Effects of New Antiepileptic Drugs on Homocysteine in Epileptic Patients: A Systematic Review and Meta-Analysis

Zheng, Danyi; Bao, Yaya; Gu, Jiayi; Lv, Tian; Yang, Yue

doi:https://doi.org/10.1155/2023/5878004

Journal of Clinical Pharmacy and Therapeutics

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Abstract Introduction Methods Results Discussion Conclusions Data Availability Conflicts of Interest Authors’ Contributions Acknowledgments References Copyright Related Articles

Research Article | Open Access

Volume 2023 | Article ID 5878004 | https://doi.org/10.1155/2023/5878004

Effects of New Antiepileptic Drugs on Homocysteine in Epileptic Patients: A Systematic Review and Meta-Analysis

Danyi Zheng,¹Yaya Bao,²Jiayi Gu,³Tian Lv,¹and Yue Yang¹

Academic Editor: Claudio De Lucia

Received09 Dec 2022

Revised09 Mar 2023

Accepted11 Mar 2023

Published21 Apr 2023

Abstract

Background. Previous studies have reported inconsistent findings regarding the association between elevated plasma homocysteine (Hcy) levels and new antiepileptic drugs (AEDs). In this meta-analysis, we aimed to assess the effects of new AEDs on Hcy. Methods. PubMed, Embase, Cochrane, and Web of Science databases were searched from inception to June 2022 for articles that focused on the effects of new AEDs on Hcy. A meta-analysis was performed using Stata 16.0 software. The results were presented as the mean difference (MD) and corresponding to 95% confidence intervals (CIs) comparing epileptic patients with new AEDs to the control subjects. Results. A total of 11 studies were included in the meta-analysis. Hcy was markedly increased in the new AEDs group compared with the control group (MD = 2.220, 95% CI: 0.596–3.844, ), with a high degree of heterogeneity (I² = 99.5%). In the drugs subgroup, the oxcarbazepine (OXC) (MD = 2.30, 95% CI: −1.11–5.72, ) and lamotrigine (LTG) (MD = 1.14, 95% CI: −0.209–2.482, ) groups had no significant differences when compared with the control group. The levetiracetam (LEV) (MD = 1.81, 95% CI: 1.03–2.18, ) and topiramate (TPM) (MD = 6.922, 95% CI: 0.788–13.055, ) groups were significantly higher than the control group. Conclusions. The new AEDs, especially TPM and LEV, may increase the plasma of Hcy. The role of Hcy in patients with epilepsy who are given TPM and LEV should not be ignored in clinical situations. Patients with epilepsy who also have a high-risk vascular profile are recommended to use OXC and LTG.

1. Introduction

Epilepsy is a chronic neurological disorder that affects people of all ages, races, and social classes across the world [1]. Epilepsy requires long-term or lifelong therapy with antiepileptic drugs (AEDs). However, long-term AED therapy is associated with a wide range of chronic adverse effects, including metabolic and endocrine disturbances, impairments in cognition and vascular risks, such as hyperlipidaemia, endocrine disturbances, and hyperhomocysteinemia (HHcy) [2–4].

Homocysteine (Hcy), which is an intermediate product in one-carbon metabolism, is a hydroxy-containing amino acid generated by the demethylation of methionine in the liver and certain other tissues [5, 6]. Hcy can be remethylated and resynthesized into methionine with the assistance of folic acid and vitamin B12. Older AEDs, such as carbamazepine, phenytoin, and phenobarbital, may enhance the activity of the hepatic enzymes and cause a deficiency of folate and vitamin B12 in patients with epilepsy [7]. Valproic acid (VPA),one of most commonly used AEDs ,increased serum Hcy levels in epileptic children receiving VPA monotherapy [8].

Topiramate (TPM), oxcarbazepine (OXC), lamotrigine (LTG), and levetiracetam (LEV) are the most common new AEDs used in monotherapy or polytherapy worldwide. Compared with older AEDs, these new AEDs are less likely to influence hepatic enzymes [9] and are supposed to be less likely to disrupt Hcy metabolism [10]. In recent years, some case-control studies have been conducted to explore the correlation between Hcy and new AEDs [11–20]. In a case study, Sun et al. argued that the new AEDS do not cause elevated blood ammonia and Hcy levels, so they have high drug safety. [11]. However, some studies believe that the two are related [12, 15, 19]. For example, Zhu et al. demonstrated that AED monotherapy with OXC (vs control: ) was an independent risk factor for higher Hcy levels [19]. Thus, in this meta-analysis, the effects of new AEDs on plasma Hcy levels in patients with epilepsy were investigated.

