YEBEH-05485; No of Pages 3 Epilepsy & Behavior xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Brief Communication
The effects of lifestyle modification and statin therapy on the circulatory markers for vascular risk in patients with epilepsy Dong Wook Kim a, Hyun Kyung Kim b,⁎, Eun-Kee Bae c a b c
Department of Neurology, Konkuk University School of Medicine, Seoul, Republic of Korea Department of Neurology, National Medical Center, Seoul, Republic of Korea Department of Neurology, Inha University Hospital, Incheon, Republic of Korea
a r t i c l e
i n f o
Article history: Received 11 August 2017 Revised 25 August 2017 Accepted 27 August 2017 Available online xxxx Keywords: Antiepileptic drugs Cholesterol Homocysteine Uric acid Atherosclerosis
a b s t r a c t Although long-term therapy with antiepileptic drugs can increase the risk of vascular diseases, there have been little attempts to reduce the increased vascular risk in patients with epilepsy. We conducted a prospective longitudinal study to assess the effects of lifestyle modification and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (statin) therapy on the increased circulatory markers for vascular risk in patients with epilepsy. We recruited patients with increased vascular risk such as a history of vascular events or hypercholesterolemia, and they decided whether to be treated with statin or just to modify their lifestyle. The circulatory markers of vascular risk were measured twice before and after a 3-month intervention. A total of 78 patients completed the study, and 37 of them chose to be treated with statin. A 3-month intervention with statin results in significant decreases in homocysteine (p = 0.010) and uric acid (p = 0.015) as well as total cholesterol (p b 0.001) and low-density lipoprotein (LDL) cholesterol (p b 0.001). The lifestyle modification group experienced less prominent decreases in total cholesterol (p = 0.010) and LDL cholesterol (p = 0.012). There were no reports of serious adverse events or seizure aggravation related to the statin treatment. Our findings suggest that lifestyle education is necessary in patients with epilepsy with increased vascular risk and that treatment with statin would be a well-tolerated and effective option for these patients. © 2017 Published by Elsevier Inc.
1. Introduction Antiepileptic drugs (AEDs) are commonly used in the treatment of epilepsy, and a considerable number of patients with epilepsy have a long-term or lifelong exposure to AEDs. In addition to the welldocumented metabolic derangements by the long-term use of AEDs such as body weight changes and abnormal bone metabolism [1], epidemiologic studies have demonstrated significant associations between epilepsy and comorbid cardiovascular or cerebrovascular diseases [2]. The prolonged use of some older AEDs such as carbamazepine, phenytoin, and phenobarbital was frequently implicated in the increased risk for atherosclerosis because these AEDs are potent inducers of the hepatic cytochrome P450 (CYP450) system that is extensively involved in the synthesis and metabolism of cholesterols [3]. The inducing AEDs are also related to the predisposition to atherosclerosis by altering other markers of vascular risk including homocysteine, uric acid, and C-reactive protein (CRP) [4]. In addition, several recent clinical studies observed that the prolonged use of new AEDs may also increase the vascular risk in patients with epilepsy [5]. ⁎ Corresponding author at: Department of Neurology, National Medical Center, 245 Eulji-ro, Jung-gu, Seoul, Republic of Korea. E-mail address: [email protected] (H.K. Kim).
Despite the well-established increased vascular risk in patients with epilepsy, there have been little attempts to reduce that risk in patients with epilepsy except for the recommendation of new AEDs as firstline agents [6]. However, old AEDs are still widely used with their established potency [7], and switching from an old to new AED may aggravate seizure frequency and increase the risk of adverse effects in some patients [8]. In the present study, we evaluate the effects of lifestyle modification and the use of 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase inhibitor (statins) in patients with epilepsy with increased vascular risk. 2. Methods 2.1. Patients In three tertiary referral epilepsy centers, adult patients with epilepsy between the ages of 18 and 80 years who had increased risk of cardiovascular/cerebrovascular diseases were prospectively recruited from March 2015 to February 2017. The increased risk of cardiovascular/cerebrovascular diseases was defined as (1) a previous history of cardiovascular/cerebrovascular diseases, (2) presence of radiologically identified cerebral ischemic lesions or atherosclerosis, (3) high total cholesterol (N220 mg/dl) and/or high low-density lipoprotein
http://dx.doi.org/10.1016/j.yebeh.2017.08.041 1525-5050/© 2017 Published by Elsevier Inc.
