OBJECTIVE: Long-term treatment with topiramate reduces body weight and improves 
insulin sensitivity in obese humans. Our aim was to evaluate the effect of 
topiramate treatment for 4 weeks on insulin sensitivity and secretion, 
independent of weight loss.
DESIGN: Randomized, double-blind, crossover, placebo-controlled study.
METHODS: Thirteen obese (BMI 36.6 ± 1.3 kg/m(2) (mean ± s.e.m.)), 
insulin-resistant (homeostasis model of assessment-insulin resistance 2.0 ± 0.2) 
women received topiramate (T, maximum dose of 75 mg) and placebo (P) for 4 
weeks, separated by a 4-week washout period. Insulin sensitivity and β-cell 
function were assessed using a two-step hyperinsulinemic euglycemic clamp with 
stable isotopes and a hyperglycemic clamp.
RESULTS: Hepatic and peripheral insulin sensitivities were not affected by 
topiramate treatment (glucose disposal rate (step 1 (insulin infusion rate 10 
MU/M(2) per min) T: 17.5 ± 0.8 vs P: 18.5 ± 1.0 μmol/kg(LBM) per min, t=1.016, 
P=0.33; step 2 (insulin infusion rate 40 mU/m(2) per min) T: 27.9 ± 3.2 vs P: 
28.8 ± 1.9 μmol/kg(LBM) per min, t=0.418, P=0.68)). Subjects lost a small amount 
of weight during the topiramate period (T: -1.0 ± 0.2 vs P: -0.1 ± 0.2 kg, 
t=2842, P=0.15). There were no changes in body fat mass, blood pressure, and 
fasting glucose. β-Cell function was not affected by topiramate as evidenced by 
an unaltered area under the curve of early (0-10 min; T: 1929.6 ± 265.7 vs P: 
2024.7 ± 333.6 pmol/l, t=-0.357, P=0.73) and late (80-120 min; T: 28,017.7 ± 
5029.9 vs P: 31,567.7 ± 5376.2 pmol/l, t=-1.481, P=0.16) phase insulin levels 
during hyperglycemia. The use of topiramate was associated with significant side 
effects such as paresthesia, nausea, dizziness, and concentration problems.
CONCLUSIONS: Low-dose topiramate treatment for 4 weeks, relative to placebo, had 
no significant effect on insulin sensitivity in overweight/obese adult females 
without established diabetes.