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Anthropometric indexes, insulin resistance, and serum leptin and lipid levels in women with cryptogenic epilepsy receiving topiramate treatment
Journal of Clinical Neuroscience 17 (2010) 1256–1259
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical Study
Anthropometric indexes, insulin resistance, and serum leptin and lipid levels in women with cryptogenic epilepsy receiving topiramate treatment Bulent Oguz Genc a, Ebru Apaydın Dogan a,*, Umuttan Dogan b, Emine Genc a a b
Department of Neurology, Meram School of Medicine, Selcuk University, Ana Bilim Dalı, Meram-Konya 42080, Turkey Department of Cardiology, Meram School of Medicine, Selcuk University, Meram-Konya, Turkey
a r t i c l e
i n f o
Article history: Received 15 November 2009 Accepted 11 January 2010
Keywords: Body mass index HDL cholesterol Insulin resistance Leptin topiramate Waist circumference
a b s t r a c t We aimed to investigate the effects of topiramate monotherapy on anthropometric indexes, insulin resistance, and serum leptin and lipid levels in 33 premenopausal women (mean age ± standard deviation: 26.7 ± 7.1 years) with cryptogenic epilepsy. Body mass index (BMI), waist circumference and serum leptin, insulin and lipid levels were measured at baseline and at 6 months after initiation of topiramate. We found reductions in BMI (p < 0.001), waist circumference (p < 0.001) and serum high-density lipoprotein (HDL) cholesterol levels (p = 0.011). We also found significant improvements in insulin resistance (p = 0.023), but not in serum leptin levels (p = 0.45). Our results suggest that topiramate treatment in women with epilepsy is associated with reduced BMI and waist circumference and improvement in insulin resistance; however, according to our data, topiramate treatment is also associated with lower HDL cholesterol levels, which may substantially increase vascular disease. Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction Topiramate is an antiepileptic drug approved for the treatment of epilepsy and prophylaxis of migraine. It is structurally distinct from other antiepileptic drugs, has multiple mechanisms of action and a broad-spectrum of efficacy.1 Epidemiologic studies indicate that the prevalence of cerebrovascular and cardiovascular diseases is higher in patients with epilepsy and that some of the antiepileptic drugs may have detrimental metabolic effects.2–4 Therefore, we aimed to evaluate the effects of topiramate in premenopausal women with epilepsy. 2. Patients and methods This open-label and prospective study was conducted at the outpatient clinic of the School of Medicine, Selcuk University, with the approval of the local ethics committee. Informed consent was obtained from all participants. A database, which included information on epilepsy-related issues and epilepsy diagnosis according to the 1989 International League Against Epilepsy (ILAE) criteria, was set up for each individual.5 Clinical assessments, electroencephalograms and brain CT scans or MRI were performed for all patients. Only women of reproductive age with cryptogenic epilepsy were included in the study. Women were excluded if: (i) they had * Corresponding author. Tel.: +90 3322236260; fax: +90 3322236181. E-mail address: [email protected] (E.A. Dogan). 0967-5868/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.jocn.2010.01.045
any endocrine/medical disorder, including irregular menstrual cycles; (ii) they were pregnant or were breast-feeding; (iii) they had any co-morbidity requiring continuous treatment that might alter the lipid/hormonal profile or they smoked cigarettes. 2.1. Topiramate monotherapy Topiramate monotherapy started at a dose of 25 mg/day and was escalated by 50 mg biweekly. The dose regimens were adjusted individually according to the investigators’ judgment, which was based on best seizure control and tolerability. Patients were evaluated at two visits: (i) the first (baseline) and (ii) the second (after 6 months of treatment). No dietary restriction was imposed. Additional clinical visits were planned in case of further seizure(s) or drug intolerance. Neurological and physical examinations and laboratory tests were performed during these visits, which included an assessment of: thyroid hormones, fasting levels of serum glucose, liver enzymes, leptin, insulin, triglyceride, total cholesterol, high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol. Body weight (a standardized calibrated scale was used while patients were wearing light clothing without shoes) and waist circumference were measured. The waist circumference was measured with a measuring tape placed in a horizontal plane around the abdomen at the level of the iliac crest at the end of a normal expiration. Insulin resistance was evaluated with the homeostasis model assessment (HOMA) index before and after topiramate treatment.
