Kishore Gadde, MD

Kishore Gadde, MD, director of Duke’s obesity clinical trials program, talks about the promising results of a recent multicenter clinical trial that showed a new combination of existing drugs may help some patients who are struggling with obesity.

What’s the story of this trial in a nutshell?

We showed that a combination of phentermine and topiramate, drugs which are already approved to treat obesity (phentermine) and migraine and epilepsy (topiramate), achieves about 19 more pounds of weight loss than placebo -- or up to a 10 percent weight loss -- in obese people over the course of one year.

The participants who took the combo also showed significant improvements in blood pressure, blood sugar measurements (hemoglobin A1C), cholesterol, triglycerides, and inflammatory markers, including C-reactive protein.

Is this drug combo an improvement over orlistat?

The drug combo appears to be more effective than orlistat, which is the only drug currently available for the long-term treatment of obesity.

Meta-analysis studies have shown that treatment with orlistat, at maximum strength, can lead to approximately seven-pound greater weight loss than placebo after one year.

How does the drug combination work?

We believe it works mainly by reducing hunger and increasing satiety. Phentermine increases the release of norepinephrine, a brain chemical that may influence hunger and satiety.

Topiramate has numerous mechanisms of action including effects on sodium channels, glutamate and GABA transmission, and carbonic anhydrase inhibition, although the mechanism responsible for weight loss is not clearly known.

There may also be an independent effect on glucose control: More patients on placebo developed diabetes during one year than patients who were on the combination drug. More patients on the combination drug were also able to reduce the number of their diabetes and blood pressure medicines.

This study was funded by Vivus, which is seeking FDA approval to market the combination therapy under the trade name Qnexa. In October 2010, the FDA asked the company for more safety data. Why, and does this study satisfy those concerns?

In March, the FDA issued a warning regarding the use of topiramate during pregnancy, stating that pregnant women who take the drug are at increased risk of having babies born with cleft lip or cleft palate.

Thirty-four women became pregnant while in Qnexa clinical trials, and no birth defects were reported for the babies born -- but pregnant women would not be candidates for use of this drug; there is no reason for women to use weight loss drugs while they are pregnant or trying to become pregnant.

What other patients should not take this drug?

Topiramate has also been associated with memory problems and mood changes, including depression and anxiety, and we did see a dose-specific increase in depression and anxiety during the study.

Though the overall incidence of these events was relatively small, it’s still something to consider in terms of which patients are good candidates for this formulation.

Why are you excited about this drug?

This kind of weight loss, coupled with significant reductions in heart and metabolic risk factors, could be an important advancement in the management of obesity.

Two-thirds of Americans are overweight or obese, and for obese patients who have failed to achieve meaningful weight loss with diet and exercise, we have just one available drug -- orlistat -- to try before jumping to bariatric surgery. We need more treatment options that work via different mechanisms.

The 56-week, phase 3 study was conducted in 93 U.S. centers with 2,487 patients who had a BMI of 27 to 45, and two or more comorbidities such as diabetes, hypertension, and high triglycerides.

Patients in the study also received diet and exercise advice in addition to the drugs.The study was published in April in Lancet. Gadde was a paid consultant to Vivus until 2008.