Predictors of Weight Loss in Adults with Topiramate-Treated Epilepsy

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1 Predictors of Weight Loss in Adults with Topiramate-Treated Epilepsy Elinor Ben-Menachem,* Mette Axelsen,* Else Hellebö Johanson,* Anna Stagge, and Ulf Smith* Abstract BEN-MENACHEM, ELINOR, METTE AXELSEN, ELSE HELLEBÖ JOHANSON, ANNA STAGGE, AND ULF SMITH. Predictors of weight loss in adults with topiramatetreated epilepsy. Obes Res. 2003;11: Objective: We examined predictors of weight loss with topiramate, an anticonvulsant associated with weight loss in adults. Research Methods and Procedures: In this uncontrolled, prospective clinical trial, topiramate was added to existing anticonvulsants in adults (40 to 110 kg) with partial-onset seizures. Primary measurements were change from baseline weight after 3 months and 1 year in patients completing 1 year of topiramate treatment (N 38). Physiological and metabolic measures were analyzed for correlation with weight loss during topiramate treatment. Results: In patients who completed 1 year of topiramate treatment, baseline weight was reduced in 82% at 3 months and in 86% at 1 year. Mean body weight was reduced 3.0 kg (3.9% of baseline) at 3 months and 5.9 kg (7.3%) at 1 year. In obese patients [body mass index (BMI) 30 kg/m 2 ], mean weight loss was 4.2 kg (4.3%) at 3 months and 10.9 kg (11.0%) at 1 year. Weight loss was primarily caused by reduction in body fat mass. For all patients, weight loss at 3 months correlated most strongly with reduced caloric intake (p 0.02). At 1 year, caloric intake had returned to baseline levels; weight loss correlated most strongly with higher baseline BMI (p ). Discussion: Our results suggest that weight loss occurs in most adults treated with topiramate and is sustained for at least 1 year. Reduced caloric intake may account, in part, for weight loss during early treatment. The pattern of weight Received for review July 16, Accepted in final form December 30, *Sahlgrenska Academy at Göteborg University, Göteborg, Sweden; and Janssen-Cilag, Stockholm, Sweden. Address correspondence to Elinor Ben-Menachem, Institute of Clinical Neuroscience, Division of Neurology, Sahlgrenska Academy at Göteborg University, Göteborg , Sweden. ebm@neuro.gu.se Copyright 2003 NAASO loss differs according to baseline BMI, with obese patients experiencing greater weight loss during continued therapy. Key words: anticonvulsant, body composition, caloric intake, glucose, insulin Introduction Many agents used in the chronic management of neuropsychiatric disorders, including certain anticonvulsants and mood-stabilizing agents, can induce significant weight gain in adults (1,2). Because even modest degrees of sustained weight gain (e.g., 5 to 7 kg) are associated with increased risk of complications, such as hypertension, diabetes, heart disease, and ischemic stroke (3,4), drug-induced weight gain may represent a potential safety issue, especially in patients with pre-existing health risks that could be aggravated by added weight. For such patients, therapies that have positive effects on weight control by not causing inappropriate weight gain or by producing weight loss in overweight/obese patients should be considered. Topiramate is a structurally novel neurotherapeutic agent approved to treat epilepsy (5 7) and under investigation for the treatment of other disorders (8 12). In clinical studies in adults with epilepsy, topiramate was associated with weight loss, with data suggesting a correlation between the degree of weight loss and both topiramate dose and pretreatment weight (5). However, these studies were generally limited in duration (3 to 5 months) and were not specifically designed to evaluate the effect of topiramate on weight or factors correlating with weight loss. We, therefore, undertook a 1-year prospective study to assess the effects of topiramate on weight and associated physiological and metabolic measures in adults with epilepsy to identify potential predictors of weight loss. Research Methods and Procedures Patients Patients eligible for study entry were at least 16 years of age, between 40 and 110 kg, and diagnosed with localiza- 556 OBESITY RESEARCH Vol. 11 No. 3 March 2003