2. Methods

2.1. Search Strategy

Following the PRISMA2020 statement, three English databases such as PubMed, Web of Science, and Cochrane Library, and three Chinese databases such as China National Knowledge Infrastructure (CNKI), Wanfang Database, and Weipu Database were systematically searched. The retrieval time is from the establishment of the database to July 2022. Medical subject heading (MeSH) term was used to search the English database. The search terms were as follows: levetiracetam, lamotrigine, topiramate, oxcarbazepine, and homocysteinemia. In addition, in order to expand the scope of the target literature search, we obtained the target literature by reviewing the references included in the study.

2.2. Inclusion Criteria

Eligible research met the following criteria: P: Patients treated with new AED monotherapy were included. Patients with the following conditions were excluded: multiple treatment of two or more AEDs; illness known to influence lipid profiles, such as metabolic syndromes, diabetes, thyroid dysfunction, and autoimmune diseases requiring medications; a history of alcohol and substance dependence or abuse; and malignancies. I: The intervention applied in the experimental group was new AED (LTG, LEV, TPM, and OXC) monotherapy. The doses of new AEDs were not limited. C: The comparison was the healthy control group. O: The primary outcome indicator was the level of Hcy.

2.3. Data Extraction

According to the inclusion criteria, two authors performed the study selection independently. After two authors excluded duplicate studies, article titles and abstracts were screened, and potential studies were further reviewed in full-text articles. Any disagreement was resolved by discussion with a third author.

The data were recorded in a Microsoft Excel spreadsheet table format and included categories of the first author, publication year, study country, study design, sex, sample size, age, new AEDs, and duration.

2.4. Quality Assessment

Two authors separately assessed the quality of the study using the Newcastle–Ottawa Scale (NOS) to assess cross-sectional studies. Generally, studies with no fewer than six stars were considered to be high quality. Any disagreement was resolved via discussion with a third author.

2.5. Statistical Analysis

All statistical analyses were performed using Stata 16.0 (Stata Corp., College Station, TX, USA). The Hcy was measured using the same scales in each study; therefore, the mean difference (MD) and the 95% confidence interval (CI) were employed. The I² was used to examine between-study heterogeneity. An I² value >50% was considered as significant heterogeneity. The data were analysed using a random-effects model. If the I² value was <50%, the heterogeneity was acceptable. The data were analysed with a fixed-effects model. Statistical significance was set at . An obvious heterogeneity was treated by subgroup analysis or sensitivity analysis, or descriptive analysis only. A meta-regression analysis was used to identify the source of heterogeneity among studies. Publication biases were assessed by Egger’s tests (Stata 16.0) [20]. Two-sided was considered statistically significant.

3. Results

3.1. Study Identification and Selection

A flow diagram of the identification of studies is shown in Figure 1. From a total of 134 studies that were identified from the initial search, after removing duplication, 73 articles remained. After the abstracts and titles of 54 studies were reviewed, 18 articles remained. Through the full-text review, seven studies were excluded. Finally, 11 studies were included in the meta-analysis.

3.2. Characteristics of Included Studies

From the 11 studies included, five compared LTG with a control group [11, 12, 14, 15, 17]; seven compared LEV with a control group [11, 14, 16–19]; five compared OXC with a control group [10, 11, 13, 18]; and two compared TPM with a control group [11, 14].

Six of the studies recruited patients from Iran, Turkey, and Egypt [10, 13, 14, 16, 17, 19]; four studies recruited patients from China [11, 12, 15, 18]; and one study recruited patients from Europe [11].

Three of the studies [14, 18, 19] involved child patients and eight [10–13, 15–17] studies enrolled adult patients. Among the included studies, all 11 were case-control studies. The characteristics of the individual studies are presented in Table 1.

3.3. Quality Assessment of the Risk of Bias

For the included studies, the risk of bias was assessed using the NOS. The results of quality assessments of the 11 included studies are presented in Table 2.

3.4. Outcome

3.4.1. Meta-Analysis of Hcy

All 11 studies (n = 1265) reported effects on Hcy related to new AEDs. The random-effects model showed that Hcy in the new AEDs was significantly higher than in the control group (MD = 2.22, 95% CI: 0.6–3.84, ), with high heterogeneity (I² = 99.5%) (Figure 2).