Please cite this article as: Kim DW, et al, The effects of lifestyle modification and statin therapy on the circulatory markers for vascular risk in patients with epilepsy, Epilepsy Behav (2017), http://dx.doi.org/10.1016/j.yebeh.2017.08.041
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D.W. Kim et al. / Epilepsy & Behavior xxx (2017) xxx–xxx
cholesterol (LDL-C) (N140 mg/dl), (4) the presence of diabetes, and (5) high homocysteine level (N20 mg/dl). After receiving an explanation of their increased vascular risk, all patients were advised to modify their lifestyle (i.e., adhering to a heart-healthy diet, regular exercise habits, avoidance of tobacco products, and maintenance of a healthy weight) and were asked to decide whether to be treated also with statins or to solely modify their lifestyle. The type of statin that was chosen was based on each clinician's decision, but clinicians were recommended to follow the recent guidelines of statin therapy [9]. The study was complete after a 3-month intervention of lifestyle modification with or without statin therapy. In the group of patients receiving statin therapy, commonly known adverse events of statins such as allergic skin rash, dizziness, muscle pains, and sleep problems were more carefully evaluated during their follow-up visits. Patients were not eligible if they had a history of hemorrhagic stroke, chronic renal/hepatic disease, and concomitant administration of lipid-lowering agents and vitamin supplements. Patients who had other AED(s) added to their treatment or initial AED(s) changed to another because of inadequate seizure control or adverse events of the AED(s) were excluded from the analysis. Patients who had not taken AED(s) or statin for more than 2 weeks during the study period were also excluded. The local ethics committees approved this study, and all participants gave written informed consent. 2.2. Laboratory test and statistical analysis For all participants, venous blood samples were collected twice at baseline and at the end of 3 months of treatment after an overnight fasting. Laboratory tests for vascular risk markers included total cholesterol, triglyceride, high-density lipoprotein cholesterol (HDL-C), LDL-C, homocysteine, vitamin B12, folate, CRP, and uric acid. Patients were divided into two groups according to statin use. Between-group differences in demographics and clinical data were
tested using a Student t-test, chi-square test, or Fisher's exact test. Paired t-tests were used to assess changes in vascular risk markers before and after treatment in each group. 3. Results A total of 78 patients were recruited, and all of them completed 3 months of intervention. Thirty-seven patients chose to be treated with statins, while 41 patients wanted to only modify their lifestyle. Demographic features, clinical data, and baseline and follow-up values as well as summary results for changes in vascular risk markers are presented in Table 1. There were no significant differences in the baseline values of circulatory markers of vascular risk between the statin and lifestyle modification groups. However, patients in the lifestyle modification group were younger than patients in the statin group (48.6 ± 14.4 vs 60.8 ± 14.8, p b 0.001). In the 3-month statin therapy group, there were significant decreases in blood levels of homocysteine (from 17.6 to 12.9 μmol/l, p = 0.010) and uric acid (from 6.3 to 5.5 mg/dl, p = 0.015), as well as total cholesterol (from 201.2 to 153.5 mg/dl, p b 0.001) and LDL-C (from 121.4 to 84.6 mg/dl, p b 0.001). The lifestyle modification group experienced significant decreases in blood levels of total cholesterol (from 200.0 to 180.7 mg/dl, p = 0.010), LDL-C (from 122.7 to 107.8 mg/dl, p = 0.012), and triglyceride (from 145.5 to 110.4 mg/dl, p = 0.038). When the changes in the vascular risk markers were compared between the two groups, the changes in the blood levels of LDL-C (− 36.7 ± 38.9 vs − 14.9 ± 36.4, p = 0.013) and homocysteine (− 4.6 ± 10.7 vs 0.2 ± 7.6, p = 0.022) were significantly higher in the statin group. The changes in blood levels of total cholesterol, triglyceride, and uric acid experienced by both groups were not significantly different. None of the patients complained of adverse effects from the statin treatment or experienced aggravation of their seizures related to the
Table 1 Demographics, clinical data, and comparison of changes in vascular risk markers between the statin and lifestyle modification groups.
Age (years) Sex (female:male) Number of AEDs Measured variable
TC (mg/dl) HDL-C (mg/dl) TG (mg/dl) LDL-C (mg/dl) Homocysteine (μmol/l) Vitamin B12 (pg/ml) Folate (ng/ml) CRP (mg/l) Uric acid (mg/dl) Measured variable
TC (mg/dl) HDL-C (mg/dl) TG (mg/dl) LDL-C (mg/dl) Homocysteine (μmol/l) Vitamin B12 (pg/ml) Folate (ng/ml) CRP (mg/l) Uric acid (mg/dl)
Statin group (n = 37)
Lifestyle modification group (n = 41)
p-Value
60.8 ± 14.8 13:24 2.0 ± 1.2
48 6 ± 14.4 14:27 1.7 ± 0.8
b0.001 1.000 0.26
Statin group (n = 37)
Lifestyle modification group (n = 41)
p-Value for baseline value
Baseline value
Follow-up value
Baseline value
Follow-up value