2 tion-related epilepsy. All patients were taking at least one anticonvulsant, which had not been changed for at least 1 month before study entry. Women had to be postmenopausal or incapable of bearing children; women of childbearing potential had to be practicing an acceptable method of birth control and had to have a negative serum pregnancy test within 1 week before study entry. Patients were excluded from the trial if they had any rapidly progressive disorders that could alter their weight or affect their study participation. In addition, patients with uncontrolled malabsorption and/or metabolic disorders, mental retardation or impairment, or a history of alcohol or drug abuse were ineligible. Patients with a history of psychiatric or mood disorders requiring electroconvulsive therapy, major tranquilizers, monoamine oxidase inhibitors, or centrally acting sympathomimetics within the past 6 months were excluded, as were patients with a history of poor compliance with prior anticonvulsant therapy or a history of suicide and those who could not take their medication independently. Study Design This was a prospective, open-label, single-center study in adults with epilepsy treated with topiramate for 1 year. Topiramate was added to existing anticonvulsant therapy at a starting dose of 25 mg/d and increased biweekly in 25- or 50-mg increments to the best tolerated dosage providing maximum seizure control. The maximum allowed dosage was 1000 mg/d, with 50 to 400 mg/d as the expected dosage range based on previous clinical experience. Topiramate was dispensed as 25-, 50-, 100-, and 200-mg tablets. Dosages of topiramate and other anticonvulsants could be adjusted as needed. Patients were instructed not to change their diet or exercise regimen while receiving topiramate. Patients completed the study after 1 year of topiramate treatment. Reasons for early withdrawal were an adverse event, inadequate seizure control, patient choice, or loss to follow-up. Patients were evaluated at four study visits: screening visit; baseline visit on the first day of topiramate treatment (within 7 days of screening visit); after 3 months of topiramate treatment; and after 1 year of treatment (or when the patient left the study). Screening procedures included physical examination, 12-lead electroencephalogram, medical history, 1-month seizure history, and clinical laboratory tests. Patients received 2 hours of instruction by dietitians on how to record daily food intake. Training was individualized to the most common foods in a patient s diet, portion sizes, and fat content. At the baseline visit and subsequent visits, body weight was measured with a standardized calibrated scale, vital signs were taken, and seizure and food intake data were collected. Food diaries were reviewed with a dietitian. Portion sizes were confirmed with an aid produced by the Swedish Nutritional Board in which pictures are used to calculate grams of food consumed. Interviews with the dietitian ensured completeness of information in food diaries. Laboratory studies included a 75-g oral glucose tolerance test, thyroid hormones (T 3,rT 3,T 4, TSH), a fasting lipid profile (total cholesterol, high-density lipoprotein-cholesterol, triglycerides), and a leptin radioimmunoassay. Body composition was measured in a whole-body counter detecting naturally occurring potassium-40 (K40). Between visits, each patient or the patient s caregiver used a seizure diary to record seizure events. For each of the 7 days before a study visit, a food intake diary was used to record total dietary energy intake (kilocalories), fat (grams), carbohydrates (grams), protein (grams), and portion size. Adverse event data were collected at 3 months and 1 year. Statistical Methods Statistical analyses were performed using SAS version 6.12 (SAS Institute, Inc., Cary, NC). Efficacy variables consisted of body weight, body composition, food intake, metabolic parameters, and monthly seizure rates. Safety variables consisted of adverse events, clinical laboratory values, topiramate plasma concentrations, electrocardiograms, vital signs, and concurrent antiepileptic drugs and other medications. Paired Student s t test was used to assess changes from baseline at 3 months and 1 year. A stepwise regression model was used to detect any association between absolute change at 3 months and 1 year and potential predictors, i.e., baseline BMI, fat body mass at baseline, leptin levels, baseline caloric intake, caloric