Efficacy and safety of topiramate in combination with metformin in the treatment of obese subjects with type 2 diabetes: a randomized, double-blind, placebo-controlled study.
OBJECTIVE
To investigate the efficacy and safety of topiramate in obese subjects with type 2 diabetes treated with metformin.


METHODS
This was a multicenter, double-blind, placebo-controlled trial. All subjects received a non-pharmacological program of diet, exercise and behavioral modification throughout the study; the assigned diet was 600 kcal/day less than the subject's individually calculated energy expenditure. After a 6-week single-blind placebo run-in, subjects were randomized to placebo, topiramate 96 mg/day or topiramate 192 mg/day. Following an 8-week titration period, subjects remained on their assigned dose for 52 weeks. However, the sponsor ended the study early in order to develop a new controlled-release formulation with the potential to enhance tolerability and simplify dosing in this patient population. A total of 646 obese men and women (age: 18-75 years, body mass index: 27-50 kg/m(2)) with an established history of type 2 diabetes mellitus controlled by metformin monotherapy were randomized. Efficacy was assessed in a pre-determined modified intent-to-treat (MITT) population of 307 subjects whose randomization date would have allowed them to complete 24 weeks on study medication before the announcement of study termination.


METHODS
Joint primary efficacy parameters were mean percent change in weight and change in glycosylated hemoglobin (HbA(1c)) from baseline to week 24.


RESULTS
Subjects in the placebo, topiramate 96 mg/day and topiramate 192 mg/day groups lost 1.7%, 4.5% (P<0.001) and 6.5% (P<0.001), respectively, of their baseline body weight and had absolute decreases in HbA(1c) of 0.1%, 0.4% (P<0.001) and 0.6% (P<0.001) (MITT, last observation carried forward). Topiramate-treated subjects also experienced statistically significant decreases in systolic blood pressure. Most common adverse events were paresthesia and events related to the central nervous system.


CONCLUSIONS
Topiramate was effective for weight reduction and improvement in glycemic control in obese subjects with type 2 diabetes treated with metformin monotherapy. Further study in obese diabetics is warranted.
Toplak
H
H
Department of Medicine, Institute for Diabetes and Metabolism, Medical University, Graz, Austria. hermann.toplak@meduni-graz.at
Hamann
A
A
Moore
R
R
Masson
E
E
Gorska
M
M
Vercruysse
F
F
Sun
X
X
Fitchet
M
M
D000293:Adolescent; D000328:Adult; D000368:Aged; D019440:Anti-Obesity Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001786:Blood Glucose / Q000032:analysis; D001794:Blood Pressure / Q000502:physiology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D005632:Fructose / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008687:Metformin / Q000009:adverse effects / Q000627:therapeutic use*; D008875:Middle Aged; D009765:Obesity / Q000150:complications / Q000188:drug therapy*; D000077236:Topiramate; D016896:Treatment Outcome; D015431:Weight Loss / Q000187:drug effects
D019440:Anti-Obesity Agents; D001786:Blood Glucose; D005632:Fructose; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D008687:Metformin; D000077236:Topiramate