201.2 ± 41.6 51.4 ± 21.2 132.2 ± 99.3 121.4 ± 35.2 17.6 ± 10.7 816.1 ± 461.8 10.4 ± 5.7 0.30 ± 0.36 6.3 ± 2.6
153.5 ± 36.2 51.2 ± 19.7 123.7 ± 101.0 84.6 ± 30.9 12.9 ± 3.7 811.2 ± 430.6 10.3 ± 5.6 0.25 ± 0.38 5.5 ± 1.6
200.0 ± 41.4 54.5 ± 20.7 145.5 ± 132.5 122.7 ± 25.8 14.4 ± 10.2 649.5 ± 352.2 9.5 ± 4.5 0.44 ± 1.91 6.0 ± 2.3
180. 7 ± 32.0 55.6 ± 18.2 110.4 ± 64.9 107.8 ± 26.5 14.5 ± 8.7 592.5 ± 225.7 9.2 ± 5.2 0.14 ± 0.18 5.7 ± 1.8
Lifestyle modification group (n = 41)
Statin group (n = 37)
0.904 0.507 0.843 0.620 0.183 0.075 0.454 0.647 0.684 p-Value for between groups
Change in variable
p-Value
Change in variable
p-Value
−47.6 ± 46.4 −0.1 ± 15.3 −8.5 ± 131.6 −36.7 ± 38.9 −4.6 ± 10.7 −4.9 ± 168.3 −0.08 ± 4.93 −0.04 ± 0.45 −0.8 ± 1.9
b0.001 0.957 0.698 b0.001 0.010 0.860 0.992 0.566 0.015
−19.3 ± 45.5 1.1 ± 9.6 −35.1 ± 104.8 −14.9 ± 36.4 0.2 ± 7.6 −57.0 ± 220.8 −0.30 ± 4.53 −0.30 ± 1.92 −0.38 ± 2.0
0.010 0.467 0.038 0.012 0.900 0.106 0.671 0.321 0.224
0.080 0.667 0.324 0.013 0.022 0.249 0.836 0.425 0.362
AED, antiepileptic drug; TC, total cholesterol; HDL-C, high-density lipoprotein cholesterol; TG, triglyceride; LDL-C, low-density lipoprotein cholesterol; CRP, C-reactive protein. All values are given as means ± SE or number. Statistical analyses were conducted using SPSS software (SPSS Inc., version 17.0, Chicago, IL). A p-value b0.05 is considered statistically significant in all analyses.
Please cite this article as: Kim DW, et al, The effects of lifestyle modification and statin therapy on the circulatory markers for vascular risk in patients with epilepsy, Epilepsy Behav (2017), http://dx.doi.org/10.1016/j.yebeh.2017.08.041
D.W. Kim et al. / Epilepsy & Behavior xxx (2017) xxx–xxx
seizure-threshold-lowering effect of statin or potential drug interaction with other AEDs. However, one patient reduced the dose of statin after a month of treatment because of mild muscle pain, and another patient changed statins from atorvastatin to pravastatin because of asymptomatic increases in blood transaminase enzymes. 4. Discussion This prospective longitudinal study shows that statin therapy is an effective and safe way to decrease atherogenic markers such as total cholesterol, LDL-C, homocysteine, and uric acid. Although recent guidelines on the treatment of blood cholesterol emphasized lifestyle modification as a critical component of health promotion and cardiovascular/cerebrovascular risk reduction [9], our study shows that statin therapy in combination with lifestyle modification may be more effective in lowering the increased vascular risk. Statins are the most popular cholesterol-lowering agents and can be beneficial in the treatment of hypercholesterolemia and other related diseases. Statins act by reducing the hepatic cholesterol biosynthesis and upregulation of LDL-C receptors on the surface of hepatocytes, which then leads to enhanced removal of LDL-C from circulation. Statins also exert pleiotropic actions such as reducing the accumulation of esterified cholesterol into macrophages, increasing endothelial nitric oxide synthetase, decreasing inflammation, and increasing the stability of the atherosclerotic plaque. Furthermore, statins possess antioxidant, antiinflammatory, and antithrombotic properties. Despite the concern regarding the lowering of the seizure threshold or potential drug interaction with other AEDs [7], a number of experimental studies demonstrated that statins could show anticonvulsant effects via their influence on the neurosteroid or nitric oxide synthesis in the brain [10]. Interestingly, recent clinical studies showed that the early use of statins in patients experiencing their first ischemic stroke reduced the risk of poststroke seizures [11]. In addition, previous exposure to statin may lower the mortality risk in patients with status epilepticus [12]. Homocysteine, a nonessential amino acid with prothrombotic properties, has been implicated as an important risk factor for vascular diseases. It has been suggested that older AEDs, mostly being strong CYP450 inducers, increase homocysteine by way of the deficient cofactors for homocysteine metabolism, such as folate and vitamin B12. Hyperhomocysteinemia and hypercholesterolemia are linked to the development of atherosclerotic diseases, and the risk associated with combined hyperhomocyteinemia and hypercholesterolemia is greater than that associated with only one risk factor. Hyperhomocysteinemia can induce derangement of lipid metabolism by hyperhomocysteinemia-associated hypomethylation, which results in lower HDL-C and disturbance of blood lipids or fatty liver [13]. Several clinical studies demonstrated that statins can reduce blood homocysteine as well as cholesterol [14], and our study replicated that finding in patients with epilepsy. One unexpected but interesting result of our study was that patients in the statin group showed marked decrease in blood uric acid concentrations. Uric acid is the final product of purine metabolism in humans. Hyperuricemia not only increases the risk of gout but also possibly increases cardiovascular risk due to its relationship with atherosclerosis and increased oxidative stress. Some drugs used to treat hypercholesterolemia, such as