Prevalence of clinical manifestations of metabolic syndrome in patients with epilepsy treated with antiepileptic drugs (a pilot study)

Background. Pharmacotherapy of secondary metabolic syndrome (MetS) induced by antiepileptic drugs (AEDs) remains unresolved issue in epileptology. The mechanisms of development and incidence of metabolic disorders (changes in eating behavior, weight gain, lipid and carbohydrate metabolism disturbances, etc.) in patients with epilepsy taking AEDs long-term remain poorly understood. AED-induced MetS (AED-MetS) impairs quality of life and reduces life expectancy in patients with epilepsy, increasing the risk of cardiovascular disease, type 2 diabetes mellitus, and abdominal obesity.

Objective: To investigate incidence of metabolic disorders induced by long-term use of AEDs of various generations in monotherapy and polytherapy regimens in adult patients with epilepsy.

Material and Methods. A pilot, single-center, open-label, observational, clinical, cross-sectional, comparative study was conducted in patients with epilepsy taking valproic acid (VPA), lamotrigine (LTG), and levetiracetam (LEV). The total sample consisted of 60 participants, including 45 patients with epilepsy (study group) and 15 clinically healthy volunteers (control group). Patients in main group were divided into subgroups based on the prescribed AED. The mean age of the participants was 37.5±12.6 years. The scope of the research included a clinical somatic and neurological examination, anthropometry (height, weight, waist and hip circumferencеs), a pharmacological history, as well as clinical and biochemical blood tests (serum biomarker analysis, AED-MetS).

Results. It was found that AED-MetS anthropometric biomarkers peaked for body mass index (p=0.015), waist circumference (p=0.048), and hip circumference (p=0.024), which were significantly higher in the VPA subgroup compared to control group. In contrast, no such changes were observed in LTG and LEV subgroups when compared to control group (p>0.05). Abdominal fat distribution was significantly more common in VPA subgroup compared to newer-generation AEDs (LTG and LEV) and control group. C-reactive protein with significantly higher level in VPA subgroup (p=0.02) was most sensitive laboratory biomarker for AED-MetS, confirming the role for AED-induced systemic inflammation in developing metabolic disorders.

Conclusion. The prevalence of the examined AED-induced metabolic disorders was higher in patients receiving VPA vs. LTG and LEV. However, AED-MetS laboratory (biochemical) biomarkers excepting C-reactive protein, had no clinical significance. Thus, it may account for a need to search for new specific and sensitive AED-MetS biomarkers to be introduced in real-world clinical practice.

1. World Health Organization. Epilepsy: a public health imperative. Available at: https://www.who.int/publications/i/item/epilepsy-a-public-health-imperative (accessed 15.08.2025).

2. Avakyan G.N. Questions modern epileptology. Epilepsia i paroksizmal'nye sostoania / Epilepsy and Paroxysmal Conditions. 2015; 7 (4): 16–21 (in Russ.).

3. Romanov A.S., Sharakhova E.F., Shova N.I., Mikhailov V.A. Cost of epilepsy in the Russian Federation. Epilepsia i paroksizmal'nye sostoania / Epilepsy and Paroxysmal Conditions. 2024; 16 (3): 212–22 (in Russ.). https://doi.org/10.17749/2077-8333/epi.par.con.2024.186.

4. Zhang Y.J., Kong X.M., Lv J.J., et al. Analysis of the global burden of disease study highlights the global, regional, and national trends of idiopathic epilepsy epidemiology from 1990 to 2019. Prev Med Rep. 2023; 36: 102522. https://doi.org/10.1016/j.pmedr.2023.102522.

5. Willems L.M., Watermann N., Richter S., et al. Incidence, risk factors and consequences of epilepsy-related injuries and accidents: a retrospective, single center study. Front Neurol. 2018; 9: 414. https://doi.org/10.3389/fneur.2018.00414.

6. Shnayder N.A., Sadikova A.V., Nikulina S.Yu., Shnayder V.A. Sudden unexpected death in epilepsy. Medicine of Extreme Situations. 2011; 2: 54–64 (in Russ.).

7. Terian R.A., Serdyuk S.E., Davtyan K.V., Drapkina O.М. Electrocardiographic presentation at ictal and postictal periods of epileptic seizure. Russian Journal of Cardiology. 2018; 23 (7): 92–102 (in Russ.). https://doi.org/10.15829/1560-4071-2018-7-92-102.

8. Shnayder N.A., Petrova M.M., Petrov K.V., et al. Heart rate and conductivity disorders in juvenile myoclonic epilepsy: genetic predictors. Epilepsia i paroksizmal'nye sostoania / Epilepsy and Paroxysmal Conditions. 2020; 12 (4): 237–47. https://doi.org/10.17749/2077-8333/epi.par.con.2020.045.

9. Dreier J.W., Laursen T.M., Tomson T., et al. Cause-specific mortality and life years lost in people with epilepsy: a Danish cohort study. Brain. 2023; 146 (1): 124–34. https://doi.org/10.1093/brain/awac042.