reduction at 3 months and 1 year, baseline metabolic T 3, and baseline metabolic rt 3. A significance level of 0.15 was used for determination of a positive predictor. Results Study Population A total of 49 adults with refractory epilepsy were enrolled. Median time since the diagnosis of epilepsy was 18 years; median seizure frequency was three seizures per month at baseline. Topiramate was added to one anticonvulsant in 23 (59%) patients and to two anticonvulsants in 18 (37%); doses of background anticonvulsants were not changed during the study. The most common background anticonvulsants were carbamazepine (17 of 49, 35%), lamotrigine (16 of 49, 33%), valproate (12 of 49, 24%), and phenytoin (11 of 49, 22%). Thirty-eight (77%) patients completed 1 year of topiramate treatment. Of the 11 patients who withdrew, 7 (14%) withdrew because of adverse events and 4 (8%) because of subject choice. Topiramate Dose and Effects on Seizures The mean topiramate dose after 3 months was 81 mg/d (range, 21 to 154 mg/d). Seizure frequency was reduced by OBESITY RESEARCH Vol. 11 No. 3 March

3 Table 1. Patient characteristics at baseline ( SD) Enrolled (n 49) Completed 1 year (n 38) Male/female 21/28 16/22 Age, mean (year) Mean body weight (kg) Mean BMI (kg/m 2 ) BMI 25 kg/m 2, no. (%) 24 (49) 20 (53) BMI 25 to 29.9 kg/m 2, no. (%) 12 (25) 10 (26) BMI 30 kg/m 2, no. (%) 13 (27) 8 (21) Mean body fat mass (kg) Mean lean body mass (kg) % (median reduction). A clinically significant response ( 50% seizure frequency reduction from baseline) was recorded in 53% of patients, with 35% of patients reporting no seizures during the first 3 months of treatment. After 1 year, the mean topiramate dose was 129 mg/d (range, 45 to 262 mg/d). With topiramate treatment, seizure frequency was reduced 67% (median reduction); 49% of patients responded with 50% seizure reduction, and 18% were seizure-free for the duration of topiramate treatment. Topiramate Effects on Body Weight, Body Composition, and Metabolic Variables Demographics and baseline weight characteristics for the enrolled population (N 49) and for study completers (N 38) were similar (Table 1). The proportion of patients who were overweight/obese (BMI 25 kg/m 2 ) was approximately equal to the proportion who were normal weight (BMI 25 kg/m 2 ). In patients completing 1 year of topiramate treatment, mean weight change was 3.0 kg (3.9% of baseline body weight) after 3 months and 5.9 kg (7.3%) after 1 year. The majority of patients had lost weight at 3 months and 1 year (Table 2); 58% (22 of 38) lost at least 5% of their baseline body weight after 1 year and 32% (12 of 38) lost 10% or more. When weight changes were analyzed in subgroups defined by baseline BMI, mean weight loss was greatest in obese patients (BMI 30 kg/m 2 ): 4.2 kg (4.3% of baseline weight) at 3 months and 10.9 kg (11%) at 1 year (Figure 1). At 3 months, 88% of obese patients had lost weight. All obese patients had lost weight after 1 year of Table 2. Weight change during topiramate treatment ( SD) 3 Months 1 Year Weight change, no. patients (%) Weight loss 31 (82%) 32 (86%) Mean loss (kg) % Change Weight gain 4 (11%) 5 (14%) Mean gain (kg) % Change No weight change 3 (8%) 0 Body fat mass, % change* BMI 25 kg/m BMI 25 to 29.9 kg/m BMI 30 kg/m Lean body mass, % change* BMI 25 kg/m BMI 25 to 29.9 kg/m BMI 30 kg/m * Patients with weight loss. topiramate treatment, with 50% of patients losing 10% of their baseline body weight. In patients with BMI 30 kg/m 2, weight was reduced in 80% of patients at 3 months and at 1 year; one-third of patients had lost 10% of baseline body weight at 1 year. Patients lost more body fat than lean mass. In patients who lost weight, body fat mass was reduced 9.4% at 3 months and 14.7% at 1 year; lean body mass reductions at Figure 1: Percentage change from baseline body weight at 3 months and 1 year of topiramate treatment vs. baseline BMI. 558 OBESITY RESEARCH Vol. 11 No. 3 March 2003

