Recent Advances in Pharmacological Treatment of Obesity

Louis J. Aronne, MD
Clinical Professor of Medicine Weill Cornell Medical College

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Q:How did you become interested in obesity?

A: I got interested in obesity as a healthcare economics fellow with Kaiser. I was in the medical clinic seeing patients with diabetes, high blood pressure, heart disease and the many complications that we associate with obesity. It came to me - if I got these patients to lose weight, their health would be better and we would not have to give them all of these medications to treat all these other problems. It turned out that treating obesity was a lot tougher than it looked.

Q:What have been the most significant changes in the last 20 years in the field of obesity treatment?

A: Probably the most significant  change has been the recent discovery of leptin, a hormone that comes from adipocytes (fat cells) and tells the brain how much fat is stored. Leptin triggers certain endocrine events, including puberty, but it is the lack of leptin that seems to trigger the  "plateau" phenomenon when people lose weight. All of our research has flowed from the understanding that maybe there are disorders of the  regulating mechanism, so the brains of obese people can't tell how much fat is stored, thus, allowing more fat to accumulate.

Q: Please explain your "feed-forward" theory and how leptin relates to it.

A: There's some evidence that if you start giving fattening foods to animals who have been bred to be research models of obesity, they become resistant to leptin in a very short time. So that may be one of the key events that drives weight up and becomes part of a "feeding-forward" mechanism. Thus, when you begin eating fattening foods, you lose your sense of fullness and actually develop craving for the foods because of a lack of sensitivity to leptin, which in turn stems from eating these types of foods.

Q:Is this why it is so difficult for obese patients to lose and maintain weight?

A:When people try to lose weight, there are resistance mechanisms that kick in and stop weight from being lost. It's not just a behavioral problem, there are physical things occurring that make it difficult for people to reach their desired weight loss outcomes.

Q:For those who are resistant to leptin, what happens to their insulin levels?

A:I would predict that insulin levels are very low in these individuals. Some strategies that improve insulin levels, such as use of metformin will also prevent weight gain (see Klein DJ, Cottingham EM, Sorter M, Barton BA, Morrison JA. A randomized, double-blind, placebo-controlled trial of metformin treatment of weight gain associated with initiation of atypical antipsychotic therapy in children and adolescents. A J Psychiatry 2006: 163(12):2072-9).

Q:Can you comment on the controversy over using Beta 3(β3)-agonists for weight loss?

A: β3-agonists stimulate the β3-adrenergic mechanism and skeletal muscle metabolism. There are a few drugs in evaluation right now; however, my opinion is that the companies evaluating these drugs made a mistake - they were looking for an effect that was not there. An agent that stimulates muscle metabolism may help to prevent the metabolic compensation that occurs with weight loss (reduced appetite). I have been urging them to go back and look at using these drugs in smaller doses for this purpose. The problem is trying to get a drug registered as a second-line therapy in obesity when we already have a handful of first-line therapies.

Q:Can you comment on the use of homeopathic dosages of Topomax® (topiramate) as an adjunct for weight gain?

A:In studying combination therapies, 150 - 200 mg of Topomax® is more effective than phentemine, an approved drug for weight loss. However, doses even lower than 50 mg may lead to clinically significant weight loss or prevention of weight gain. This is especially useful in patients with impaired fasting glucose or those on anti-epileptic drugs. Topomax® is not tolerated by a majority of patients because of cognitive side effects, fatigue, metabolic acidosis, and risk of kidney stones.

Q:Please tell us about prescription Meridia® as a weight loss option.

A:Meridia® (sibutramine) is a serotonin and norepinephrine reuptake inhibitor in the drug category of antidepressants. People tend to feel full sooner and have fewer cravings on this drug. The average patient taking Meridia® in conjunction with diet and exercise will lose 4 kg over placebo. It can reduce cholesterol and improve other complications associated with obesity, except as a side effect, it can actually increase blood pressure.

Q:What about prescription Xenical® (orlistat) for weight loss? How does it work?

A:Orlistat is a blocker of pancreatic enzymes that digest fat. As a major side effect, it causes upset stomach after eating fattening foods, such as consuming a very oily meal or using mineral oil as a laxative. The average patient taking orlistat in conjunction with diet and exercise will lose about 2.5 kg over placebo.