3.4.2. Meta-Analysis of the Effects of OXC on Hcy

Five studies (n = 615) reported data related to the effects of Hcy. The random-effects model showed that in the OXC group there was no significant difference in Hcy compared with the control group (MD = 2.30, 95% CI: −1.11–5.72, ), with high heterogeneity (I² = 97.7%) (Figure 3).

A subgroup analysis was performed according to the country and age (children: <18 years, adults: >18 years) of the patients. For patients being treated with OXC in the Middle East, there was no significant difference in Hcy (MD = 0.43, 95% CI: −1.13–1.99, ) compared with the control group. Patients being treated with OXC in China also demonstrated no significant difference in Hcy (MD = 1.62, 95% CI: −0.12–3.36, ) compared with the control group. The results of other subgroup analyses on the ages of the patients in the five studies are presented in Table 3.

3.4.3. Meta-Analysis of the Effects of LEV on Hcy

Seven studies (n = 704) reported data related to the effects of Hcy. The random-effects model showed that in the LEV group, Hcy was significantly higher than in the control group (MD = 1.81, 95% CI: 1.03–2.18, ), with high heterogeneity (I² = 77%) (Figure 4).

A subgroup analysis was performed according to the country and age of the patients. The Hcy in patients being treated with LEV in the Middle East (MD = 1.77, 95% CI: 0.01–3.54, ) was higher than in the control group. Patients being treated with LEV in China demonstrated no significant difference (MD = 0.87, 95% CI: −0.09–1.83, ) in Hcy compared with the control group. The results of other subgroup analyses on the age of the patients in the seven studies are presented in Table 3.

3.4.4. Meta-Analysis of the Effects of LTG on Hcy

Five studies (n = 575) reported that LTG was related to the effects on Hcy. The random-effects model showed that for patients in the LTG group, Hcy was significantly higher than for those in the control group (MD = 1.14, 95% CI: −0.21–2.48, ), with high heterogeneity (I² = 86.3%) (Figure 5). A subgroup analysis was performed according to the country and age.

The Hcy in patients being treated with LTG in the Middle East (MD = 3.900, 95% CI: 2.178–5.622, ) was higher than that in the control group. There was also no significant difference in the Hcy of patients being treated with LTG in China (MD = −0.087, 95%CI: −0.915–0.742, ) when compared with the control group. The results of other subgroup analyses on the age of the patients in the five studies are presented in Table 3.

3.4.5. Meta-Analysis of the Effects of TPM on Hcy

Two studies (n = 318) reported data related to the effects of Hcy. The random-effects model showed that Hcy in patients being treated with TPM was significantly higher than in the control group (MD = 6.92, 95% CI: 0.79–13.06, ) (Figure 6), with high heterogeneity (I² = 98.3%).

3.5. Sensitivity Analysis

Excluding the included studies one by one and reconducting the meta-analysis did not significantly influence the outcomes, indicating that the results of the present meta-analysis were promising. Meta-regression utilised the method of country, age, duration of drugs (≥1 Y, <1 Y), and sample size (>20, ≤20), but none of these factors were found to be significant in the model.

3.6. The Risk of Bias

The Egger test was employed to assess the potential for publication bias. As shown in Table 4 and Figure 7, no potential publication bias was shown when comparing the Hcy level in patients treated with new AEDs and all subgroups (LEV, LTG, TPM, and OXC monotherapy) with healthy control groups based on evidence from the Egger tests.

4. Discussion

The meta-analysis showed that new AEDs significantly increased the plasma of Hcy levels with controls. Regarding specific new AEDs, the use of TPM or LEV monotherapy had a significant effect on the plasma of Hcy, while LTG and OXC did not. However, these findings must be interpreted with caution due to the presence of significant heterogeneity.

Hcy is synthesized as an intermediate metabolite from methionine metabolism. It is converted to cysteine via the transsulfuration pathway or resynthesized back to methionine via the remethylation pathway [21, 22]. Hcy is also affected by multiple factors, such as chronic disease, being overweight or obese, alcohol consumption, unhealthy diet, drugs, and physical exercise. HHcy is a risk factor for several neurological disorders, such as stroke, cognitive impairment, Parkinson’s disease, multiple sclerosis, and epilepsy [23, 24]. In the meantime, Hcy leads to cognitive changes and a significantly increased risk of cerebrovascular disease in children and young adults with HHcy. The current studies demonstrated that AEDs, especially the new AEDs, influence Hcy levels.

