Point Ask Your Doctor...
by Dr. Amy Rothberg
Counterpoint Side Effects Include...
by Nonie Arora
Obesity is known to increase the risk of many chronic diseases, including coronary artery disease, diabetes, hypertension, high cholesterol, osteoarthritis, and some cancers. In the United States, obesity contributes to about 400,000 deaths annually, making it the second greatest cause of preventable death next to smoking, and costing us approximately $100 billion in healthcare costs each year. The number of adults trying to lose weight and the amount of money spent on weight loss interventions of little or unproven efficacy adds to the national cost of excess weight. Therefore, obesity demands new treatments, including lifestyle, surgical and new pharmacological options.
While there are marked benefits from intensive lifestyle intervention alone, these benefits are typically limited to the short-term. In other words, it’s keeping weight off that is the challenge. In most studies, 1/3 to 2/3 of weight loss is regained within 1 year and all of the weight loss is regained by 5 years.
It is neither volitional nor due to an inherent moral weakness that obese individuals remain obese or regain weight after weight reduction. Obesity is not a lifestyle choice. Genetic predisposition and environmental influences underlie differences in our food consumption and physical activity patterns. Denying an obese individual a safe therapeutic option is discriminatory. Health care providers who deny medications to patients with diabetes or hypertension would be considered negligent. There must be a paradigm shift with regards to how aggressively we treat those with obesity. Obesity not only contributes to other comorbid conditions, but it also leads to a poor quality-of-life, reduced longevity, and increased health care expenditures.
More recently, we have gained a better understanding of weight regulation and the complex interplay of the overlapping systems that contribute to obesity. The neuroendocrine axis, gut satiety signals, peripheral adiposity indicators, and a host of genetic, environmental, cultural, and hedonic factors influence obesity. Obesity is complicated, but this new understanding has provided additional insight into effective treatments. Unfortunately, targeting one pathway alone is unlikely to result in sustained weight loss for all individuals. Combination therapies are needed that may include medications along with behavioral modification including diet and exercise.
Historically, medications for the treatment of obesity were classified according to their mechanism of action: to reduce food intake, to alter metabolism, or to increase energy expenditure. Appetite suppressing drugs have been used in the past for weight loss. These included the combination medication Fen-Phen, which was withdrawn and discredited because of increased risk of heart valve problems.
But in June and July of 2012, the US Food and Drug Administration (FDA) approved two new medications for weight management. One was Belviq, a medication that treats obesity by suppressing appetite. A two-year phase III clinical trial with 4,000 obese adults showed a 5 percent weight loss in 47 percent of participants who were randomized to receive the medication twice daily. Among patients who lost 5 percent or more of their baseline weight at one year, the loss was maintained in more patients who continued to receive Belviq during year two (68 percent) than in patients who received placebo during year two (50 percent). At both year one and two, the study found no increase in heart valve problems. Side effects included headaches, fatigue, dizziness and nausea, but occurred in fewer than 5 percent of participants.
The second medication, Qsymia, is a combination of two FDA approved medications, phentermine and topiramate, in an extended release formulation. Phentermine is indicated for short-term weight loss in patients who are eating a low calorie diet and exercising. Topiramate is used to treat seizure disorders and migraine headaches. A 56-week randomized, controlled clinical trial of this combination medication showed that a significantly greater percentage of obese individuals lost 5-10 percent of their body weight compared to placebo. Only 21 percent in the placebo group compared to 62 percent and 70 percent in the low dose and high dose combination groups, respectively, lost greater than or equal to 5 percent of their initial weight. The percentage achieving greater than or equal to 10 percent weight loss was 7 percent in the placebo group, 37 percent in the low dose, and 48 percent for the high dose combination groups. Common side effects include tingling sensations in the fingers and toes, altered taste sensation, dry mouth, constipation and insomnia. Women will be required to use birth control, as topiramate is known to cause birth defects.
These approved drugs do have side effects, but few, if any medications of proven efficacy are free of risk. The risks must be weighed against the potential benefits. While lifestyle interventions remain the optimal treatment for the prevention and treatment of obesity, they may not result in enduring effects or necessarily be sufficient as a single therapy for all patients. Obesity is a global pandemic and it is important to recognize its associated comorbidities. It is imperative that physicians and patients have all effective and safe therapeutic options at their disposal. The risks and benefits of weight loss medications, like any medication, must be understood by the patient and health care provider, but the ultimate decision as to the best therapeutic approach must be an individual decision. To deny physicians and patients appropriate therapeutic options simply does not make sense.