4 Figure 2: Percentage change in baseline caloric intake in patients who lost weight at 3 months and 1 year vs. degree of weight loss (any weight loss, 5% to 9% of baseline weight, or 10% of baseline weight). 3 months and 1 year were 3.4% and 4.8%, respectively. Obese patients with a BMI 30 kg/m 2 lost 17.8% of body fat mass vs. 5.2% of lean body mass after 1 year of topiramate treatment (Table 2). In patients who lost 10% of their baseline weight, regardless of their baseline BMI, body fat mass was reduced 27.9% at 1 year vs. a reduction of 6.5% in lean body mass. Early in therapy, caloric intake paralleled weight loss (Figure 2). At 3 months, mean caloric intake was reduced to kcal/d from kcal/d at baseline, and those patients who lost 10% of their baseline weight reported a nearly 40% reduction in their caloric intake at the 3-month visit. However, with continued topiramate treatment, caloric intake returned to baseline levels ( kcal/d) at 1 year (Figure 2), whereas weight loss continued. Topiramate treatment was associated with a significant reduction in fasting total cholesterol at 3 months and 1 year. A statistically significant reduction in thyroxine and rt 3 levels was observed at 1 year (Table 3), although all thyroid parameters remained within the normal reference range, and all patients remained clinically euthyroid. Significant changes in thyroid hormone parameters have not been observed in other topiramate studies. Serum leptin levels were also significantly reduced after 1 year. Among patients who lost weight during topiramate treatment, leptin levels were reduced 11% from baseline at 3 months (p 0.03) and at 1 year (p 0.006). In patients losing between 5% and 10% body weight, baseline leptin levels were reduced 18% at 3 months and 1% at 1 year; among those losing 10% or more, leptin levels were reduced 36% at 3 months and 16% at 1 year. Glucose levels measured during the oral glucose tolerance test were reduced in patients with BMI 25 kg/m 2, although differences were not statistically significant. Greater improvements in glucose tolerance were observed in obese patients (Figure 3). Postoral glucose load insulin levels tended to be lower at 1 year; changes were most marked for the 60- and 90-minute measurements, compared with the 2-hour values, in obese patients. In a multiple regression analysis, factors correlating with weight loss during topiramate treatment were explored. At 3 months, factors correlating with absolute weight change from baseline were caloric intake reduction (p 0.02), higher baseline rt 3 levels (p 0.04), and lower baseline caloric intake (p 0.05). Together, these three factors predicted 30% of absolute weight loss at 3 months (r ). At 1 year, baseline BMI was the only factor correlating with absolute weight reduction (p ), predicting 30% of absolute weight loss (r ). In the Table 3. Changes in laboratory assessments (mean SD) Analyte Baseline Change from baseline at 3 months Change from baseline at 1 year Triglycerides (mm) Total cholesterol (mm) * HDL-cholesterol (mm) Serum leptin (ng/ml) TSH (mu/l) Thyroxine (nm) * T 3 (nm) RT 3 (nm) * * p p OBESITY RESEARCH Vol. 11 No. 3 March

5 Figure 3: (A) Glucose levels during an oral glucose tolerance test in patients with baseline BMI 30 kg/m 2. (B) Insulin levels in patients with baseline BMI 30 kg/m 2. Baseline levels (Œ), levels at 3 months (F), and levels at 1 year (f). multiple regression analysis for weight loss measured as percentage of weight change, serum leptin became a predictor of weight loss at 3 months, in addition to the three factors predicting absolute weight reduction. Higher baseline leptin level was the one significant correlation factor for percent weight loss, but predicted only 11% of weight loss. Adverse Events The only adverse events reported by 10% of patients in this 1-year study were fatigue (17 of 49, 35%) and nervousness (6 of 49, 12%). Adverse events reported by 5% of patients were concentration/attention difficulty (8%), depressed mood (8%), paresthesia (6%), language problems (6%), and dizziness (6%). No serious adverse events or deaths occurred during the study. Treatment-emergent adverse events caused seven patients (14%) to discontinue topiramate treatment. The most common complaints in patients discontinuing topiramate were nervousness (n 2), fatigue (n 2), and depressed mood (n 2). Discussion This is the first prospective study specifically evaluating weight change as a result of topiramate treatment. Our study recorded weight loss in more than 80% of patients, even though patients were encouraged not to change their diet or exercise regimens. Weight loss occurred within 3 months and continued to the study s end at 1 year. Although weight loss was observed in all three patient subsets