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2.2. Definition of terms The BMI was calculated according to the formula: 2
BMI ¼ weight ðkgÞ=height ðm2 Þ
ð1Þ 2
Patients’ BMI was classified as: normal (BMI < 25 kg/m ); overweight (BMI = 25–29.9 kg/m2); or obese (P30 kg/m2).6 Abdominal obesity (AO) was defined as waist circumference P80 cm according to the International Diabetes Federation criteria.7 The following formula was used8 for the HOMA index:
Fasting serum insulin ðlIU=mLÞ fasting plasma glucose ðmg=dLÞ=405
ð2Þ
HOMA is a validated index and the HOMA-based insulin resistance score is strongly correlated with insulin sensitivity assessed by the glucose clamp technique both in healthy individuals and in patients with different insulin resistance states.8,9 2.3. Assays Blood samples were taken after the participants had fasted overnight. Serum leptin levels were measured using a DSL-1023100 Active™ Human Leptin Enzyme-Linked Immunosorbent (ELISA) kit (Diagnostic Systems Laboratories; Webster, TX, USA). Serum insulin levels were measured with the a chemiluminescence immunoassay. 2.4. Statistical analyses The statistical data were analysed using the Statistical Package for the Social Sciences for Windows software version 15 (SPSS; Chicago, IL, USA). The continuous variables were expressed as mean ± standard deviation (SD). A paired sample t-test was used for normally distributed variables and the Wilcoxon signed rank test was used for the variables that were not distributed normally. A Pearson correlation test was used to analyze the correlations between the dose of topiramate and changes in body measurements and metabolic parameters. A p value less than 0.05 was considered to be statistically significant.
Fig. 1. Weight changes (kg) after topiramate monotherapy for 33 premenopausal women with cryptogenic epilepsy showing that most women lost weight over the treatment period.
The mean weight loss was 4.2 ± 3.4 kg. Prior to the study, 30.3% (n = 10) of the patients were obese; 54.5% (n = 18) were overweight and 15.2% (n = 5) had normal weight. After 6 months of topiramate therapy, 24.2% (n = 8) of patients were obese, 42.4% (n = 14) were overweight and 33.3% (n = 11) had normal weight. The range of weight loss in the study population is shown in Fig. 1. When compared to baseline levels, the following anthropometric and metabolic parameters of patients were reduced after treatment: body weight, BMI, waist circumference, serum insulin, HOMA and HDL cholesterol levels (Table 1). There were no statistically significant differences between LDL cholesterol and triglyceride levels before and after treatment. At baseline the mean values of total cholesterol levels were modestly greater; however, this difference did not reach statistical significance (p = 0.18; Table 1). The dose of the topiramate was not correlated with reduction of BMI, waist circumference, HOMA or HDL cholesterol levels.
3. Results 4. Discussion A total of 33 women aged from 15 to 42 years old (26.7 ± 7.1 years) were eligible for the study. The mean dose of topiramate was 135 ± 68.5 mg/day.
The findings of our study suggest that 6 months of topiramate treatment is associated with reduced BMI and waist circumference,
Table 1 Anthropometric indexes, insulin resistance, and serum leptin and lipid levels in women with cryptogenic epilepsy receiving topiramate monotherapy Anthropometric and metabolic parameters (n = 33)
At baseline
After TPM treatment
Change
p value
Body weight (kg) BMI (kg/m2) Waist circumference (cm) Blood glucose (mg/dL) Insulin (lIU/mL) HOMA Leptin (ng/mL) Total cholesterol (mg/dL) LDL cholesterol (mg/dL) HDL cholesterol (mg/dL) Triglyceride (mg/dL)
74.8 ± 12.2 29.1 ± 5.1 88.8 ± 12.7 90.1 ± 7.8 8.7 ± 4.1 1.95 ± 0.97 40 ± 21.4 190.2 ± 37.6 114.8 ± 36.1 49.4 ± 9.2 130.2 ± 59.9
70.6 ± 12.2 27.5 ± 5 86.2 ± 12 91.5 ± 9.4 7.3 ± 2.6 1.66 ± 0.66 37.3 ± 18.9 185.1 ± 35.5 114.5 ± 36.5 45.2 ± 9.4 126.8 ± 48.4
4.2 ± 3.4 1.6 ± 1.3 2.7 ± 3.5 1.4 ± 7.3 1.4 ± 2.9 0.29 ± 0.70 2.7 ± 20.4 5.1 ± 21.2 0.29 ± 24 4.1 ± 8.8 0.2 ± 22.5
<0.001 <0.001 <0.001 NS (0.28) 0.01 0.023 NS (0.45) NS (0.18) NS (0.95) 0.011 NS (0.39)
BMI = body mass index, HDL = high-density lipoprotein, HOMA = homeostasis model assessment, IU = international units, LDL = low-density lipoprotein, TPM = topiramate, NS = not significant.