fenofibrate, could play a possible role in decreasing the blood concentration of uric acid via an enhanced urinary excretion of uric acid. A recent meta-analysis demonstrated a significant reduction in blood uric acid levels following statin therapy, and it was suggested that this effect is not related to lowering lipids but could be attributed to the pleiotropic effects of statins [15]. An advantage of our study is the use of a prospective longitudinal design. The large majority of previous studies investigating relationships between epilepsy and atherosclerosis used a cross-sectional design. Clinical complexities and considerable confounding variables within the patient population in a cross-sectional study can obscure the pure effects of statins on vascular risk markers. We also acknowledge several
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limitations in our study. First of all, our study failed to randomly assign patients to the statin and lifestyle modification groups. Therefore, the two groups were significantly different in age because younger patients preferred only lifestyle modification as treatment. We admit that this demographic difference could affect the results, but we could not randomly assign patients due to the well-documented effects of statins in patients with increased vascular risk. The small number of patients recruited for each group and allowing clinicians to choose the type of statin used also leave the possibility of selection bias. It is possible that patients with higher vascular risk were more strongly recommended the statin treatment. Neglecting to measure other well-documented markers of atherosclerosis such as carotid artery intima media thickness was also a limitation. Finally, our study investigated the relatively shortterm effects of statin therapy, so the changes we observed may be merely temporary in nature. The long-term effects of lifestyle modification would be more apparent in studies using long-term observations. Despite these limitations, we believe that the present study has a clinical implication in that it shows that lifestyle modification and statin therapy in patients with epilepsy with increased vascular risk exhibit improved circulatory markers of vascular risk that may contribute to the acceleration of the atherosclerotic process. Future studies with a complete constellation of circulatory markers and long-term use of statins would be needed to corroborate our findings. Conflict of interest None. Acknowledgments The authors are grateful to the participants for taking part in the present study. This work was supported by Konkuk University Medical Center Research Grant 2017. References [1] Sheth RD. Metabolic concerns associated with antiepileptic medications. Neurology 2004;63(Suppl. 4):S24–9. [2] Nilsson L, Tomson T, Farahmand BY, Diwan V, Persson PG. Cause-specific mortality in epilepsy: a cohort study of more than 9,000 patients once hospitalized for epilepsy. Epilepsia 1997;38:1062–8. [3] Hamed SA. Atherosclerosis in epilepsy: its causes and implications. Epilepsy Behav 2014;41:290–6. [4] Katsiki N, Mikhailidis DP, Nair DR. The effects of antiepileptic drugs on vascular risk factors: a narrative review. Seizure 2014;23:677–84. [5] Kim DW, Lee SY, Shon YM, Kim JH. Effects of new antiepileptic drugs on circulatory markers for vascular risk in patients with newly diagnosed epilepsy. Epilepsia 2013; 54:e146-. [6] Mintzer S, Mattson RT. Should enzyme-inducing antiepileptic drugs be considered first-line agents? Epilepsia 2009;50(Suppl. 8):S42–50. [7] Gidal BE, French JA, Grossman P, Le Teuff G. Assessment of potential drug interactions in patients with epilepsy: impact of age and sex. Neurology 2009;72:419–25. [8] Lee SA, Heo K, Kim WJ, Song HK, Kim SE, Kim SH, et al. Clinical feasibility of immediate overnight switching from slow-release carbamazepine to oxcarbazepine in Korean patients with refractory partial epilepsy. Seizure 2010;19:356–8. [9] Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/ American Heart Association task force on practice guidelines. Circulation 2014; 129(Suppl. 2):S1–45. [10] Scicchitano F, Constanti A, Citraro R, De Sarro G, Russo E. Statins and epilepsy: preclinical studies, clinical trials and statin-anticonvulsant drug interactions. Curr Drug Targets 2015;16:747–56. [11] Guo J, Guo J, Li J, Zhou M, Qin F, Zang S, et al. Statin treatment reduces the risk of poststroke seizures. Neurology 2015;85:701–7. [12] Sierra-Marcos A, Alvarez V, Faouzi M, Burnand B, Rossetti AO. Statins are associated with decreased mortality risk after status epilepticus. Eur J Neurol 2015;22:402–5. [13] Obeid R, Herrmann W. Homocysteine and lipids: S-adenosyl methionine as a key intermediate. FEBS Lett 2009;583:1215–25. [14] Jiang S, Chen Q, Venners SA, Zhong G, Hsu YH, Xing H, et al. Effect of simvastatin on plasma homocysteine levels and its modification by MTHFR C677T polymorphism in Chinese patients with primary hyperlipidemia. Cardiovasc Ther 2013;31:e27-3. [15] Derosa G, Maffioli P, Reiner Z, Simental-Mendia LE, Sahebkar A. Impact of statin therapy on plasma uric acid concentrations: a systematic review and metaanalysis. Drugs 2016;76:947–56.
