2025) · cites this paper as [15]
The Early Data Release and Study Termination section reports that the LIGHT trial was terminated early, and the Discussion says this prevented it from reaching its planned endpoint. The Adverse Events and Outcome Measures sections do not report cancer outcomes or state that no oncogenic signals were observed; that part of the claim is unsupported by our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredSome studies were designed for other purposes, for example, prevention of CVD or T2D.
“However, some studies were designed for other purposes17,18,30,41–44—for example, prevention of CVD or T2D.”
From A systematic review and meta-analysis of the efficacy and safety of pharmacological treatments for obesity in adults (2025) · cites this paper as [18]
The Study Design section (page unavailable) confirms that this was a cardiovascular outcomes trial, supporting its identification as a study designed for a purpose other than weight-loss efficacy. But the paper describes its objective as assessing whether naltrexone-bupropion increased cardiovascular events, not preventing CVD or T2D; participants with T2D were eligible. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe concept of treating obesity to reduce the risk of cardiovascular complications has been hampered by the lack of evidence from trials indicating that lifestyle or pharmacologic interventions for overweight or obesity improve cardiovascular outcomes.
“the concept of treating obesity to reduce the risk of cardiovascular complications has been hampered by the lack of evidence from trials indicating that lifestyle or pharmacologic interventions for overweight or obesity improve cardiovascular outcomes. 11-15”
From Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes (2023) · cites this paper as [15]
The impact of naltrexone/bupropion on MACE remains unknown because the LIGHT trial was terminated early.
“The LIGHT trial was terminated early; the impact of MACE remains unknown [15].”
From Precision obesity medicine: A phenotype-guided framework for pharmacologic therapy across the lifespan (2025) · cites this paper as [15]
In people with type 2 diabetes, phentermine/topiramate-extended release led to placebo-subtracted weight loss of 9% to 10% at 1 year and reduced A1C by 0.4% in those with baseline mean A1C 7.0% and by 1.6% in those with baseline mean A1C 8.6% who had long-standing type 2 diabetes treated with multiple medications.
“In persons with T2D, phentermine/topiramate-ER administration led to placebo-subtracted weight loss of 9% to 10% at 1 year, and reduced A1C by 0.4% in persons with a baseline mean A1C of 7.0% and by 1.6% in those with a baseline mean A1C of 8.6% who had long-standing T2D treated with multiple medications.740,749”
From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [749]
Split into 2 atoms — 0 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 2 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredPhentermine/topiramate ER shows efficacy in weight loss and cardiometabolic risk factors, but renal outcomes were not evaluated.
“The EQUIP trial (15) showed efficacy in weight loss and cardiometabolic risk factors, but renal outcomes were not evaluated.”
From Precision obesity medicine: A phenotype-guided framework for pharmacologic therapy across the lifespan (2025) · cites this paper as [15]
The Abstract and Outcome Measures describe a trial of naltrexone-bupropion assessing cardiovascular events, not the EQUIP trial. Searches for EQUIP, phentermine/topiramate, and renal outcomes found no passage in our copy addressing the cited claim. (LLM, conf=0.78)
Experimental — accuracy not yet measuredNaltrexone/bupropion has not been associated with increased cancer risk.
“Other pharmacotherapies, such as naltrexone/bupropion, have not been associated with increased cancer risk.”
From Precision obesity medicine: A phenotype-guided framework for pharmacologic therapy across the lifespan (2025) · cites this paper as [15]
The Outcome Measures section lists cardiovascular events, weight measures, blood pressure, and heart rate, but not cancer outcomes. Searches of our copy for cancer, malignancy, and tumors found no passage assessing whether naltrexone-bupropion increases cancer risk. (LLM, conf=0.76)
Experimental — accuracy not yet measuredProspective studies that evaluated the effect of nonsurgical weight loss interventions on cardiovascular event reduction have been disappointing.
“Prospective studies that evaluated the effect of nonsurgical weight loss interventions on CV event reduction have been disappointing [4, 5, 6, 7, 8].”
From Semaglutide for cardiovascular event reduction in people with overweight or obesity: <scp>SELECT</scp> study baseline characteristics (2023) · cites this paper as [7]
Across the obesity CVOTs, SELECT is the only study to our knowledge that only enrolled participants with established CVD, whereas in the other obesity CVOTs, 24.9% to 50.5% of participants had no prior events.
“Specifically, across the obesity CVOTs, SELECT is the only study to our knowledge that only enrolled participants with established CVD, whereas in the other obesity CVOTs, 24.9% to 50.5% of participants had no prior events [5, 6, 7, 8].”
From Semaglutide for cardiovascular event reduction in people with overweight or obesity: <scp>SELECT</scp> study baseline characteristics (2023) · cites this paper as [7]
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References 13 · Cited by 273
Research works printed but not linked: 1
- [92]92. Michael G. Del Core, CHI Health Alegent Creighton Clinic Cardiology, Omaha, NE (11);
- Authors
- Nissen, S. E., Wolski, K. E., Prcela, L., Wadden, T., Buse, J. B., Bakris, G., Perez, A., & Smith, S. R.
- Affiliations
- Cleveland Clinic (US)
- University of Pennsylvania (US)
- University of North Carolina at Chapel Hill (US)
- University of Chicago (US)
- Takeda Pharmaceuticals, Deerfield, Illinois
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Corresponding author
- Nissen, Steven E.
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 2016-03-08
- Volume
- 315
- Issue
- 10
- Pages
- 990
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- OpenAlex
- W2294274888
- Cited by
- 273
- References
- 13
- Citations by year
- 2026: 17 · 2025: 33 · 2024: 35 · 2023: 41 · 2022: 20 · 2021: 29 · 2020: 23 · 2019: 22 · 2018: 21 · 2017: 16 · 2016: 14 · 2014: 1
- FWCI
- 19.69
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Diabetes Association
- Amgen
- Bristol-Myers Squibb
- Eli Lilly and Company
- Pfizer
- AstraZeneca
- GlaxoSmithKline
- McKnight Foundation
- University of Pennsylvania
- Medical University of South Carolina
- Cleveland Clinic
- Cleveland Clinic Foundation
- Intarcia Therapeutics
- Orexigen Therapeutics
- Medicines Company
- AstraZeneca HealthCare Foundation
- MacroGenics
- Astellas Pharma
- Esperion Therapeutics
- Perelman School of Medicine, University of Pennsylvania
- Takeda Pharmaceuticals International
- Relypsa
- Topics
- Health Sciences › Medicine › Pharmacology › Pharmacology and Obesity Treatment
- Health Sciences › Medicine › Surgery › Bariatric Surgery and Outcomes
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Obesity, Physical Activity, Diet
- Keywords
- naltrexone/bupropion, major adverse cardiovascular events, obesity, overweight, cardiovascular risk, drug safety, non-inferiority, cardiovascular mortality, myocardial infarction, stroke, drug withdrawal, trial termination, body mass index, naltrexone, bupropion, cardiovascular safety
- MeSH terms
- Aged, Blood Pressure, Cardiovascular Diseases, Confidentiality, Double-Blind Method, Drug Therapy, Combination, Female, Humans, Male, Middle Aged, Myocardial Infarction, Naltrexone, Obesity, Risk Factors, United States, Placebo Effect, Body Mass Index, Confidence Intervals, Bupropion, Sample Size, Patient Selection, Anti-Obesity Agents, Internet, Overweight, Early Termination of Clinical Trials, Weight Reduction Programs
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