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improved insulin resistance and lower HDL cholesterol levels in women with epilepsy. In our study, the finding of weight loss irrespective of dietary restriction is consistent with the clinical experience and animal studies.10 The mean weight loss in our study population is also concordant with the previous clinical studies.11–13 According to our data, the dose of topiramate was not related to the reduction in BMI, which is consistent with Klein et al.’s study.11 A significant reduction in waist circumference was achieved in our patients at the end of 6 months. Waist circumference is strongly associated with vascular disease and is defined as a major independent risk factor for myocardial infarction.14,15 In addition to this, topiramate treatment also led to improved insulin resistance when compared to basal levels. This finding is concordant with the recent data suggesting meaningful improvements in glycemic control parameters after topiramate treatment.10,16–19 Although reduction of waist circumference can be associated with weight reduction, there is no unequivocal report regarding whether topiramate’s effects on glycemic parameters are dependent on its weight loss effects. Therefore, contrary to the reduction in waist circumference, the improvement in insulin resistance may not be directly attributed to the weight loss effects of topiramate, according to the available data.10,16–19 In our study, leptin levels did not change when compared to basal levels. Leptin is a hormone derived from fat cells and has an important role in the regulation of body weight and food intake.20 Although the effects of topiramate on serum leptin levels have been investigated in several studies, acquired data are inconclusive and demand careful consideration because the association between serum leptin and gender has been disregarded.12 However, in a study designed to evaluate the effects of topiramate on weight factors including serum leptin levels and gender differences, no evidence of a direct causal involvement of leptin in topiramate-related weight loss was found.21 Our results regarding leptin are comparable to this study. These findings are also consistent with a study executed in leptin-deficient rodents that has shown that topiramate does not require the presence of leptin to exert its effects on weight loss.22 Despite favorable changes in some of the important metabolic markers including weight, abdominal obesity and insulin resistance, we observed that serum HDL cholesterol levels were lower at the end of the study. The cytochrome P450 (CYP450) system is the most important system for antiepileptic drug metabolism and is essential in the synthesis, metabolism and elimination of cholesterol.23 Although contradictory data do exist, patients treated with antiepileptic drugs that induce CYP450 mostly show increased total cholesterol levels with increases in both LDL and HDL cholesterol levels.23–28 Elevated HDL cholesterol levels in adult patients with epilepsy, associated with inducing antiepileptic drugs, such as carbamazepine and phenytoin, have been shown in a recent study.29 Topiramate is an inhibitor of CYP2C19 which is a CYP450 isoenzyme, and this might explain the lower HDL cholesterol levels in our study.30 Consistent with our findings, lower HDL levels associated with topiramate treatment have been reported in a limited number studies.10,24 We also observed a trend to modestly lower total cholesterol levels at the end of the study. However, this difference did not reach significance, probably due to the limited statistical power of the study. BMI is inversely and linearly correlated with HDL cholesterol levels in non-smoking men and women.31 Therefore, higher HDL cholesterol levels are expected after BMI reduction. However, in our study population, HDL cholesterol levels were lower despite a significant weight loss. Thus, low HDL cholesterol levels might be as a result of topiramate treatment. Although other clinical markers of cardiovascular risk factors such as apolipoproteins, C-reactive protein or homocysteine have not been evaluated in our study, the link between topira-