Q:What about patient compliance with these types of drugs, especially with so many side effects?

A:This is a huge issue - in any obesity trial I've ever seen, the dropout rate is very high: 30 - 50%. If patients see a result they like or do not like, they may cease their participation in the therapy. Patients don't usually look at the clinical endpoints like improved glucose or triglyceride levels, or prevention of chronic diseases.

Q:Please give us your viewpoint of the different bariatric procedures for weight loss.

A:For patients with a body mass index (BMI) of 40 and above (or 35 and above with comorbidities), the most effective treatment is gastric bypass with the average patient losing about 30% of their body weight. The Lap-Band® is an effective treatment as well; however, the average patient loses about 20% of their body weight.

Q:Is Lap-Band® a safer alternative for those considering bariatric procedures for weight loss?

A:The Lap-Band® has a lower complication rate compared to gastric bypass, but some people who have the Lap-Band® don't do as well and need to convert to a gastric bypass. While gastric bypass changes hormonal levels in the intestine which impact eating - actually reducing the drive to eat, with Lap-Band®, people usually retain that drive to eat and some eventually convert to gastric bypass because of this.

Q:What can we expect of obesity treatments in the future?

A:The future of obesity therapy is in multiple interventions - we can stimulate one part of the system while blocking something else, or possibly stimulate the central nervous system and skeletal muscle. In phase II trials of Orexigen's Contrave™ (Bupropion and Naltrexone combined), at 28-weeks participants lost an average of 6 kg over placebo. There are a tremendous number of options being explored - new medications, less-invasive bariatric procedures, etc.

Q:What about plain old diet and exercise? Is that enough?

A:Yes, diet and exercise for the average person is a great way to go. A reasonable goal is to lose just 5-10% of body weight. You must have a reasonable goal when you think of how much weight you want to lose. You can't always get to your "ideal" weight. It's what is feasible now, and the average person can do 5-10% (or more). If you can do at least that much, you will improve your overall health and be at a point in your life where you are maintaining instead of at a high weight and gaining.

Q:So what about the morbidly obese cases with high levels of leptin? Will losing 5-10% of body weight cause leptin levels to regulate to the point that craving is no longer a problem?

A:In animal studies satiety is shown to be improved. However, we have a lot more to learn. Unfortunately, the field has been constrained by industrial developmental forces - leptin has not been available for human trials to help answer this.

Q:We live in an environment of caloric excess - what preventive measure can we use to reduce access to excess caloric intake and the cycle of obesity?

A:Trying to intervene in this way is extremely unpopular. My colleagues at Yale (Kelly Brownell et al.) have had tremendous difficulty trying to intervene at the level of the food and beverage industry, but "experts" in these areas always reveal some study that elevates the contrary - saying the food is not the problem. However, if there is a study published that reveals the physiology of what happens with eating and obesity, the evidence will be so compelling that everyone will have to listen. Overall, a better understanding of these psysiological mechanisms will enable legislatures to help us prevent obesity.

Q:There is a trend of treating hypertension early, before it becomes severe. Why not use this same idea and treat people who are overweight, before obesity has a chance to develop?

A:This idea is a different way of thinking that we should begin to embrace. Should we have a food additive to slightly increase our metabolic rates? It only takes a fraction of a percent change in metabolic rate to cause weight gain - less than one percent of the calories you consume actually add weight to your body. If we include a small dose of this food additive in proportion to the number of calories in the food we could possible increase your metabolic rate. It may sound crazy right now, but when 80% of the population is overweight/obese and ~20% will have diabetes in the future, it may be that these types of measures should be considered. Overall, I do believe earlier treatment is necessary.

Q:There have been reports of schools actually sending BMI reports home to parents - as you can imagine, this caused quite an uproar. Can you comment?

A:Yes, I've ready about this. I think these are the kinds of things that need to be done - the average person in the U.S. is overweight, so it is easy to lose perspective with your children. For the people who think these measures are really blowing overweight/obesity out of proportion, go to the local pediatric diabetes clinic. Become a pediatric endocrinologist - Cornell and Columbia are hiring a new one each year. Fifteen years ago, it was extremely rare to see a child with type II diabetes. Now, two-thirds of adolescents seen at the Columbia clinic have type II diabetes.