Please cite this article as: Kim DW, et al, The effects of lifestyle modification and statin therapy on the circulatory markers for vascular risk in patients with epilepsy, Epilepsy Behav (2017), http://dx.doi.org/10.1016/j.yebeh.2017.08.041
Contents lists available at ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Brief Communication
The effects of lifestyle modification and statin therapy on the circulatory markers for vascular risk in patients with epilepsy Dong Wook Kim a, Hyun Kyung Kim b,⁎, Eun-Kee Bae c a b c
Department of Neurology, Konkuk University School of Medicine, Seoul, Republic of Korea Department of Neurology, National Medical Center, Seoul, Republic of Korea Department of Neurology, Inha University Hospital, Incheon, Republic of Korea
a r t i c l e
i n f o
Article history: Received 11 August 2017 Revised 25 August 2017 Accepted 27 August 2017 Available online xxxx Keywords: Antiepileptic drugs Cholesterol Homocysteine Uric acid Atherosclerosis
a b s t r a c t Although long-term therapy with antiepileptic drugs can increase the risk of vascular diseases, there have been little attempts to reduce the increased vascular risk in patients with epilepsy. We conducted a prospective longitudinal study to assess the effects of lifestyle modification and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (statin) therapy on the increased circulatory markers for vascular risk in patients with epilepsy. We recruited patients with increased vascular risk such as a history of vascular events or hypercholesterolemia, and they decided whether to be treated with statin or just to modify their lifestyle. The circulatory markers of vascular risk were measured twice before and after a 3-month intervention. A total of 78 patients completed the study, and 37 of them chose to be treated with statin. A 3-month intervention with statin results in significant decreases in homocysteine (p = 0.010) and uric acid (p = 0.015) as well as total cholesterol (p b 0.001) and low-density lipoprotein (LDL) cholesterol (p b 0.001). The lifestyle modification group experienced less prominent decreases in total cholesterol (p = 0.010) and LDL cholesterol (p = 0.012). There were no reports of serious adverse events or seizure aggravation related to the statin treatment. Our findings suggest that lifestyle education is necessary in patients with epilepsy with increased vascular risk and that treatment with statin would be a well-tolerated and effective option for these patients. © 2017 Published by Elsevier Inc.
1. Introduction Antiepileptic drugs (AEDs) are commonly used in the treatment of epilepsy, and a considerable number of patients with epilepsy have a long-term or lifelong exposure to AEDs. In addition to the welldocumented metabolic derangements by the long-term use of AEDs such as body weight changes and abnormal bone metabolism [1], epidemiologic studies have demonstrated significant associations between epilepsy and comorbid cardiovascular or cerebrovascular diseases [2]. The prolonged use of some older AEDs such as carbamazepine, phenytoin, and phenobarbital was frequently implicated in the increased risk for atherosclerosis because these AEDs are potent inducers of the hepatic cytochrome P450 (CYP450) system that is extensively involved in the synthesis and metabolism of cholesterols [3]. The inducing AEDs are also related to the predisposition to atherosclerosis by altering other markers of vascular risk including homocysteine, uric acid, and C-reactive protein (CRP) [4]. In addition, several recent clinical studies observed that the prolonged use of new AEDs may also increase the vascular risk in patients with epilepsy [5]. ⁎ Corresponding author at: Department of Neurology, National Medical Center, 245 Eulji-ro, Jung-gu, Seoul, Republic of Korea. E-mail address: [email protected] (H.K. Kim).
Despite the well-established increased vascular risk in patients with epilepsy, there have been little attempts to reduce that risk in patients with epilepsy except for the recommendation of new AEDs as firstline agents [6]. However, old AEDs are still widely used with their established potency [7], and switching from an old to new AED may aggravate seizure frequency and increase the risk of adverse effects in some patients [8]. In the present study, we evaluate the effects of lifestyle modification and the use of 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase inhibitor (statins) in patients with epilepsy with increased vascular risk. 2. Methods 2.1. Patients In three tertiary referral epilepsy centers, adult patients with epilepsy between the ages of 18 and 80 years who had increased risk of cardiovascular/cerebrovascular diseases were prospectively recruited from March 2015 to February 2017. The increased risk of cardiovascular/cerebrovascular diseases was defined as (1) a previous history of cardiovascular/cerebrovascular diseases, (2) presence of radiologically identified cerebral ischemic lesions or atherosclerosis, (3) high total cholesterol (N220 mg/dl) and/or high low-density lipoprotein
http://dx.doi.org/10.1016/j.yebeh.2017.08.041 1525-5050/© 2017 Published by Elsevier Inc.