mate and low HDL cholesterol, which is a major risk factor, needs investigation as individuals with epilepsy have a greater prevalence of cardiovascular and cerebrovascular disease than the general population.2–4 However, to confirm the finding of lower HDL cholesterol levels associated with topiramate treatment, a comparative analysis of lipid parameters in patients receiving topiramate and other enzyme-inducing antiepileptic drugs is essential. In view of our findings, we conclude that topiramate effectively reduces BMI and waist circumference and improves insulin resistance in premenopausal women with epilepsy. However, the HDL cholesterol lowering effect may require the consideration of the development of dyslipidemia during the course of topiramate treatment. This finding may have clinical relevance in patients receiving topiramate as there is a strong link between low HDL cholesterol levels and vascular disease. Although our study has several limitations, including its small sample size, the relatively short observation period and the lack of a control group, we think these preliminary findings should be verified in large-scale studies. References 1. Vajda FJE. Pharmacotherapy of epilepsy: new armamentarium, new issues. J Clin Neurosci 2007;14:813–23. 2. Annegers JF, Hauser WA, Shirts SB. Heart disease mortality and morbidity in patients with epilepsy. Epilepsia 1984;25:699–704. 3. Gaitatzis A, Carroll K, Majeed A, et al. The epidemiology of the comorbidity of epilepsy in the general population. Epilepsia 2004;45:1613–22. 4. Nilsson L, Tomson T, Farahmand BY, et al. Cause-specific mortality in epilepsy: a cohort study of more than 9,000 patients once hospitalized for epilepsy. Epilepsia 1997;38:1062–8. 5. Proposal for revised classification of epilepsies and epileptic syndromes. Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia 1989;30:389–99. 6. Physical status: the use and interpretation of anthropometry. Report of a WHO Expert Committee. World Health Organ Tech Rep Ser 1995;854:1–452. 7. Alberti KG, Zimmet P, Shaw J. IDF Epidemiology Task Force Consensus Group. The metabolic syndrome – a new worldwide definition. Lancet 2005;366:1059–62. 8. Matthews DR, Hosker JP, Rudenski AS, et al. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28:412–9. 9. Bonora E, Targher G, Alberiche M, et al. Homeostasis model assessment closely mirrors the glucose clamp technique in the assessment of insulin sensitivity: studies in subjects with various degrees of glucose tolerance and insulin sensitivity. Diabetes Care 2000;23:57–63. 10. Rosenstock J, Hollander P, Gadde KM, et al. A randomized, double-blind, placebo-controlled, multicenter study to assess the efficacy and safety of topiramate controlled release in the treatment of obese type 2 diabetic patients. Diabetes Care 2007;30:1480–6. 11. Klein KM, Theisen F, Knake S, et al. Topiramate, nutrition and weight change: a prospective study. J Neurol Neurosurg Psychiatry 2008;79:590–3. 12. Ben-Menachem E, Axelsen M, Johanson EH, et al. Predictors of weight loss in adults with topiramate-treated epilepsy. Obes Res 2003;11:556–62. 13. Bray GA, Hollander P, Klein S, et al. A 6-month randomized, placebo-controlled, dose-ranging trial of topiramate for weight loss in obesity. Obes Res 2003;11:722–33. 14. Menke A, Muntner P, Wildman RP, et al. Measures of adiposity and cardiovascular disease risk factors. Obesity (Silver Spring) 2007;15:785–95. 15. Yusuf S, Hawken S, Ounpuu S, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 2004;364:937–52. 16. Khanna V, Arumugam S, Roy S, et al. Topiramate and type 2 diabetes: an old wine in a new bottle. Expert Opin Ther Targets 2008;12:81–90. 17. Eliasson B, Gudbjornsdottir S, Cederholm J, et al. Weight loss and metabolic effects of topiramate in overweight and obese type 2 diabetic patients: randomized double-blind placebo-controlled trial. Int J Obes (Lond) 2007;31:1140–7. 18. Wilkes JJ, Nguyen MT, Bandyopadhyay GK, et al. Topiramate treatment causes skeletal muscle insulin sensitization and increased Acrp30 secretion in highfat-fed male Wistar rats. Am J Physiol Endocrinol Metab 2005;289:E1015–22. 19. Halpern A, Mancini MC. Diabesity: are weight loss medications effective? Treat Endocrinol 2005;4:65–74. 20. Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature 1998;395:763–70. 21. Theisen FM, Beyenburg S, Gebhardt S, et al. A prospective study of body weight and serum leptin levels in patients treated with topiramate. Clin Neuropharmacol 2008;31:226–30. 22. Lalonde J, Samson P, Poulin S, et al. Additive effects of leptin and topiramate in reducing fat deposition in lean and obese ob/ob mice. Physiol Behav 2004;80:415–20.
B.O. Genc et al. / Journal of Clinical Neuroscience 17 (2010) 1256–1259 23. Mintzer S, Mattson RT. Should enzyme-inducing antiepileptic drugs be considered first-line agents? Epilepsia 2009;50(Suppl. 8):42–50. 24. Isojärvi JI, Pakarinen AJ, Myllylä W. Serum lipid levels during carbamazepine medication. Arch Neurol 1993;50:590–3. 25. Nikolaos T, Stylianos G, Chryssoula N, et al. The effect of long-term antiepileptic treatment on serum cholesterol (TC, HDL, LDL) and triglyceride levels in adult epileptic patients on monotherapy. Med Sci Monit 2004;10:MT50–2. 26. Calandre EP, Rodriquez-Lopez C, Blazquez A, et al. Serum lipids, lipoproteins and apolipoproteins A and B in epileptic patients treated with valproic acid, carbamazepine or phenobarbital. Acta Neurol Scand 1991;83:250–3. 27. Eiris JM, Lojo S, Del Rio MC, et al. Effects of long-term treatment with antiepileptic drugs on serum lipid levels in children with epilepsy. Neurology 1995;45:1155–7.
