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NIH addresses barriers, solutions to improving weight-loss maintenance
Enhancing efforts and dialogue across the spectrum of specialties that intersect with obesity surfaced as top priority when an NIH working group, led by the National Heart, Lung, and Blood Institute, convened to merge perspectives on barriers to scientific progress and novel ways to improve long-term outcomes.
Published in Obesity, the working group report by Paul S. MacLean, PhD, of the University of Colorado, with Rena R. Wing, PhD, of Brown University, and colleagues includes views from experts in integrative physiology, genetics, endocrinology, and behavioral and cognitive sciences.
“Greater collaboration is needed between a diverse group of investigators to develop an understanding of the behavioral and physiological interactions that result in the alarmingly high rate of recidivism following otherwise successful weight loss,” Michael Rosenbaum, MD, of Columbia University, a member of the working group, told Endocrine Today.
Michael Rosenbaum
“Facilitation of sustained weight loss by reversal of the biological and behavioral changes that occur as a result of weight reduction is the ideal candidate for translational work that goes from bench to brain to behavior and to bedside,” he said.
The report highlights genetic, epigenetic and neuro-hormonal differences among individuals as key challenges to weight loss and weight control over time and recommends ways to improve obesity therapeutics, with an emphasis on individualized approaches and integration of clinical, behavioral, and basic science disciplines to arrive at sustainable interventions.
“Obesity is a disease that continues to manifest itself in the form of potent behavioral and metabolic barriers to sustained weight loss even after the disease has supposedly been ‘cured’ by weight reduction,” Rosenbaum said. “Therapy must be individualized and may involve a combination of behavioral, nutritional, pharmacological, exercise and/or surgical therapies.”
Individualized treatment and teamwork
Enhancing long-term adherence to prescribed regimens and designing and implementing studies on maintenance are listed as main behavioral challenges in the report, whereas attenuating adaptations encouraging weight regain and translating animal observations to the clinical setting are highlighted as physiologic challenges. Individual variability is included in both categories.
“There is a large inter-individual variability in response to weight loss and reduced weight maintenance interventions; a one-size-fits-all approach is just not going to work,” Rosenbaum said.
Through the working group, he said it became clear that guidance to simply “move more and eat less” ignores biological and behavioral resistance to sustaining weight loss and adds to negative stigma that patients with overweight and obesity simply “lack willpower.”
As impetus for the working group and report, findings from the Diabetes Prevention Program (DPP) and Look Ahead Trial are representative, according to George A. Bray, MD, Endocrine Today Editorial Board member, of the Pennington Biomedical Research Center, Louisiana State University, who penned an attached commentary with Thomas A. Wadden, PhD, of the Perelman School of Medicine, University of Pennsylvania.
George A. Bray
“The challenge that occurred with these trials occurs with most others: Why don’t people maintain weight loss?” Bray said.
In addition to the many patients unable to sustain reduced weight, Bray said he is struck by those unable to lose weight, even with intensive therapies, or the few who gain weight.
“This is true for lifestyle interventions, but also for every medication that I know,” Bray said. “The major highlight of this report is there are enormous differences in individual responses.”
In the Look Ahead Trial, only 38% of patients lost ≥10% of their body weight, and only 42% of those patients were able to keep it off.
“This means that even with such an intense intervention, only 16% of subjects managed to achieve and sustain a 10% or greater weight loss,” Rosenbaum said. He noted the statistic is almost identical to the 14% success rate reported in a meta-analysis of dietary weight loss programs by William Bennett, MD, of Harvard Medical School, Boston, and colleagues, published nearly three decades ago in the Annals of the New York Academy of Sciences.
“The reasons for these differences are unclear to anyone that I know of, including the working group,” Bray said. “We need to have more information about individualized medicine.”
Working with patients to sustain weight loss may be the most difficult phase in the treatment of obesity, Rosenbaum said, but improved outcomes should be achievable via a multi-disciplinary and more personalized approach.
“Critical physician obligations extend into integrated multispecialty medical care that support patients in their efforts to sustain weight loss,” Rosenbaum said.
Successful strategies and solutions
Advancing science to develop effective therapies means countering biology to reduce the gap between appetite and expenditure, according to the working group.
“Implicit in the focus on weight-loss maintenance is the idea that therapeutic interventions to keep weight off (a state of energy balance) may not be the same as those utilized to lose weight (a state of negative energy balance),” Rosenbaum said.
Instead, weight maintenance therapies should aim to override the disproportionate decline in energy expenditure and increase in appetite that occur as a result of weight loss, he added.
The report lists deepening the understanding of exercise, including enhancing adherence to prescribed activity, along with diet innovations, such as engineering foods and modifying response to food cues, as potential approaches.
Learning more about cognitive function and behavioral skill development, as well as leptin and leptin sensitizers and new drug combinations or dosing regimens, then targeting strategies that combine both, are outlined as essential to reduce the appetite-expenditure gap.
“Novel pharmacological combinations and synergistic integrations of different therapeutic modalities, such as pharmacology and behavior, to enhance adherence to the lifestyle changes necessary to sustain weight loss should be forthcoming based on a more sophisticated understanding of the factors influencing weight regain,” Rosenbaum said.
Bray and Wadden add the POUNDS Lost Trial to DPP and Look Ahead as offering guidance on examining genetic markers to identify individuals’ response to certain therapies.
“Making better use of this may be an important path forward in the field,” Bray said. At the moment, however, he noted the medical community does not even possess the methods necessary to gather useful individual information due to costs.
“We don’t know which tests to run,” Bray said. “There are a lot of markers out there, but you certainly can’t run all of them on everybody who is going to lose weight.”
If patients are unable to lose weight or maintain weight loss on their current therapies, Bray said the message to patients should be to try something else. “If it doesn’t work, it’s not going to work if you continue doing it.”
Moving forward
The working group acknowledges in the report that the available selection of tools and paradigms used to study weight-loss maintenance and energy balance is limiting and stresses the importance of developing and validating instruments to objectively evaluate patients.
The constructs and mechanisms underlying motivation to adhere to a weight-loss prescription are another area underscored as needing better measures.
However, the report touts information technology and social networking as opportunities to not only improve current trials, but to boost the delivery of personal interventions.
Additional research is needed in areas of precision medicine in which genetic, biochemical and/or behavioral traits can be utilized to predict the most effective therapeutic interventions to produce and to sustain weight loss, Rosenbaum said.
Multi-specialty coordination for the study of obesity is essential.
“Training of young investigators in obesity research should endeavor to create a common genetic, behavioral and physiological lexicon and skill set that will optimize rapid collaboration, translation, and implementation of new ideas and treatments,” Rosenbaum said. – by Allegra Tiver
References:
Bray GA. Obesity. 2014;doi:10.1002/oby.20964.
MacLean PS. Obesity. 2014;doi:10.1002/oby.20967.
Bennett W. Ann N Y Acad Sci. 1987;doi:10.1111/j.1749-6632.1987.tb36216.x.
For more information:
George Bray, MD, can be reached at Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA 70808; email: George.Bray@pbrc.edu.
Michael Rosenbaum, MD, can be reached at Columbia University Medical Center, 622 W. 168th St., New York, NY 10032; email: mr475@cumc.columbia.edu.
Disclosure: Bray reports serving on advisory boards for Herbalife and Medifast and on speakers’ bureaus for Novo Nordisk and Takeda. Wadden reports serving on advisory boards for Novo Nordisk, Nutrisystem, Orexigen Therapeutics and Shire Pharmaceuticals, and receiving grant support, on behalf of the University of Pennsylvania, from the first three of these organizations, as well as Weight Watchers International.