Obesity is a growing worldwide epidemic that affects both sexes of all ages and all socioeconomic groups.1 As of 2000, there are over 300 million obese (203 lbs or more, or a BMI of 30 or higher2) adults worldwide, approximately the size of the entire population of the United States.1 Men have a higher rate of being classified into the category of overweight (169 lbs to 202 lbs or a BMI of 25.0 to 29.92) while women have higher rates of obesity. As of 2008, the prevalence of obesity in the United States is about one-third of the adult population and the numbers are increasing every year.2 Obesity is a complex condition caused by a combination of genetic, environmental, behavioral factors. 2 For all persons affected, obesity is a major risk factor for developing diabetes mellitus, cardiovascular disease, hypertension, stroke, and cancer. 1 The most serious consequence of obesity is pre-mature death. 1
Clinical trials on the safety and efficacy of the TopamaxÂ® (topiramate) for epilepsy demonstrated that those patients taking the drug actually experienced weight loss.3 TopamaxÂ® is manufactured by Ortho-McNeil-Janssen Pharmaceuticals, Inc. and was approved in 1996.4 In 2009, the FDA approved the generic manufacturing of the tablet form of the drug in several different strengths from 17 different manufacturers.5 It is an anti-epileptic drug (AED) with FDA indication approval for monotherapy epilepsy and adjunctive therapy epilepsy in children and adults, as well as for the treatment of adults for prophylaxis of migraines.4 The Food and Drug Administration did an analysis of studies and showed that when taking topiramate, patients have increased thoughts of suicide as well as suicidal behavior.6 In clinical trials, the most common adverse reactions that patients reported were "paresthesia, anorexia, weight decrease, fatigue, dizziness, somnolence, nervousness, psychomotor slowing, difficulty with memory, difficulty with concentration/attention, and confusion." 4
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Literature search was conducted using EMBASE Drugs and Pharmacology (1980 to 4th Quarter 2003), and MEDLINE databases (1966 to November week 1 2003). Key words used were: topiramate, weight, weight loss. The limits were: humans, English language, and clinical trials. The number of articles found was 80 and 3 articles were chosen for further evaluation.
Bray G et al. performed a six-month, placebo-controlled, dose-ranging study with 385 obese patients randomized to placebo or topiramate. 7 The objective was to "evaluate the efficacy and safety of topiramate for weight loss in healthy obese subjects." 7 There were 385 subjects (18 to 75 years of age with a BMI greater or equal to 30 or 27 to 50 kg/m2 for people with hypertension that was controlled and/or dyslipidemia) were randomized to receive either placebo or topiramate at 64-, 96-, 192-, or 384- mg daily. 7 Patients were excluded if they have any "weight changeâ€¦diabetes, uncontrolled hypertension, liver disease, renal dysfunction, and/or cardiovascular, endocrine, neurological, or psychiatric disease." 7 Recruitment took place across 17 centers in the United States. 7 Dosing began at 16 mg once daily. 7 At week 2, the dose was increased to 16 mg twice daily. 7 Thereafter, the dose was raised every week by 32 mg/d (16 mg twice daily) until study subjects reached their target dose.7 Twenty-four weeks after the start of treatment, all subjects were tapered off by a 50% reduction in the dose per week. 7 All participants did the same lifestyle program (dietary restriction combined with exercise and behavioral modification). 7 Mean percent weight loss from baseline to week 24 was 2.6% in placebo-treated patients vs. 5.0%, 4.8%, 6.3%, and 6.3% in the 64 mg/d, 96 mg/d, 192 mg/d, and 384 mg/d topiramate groups, respectively. 7 Topiramate-treated patients lost more weight than non-topiramate patients (5% or 10% of body weight). 7 Paresthesia, somnolence, difficulty with memory, concentration, and attention were most frequently reported and most events were was related to the dose that the patients were taking. 7 These adverse events were experienced early on and usually resolved without any further additional treatment; only 21% receiving topiramate withdrew from the study due to adverse events whereas 11% withdrew if they were taking placebo. 7 At all doses topiramate produced more weight loss than in patients who were not taking the drug. 7
Wilding J et al performed a randomized, double-blind, placebo-controlled study. The objective was to "investigate the long-term efficacy and safety of topiramate in obese subjects."8 The total number of patients was 1289. 8 They were obese (18-75 y with a body mass index >/=30 kg/m(2) and <50 kg/m(2) in the absence of comorbidities, or >/=27 kg/m(2) and <50 kg/m(2) in the presence of controlled hypertension and/or dyslipidemia) and were randomized to placebo or topiramate doses of 96-, 192-, or 256-Â mg/day. 8 All subjects participated in a weight-loss program. 8 This trial was did run to its planned end date because the sponsor wanted to pursue a time-release formulation. 8 854 subjects completed one year of the trial before it was terminated. 8 These patients lost 1.7%, 7%, 9.1%, and 9.7% of their initial body weight in the placebo, 89-, 192-, and 256-mg groups, respectively (P<0.001) 8 An improvement in blood pressure and tolerance for glucose was noted in the topiramate groups. 8 Obese subjects significantly lost weight after 1 year of taking topiramate. 8
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Astrup A et al performed a "randomized, double-blind, placebo-controlled, parallel-group multicenter trial" 9 and stated that the objective of the study was "to examine the safety and efficacy of topiramate for maintaining weight following a low-calorie diet." 9 701 obese subjects from Europe and Australia (ages 18-75 with a BMI of 30 < or = BMI < 50 kg/m2) were enrolled. 9 Subject were excluded if they had a history of diabetes, "significant cardiovascular, hepatic, or renal disease, a history or family history of kidney stones, uncontrolled thyroid disease, or significant central nervous system (CNS)-related or psychiatric disorders." 9 Everyone was on a lifestyle modification plan (dietary restriction in combination with exercise and behavioral modification). 9 Study subjects ate a "low-calorie diet," 9 defined as "a nutritionally balanced diet containing 800 to 1000 kcal daily" 9 for the duration of the trial which was 8 weeks. 9 Those who lost greater to or equal to "8% of their initial weight" 9 received 96 mg daily of topamax or 192 mg daily of topamax, or placebo. 9 44 weeks of treatment must have been completed by the study subjects to be included in the data analysis for drug efficacy. 9 Subjects were treated with a very low-calorie diet to induce an 8% loss of initial body weight. 9 560 subjects achieved an 8% weight loss and were randomized to take topiramate doses of 96- or 192-Â mg/day, or placebo. 9 293 subjects completed the 44 week trial. 9 Those in the topiramate groups lost 15.4% and 16.5% of their baseline weight and those in the placebo group lost 8.9% (p < 0.001). 9 Weight loss was maintained by subjects at the beginning of the trial, but not later on and subjects did not report many adverse events. 9
TopamaxÂ® (topiramate) does not have an FDA indication for weight loss4; but based on study results, it may be used off-label as a weight loss agent.
Begin TopamaxÂ® (topiramate) 16 mg my mouth once daily, then increase dose to 16 mg twice daily, then increase dose by 32 mg daily every week until a target dose of 64 mg daily is reached. 7 If tolerated, adjust target dose to 96-, 192-, or 384- mg by mouth daily.7
Initiate a nutritionally balanced diet consisting of 800 to 1000 kcal daily.9
Advise patient about possible adverse effects that may occur early on in treatment such as: paresthesia, somnolence, difficulty with memory, concentration, and attention. 7
Encourage patient to implement a lifestyle modification plan for weight loss such as a combination of dietary restriction, exercise and behavioral modification. 7,8,9