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28. Verrotti A, Domizio S, Angelozzi B, et al. Changes in serum lipids and lipoproteins in epileptic children treated with anticonvulsants. J Paediatr Child Health 1997;33:242–5. 29. Mintzer S, Skidmore CT, Abidin CJ, et al. Effects of antiepileptic drugs on lipids, homocysteine, and C-reactive protein. Ann Neurol 2009;65:448–56. 30. Patsalos PN, Froscher W, Pisani F, et al. The importance of drug interactions in epilepsy therapy. Epilepsia 2002;43:365–85. 31. Lamon-Fava S, Wilson PW, Schaefer EJ. Impact of body mass index on coronary heart disease risk factors in men and women. The Framingham Offspring Study. Arterioscler Thromb Vasc Biol 1996;16:1509–15.
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical Study
Anthropometric indexes, insulin resistance, and serum leptin and lipid levels in women with cryptogenic epilepsy receiving topiramate treatment Bulent Oguz Genc a, Ebru Apaydın Dogan a,*, Umuttan Dogan b, Emine Genc a a b
Department of Neurology, Meram School of Medicine, Selcuk University, Ana Bilim Dalı, Meram-Konya 42080, Turkey Department of Cardiology, Meram School of Medicine, Selcuk University, Meram-Konya, Turkey
a r t i c l e
i n f o
Article history: Received 15 November 2009 Accepted 11 January 2010
Keywords: Body mass index HDL cholesterol Insulin resistance Leptin topiramate Waist circumference
a b s t r a c t We aimed to investigate the effects of topiramate monotherapy on anthropometric indexes, insulin resistance, and serum leptin and lipid levels in 33 premenopausal women (mean age ± standard deviation: 26.7 ± 7.1 years) with cryptogenic epilepsy. Body mass index (BMI), waist circumference and serum leptin, insulin and lipid levels were measured at baseline and at 6 months after initiation of topiramate. We found reductions in BMI (p < 0.001), waist circumference (p < 0.001) and serum high-density lipoprotein (HDL) cholesterol levels (p = 0.011). We also found significant improvements in insulin resistance (p = 0.023), but not in serum leptin levels (p = 0.45). Our results suggest that topiramate treatment in women with epilepsy is associated with reduced BMI and waist circumference and improvement in insulin resistance; however, according to our data, topiramate treatment is also associated with lower HDL cholesterol levels, which may substantially increase vascular disease. Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction Topiramate is an antiepileptic drug approved for the treatment of epilepsy and prophylaxis of migraine. It is structurally distinct from other antiepileptic drugs, has multiple mechanisms of action and a broad-spectrum of efficacy.1 Epidemiologic studies indicate that the prevalence of cerebrovascular and cardiovascular diseases is higher in patients with epilepsy and that some of the antiepileptic drugs may have detrimental metabolic effects.2–4 Therefore, we aimed to evaluate the effects of topiramate in premenopausal women with epilepsy. 2. Patients and methods This open-label and prospective study was conducted at the outpatient clinic of the School of Medicine, Selcuk University, with the approval of the local ethics committee. Informed consent was obtained from all participants. A database, which included information on epilepsy-related issues and epilepsy diagnosis according to the 1989 International League Against Epilepsy (ILAE) criteria, was set up for each individual.5 Clinical assessments, electroencephalograms and brain CT scans or MRI were performed for all patients. Only women of reproductive age with cryptogenic epilepsy were included in the study. Women were excluded if: (i) they had * Corresponding author. Tel.: +90 3322236260; fax: +90 3322236181. E-mail address: [email protected] (E.A. Dogan). 0967-5868/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.jocn.2010.01.045
any endocrine/medical disorder, including irregular menstrual cycles; (ii) they were pregnant or were breast-feeding; (iii) they had any co-morbidity requiring continuous treatment that might alter the lipid/hormonal profile or they smoked cigarettes. 2.1. Topiramate monotherapy Topiramate monotherapy started at a dose of 25 mg/day and was escalated by 50 mg biweekly. The dose regimens were adjusted individually according to the investigators’ judgment, which was based on best seizure control and tolerability. Patients were evaluated at two visits: (i) the first (baseline) and (ii) the second (after 6 months of treatment). No dietary restriction was imposed. Additional clinical visits were planned in case of further seizure(s) or drug intolerance. Neurological and physical examinations and laboratory tests were performed during these visits, which included an assessment of: thyroid hormones, fasting levels of serum glucose, liver enzymes, leptin, insulin, triglyceride, total cholesterol, high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol. Body weight (a standardized calibrated scale was used while patients were wearing light clothing without shoes) and waist circumference were measured. The waist circumference was measured with a measuring tape placed in a horizontal plane around the abdomen at the level of the iliac crest at the end of a normal expiration. Insulin resistance was evaluated with the homeostasis model assessment (HOMA) index before and after topiramate treatment.