Please cite this article as: Kim DW, et al, The effects of lifestyle modification and statin therapy on the circulatory markers for vascular risk in patients with epilepsy, Epilepsy Behav (2017), http://dx.doi.org/10.1016/j.yebeh.2017.08.041
2
D.W. Kim et al. / Epilepsy & Behavior xxx (2017) xxx–xxx
cholesterol (LDL-C) (N140 mg/dl), (4) the presence of diabetes, and (5) high homocysteine level (N20 mg/dl). After receiving an explanation of their increased vascular risk, all patients were advised to modify their lifestyle (i.e., adhering to a heart-healthy diet, regular exercise habits, avoidance of tobacco products, and maintenance of a healthy weight) and were asked to decide whether to be treated also with statins or to solely modify their lifestyle. The type of statin that was chosen was based on each clinician's decision, but clinicians were recommended to follow the recent guidelines of statin therapy [9]. The study was complete after a 3-month intervention of lifestyle modification with or without statin therapy. In the group of patients receiving statin therapy, commonly known adverse events of statins such as allergic skin rash, dizziness, muscle pains, and sleep problems were more carefully evaluated during their follow-up visits. Patients were not eligible if they had a history of hemorrhagic stroke, chronic renal/hepatic disease, and concomitant administration of lipid-lowering agents and vitamin supplements. Patients who had other AED(s) added to their treatment or initial AED(s) changed to another because of inadequate seizure control or adverse events of the AED(s) were excluded from the analysis. Patients who had not taken AED(s) or statin for more than 2 weeks during the study period were also excluded. The local ethics committees approved this study, and all participants gave written informed consent. 2.2. Laboratory test and statistical analysis For all participants, venous blood samples were collected twice at baseline and at the end of 3 months of treatment after an overnight fasting. Laboratory tests for vascular risk markers included total cholesterol, triglyceride, high-density lipoprotein cholesterol (HDL-C), LDL-C, homocysteine, vitamin B12, folate, CRP, and uric acid. Patients were divided into two groups according to statin use. Between-group differences in demographics and clinical data were
tested using a Student t-test, chi-square test, or Fisher's exact test. Paired t-tests were used to assess changes in vascular risk markers before and after treatment in each group. 3. Results A total of 78 patients were recruited, and all of them completed 3 months of intervention. Thirty-seven patients chose to be treated with statins, while 41 patients wanted to only modify their lifestyle. Demographic features, clinical data, and baseline and follow-up values as well as summary results for changes in vascular risk markers are presented in Table 1. There were no significant differences in the baseline values of circulatory markers of vascular risk between the statin and lifestyle modification groups. However, patients in the lifestyle modification group were younger than patients in the statin group (48.6 ± 14.4 vs 60.8 ± 14.8, p b 0.001). In the 3-month statin therapy group, there were significant decreases in blood levels of homocysteine (from 17.6 to 12.9 μmol/l, p = 0.010) and uric acid (from 6.3 to 5.5 mg/dl, p = 0.015), as well as total cholesterol (from 201.2 to 153.5 mg/dl, p b 0.001) and LDL-C (from 121.4 to 84.6 mg/dl, p b 0.001). The lifestyle modification group experienced significant decreases in blood levels of total cholesterol (from 200.0 to 180.7 mg/dl, p = 0.010), LDL-C (from 122.7 to 107.8 mg/dl, p = 0.012), and triglyceride (from 145.5 to 110.4 mg/dl, p = 0.038). When the changes in the vascular risk markers were compared between the two groups, the changes in the blood levels of LDL-C (− 36.7 ± 38.9 vs − 14.9 ± 36.4, p = 0.013) and homocysteine (− 4.6 ± 10.7 vs 0.2 ± 7.6, p = 0.022) were significantly higher in the statin group. The changes in blood levels of total cholesterol, triglyceride, and uric acid experienced by both groups were not significantly different. None of the patients complained of adverse effects from the statin treatment or experienced aggravation of their seizures related to the
Table 1 Demographics, clinical data, and comparison of changes in vascular risk markers between the statin and lifestyle modification groups.
Age (years) Sex (female:male) Number of AEDs Measured variable
TC (mg/dl) HDL-C (mg/dl) TG (mg/dl) LDL-C (mg/dl) Homocysteine (μmol/l) Vitamin B12 (pg/ml) Folate (ng/ml) CRP (mg/l) Uric acid (mg/dl) Measured variable
TC (mg/dl) HDL-C (mg/dl) TG (mg/dl) LDL-C (mg/dl) Homocysteine (μmol/l) Vitamin B12 (pg/ml) Folate (ng/ml) CRP (mg/l) Uric acid (mg/dl)
Statin group (n = 37)
Lifestyle modification group (n = 41)
p-Value
60.8 ± 14.8 13:24 2.0 ± 1.2
48 6 ± 14.4 14:27 1.7 ± 0.8
b0.001 1.000 0.26
Statin group (n = 37)
Lifestyle modification group (n = 41)
p-Value for baseline value
Baseline value
Follow-up value
Baseline value
Follow-up value
201.2 ± 41.6 51.4 ± 21.2 132.2 ± 99.3 121.4 ± 35.2 17.6 ± 10.7 816.1 ± 461.8 10.4 ± 5.7 0.30 ± 0.36 6.3 ± 2.6
