In 1993, when I started performing bariatric surgery to help patients with obesity lose weight, I thought that this procedure would disappear within 10 years because a drug to treat obesity would surely emerge. After all, in the 1970s, peptic ulcer surgery was nearly eliminated after a class of drugs called H2-blockers were introduced. Several years later, the 10 years I envisioned as the life span for bariatric surgery seemed too generous an estimate because a combination of drugs, phentermine and fenfluramine, resulted in spectacular weight loss for many people. Even if these drugs did not pan out, there were other weight-loss drugs in the wings, such as dexfenfluramine and sibutramine, that held promise.
But dexfenfluramine, fenfluramine, and sibutramine eventually were withdrawn from the market. Now, 19 years after I started performing surgery to treat obesity, bariatric operations are still with us and they remain the only intervention resulting in sustained and profound weight loss. We are down to 3 drugs for treating obesity: the fat absorption blocker orlistat and the sympathetic nervous system stimulators phentermine and diethylpropion. Of these, only orlistat is approved for long-term use.
Last year, hopes for a new medication, Qnexa, were dashed when a US Food and Drug Administration (FDA) advisory panel voted against its approval. The drug—which is a combination of 2 drugs, phentermine and topiramate (an antiseizure medication)—did meet the threshold for effective weight loss. However, safety concerns regarding an increased heart rate and certain birth defects in offspring of women taking the drug during pregnancy precluded FDA approval.
When a new FDA advisory panel evaluated Qnexa last week and overwhelmingly recommended (by a 20 to 2 vote) approval for the medication’s release, many obesity experts greeted the news with enthusiasm because 1999 was the last year that a new drug for obesity treatment was approved by the FDA. “The new combination of topiramate and phentermine [Qnexa] is a welcome advance for physicians who treat patients with obesity-related complications like prediabetes, diabetes, sleep apnea, NAFLD [nonalcoholic fatty liver disease], and impaired movement,” said Donna Ryan, of the Pennington Biomedical Research Center, in Baton Rouge, La, one of the investigators who performed the trials leading to this panel review.
In its deliberations regarding Qnexa, the FDA panel considered a large amount of data, including information from published trials, specifically the EQUIP trial , which investigated weight-loss outcomes at 1 year for 2 doses of Qnexa compared with placebo in severely obese individuals; the CONQUER trial , which was similar to EQUIP but selected patients who were obese and had medical complications of their obesity; and the SEQUEL trial , which followed up some of the CONQUER trial’s patients for 2 years. Weight loss was dose-dependent and sustained for those who kept taking the medication.
Similar to many prior trials of weight-loss interventions, about 40% of patients did not complete the studies. Adverse effects of dry mouth, paresthesias (sensation of tingling, burning, pricking, or numbness), and constipation were seen in about one-fifth of patients who received the drug. Patients tend to drop out of these sorts of drug studies because they become frustrated with the lack of progress, regain weight, or experience unpleasant adverse effects from the drugs. Consequently, the high dropout rates may bias weight-loss outcomes to a more favorable result than would have been observed if all participants remained in the trial. Nevertheless, a fair number of patients did achieve significant, long-term weight loss. Complications of obesity such as hypertension and diabetes were improved in patients who lost weight.
Although the panel remained concerned about potential complications, they did recognize that there are only 3 approved medications for obesity, that there are risks for leaving obesity untreated, and that Qnexa might help some high-risk obese patients. The panel also recognized that weight loss should not be the sole criterion for considering obesity-treatment drugs. Because even small reductions in weight result in substantial improvement in conditions such as diabetes that are associated with obesity, approval of weight-loss medications takes into account the limited armamentarium for treating obesity that currently exists and how modest weight loss can affect these obesity-related conditions.
The FDA usually follows its advisory panel’s advice regarding approval of a drug, and the agency’s decision is expected no later than April 17. The panel advised that if Qnexa is approved, the FDA should impose certain restrictions on its use. These include either a premarket or postmarket safety study, requiring education for clinicians prescribing the medication, and limiting its distribution to mail-order pharmacies to facilitate monitoring of the drug’s use. Women of child-bearing age should undergo frequent pregnancy testing, the panel said, because of a risk for cleft lip in the children of patients using topiramate, one of the drug’s 2 components.
The data suggest that Qnexa might be useful to treat some obese individuals. In contrast to its component drugs, Qnexa’s safety profile reflects studies of the drug used to treat obesity in patients for up to 2 years; phentermine is only approved for short-term use (3 months), and topiramate does not have an obesity indication. Moreover, Qnexa contains much lower doses of phentermine and topiramate than are typically used for each drug when they are administered alone. An elevated heart rate in patients taking obesity-treatment drugs can be a marker for cardiovascular events, and the lesser presence of this cardiac effect associated with Qnexa compared with phentermine alone might be advantageous. However, if the drug is approved, it will be important that prescribing physicians adhere to the labeling guidelines.
The FDA noted in a briefing document that it is unknown whether Qnexa’s cardiovascular effects and metabolic effects will have clinical significance in a higher-risk cardiovascular population when used as a chronic treatment (the majority of participants in the Qnexa trials were middle-aged white women). “Ultimately, only a long-term, cardiovascular outcome trial can define the effect of [Qnexa] treatment on risk for major adverse cardiovascular events in an obese at-risk population,” the FDA noted. According to news reports, the manufacturer has said that if Qnexa is approved, it would conduct a long-term study of the drug’s cardiovascular effects.