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2.2. Definition of terms The BMI was calculated according to the formula: 2
BMI ¼ weight ðkgÞ=height ðm2 Þ
ð1Þ 2
Patients’ BMI was classified as: normal (BMI < 25 kg/m ); overweight (BMI = 25–29.9 kg/m2); or obese (P30 kg/m2).6 Abdominal obesity (AO) was defined as waist circumference P80 cm according to the International Diabetes Federation criteria.7 The following formula was used8 for the HOMA index:
Fasting serum insulin ðlIU=mLÞ fasting plasma glucose ðmg=dLÞ=405
ð2Þ
HOMA is a validated index and the HOMA-based insulin resistance score is strongly correlated with insulin sensitivity assessed by the glucose clamp technique both in healthy individuals and in patients with different insulin resistance states.8,9 2.3. Assays Blood samples were taken after the participants had fasted overnight. Serum leptin levels were measured using a DSL-1023100 Active™ Human Leptin Enzyme-Linked Immunosorbent (ELISA) kit (Diagnostic Systems Laboratories; Webster, TX, USA). Serum insulin levels were measured with the a chemiluminescence immunoassay. 2.4. Statistical analyses The statistical data were analysed using the Statistical Package for the Social Sciences for Windows software version 15 (SPSS; Chicago, IL, USA). The continuous variables were expressed as mean ± standard deviation (SD). A paired sample t-test was used for normally distributed variables and the Wilcoxon signed rank test was used for the variables that were not distributed normally. A Pearson correlation test was used to analyze the correlations between the dose of topiramate and changes in body measurements and metabolic parameters. A p value less than 0.05 was considered to be statistically significant.
Fig. 1. Weight changes (kg) after topiramate monotherapy for 33 premenopausal women with cryptogenic epilepsy showing that most women lost weight over the treatment period.
The mean weight loss was 4.2 ± 3.4 kg. Prior to the study, 30.3% (n = 10) of the patients were obese; 54.5% (n = 18) were overweight and 15.2% (n = 5) had normal weight. After 6 months of topiramate therapy, 24.2% (n = 8) of patients were obese, 42.4% (n = 14) were overweight and 33.3% (n = 11) had normal weight. The range of weight loss in the study population is shown in Fig. 1. When compared to baseline levels, the following anthropometric and metabolic parameters of patients were reduced after treatment: body weight, BMI, waist circumference, serum insulin, HOMA and HDL cholesterol levels (Table 1). There were no statistically significant differences between LDL cholesterol and triglyceride levels before and after treatment. At baseline the mean values of total cholesterol levels were modestly greater; however, this difference did not reach statistical significance (p = 0.18; Table 1). The dose of the topiramate was not correlated with reduction of BMI, waist circumference, HOMA or HDL cholesterol levels.
3. Results 4. Discussion A total of 33 women aged from 15 to 42 years old (26.7 ± 7.1 years) were eligible for the study. The mean dose of topiramate was 135 ± 68.5 mg/day.
