Obesity as a "Brain Disease"; a Driver for New Therapies

May 08, 2015

PRAGUE — Obesity is a complex multifactorial disease that acts as a gateway to many other chronic conditions — with resultant enormous impact — and should actually be viewed as a brain disease, one expert argues.

Speaking at the 2015 European Congress on Obesity today, bariatric surgeon Carel Le Roux, MBChB, PhD, of University College Dublin, Ireland, explained, "Obese people have a functional deficiency in many of the hormones that should rise after a meal," but in fact the receptors for these hormones lie in the brain, and in addition the gut relays messages about satiety to the brain via the vagus nerve.

"We used to think of obesity and the brain in terms of psychology," he explained in a media master class here. But in genomewide-association studies for obesity, "although we only get a few hits, most point to the brain," and, in support of this observation, the effects of bariatric surgery are mainly mediated in the brain, he added.

Labeling obesity as a brain disease "is controversial," he acknowledged, but it is necessary to "allow us to shift our thinking" and better understand the physiology of the condition for the development of new treatments.

Indeed, a shift in thinking is required to enable doctors worldwide to treat the obesity epidemic, recognizing that it is important to differentiate "how we prevent obesity from how we treat it," he observed.

Personalizing Treatment for Obesity

Immediate past president of the European Association for the Study of Obesity, Gema Frübeck, MD, PhD, of University of Navarra, Pamplona, Spain, told assembled journalists that it is important for doctors to recognize that for any one person, there are different causes for obesity.

Going forward, it will be key to bring the concept of personalized medicine to obesity and "have much more detailed phenotypes in each individual," she noted.

Genetics is known to play a role, but only around 20% of cases of obesity are accounted for by genetic variations, explained Luc van Gaal, from the University of Antwerp, Belgium.

There are, however, numerous other factors that contribute to the mix, including endocrine disruptors; medicines that affect body weight — such as corticosteroids and antidepressants; psychological factors — such as lack of sleep and anxiety and depression; and physiological explanations, such as hypothyroidism — although the last accounts for a very small minority of cases, he admitted.

Going forward, "understanding the physiology of obesity is very important for the development of new treatments," Dr van Gaal stressed.

Renewed understanding of the role of hormones such as ghrelin and leptin, as well as determining how, for example, brown fat fits into the mix, may help with future pharmacological approaches, he added.

Managing Expectations for Treatment of Obesity

It is also vital for doctors to understand that "management of obesity is feasible," but patients need to be properly informed of the anticipated benefits, Dr Le Roux said.

Current president of the European Association for the Study of Obesity, Hermann Toplak, MD, of the University of Graz, Austria, told journalists that "we only need a 5% to 10% weight loss to get benefits in terms of a reduction in cardiovascular risk, for example, but this often doesn't meet the expectation of the patient."

Newer obesity drugs will generally provide only this level of weight loss, and it is key to get patients to understand that they also need to institute — and maintain — lifestyle changes, in terms of diet and physical activity, to gain maximum benefit, he noted.

And such obesity agents work effectively only in patients who "respond" to them, Dr Toplak explained, although he added that, thankfully, it is possible to identify, very early on — within the first 3 months of use — which patients will respond to a given drug.

Indeed, for the first time, the European Medicines Agency has instituted a "stopping" rule in its recent approval of two new obesity agents, liraglutide (Saxenda, Novo Nordisk) and naltrexone/buproprion (Mysimba, Orexigen Therapeutics), such that if a patient hasn't lost a certain amount of weight by week 16, therapy should be ceased.

This will be "a big advantage" in helping to limit treatment to responders only, Dr van Gaal explained.

And although it is early days to be able to predict the uptake of these new obesity drugs in Europe — which are the first new agents approved there for many years — as reimbursement issues are still to be sorted out in all countries, he suggested that national health authorities could perhaps somehow tie reimbursement to response in their authorization of use of these agents.

New Aim: 15% Weight Loss With Pharmacological Agents?

And while current pharmacologic agents only provide 5% to 10% weight loss, "regardless of the mechanism," there is a big contrast with bariatric surgery, where weight loss can be much greater, up to 30% to 40% in some patients, Dr van Gaal commented.

But if a 15% weight loss could be achieved through pharmacological means, this would be a huge step forward, he said.

"If we want to see the effects on total mortality [in obesity] that so far have only been seen in surgery, we will need combination [pharmacological] therapy," in the same way as hypertension and diabetes are treated today, he added.

To Medscape Medical News, Dr van Gaal explained that he is not talking about combining therapy with existing obesity agents; rather "it must be based on physiology."

Going forward, for example, "I think combining peptide therapy — for instance liraglutide plus leptin, or liraglutide plus [peptide tyrosine-tyrosine] PYY — could be beneficial. There must be a scientific background."

And Dr Le Roux stressed that "losing weight is relatively easy, but maintaining weight loss is hard."

With surgery, "we know we can maintain 25% weight loss at 20 years" in some individuals, and "I agree that if we can get 15% weight loss after 10 years" with pharmacological agents, this will be a huge advance.

"There is no one silver bullet, it must be a combination of approaches."

Dr Le Roux reported financial relationships with Boehringer-Ingelheim, Herbalife, Novo Nordisk, Johnson & Johnson, ONO Pharmaceuticals, Covidien, Fractyl, GI Dynamics, Roche, and AstraZeneca. Dr Frübeck reported that she is on the global science advisory board for Novo Nordisk. Dr Toplak reported he is on the global science advisory board for Vivus and the international advisory board for Novo Nordisk.

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