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Question: What is the effect of topiramate (Topamax) on weight loss? Is it premature to use it?
Answer: About half of our adult patients in the United States are overweight. Most of these patients are aware of at least some of the negative health effects associated with being overweight. Many will ask us the age-old question, "Is there a medication that I can take to help me lose weight?"
Americans are so overweight and so obsessed by their weight that we have elevated the latest diet-du-jour books to the coveted #1 position in prestigious readers' polls. The search for the magic pharmacologic weight-loss bullet is being pursued by an endless number of research teams.
Data on fat metabolism from the past decade tell us two things: 1) genetics plays an important role in obesity; and 2) there is probably not one simple metabolic pathway that governs fat disposition but instead, a complex multifaceted system.
Medications that have been or are being used to aid weight loss include stimulants such as phentermine (Adipex-P, Gate) and diethylpropion (Tenuate, Marion Merrell Dow). These agents suppress appetite, but only for the short term, and have not consistently been shown to provide long-term weight loss.
Orlistat (Xenical, Roche), an agent that suppresses fat absorption, and sibutramine (Meridia, Knoll), a medication that blocks the reuptake of norepinephrine, serotonin, and dopamine, have both been shown to reduce weight by about 10% over a period of 1 year.
Amphetamines, bupropion (Wellbutrin, GlaxoSmithKline), some of the selective serotonin reuptake inhibitors (SSRIs), and myriad over-the-counter and herbal formulations have also been used for weight loss with varied responses.
More recently, an anticonvulsant medication, topiramate (Topamax, Ortho-McNeil), has been used for weight loss with significant success in some populations. Populations that have been studied include patients with uncomplicated obesity, patients with weight gain associated with psychotropic drugs, patients with binge eating disorder, and migraine patients.
The precise mechanism of action has not been delineated. However, several mechanisms have been proposed, including: 1) energy expenditure elevations in the face of reduced caloric intake secondary to anorexia; 2) reduction in the activity of salivary enzymes, which are partially responsible for taste; 3) reduction in leptin and corticosteroid concentrations; and 4) reduction in serum glucose and insulin concentrations.
Unfortunately, a relatively high frequency of adverse events has been reported with topiramate. Adverse events have included parasthesias, memory impairment, taste distortion, fatigue, insomnia, difficulty concentrating, and dizziness.
The adverse-event profile in clinical trials evaluating weight loss with topiramate was unacceptable to Ortho-McNeil, which was developing the drug as a weight-loss compound. Studies with the conventional dosage form were discontinued. Currently, new formulations with extended absorption patterns are being evaluated with the working assumption that slow-release formulations will have better adverse event profiles and be more widely accepted.
Several studies with different designs evaluating weight loss in patients receiving daily doses of topiramate, ranging from 32 to 384 mg per day, reported weight loss in the range from 4.8% to as high as 16.5% from baseline. In most studies, 75% or more patients treated experienced weight loss.
While there are compelling data that suggest that topiramate does promote weight loss in a majority of patients, large studies to evaluate safety in this setting have not been carried out.
Given the adverse-event profile of the current formulation of this medication, it would be premature to recommend it for the sole indication of weight loss. Conversely, it may be useful in patients who have other indications, such as seizure disorders, in addition to obesity.
EDITOR'S NOTE: At press time in early December, Johnson & Johnson announced the discontinuation of the clinical development program for a controlled release formulation of topiramate in obesity and type 2 diabetes. According to the company, a phase II clinical trial found that the controlled release formulation did not provide significant advantages over the immediate release formulation.
Footnotes
Do you have a clinical question? Send it to docnews{at}diabetes.org.
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