The findings of our study suggest that 6 months of topiramate treatment is associated with reduced BMI and waist circumference,
Table 1 Anthropometric indexes, insulin resistance, and serum leptin and lipid levels in women with cryptogenic epilepsy receiving topiramate monotherapy Anthropometric and metabolic parameters (n = 33)
At baseline
After TPM treatment
Change
p value
Body weight (kg) BMI (kg/m2) Waist circumference (cm) Blood glucose (mg/dL) Insulin (lIU/mL) HOMA Leptin (ng/mL) Total cholesterol (mg/dL) LDL cholesterol (mg/dL) HDL cholesterol (mg/dL) Triglyceride (mg/dL)
74.8 ± 12.2 29.1 ± 5.1 88.8 ± 12.7 90.1 ± 7.8 8.7 ± 4.1 1.95 ± 0.97 40 ± 21.4 190.2 ± 37.6 114.8 ± 36.1 49.4 ± 9.2 130.2 ± 59.9
70.6 ± 12.2 27.5 ± 5 86.2 ± 12 91.5 ± 9.4 7.3 ± 2.6 1.66 ± 0.66 37.3 ± 18.9 185.1 ± 35.5 114.5 ± 36.5 45.2 ± 9.4 126.8 ± 48.4
4.2 ± 3.4 1.6 ± 1.3 2.7 ± 3.5 1.4 ± 7.3 1.4 ± 2.9 0.29 ± 0.70 2.7 ± 20.4 5.1 ± 21.2 0.29 ± 24 4.1 ± 8.8 0.2 ± 22.5
<0.001 <0.001 <0.001 NS (0.28) 0.01 0.023 NS (0.45) NS (0.18) NS (0.95) 0.011 NS (0.39)
BMI = body mass index, HDL = high-density lipoprotein, HOMA = homeostasis model assessment, IU = international units, LDL = low-density lipoprotein, TPM = topiramate, NS = not significant.
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improved insulin resistance and lower HDL cholesterol levels in women with epilepsy. In our study, the finding of weight loss irrespective of dietary restriction is consistent with the clinical experience and animal studies.10 The mean weight loss in our study population is also concordant with the previous clinical studies.11–13 According to our data, the dose of topiramate was not related to the reduction in BMI, which is consistent with Klein et al.’s study.11 A significant reduction in waist circumference was achieved in our patients at the end of 6 months. Waist circumference is strongly associated with vascular disease and is defined as a major independent risk factor for myocardial infarction.14,15 In addition to this, topiramate treatment also led to improved insulin resistance when compared to basal levels. This finding is concordant with the recent data suggesting meaningful improvements in glycemic control parameters after topiramate treatment.10,16–19 Although reduction of waist circumference can be associated with weight reduction, there is no unequivocal report regarding whether topiramate’s effects on glycemic parameters are dependent on its weight loss effects. Therefore, contrary to the reduction in waist circumference, the improvement in insulin resistance may not be directly attributed to the weight loss effects of topiramate, according to the available data.10,16–19 In our study, leptin levels did not change when compared to basal levels. Leptin is a hormone derived from fat cells and has an important role in the regulation of body weight and food intake.20 Although the effects of topiramate on serum leptin levels have been investigated in several studies, acquired data are inconclusive and demand careful consideration because the association between serum leptin and gender has been disregarded.12 However, in a study designed to evaluate the effects of topiramate on weight factors including serum leptin levels and gender differences, no evidence of a direct causal involvement of leptin in topiramate-related weight loss was found.21 Our results regarding leptin are comparable to this study. These findings are also consistent with a study executed in leptin-deficient rodents that has shown that topiramate does not require the presence of leptin to exert its effects on weight loss.22 Despite favorable changes in some of the important metabolic markers including weight, abdominal obesity and insulin resistance, we observed that serum HDL cholesterol levels were lower at the end of the study. The cytochrome P450 (CYP450) system is the most important system for antiepileptic drug metabolism and is essential in the synthesis, metabolism and elimination of cholesterol.23 Although contradictory data do exist, patients treated with antiepileptic drugs that induce CYP450 mostly show increased total cholesterol levels with increases in both LDL and HDL cholesterol levels.23–28 Elevated HDL cholesterol levels in adult patients with epilepsy, associated with inducing antiepileptic drugs, such as carbamazepine and phenytoin, have been shown in a recent study.29 Topiramate is an inhibitor of CYP2C19 which is a CYP450 isoenzyme, and this might explain the lower HDL cholesterol levels in our study.30 Consistent with our findings, lower HDL levels associated with topiramate treatment have been reported in a limited number studies.10,24 We also observed a trend to modestly lower total cholesterol levels at the end of the study. However, this difference did not reach significance, probably due to the limited statistical power of the study. BMI is inversely and linearly correlated with HDL cholesterol levels in non-smoking men and women.31 Therefore, higher HDL cholesterol levels are expected after BMI reduction. However, in our study population, HDL cholesterol levels were lower despite a significant weight loss. Thus, low HDL cholesterol levels might be as a result of topiramate treatment. Although other clinical markers of cardiovascular risk factors such as apolipoproteins, C-reactive protein or homocysteine have not been evaluated in our study, the link between topira-