153.5 ± 36.2 51.2 ± 19.7 123.7 ± 101.0 84.6 ± 30.9 12.9 ± 3.7 811.2 ± 430.6 10.3 ± 5.6 0.25 ± 0.38 5.5 ± 1.6
200.0 ± 41.4 54.5 ± 20.7 145.5 ± 132.5 122.7 ± 25.8 14.4 ± 10.2 649.5 ± 352.2 9.5 ± 4.5 0.44 ± 1.91 6.0 ± 2.3
180. 7 ± 32.0 55.6 ± 18.2 110.4 ± 64.9 107.8 ± 26.5 14.5 ± 8.7 592.5 ± 225.7 9.2 ± 5.2 0.14 ± 0.18 5.7 ± 1.8
Lifestyle modification group (n = 41)
Statin group (n = 37)
0.904 0.507 0.843 0.620 0.183 0.075 0.454 0.647 0.684 p-Value for between groups
Change in variable
p-Value
Change in variable
p-Value
−47.6 ± 46.4 −0.1 ± 15.3 −8.5 ± 131.6 −36.7 ± 38.9 −4.6 ± 10.7 −4.9 ± 168.3 −0.08 ± 4.93 −0.04 ± 0.45 −0.8 ± 1.9
b0.001 0.957 0.698 b0.001 0.010 0.860 0.992 0.566 0.015
−19.3 ± 45.5 1.1 ± 9.6 −35.1 ± 104.8 −14.9 ± 36.4 0.2 ± 7.6 −57.0 ± 220.8 −0.30 ± 4.53 −0.30 ± 1.92 −0.38 ± 2.0
0.010 0.467 0.038 0.012 0.900 0.106 0.671 0.321 0.224
0.080 0.667 0.324 0.013 0.022 0.249 0.836 0.425 0.362
AED, antiepileptic drug; TC, total cholesterol; HDL-C, high-density lipoprotein cholesterol; TG, triglyceride; LDL-C, low-density lipoprotein cholesterol; CRP, C-reactive protein. All values are given as means ± SE or number. Statistical analyses were conducted using SPSS software (SPSS Inc., version 17.0, Chicago, IL). A p-value b0.05 is considered statistically significant in all analyses.
Please cite this article as: Kim DW, et al, The effects of lifestyle modification and statin therapy on the circulatory markers for vascular risk in patients with epilepsy, Epilepsy Behav (2017), http://dx.doi.org/10.1016/j.yebeh.2017.08.041
D.W. Kim et al. / Epilepsy & Behavior xxx (2017) xxx–xxx
seizure-threshold-lowering effect of statin or potential drug interaction with other AEDs. However, one patient reduced the dose of statin after a month of treatment because of mild muscle pain, and another patient changed statins from atorvastatin to pravastatin because of asymptomatic increases in blood transaminase enzymes. 4. Discussion This prospective longitudinal study shows that statin therapy is an effective and safe way to decrease atherogenic markers such as total cholesterol, LDL-C, homocysteine, and uric acid. Although recent guidelines on the treatment of blood cholesterol emphasized lifestyle modification as a critical component of health promotion and cardiovascular/cerebrovascular risk reduction [9], our study shows that statin therapy in combination with lifestyle modification may be more effective in lowering the increased vascular risk. Statins are the most popular cholesterol-lowering agents and can be beneficial in the treatment of hypercholesterolemia and other related diseases. Statins act by reducing the hepatic cholesterol biosynthesis and upregulation of LDL-C receptors on the surface of hepatocytes, which then leads to enhanced removal of LDL-C from circulation. Statins also exert pleiotropic actions such as reducing the accumulation of esterified cholesterol into macrophages, increasing endothelial nitric oxide synthetase, decreasing inflammation, and increasing the stability of the atherosclerotic plaque. Furthermore, statins possess antioxidant, antiinflammatory, and antithrombotic properties. Despite the concern regarding the lowering of the seizure threshold or potential drug interaction with other AEDs [7], a number of experimental studies demonstrated that statins could show anticonvulsant effects via their influence on the neurosteroid or nitric oxide synthesis in the brain [10]. Interestingly, recent clinical studies showed that the early use of statins in patients experiencing their first ischemic stroke reduced the risk of poststroke seizures [11]. In addition, previous exposure to statin may lower the mortality risk in patients with status epilepticus [12]. Homocysteine, a nonessential amino acid with prothrombotic properties, has been implicated as an important risk factor for vascular diseases. It has been suggested that older AEDs, mostly being strong CYP450 inducers, increase homocysteine by way of the deficient cofactors for homocysteine metabolism, such as folate and vitamin B12. Hyperhomocysteinemia and hypercholesterolemia are linked to the development of atherosclerotic diseases, and the risk associated with combined hyperhomocyteinemia and hypercholesterolemia is greater than that associated with only one risk factor. Hyperhomocysteinemia can induce derangement of lipid metabolism by hyperhomocysteinemia-associated hypomethylation, which results in lower HDL-C and disturbance of blood lipids or fatty liver [13]. Several clinical studies demonstrated that statins can reduce blood homocysteine as well as cholesterol [14], and our study replicated that finding in patients with epilepsy. One unexpected but interesting result of our study was that patients in the statin group showed marked decrease in blood uric acid concentrations. Uric acid is the final product of purine metabolism in humans. Hyperuricemia not only increases the risk of gout but also possibly increases cardiovascular risk due to its relationship with atherosclerosis and increased oxidative stress. Some drugs used to treat hypercholesterolemia, such as fenofibrate, could play a possible role in decreasing the blood concentration of uric acid via an enhanced urinary excretion of uric acid. A recent meta-analysis demonstrated a significant reduction in blood uric acid levels following statin therapy, and it was suggested that this effect is not related to lowering lipids but could be attributed to the pleiotropic effects of statins [15]. An advantage of our study is the use of a prospective longitudinal design. The large majority of previous studies investigating relationships between epilepsy and atherosclerosis used a cross-sectional design. Clinical complexities and considerable confounding variables within the patient population in a cross-sectional study can obscure the pure effects of statins on vascular risk markers. We also acknowledge several