defined by baseline BMI, obese patients (BMI 30 kg/m 2 ) experienced the greatest degree of weight loss (percentage of body weight reduction and percentage of patients with more than 5% or 10% weight loss). Reduction in body fat mass represented 60% to 70% of the absolute weight loss. The rate of fat loss differed over time in the three subgroups. In normal-weight patients (BMI 25 kg/m 2 ), most of the fat loss occurred within the first 3 months of treatment. The rate of fat mass reduction slowed from a mean of 4.3% per month in the first 3 months to 0.5% per month over the remaining 9 months of treatment. In overweight patients (BMI 25 to 29.9 kg/m 2 ), no additional reduction in fat mass occurred after that observed at 3 months. In contrast to these patterns, the rate of fat reduction in obese patients (BMI 30 kg/m 2 ) was stable over time: a mean of 1.6% per month in the first 3 months and 1.4% per month over the subsequent 9 months, resulting in a cumulative fat mass loss of 18% at 1 year. Although lean body mass was reduced at 3 months, it remained unchanged in most patients for the study duration. Therefore, the majority of weight loss could be accounted for by reduction in total body fat. Loss of appetite was reported during clinical trials of topiramate in epilepsy (5 7). This was confirmed in our study by reduced caloric intake observed at 3 months. However, caloric intake returned to baseline levels by 1 year even though weight loss continued. These observations suggest that mechanisms other than those working to suppress food intake are involved in the long-term effects of topiramate on body weight. Preclinical studies also suggest that topiramate may affect energy balance (13,14). In animal models, topiramate has had an inconsistent effect on food intake. In one model, topiramate-treated rats showed an initial reduction of food intake and then a return to control levels (13), which parallels our clinical observations. However, in some animal models, fat deposition is reduced in the absence of alterations in food consumption (13,14). Increases in lipoprotein lipase activity have been observed with topiramate treatment in animal models, which suggests a potential to promote substrate oxidation and increase metabolic rate (13,14). However, the mechanism by which topiramate alters energy balance and induces fat loss is not known and remains under investigation. Our findings of weight loss during topiramate treatment in patients with epilepsy are consistent with the observa- 560 OBESITY RESEARCH Vol. 11 No. 3 March 2003

6 tions from placebo-controlled trials in adults with epilepsy. More than 80% of patients in our study lost weight during the first 3 months of treatment; in placebo-controlled trials, 85% of topiramate-treated patients and 39% of placebotreated patients lost weight during 3 to 5 months of treatment (5). In our study, weight loss continued over the remaining 9 months of the study and was more pronounced in obese patients (BMI 30 kg/m 2 ). A similar pattern of continued weight loss was seen in open-label studies with longer patient follow-up than our study, i.e., weight loss continued over 9 to 12 months of treatment with topiramate and stabilized after 18 to 24 months of treatment (15). When data from these studies were analyzed for the subset of patients defined by baseline weight, weight loss was greater in patients weighing 100 kg at baseline. Weight loss has also been observed in patients receiving topiramate for conditions other than epilepsy. In a doubleblind, placebo-controlled migraine prevention study, 10 of 19 topiramate-treated patients lost weight (mean, 2 kg); weight increased slightly in placebo-treated patients (8). In open-label studies in patients with bipolar disorder, topiramate treatment has been associated with decreases in weight and BMI (10,11). Weight loss has also occurred with the use of topiramate in other neurological and psychiatric conditions, including binge-eating disorder (12,16 19). Our prospective study was designed to characterize more fully the effects of topiramate on weight and associated metabolic parameters in adults and to identify potential correlates of weight loss. Limitations of this study include small sample size and lack of a control group. In addition, patients in our study were receiving co-therapy with other anticonvulsants. The