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Objective: To examine the safety and efficacy of topiramate (TPM) for maintaining weight following a low‐calorie diet. Research Methods and Procedures: Obese subjects (30 ≤ BMI < 50 kg/m2) 18 to 75 years old received a low‐calorie diet for 8 weeks. Those who lost ≥8% of their initial weight received TPM (96 or 192 mg/d) or placebo; all were on a lifestyle modification plan. Sixty weeks of medication were planned. Sponsor ended study early to develop a new controlled‐release formulation with the potential to enhance tolerability and simplify dosing in this patient population. Efficacy was analyzed in subjects who completed 44 weeks of treatment before study termination. Results: Of the 701 subjects enrolled, 80% lost ≥8% of their initial body weight and were randomized; 293 were analyzed for efficacy. Most withdrawals were due to premature termination of the study. Subjects receiving TPM lost 15.4% (96 mg/d) and 16.5% (192 mg/d) of their enrollment weight by week 44, compared with 8.9% in the placebo group (p< 0.001). Subjects on TPM continued to lose weight after the run‐in, whereas those on placebo regained weight. Significantly more TPM subjects lost 5%, 10%, or 15% of their randomization weight than placebo. Most adverse events were related to the central nervous system. Discussion: During a treatment period of 44 weeks, TPM was generally well tolerated, and subjects maintained weight loss initially achieved by a low‐calorie diet—and produced additional clinically significant weight loss beyond that achieved by a low‐calorie diet.

Objective:Obesity is a major risk factor for the development of type 2 diabetes. Tumor necrosis factor (TNF)‐α is a candidate gene for the development of both obesity and insulin resistance. We investigated whether a common polymorphism in the promoter region (−308 G/A) of the TNF‐α gene was associated with increased risk for the development of insulin resistance and cardiovascular disease in an obese Australian population. Research Methods and Procedures:Obese, non‐diabetic subjects (146 women and 34 men) were genotyped with polymerase chain reaction‐restriction fragment length polymorphism techniques, and anthropometric and biochemical measurements were analyzed. A homeostasis model assessment (HOMA) score was used to gauge the level of insulin resistance. Results:The frequencies of the Gallele and the Aallele were 0.759 and 0.241, respectively. Subjects homozygous for the Aallele had higher fasting insulin levels (226 vs. 131 pM; p< 0.001), higher HOMA scores (10.2 vs. 5.3; p< 0.001), higher systolic blood pressure (143 vs. 129 mm Hg; p= 0.02), and lower high‐density lipoprotein (HDL) cholesterol (1.13 vs. 1.25 mM; p= 0.04) than did subjects homozygous for the Gallele. Whereas an association between insulin resistance and body mass index or waist circumference was seen in all subjects, a highly significant negative correlation of HDL cholesterol to HOMA scores (r= −0.710; p< 0.001) occurred in subjects with the Aallele only. Discussion:The −308 G/ATNF‐α gene variant conveys an increased risk for the development of insulin resistance in obese subjects. The presence of low HDL cholesterol levels further increases the risks associated with insulin resistance in carriers of the Aallele.