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limitations in our study. First of all, our study failed to randomly assign patients to the statin and lifestyle modification groups. Therefore, the two groups were significantly different in age because younger patients preferred only lifestyle modification as treatment. We admit that this demographic difference could affect the results, but we could not randomly assign patients due to the well-documented effects of statins in patients with increased vascular risk. The small number of patients recruited for each group and allowing clinicians to choose the type of statin used also leave the possibility of selection bias. It is possible that patients with higher vascular risk were more strongly recommended the statin treatment. Neglecting to measure other well-documented markers of atherosclerosis such as carotid artery intima media thickness was also a limitation. Finally, our study investigated the relatively shortterm effects of statin therapy, so the changes we observed may be merely temporary in nature. The long-term effects of lifestyle modification would be more apparent in studies using long-term observations. Despite these limitations, we believe that the present study has a clinical implication in that it shows that lifestyle modification and statin therapy in patients with epilepsy with increased vascular risk exhibit improved circulatory markers of vascular risk that may contribute to the acceleration of the atherosclerotic process. Future studies with a complete constellation of circulatory markers and long-term use of statins would be needed to corroborate our findings. Conflict of interest None. Acknowledgments The authors are grateful to the participants for taking part in the present study. This work was supported by Konkuk University Medical Center Research Grant 2017. References [1] Sheth RD. Metabolic concerns associated with antiepileptic medications. Neurology 2004;63(Suppl. 4):S24–9. [2] Nilsson L, Tomson T, Farahmand BY, Diwan V, Persson PG. Cause-specific mortality in epilepsy: a cohort study of more than 9,000 patients once hospitalized for epilepsy. Epilepsia 1997;38:1062–8. [3] Hamed SA. Atherosclerosis in epilepsy: its causes and implications. Epilepsy Behav 2014;41:290–6. [4] Katsiki N, Mikhailidis DP, Nair DR. The effects of antiepileptic drugs on vascular risk factors: a narrative review. Seizure 2014;23:677–84. [5] Kim DW, Lee SY, Shon YM, Kim JH. Effects of new antiepileptic drugs on circulatory markers for vascular risk in patients with newly diagnosed epilepsy. Epilepsia 2013; 54:e146-. [6] Mintzer S, Mattson RT. Should enzyme-inducing antiepileptic drugs be considered first-line agents? Epilepsia 2009;50(Suppl. 8):S42–50. [7] Gidal BE, French JA, Grossman P, Le Teuff G. Assessment of potential drug interactions in patients with epilepsy: impact of age and sex. Neurology 2009;72:419–25. [8] Lee SA, Heo K, Kim WJ, Song HK, Kim SE, Kim SH, et al. Clinical feasibility of immediate overnight switching from slow-release carbamazepine to oxcarbazepine in Korean patients with refractory partial epilepsy. Seizure 2010;19:356–8. [9] Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/ American Heart Association task force on practice guidelines. Circulation 2014; 129(Suppl. 2):S1–45. [10] Scicchitano F, Constanti A, Citraro R, De Sarro G, Russo E. Statins and epilepsy: preclinical studies, clinical trials and statin-anticonvulsant drug interactions. Curr Drug Targets 2015;16:747–56. [11] Guo J, Guo J, Li J, Zhou M, Qin F, Zang S, et al. Statin treatment reduces the risk of poststroke seizures. Neurology 2015;85:701–7. [12] Sierra-Marcos A, Alvarez V, Faouzi M, Burnand B, Rossetti AO. Statins are associated with decreased mortality risk after status epilepticus. Eur J Neurol 2015;22:402–5. [13] Obeid R, Herrmann W. Homocysteine and lipids: S-adenosyl methionine as a key intermediate. FEBS Lett 2009;583:1215–25. [14] Jiang S, Chen Q, Venners SA, Zhong G, Hsu YH, Xing H, et al. Effect of simvastatin on plasma homocysteine levels and its modification by MTHFR C677T polymorphism in Chinese patients with primary hyperlipidemia. Cardiovasc Ther 2013;31:e27-3. [15] Derosa G, Maffioli P, Reiner Z, Simental-Mendia LE, Sahebkar A. Impact of statin therapy on plasma uric acid concentrations: a systematic review and metaanalysis. Drugs 2016;76:947–56.
Please cite this article as: Kim DW, et al, The effects of lifestyle modification and statin therapy on the circulatory markers for vascular risk in patients with epilepsy, Epilepsy Behav (2017), http://dx.doi.org/10.1016/j.yebeh.2017.08.041