Nevitt et al. proposed that enzyme-inducing antiepileptic drugs (EIAEDs) will increase the plasma of Hcy levels in patients with epilepsy [25]. Thus, in this study, we investigated the effects of new AEDs, specifically TPM, OXC, LTG, and LEV, on the levels of plasma Hcy in patients with epilepsy.

In our meta-analysis, OXC did not have any significant effect on Hcy levels. This is the same result as a previous meta-analysis [26]. However, the heterogeneity of the two studies differed considerably. In previous studies, some used a small sample size, which may have contributed to the inconsistent heterogeneity [26]. LEV is a new type of AED, which, compared with sodium valproate, did not inhibit or induce hepatic enzymes to produce clinically relevant interactions [9]. However, LEV significantly increased the plasma of Hcy levels with control. Furthermore, the mechanism underlying this phenomenon is currently unclear. The included studies showed that LEV had a controversial effect on the increased plasma of Hcy levels [11, 14]. In the country subgroup, the study from China showed that LEV was not related to Hcy levels [11, 18]. The study by Belcastro [17] from Europe showed that LEV significantly increased Hcy, but the literature did not report the potential effects of body mass index (BMI) and blood lipids on Hcy [27, 28]. Therefore, the positive results of LEV may be related to heterogeneity or multiple confounding factors. TPM should increase the plasma of Hcy [11, 14] as it is a mild inducer of drug-metabolizing enzymes in the liver [29]. Enzyme-inducing antiepileptic drugs (EIAEDs) attenuated serum levels of vitamin B12 and folate [7]. This is most likely the reason why plasma Hcy levels in the TPM group were significantly higher than those in the control group. Therefore, the results for TPM may be affected by the sample size and the large heterogeneity. LTG was devoid of inducing drug-metabolising effects on the liver. In our meta-analysis, LTG had no significant difference when compared with the control group. In the country subgroup, the result for LTG in patients being treated in Europe and the Middle East was inconclusive since only one study was included in the present meta-analysis.

In the present study, the subgroup relating to age revealed that Hcy levels were significantly higher in child patients receiving OXC and LEV therapy but not in adults, which further weakened the overall MD. We speculate that this age-related difference may be due to two main factors: (1) Children may have higher BMIs and lipids than the control group, especially in the Middle East [14]; (2) the sample of the child subgroup was small, which indicates the need for further research.

This is the first meta-analysis that showed the relationship between Hcy and new AEDs. Our study only included cross-sectional studies in the analysis, and there are still several potential limitations. First, there was significant heterogeneity in our study. Although we explored the source of heterogeneity through meta-regression and subgroup analysis, we could not find heterogeneity through other aspects. This discrepancy may be due to differences in diet. Second, the TPM and LTG groups in the sample were not large enough, which may have affected the accuracy of the results. Therefore, larger-scale studies should be conducted to confirm our data. Third, different methods or instruments for detecting the serum or plasma Hcy levels may have also biased the results. Fourth, some other confounding factors were unable to be taken into consideration due to the absence of the data in the included papers, such as other vascular risks (including lipid profiles and weight gain). In addition, in this meta-analysis, a few samples were excluded, which usually causes publication bias. Finally, our study would benefit from further research, as we only dealt with articles written in English.

5. Conclusions

New AEDs (especially TPM and LEV) may increase the plasma of homocysteinemia. The role of Hcy in patients with epilepsy being treated with TPM and LEV should not be ignored in clinical situations. Patients with epilepsy who also have a high-risk vascular profile are recommended to use OXC and LTG.

Data Availability

Data have been included in the article

Conflicts of Interest

The authors declare that there are no conflicts of interest.

Authors’ Contributions

ZDY and BYY conceived of the study; GJY and LT participated in its design and data analysis and statistics; and YY was contributed to methodology and supervision of the study. All authors helped to draft the manuscript, read, and approved the final manuscript. DZ and YB contributed equally to this study.

Acknowledgments

This article was funded by the Shaoxing Science and Technology Plan Project (grant no. 2018C30147).

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Copyright © 2023 Danyi Zheng et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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