concurrent use of other anticonvulsants can be a confounding factor in interpreting weight changes in topiramate-treated patients with epilepsy because reductions in dose or withdrawal of anticonvulsants causing weight gain could produce weight loss. However, in our study, topiramate was most commonly added to weight-neutral anticonvulsants; only nine patients (18%) also received valproate. Moreover, our results mirror the findings from placebo-controlled studies in which concomitant anticonvulsants were unchanged; in these studies, placebo-treated patients tended to maintain or even gain weight. We also minimized factors that could affect weight (e.g., diet and exercise) by instructing patients not to change dietary or exercise habits during the year of topiramate treatment. Thus, weight loss observed in our study can be attributed to a direct effect of topiramate. Our study showed that weight loss continued for at least 1 year and was associated with sustained fat loss. Additional prospective studies are needed to evaluate effects over longer treatment periods. Several particularly intriguing findings from our study merit attention in terms of clues to the mechanisms by which topiramate affects weight regulation. For example, initial weight loss (first 3 months) correlated with reduction in caloric intake, but caloric intake returned to pretopiramate levels even as weight loss continued. Moreover, weight loss tended to be state-dependent, correlating with baseline BMI and, therefore, body fat mass, causing obese patients to lose more weight and more fat than normal and overweight patients. Baseline serum leptin levels varied according to BMI (mean, 7.7 ng/ml in normal-weight patients; 12.9 ng/ml in overweight patients, and 27.8 ng/ml in obese patients). Leptin levels were significantly reduced during topiramate treatment; the greater the weight loss, the greater the reduction in serum leptin. Our study was not designed to determine whether the reduction in serum leptin was the consequence of body fat mass loss or the cause. Finally, as expected, weight loss was associated with the expected improvements in glucose, insulin, and total cholesterol levels. The combination of weight loss and metabolic improvements seen with topiramate may be reason to evaluate the potential benefits of topiramate for the metabolic syndrome and type 2 diabetes. Acknowledgments This study was supported by funding from Johnson & Johnson Pharmaceutical Research and Development (Raritan, NJ). References 1. Ackerman S, Nolan LJ. Bodyweight gain induced by psychotropic drugs: incidence, mechanisms and management. CNS Drugs. 1998;9: Allison DB, Mentore JL, Heo M, et al. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry. 1999;156: Must A, Spadano J, Coakley EH, Field AE, Colditz G, Dietz WH. The disease burden associated with overweight and obesity. 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7 10. Chengappa KN, Rathore D, Levine J, et al. Topiramate as add-on treatment for patients with bipolar mania. Bipolar Disord. 1999;1: McElroy SL, Suppes T, Keck PE, et al. Open-label adjunctive topiramate in the treatment of bipolar disorders. Biol Psychiatry. 2000;47: Shapira NA, Goldsmith TD, McElroy SL. Treatment of binge-eating disorder with topiramate: a clinical case series. J Clin Psychiatry. 2000;61: Richard D, Ferland J, Lalonde J, Samson P, Deshaies Y. Influence of topiramate in the regulation of energy balance. Nutrition. 2000;16: York DA, Singer L, Thomas S, Bray GA. Effect of topiramate on body weight and body composition of Osborne- Mendel rats fed a high-fat diet: alterations in hormones, neuropeptide, and uncoupling-protein mrnas. Nutrition. 2000; 16: Johnson & Johnson Pharmaceutical Research and Development. Topiramate Investigator s Brochure. Raritan, NJ: Johnson & Johnson; Gordon A, Price LH. Mood stabilization and weight loss with topiramate. Am J Psychiatry. 1999;156: Littrell KH, Petty RG, Hiligoss NM, Peabody CD, Johnson CG. Weight loss with topiramate. Ann Pharmacother. 2001; 35: Dursun SM, Devarajan S. Clozapine weight gain, plus topiramate weight loss. Can J Psychiatry. 2000;45: Dursun SM, Devarajan S. Accelerated weight loss after treating refractory depression with fluoxetine plus topiramate: possible mechanisms of action? Can J Psychiatry. 2001;46: OBESITY RESEARCH Vol. 11 No. 3 March 2003