Kate Johnson

May 26, 2012

May 26, 2012 (Philadelphia, Pennsylvania) — Two years of treatment with an investigational combination of phentermine plus topiramate (Qnexa, Vivus) resulted in improved cardiometabolic risk factors, in addition to weight loss, according to research presented here at the American Association of Clinical Endocrinologists 21st Annual Meeting and Clinical Congress.

The findings suggest "sustained efficacy and the potential amelioration of obesity-related comorbidities" for the weight-loss drug. The US Food and Drug Administration (FDA) has flip-flopped several times on approval of the drug, stalling most recently in mid-April for an additional 3 months.

The latest data are a 1-year extension of the previously published 52-week CONQUER study (Lancet. 2011;377:1341-1352). In that study, overweight/obese subjects were randomized to placebo (n = 227), a half dose of the combination (phentermine 7.5 mg and topiramate 46 mg; n = 153), or a full dose of the combination (phentermine 15 mg and topiramate 92 mg; n = 295), said Nancy Bohannon, MD, lead investigator and director of clinical research at the cardiovascular risk reduction program at St. Luke's Hospital in San Francisco, California.

Primary efficacy variables of the extension study (SEQUEL) were mean percent weight loss and the percentage of subjects with 5% weight loss from CONQUER baseline.

Other variables were cardiometabolic parameters, including change in glycated hemoglobin (HbA1c), fasting insulin, homeostasis model assessment-insulin resistance (HOMA-IR), triglycerides, and high-density lipoprotein (HDL), explained Dr. Bohannon, who is also a consultant, serves on the advisory board, and holds stock in Vivus, the company that is developing the drug.

CONQUER baseline characteristics were similar in the study groups, with patients (mean age, 52 years) weighing a median of 101 kg (median BMI, 36 kg/m²).

Mean HbA1c levels were 6% in all groups, fasting insulin was around 16 or 17 µU/mL, and HOMA-IR was elevated at around 5, she reported.

At 108 weeks from baseline (4 weeks of titration followed by two 52-week treatment periods), weight loss was 1.8% in the placebo group, 9.3% in the half-dose group, and 10.5% in the full-dose group.

The percentage of patients achieving weight loss of 5% or more by the end of the study was 30.0% in the placebo group, 75.2% in the half-dose group, and 79.3% in the full-dose group.

A subanalysis of patients 64 years and older showed the same trend and magnitude of results, she said.

There was a reduction in fasting insulin of 2.6 µU/mL in the placebo group, 5.3 µU/mL in the half-dose group, and 5.2 µU/mL in the full-dose group.

Similarly, reductions in HOMA-IR were 0.7 in the placebo group, 1.5 in the half-dose group, and 1.6 in the full-dose group.

Although HbA1c remained unchanged in the active treatment groups, it rose by 0.16% in the placebo group. "For the most part, these people were not diabetic, although they did have high cardiovascular risk factors," she noted.

Triglycerides rose by 0.4 mg/dL in the placebo group, but dropped by 12.5 mg/dL in the half-dose group and by 13.7 mg/dL in the full-dose group.

Finally, HDL rose by 7.3% in the half-dose group, 11.9% in the full-dose group, and 4.7% in the placebo group.

Similar cardiometabolic results were seen in the subgroup of subjects 64 years and older.

The most common adverse events were constipation, paresthesia, dry mouth, and dysgeusia, she said.

In delaying approval for the drug, the FDA cited teratogenicity concerns and the potential for elevated heart rate.

However, Bill Law Jr., MD, moderator of the session and a physician at Endocrinology Consultants of East Tennessee in Knoxville, is optimistic that the drug will be approved.

"Anything that can help alter the physics of obesity — calories in and calories out — can make a difference," he told Medscape Medical News.

"We know that anything that tends to help patients lose weight will help reduce blood sugars. It doesn't take monumental amounts of weight loss to have significant improvements in blood sugar and other metabolic parameters," he said. "The earlier you can intervene, the better the patient's long-term prognosis."

Dr. Bohannon reports being on the advisory board of Vivus, the developer of the study drug; and owning stock (<$25,000) in the company. Her coresearcher, Craig Peterson, MS, reports being an employee of the company; being a paid lecturer for Abbott, Biodel, Boehringer, BMS, Calibra, CeQur, Daiichi-Sankyo, Halozyme, Lilly, Novartis, NovoNordisk, sanofi-aventis, Santarus, Tethys Bioscience, and Valeritas; owning stock (<$25,000) in Halozyme, Johnson & Johnson, and Santarus; and being on the advisory boards of Abbott, Biodel, Boehringer, BMS, Calibra, CeQur, Daiichi-Sankyo, Halozyme, Lilly, Novartis, NovoNordisk, sanofi-aventis, Santarus, Tethys Bioscience, and Valeritas. Dr. Law has disclosed no relevant financial relationships.

American Association of Clinical Endocrinologists (AACE) 21st Annual Meeting and Clinical Congress: Abstract 704. Presented May 24, 2012.