HOUSTON – Nearly one-third of obese patients who had type 2 diabetes and were randomized to an extended-release formulation of phentermine plus topiramate for 1 year achieved a rigorous composite diabetes management end point comprising greater-than-10% weight loss, an HbA_1c level lower than 6.5%, and systolic blood pressure lower than 130 mm Hg.

Moreover, almost 40% of patients who were randomized to the full dose of the drug combo achieved a less-rigorous trifecta consisting of the same blood pressure and HbA1c targets, plus a greater-than-5% weight loss, Dr. Donna H. Ryan reported at the annual meeting of the Endocrine Society.

On the basis of favorable feedback from the Food and Drug Administration, she expects the combination drug (brand name, Qnexa) will receive marketing approval before year’s end and perhaps as early as mid-July.

In late February, the Endocrinologic and Metabolic Drugs Advisory Committee voted 20-2 for approval of Qnexa. The FDA is expected to issue its decision by July 17.

The approved indication will be for medical weight loss in the treatment of obesity in patients with either a body mass index of at least 30 kg/m², or a BMI of 27 plus a comorbid condition, such as type 2 diabetes, according to Dr. Ryan of the Pennington Biomedical Research Center in Baton Rouge, La.

If approved, Qnexa would join lorcaserin (Belviq), which was approved by the FDA in late June and which also is indicated for patients with either a BMI of at least 30, or a BMI of at least 27 plus weight-related comorbidities.

More than 25 million Americans have type 2 diabetes, and most of them are obese.

Because both the FDA and Vivus Inc. (Qnexa’s developer) want to avoid the widespread abuse that often has been a problem with diet medications, the drug will be subject to a risk-management program. It will be available only through certified mail-order pharmacies that will collect patient data.

"This won’t be something you can get over the Internet. Patients won’t be able to go to a doc-in-a-box and say, ‘I want a diet drug; give me a prescription for this drug I read about in the newspaper.’ It won’t be like that," she said.

Dr. Ryan presented a secondary analysis from the randomized, double-blind, phase III CONQUER trial that involved roughly 2,500 obese patients (Lancet 2011;377:1341-52).

Her new substudy focused on the 388 CONQUER participants with type 2 diabetes. Like all participants in CONQUER, the diabetic patients were placed on a well-known, structured, lifestyle/behavioral modification program known as the LEARN (lifestyle, exercise, attitudes, relationships, nutrition) program for weight management. In addition, they were randomized to phentermine 7.5 mg/topiramate 46 mg, to phentermine 15 mg/topiramate 92 mg, or to placebo once daily. The subjects had relatively well-controlled diabetes and were on metformin as their sole antidiabetic medication at baseline.

At 56 weeks, the composite goal of a greater-than-5% weight loss from baseline, an HbA_1c level lower than 6.5%, and a systolic blood pressure lower than 130 mm Hg was met by 12% of patients on lifestyle modification plus placebo, by 27% of those on the lifestyle program and the lower dose, and by 39% of those on the full dose. The tougher goal, which involved a greater-than-10% weight loss, was achieved in 4% of controls, 14% on the lower dose, and 31% on the full dose, which suggests that the drug plus lifestyle modification was roughly eightfold more effective than lifestyle modification alone.

The mean weight loss from baseline was 2% in controls, 7% in patients on the lower dose, and 9% in those on full-dose therapy.

To reach the composite goals, 12% of control subjects required a net increase in antidiabetic medications, as did 2% of those on the low dose and 0.6% of those on the full dose.

Both phentermine and topiramate have been on the market as individual drugs for many years, and their side effects in the CONQUER diabetic subgroup were the familiar ones associated with those agents. Dry mouth and paresthesia each occurred in about 8% of patients on the lower dose, and constipation occurred in 15%. Because the side effects are dose related, it’s quite likely that phentermine 7.5 mg/topiramate 46 mg will be the recommended starting dose, according to Dr. Ryan.

Topiramate is a known teratogen with a risk of four or five cases of cleft palate per 1,000 exposures during pregnancy. For this reason, the combination drug will be a category X drug.

In an interview, Dr. Ryan said that she could see physicians setting up contracts with their patients to take the drug for at least a year, then stopping it in order to see if lifestyle modification efforts enable them to avoid weight regain. If the pounds start piling up, they’ll restart the drug.

Dr. Ryan reported serving as a scientific advisor to Vivus but holds no equity interest in the company.

Weight-Loss Drug Hits Diabetes Target Trifecta