Hopefully by now we can all agree that obesity is a serious problem in the United States. More than one-third of U.S. adults are obese, and obesity continues to be one of the leading causes of preventable deaths. Walk into any hospital and you are likely to encounter many patients with obesity-related conditions such as heart disease, stroke, and diabetes. Health care in the U.S. is already comparatively expensive, but medical costs for those who are obese average over $1,400 more per year than those who are not. Despite the urgency of this problem, a quick-fix solution is not the answer. This summer, the Food and Drug Administration (FDA) approved two new obesity drugs: Belviq and Qsymia. The drugs claim to increase weight loss for obese individuals. The advisory committee to the FDA indicated for both of these drugs that the benefits outweigh the long-term harms. But there is still a lot to consider. These drugs ought to be rigorously tested in the clinical setting to maintain approval. Physicians need to consider side effects and the efficacy for patients on an individual basis.
As a result of its mechanism of action, Belviq is associated with several potential side effects. Belviq activates the serotonin 2C receptor in the brain. Activating this receptor is thought to help a person feel full after eating less food, thereby consuming fewer calories and reducing weight. It sounds like a great solution to the scourge of obesity, but Americans should be cautious. In 1997, the weight-loss drug Fen-Phen was recalled after evidence surfaced that indicated the drug caused serious damage to heart valves. Scientists thought this effect was a result of activating the serotonin 2B receptor on heart tissue. Developers of Belviq indicate that when approved at the appropriate dose, Belviq does not activate the receptor that caused heart damage in patients who took Fen-Phen. The company claims the drug only binds weakly to the receptor in cardiovascular tissue, so it will not cause valve damage. However, physicians must still remain cautious when prescribing and monitoring heart conditions in patients. As with any new drug, it is not yet time-tested and negative side effects might manifest in the future. As in the case of Fen-Phen, negative side effects were not apparent until the drug was made available to the population. Belviq comes with other serious potential side effects, such as serotonin syndrome, disturbances in attention or memory, and for pregnant women, damage to the developing fetus. Reassuringly, the FDA has required the drug’s manufacturer to conduct six post-marketing studies, and one of these will be a long-term cardiovascular outcomes trial to assess the effect of Belviq patients with cardiac problems.
Qsymia, the second obesity drug approved in July 2012, also has serious side effects, such as accelerated heart rate. For that reason, patients taking Qsymia will need to have their heart rate monitored regularly. Additionally, Qsymia can cause serious birth defects, such as oral clefts, and thus cannot be used during pregnancy. The FDA approved Qsymia only with a Risk Evaluation and Mitigation Strategy (REMS). This measure requires a Medication Guide to advise patients about safety information, especially the risk of birth defects, and provisions for prescriber training and pharmacy certification.
With such risks, the effectiveness of these drugs is surprisingly underwhelming. Patients who took Belviq lost an average of 5.8 percent of their body weight after a year, compared with 2.5 percent for patients on the placebo. The difference, 3.3 percentage points, was below the F.D.A.’s standard for approval (5 percentage points). However, since 47 percent of the patients without type 2 diabetes lost at least 5 percent of their body weight compared to 23 percent of patients treated with a placebo, the drug was considered effective by another measure. Still, these changes are minor. In the trials for Belviq, all the patients received lifestyle modification treatment with a reduced calorie diet and exercise counseling. The drugs could have the opposite effect in the general population if taking them provides a disincentive to exercise and eat well. If people consider the drugs to be a quick and easy solution, they may not adhere as rigorously to the changes in diet and exercise required to lose weight. Qsymia had higher degrees of weight loss. Patients taking the recommended dose lost 6.7 percent more, on average, than patients taking the placebo after one year. Patients taking the highest dose lost 8.9 percent more. While this drug may be more effective, at least based upon the clinical trials, physicians need to monitor individual patients to see whether they will respond well to the drug.
Ultimately, higher risk drugs yield higher rewards. Patients may lose more weight on Qsymia but are consquently exposed to slightly greater risks. It is up to physicians to determine whether the benefits of weight loss outweigh the potential harms to patients. And it is up the FDA to ascertain whether the benefits outweigh the harms enough to keep the drugs on the market. A pill cannot be the only way to combat obesity – diet and exercise remain crucially important.
About the Issue
Point author: Dr. Amy Rothberg, M.D. is the director of the investigational weight management program at the University of Michigan’s Nutrition Obesity Research Center. She is a Clinical Assistant Professor in the Department of Internal Medicine and her clinical interests include obesity, metabolism, and Diabetes.
Counterpoint author: Nonie Arora is a Duke sophomore studying biology and genome sciences and policy. She writes for the Duke Research Blog.
Edited by: Michael Guisinger and Preeta Gupta
Cover by: Lulu Tang