mate and low HDL cholesterol, which is a major risk factor, needs investigation as individuals with epilepsy have a greater prevalence of cardiovascular and cerebrovascular disease than the general population.2–4 However, to confirm the finding of lower HDL cholesterol levels associated with topiramate treatment, a comparative analysis of lipid parameters in patients receiving topiramate and other enzyme-inducing antiepileptic drugs is essential. In view of our findings, we conclude that topiramate effectively reduces BMI and waist circumference and improves insulin resistance in premenopausal women with epilepsy. However, the HDL cholesterol lowering effect may require the consideration of the development of dyslipidemia during the course of topiramate treatment. This finding may have clinical relevance in patients receiving topiramate as there is a strong link between low HDL cholesterol levels and vascular disease. Although our study has several limitations, including its small sample size, the relatively short observation period and the lack of a control group, we think these preliminary findings should be verified in large-scale studies. References 1. Vajda FJE. Pharmacotherapy of epilepsy: new armamentarium, new issues. J Clin Neurosci 2007;14:813–23. 2. Annegers JF, Hauser WA, Shirts SB. Heart disease mortality and morbidity in patients with epilepsy. Epilepsia 1984;25:699–704. 3. Gaitatzis A, Carroll K, Majeed A, et al. The epidemiology of the comorbidity of epilepsy in the general population. Epilepsia 2004;45:1613–22. 4. Nilsson L, Tomson T, Farahmand BY, et al. Cause-specific mortality in epilepsy: a cohort study of more than 9,000 patients once hospitalized for epilepsy. Epilepsia 1997;38:1062–8. 5. Proposal for revised classification of epilepsies and epileptic syndromes. Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia 1989;30:389–99. 6. Physical status: the use and interpretation of anthropometry. Report of a WHO Expert Committee. World Health Organ Tech Rep Ser 1995;854:1–452. 7. Alberti KG, Zimmet P, Shaw J. IDF Epidemiology Task Force Consensus Group. The metabolic syndrome – a new worldwide definition. Lancet 2005;366:1059–62. 8. Matthews DR, Hosker JP, Rudenski AS, et al. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28:412–9. 9. Bonora E, Targher G, Alberiche M, et al. Homeostasis model assessment closely mirrors the glucose clamp technique in the assessment of insulin sensitivity: studies in subjects with various degrees of glucose tolerance and insulin sensitivity. Diabetes Care 2000;23:57–63. 10. Rosenstock J, Hollander P, Gadde KM, et al. A randomized, double-blind, placebo-controlled, multicenter study to assess the efficacy and safety of topiramate controlled release in the treatment of obese type 2 diabetic patients. Diabetes Care 2007;30:1480–6. 11. Klein KM, Theisen F, Knake S, et al. Topiramate, nutrition and weight change: a prospective study. J Neurol Neurosurg Psychiatry 2008;79:590–3. 12. Ben-Menachem E, Axelsen M, Johanson EH, et al. Predictors of weight loss in adults with topiramate-treated epilepsy. Obes Res 2003;11:556–62. 13. Bray GA, Hollander P, Klein S, et al. A 6-month randomized, placebo-controlled, dose-ranging trial of topiramate for weight loss in obesity. Obes Res 2003;11:722–33. 14. Menke A, Muntner P, Wildman RP, et al. Measures of adiposity and cardiovascular disease risk factors. Obesity (Silver Spring) 2007;15:785–95. 15. Yusuf S, Hawken S, Ounpuu S, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 2004;364:937–52. 16. Khanna V, Arumugam S, Roy S, et al. Topiramate and type 2 diabetes: an old wine in a new bottle. Expert Opin Ther Targets 2008;12:81–90. 17. Eliasson B, Gudbjornsdottir S, Cederholm J, et al. Weight loss and metabolic effects of topiramate in overweight and obese type 2 diabetic patients: randomized double-blind placebo-controlled trial. Int J Obes (Lond) 2007;31:1140–7. 18. Wilkes JJ, Nguyen MT, Bandyopadhyay GK, et al. Topiramate treatment causes skeletal muscle insulin sensitization and increased Acrp30 secretion in highfat-fed male Wistar rats. Am J Physiol Endocrinol Metab 2005;289:E1015–22. 19. Halpern A, Mancini MC. Diabesity: are weight loss medications effective? Treat Endocrinol 2005;4:65–74. 20. Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature 1998;395:763–70. 21. Theisen FM, Beyenburg S, Gebhardt S, et al. A prospective study of body weight and serum leptin levels in patients treated with topiramate. Clin Neuropharmacol 2008;31:226–30. 22. Lalonde J, Samson P, Poulin S, et al. Additive effects of leptin and topiramate in reducing fat deposition in lean and obese ob/ob mice. Physiol Behav 2004;80:415–20.
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