Diabetes Reversed With Investigational Weight Loss Drug

Kate Johnson

December 16, 2011

December 16, 2011 (Dubai, United Arab Emirates) — Slightly more than a year of treatment with an investigational obesity drug that the US Food and Drug Administration (FDA) rejected for approval last year reversed type 2 diabetes in 15% of subjects, according to the results of a study presented here at the International Diabetes Federation World Diabetes Congress 2011.

The drug, which has the proposed name Qnexa (developed by Vivus, Mountain View, California), is a controlled-release combination of phentermine, an appetite suppressant, and topiramate, an anticonvulsant.

"We need more options to treat the twin epidemics of diabetes and obesity," said Nancy J.V. Bohannon, MD, director of clinical research in the cardiovascular risk reduction program at St. Luke's Hospital in San Francisco, California, who presented the findings.

"This could potentially be an approach that is nonsurgical for treating obesity and improving glycemic control," said Dr. Bohannon, who is a consultant to, serves on the advisory board of, and holds stock in the company that manufactures the drug.

In a subanalysis of the previously published CONQUER trial (Lancet. 2011;77:1341-1352), researchers examined the effect of 2 different doses of the drug on a subset of 146 adults with type 2 diabetes and a body mass index (BMI) of 35 kg/m² or higher.

The mean BMI of participants was 39 to 40 kg/m², the mean duration of their diabetes was 4 years, 65% were female, and diabetes treatment in the group included diet and exercise, with about 50% using metformin.

After a titration period of 4 weeks, subjects were randomized to receive 52 weeks of placebo (n = 58), a half dose daily of the study drug (phentermine 7.5 mg/topiramate 46 mg; n = 24), or a full dose daily (phentermine 15 mg/topiramate 92 mg; n = 64).

At the end of the study period, subjects on the low-dose medication had a weight loss of 6.6% (P < .05) and those on the high dose had a 12.1% loss (P < .0001); in the placebo group, weight loss was 2.8%.

The researchers measured the drug's impact on excess weight, defined as the amount of weight above an ideal BMI of 25 kg/m².

Compared with subjects on placebo, who lost 7.4% of their excess weight, subjects on the low-dose medication lost 17.8% (P <.05) and those on the full dose lost 32.6% (P <.0001).

"Fasting blood sugar and hemoglobin A1c showed statistically significant changes from baseline at the full dose," said Dr. Bohannon, although she did not elaborate.

Resolution of diabetes, defined as the absence of clinical and laboratory manifestations of diabetes was seen in 1.7% of subjects on placebo, 8.3% of those on the half dose of medication, and 15.4% of those on the full dose.

The most common adverse events included constipation, paresthesia, insomnia, dry mouth, headache, and dysgeusia, she said.

In the FDA's complete response letter rejecting the company's New Drug Application, teratogenicity was mentioned as a major concern, as was elevated heart rate.

Metabolic acidosis, depression, anxiety, and sleep disorders, along with attention, memory, language, and other cognitive disorders have been mentioned.

Compared with recent studies on laparoscopic banding for the treatment of obesity, an excess weight loss of 32.6% seen with the full dose of medication measures up well, said Dr. Bohannon.

A recent study showed a similar 32% loss in diabetic subjects 1 year after gastric banding (Surg Obes Relat Dis. 2010;6:132-137); another study showed a 47% loss 2 years after surgery (Dixon JB et al. Obes Rev. Published online August 31, 2011).

"These are promising results. The question is: Will they be able to show enough safety so the FDA will be comfortable enough to approve it? The hope is that they will," said Francine Ratner Kaufman, MD, professor of pediatrics at the Keck School of Medicine, University of South California, and head of the Center for Diabetes, Endocrinology and Metabolism at the Children's Hospital, both in Los Angeles, who cochaired the session.

"It will be part of the armamentarium of all the potential options for treating obesity and its comorbidities. I am a pediatrician, so it would be one of my last options, but certainly as a diabetologist, I am excited about as many options as possible," she told Medscape Medical News.

"Right now we don't have good pharmacotherapy options," said Arya Sharma, MD, PhD, the other cochair of the session, and also a consultant for the drug's manufacturer.

"No matter how good surgery is, at the current rate, it would take us 100 years to do everyone. So for the many patients who do not have an option for surgery but who have the comorbidities related to obesity, we desperately need pharmacologic options," said Dr. Sharma, who is professor of medicine and chair of obesity research and management at the University of Alberta, Edmonton, Canada.

"If this drug makes it to market and proves to be safe, that's one step. I don't think there will be one drug that is effective and safe for everybody. We have about 100 different compounds for treating hypertension and 20 different compounds for treating diabetes. That's what it will probably take for obesity. We'll need more than 1 drug — we'll need 5, 10, 20 different drugs, and they'll all have to be tested to see which works best in whom and which has the best side-effect profile."

Last month, Vivus resubmitted the New Drug Application for phentermine/topiramate. A decision on the approval is expected in April 2012.

Dr. Bohannon reports being on the advisory board of Vivus (the developer of the study drug), Abbott, Biodel, Boehringer, BMS, Calibra, CeQur, Daiichi-Sankyo, Halozyme, Lilly, Novartis, NovoNordisk, sanofi-aventis, Santarus, Tethys Bioscience, and Valeritas; owning stock (<$25,000) in Vivus, Halozyme, Johnson & Johnson, and Santarus; and being a paid lecturer for Abbott, Biodel, Boehringer, BMS, Calibra, CeQur, Daiichi-Sankyo, Halozyme, Lilly, Novartis, NovoNordisk, Sanofi-Aventis, Santarus, Tethys Bioscience, and Valeritas. Her 2 coauthors are employees of the company. Dr. Kaufman is chief medical officer of Medtronic and has no financial connections to the manufacturer of the study drug. Dr. Sharma is a consultant for Vivus, the developer of the study drug.

International Diabetes Federation (IDF) World Diabetes Congress 2011: Abstract O-0534. Presented December 7, 2011.

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