An experimental weight-loss drug that combines two older medications helped people drop pounds without suffering severe side effects, according to a report on a large, year-long clinical trial published online Sunday in the medical journal Lancet.
About 70 percent of U.S. adults are overweight; of those, 34 percent are obese. Despite epidemic rates of obesity and type 2 diabetes, there are still few options for men and women who need help to lose weight and keep it off. Federal officials, while acknowledging the need for weight-loss drugs, have rejected several new diet pills in the past year, citing concerns about possible long-term risks in this new generation of meds meant to be taken not for a few weeks but for months or even years.
This trial, involving 2,487 overweight and obese men and women, tested the effects of very low doses of phentermine, an appetite suppressant used for weight loss since the 1960s, with moderate doses of topiramate, a medicine prescribed to prevent seizures and migraines first approved by the U.S. Food and Drug Administration (FDA) in 1996 under the brand name Topamax. The combo was tested in two different doses and compared with a placebo. All the patients — who ranged in age from 18 to 70 — got counseling on lifestyle and dietary changes. The men and women had a body mass index of 27 (about 160 pounds for a 5-foot-5-inch person) to 45 (270 pounds for a 5-foot-5-inch person).
On the lowest dose of the combination drug, the majority of people — 62 percent — lost at least 5 percent of their body weight and sustained that weight loss over the course of a year. More than a third lost at least 10 percent of their body mass. The average weight loss for this low-dose group was about 18 pounds. A second, slightly higher dose produced even greater average weight loss — 22 pounds — while the placebo regimen yielded an average loss of only 3 pounds.
People who took the combination drug also enjoyed improvements in blood pressure, cholesterol and blood sugar.
Indeed, the contribution of this study was not so much in proving that the drugs promote weight loss — a well-known benefit in both cases — but that combining the drugs in low doses seems to result in fewer side effects while still helping patients drop excess pounds. The researchers said the combination of the two drugs along with changes in lifestyle "might be a valuable treatment for obesity that can be provided by family doctors."
The most common side effects the study participants experienced were dry mouth, a pins-and-needles sensation, constipation, insomnia, dizziness and a metallic taste. The study also found that patients on the higher-dose combo were at increased risk of depression (a problem affecting 7 percent of these patients) and anxiety (8 percent). This was not the case for patients on the lower dose, but the authors advise a "cautious approach" in using the drug combination for people with mood disorders.
Topiramate alone, especially at higher doses, has been associated with both depressive mood changes and memory problems. Phentermine by itself can boost blood pressure, an effect not seen with the combination.
Doses of phentermine given in the study were about a quarter to half the typical dosage, says lead author Kishore M. Gadde, M.D., of Duke University Medical Center. The highest dose of topiramate in the study was less than a quarter of what's usually prescribed for epilepsy.
In addition to the reduced dosages, the fact that the drugs work in different ways and have some opposing effects may help minimize unwanted symptoms. "Phentermine is stimulating," says Gadde, "and topiramate can cause fatigue. It's often taken in the evening or at night because it could put people to sleep, while the phentermine can cause insomnia. So some of these side effects could cancel each other out."
Earlier efforts to develop topiramate alone as a weight-loss drug were abandoned because of side effects.
Phentermine, meanwhile, is familiar to many as one-half of the 1990s weight-loss combo "fen-phen" that caused serious heart-valve abnormalities. But it was the other half of the combo, fenfluramine, that was identified as the culprit and banned in 1997. Phentermine remains the most commonly prescribed weight-loss drug today. It was approved by the FDA in 1959 as a short-term diet aid, the most common approach to obesity at the time. The current study examined its effects over a year, the longest period to date.
The study was sponsored by the drugmaker Vivus, which hopes to sell the combination in a gradual-release capsule under the brand name Qnexa. Last October the FDA rejected the company's application to market Qnexa, requesting more information establishing that it poses no risk to the heart or to the fetus in pregnancy. The company expects to file a new application by the end of the year.
The only drug currently approved as a long-term aid in weight loss, Orlistat, works by blocking fat absorption; results have not been as strong as those seen in the phentermine-topiramate study.
Katharine Greider lives in New York and writes about health and medicine.