10. De Bellis M., d'Orsi G., Rubino E.M., et al. Adverse effects of antiseizure medications: a review of the impact of pharmacogenetics and drugs interactions in clinical practice. Front Pharmacol. 2025; 16: 1584566. https://doi.org/10.3389/fphar.2025.1584566.

11. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002; 106 (25): 3143–421.

12. The IDF consensus worldwide definition of the metabolic syndrome. Available at: https://idf.org/media/uploads/2023/05/attachments-30.pdf (accessed 15.08.2025).

13. Nazish S. Obesity and metabolic syndrome in patients with epilepsy, their relation with epilepsy control. Ann Afr Med. 2023; 22 (2): 136–44. https://doi.org/10.4103/aam.aam_139_22.

14. Kassaw A.B., Endale H.T., Tesfa K.H., Molla M.D. Metabolic syndrome and its associated factors among epileptic patients at Dessie Comprehensive Specialized Hospital, Northeast Ethiopia; a hospital-based comparative cross-sectional study. PLoS One. 2022; 17 (12): e0279580. https://doi.org/10.1371/journal.pone.0279580.

15. Shnayder N.A., Pekarets N.A., Pekarets N.I., et al. The role of microRNAs as regulators of systemic inflammatory response in anticonvulsant-induced metabolic syndrome. Epilepsia i paroksizmal'nye sostoania / Epilepsy and Paroxysmal Conditions. 2025; 17 (2): 208–26 (in Russ.). https://doi.org/10.17749/2077-8333/epi.par.con.2025.239.

16. Shnayder N.A., Pekarets N.A., Pekarets N.I., et al. MicroRNAs as epigenetic biomarkers of pathogenetic mechanisms of the metabolic syndrome induced by antiseizure medications: systematic review. J Clin Med. 2025; 14 (7): 2432. https://doi.org/10.3390/jcm14072432.

17. Shnayder N.A., Grechkina V.V., Kissin M.Ya., et al. Role of neuropeptide Y in development of valproate-induced eating behaviour disorder. Epilepsia i paroksizmal'nye sostoania / Epilepsy and Paroxysmal Conditions. 2024; 16 (4): 349–61. https://doi.org/10.17749/2077-8333/epi.par.con.2024.207.

18. Martinc B., Grabnar I., Milosheska D., et al. A cross-sectional study comparing oxidative stress in patients with epilepsy treated with old and new generation antiseizure medications. Medicina. 2024; 60 (8): 1299. https://doi.org/10.3390/medicina60081299.

19. Meenakshi-Sundaram S., Sankaranarayanan M. Epilepsy, phenytoin, and atherogenic risk – current perspectives. Neurol India. 2021; 69 (4): 962–3. https://doi.org/10.4103/0028-3886.325320.

20. Sánchez J.D., Gómez-Carpintero J., González J.F., Menéndez J.C. Twenty-first century antiepileptic drugs. An overview of their targets and synthetic approaches. Eur J Med Chem. 2024; 272: 116476. https://doi.org/10.1016/j.ejmech.2024.116476.

21. Nair S.S., Harikrishnan S., Sarma P.S., Thomas S.V. Metabolic syndrome in young adults with epilepsy. Seizure. 2016; 37: 61–4. https://doi.org/10.1016/j.seizure.2016.03.0021-2.

22. Biton V., Mirza W., Montouris G., et al. Weight change associated with valproate and lamotrigine monotherapy in patients with epilepsy. Neurology. 2001; 56 (2): 172–7. https://doi.org/10.1212/wnl.56.2.172.

23. Adjei N.K., Samkange-Zeeb F., Boakye D., et al. Ethnic differences in metabolic syndrome in high-income countries: a systematic review and meta-analysis. Rev Endocr Metab Disord. 2024; 25 (4): 727–50. https://doi.org/10.1007/s11154-024-09879-9.

24. Fahed G., Aoun L., Bou Zerdan M., et al. Metabolic syndrome: updates on pathophysiology and management in 2021. Int J Mol Sci. 2022; 23 (2): 786. https://www.doi.org/10.3390/ijms23020786.

25. Avakyan G.N., Blinov D.V., Lebedeva A.V., et al. ILAE classification of the epilepsies: the 2017 revision and update. Epilepsia i paroksizmal'nye sostoania / Epilepsy and Paroxysmal Conditions. 2017; 9 (1): 6–25 (in Russ.). https://doi.org/10.17749/2077-8333.2017.9.1.006-025.

26. Blinov D.V., Petrukhin A.S., Voronkova K.V., et al. The ILAE classification of epileptic seizures: the 2025 update. Epilepsia i paroksizmal'nye sostoania / Epilepsy and Paroxysmal Conditions. 2025; 17 (2): 122–41 (in Russ.). https://doi.org/10.17749/2077-8333/epi.par.con.2025.251.

27. Wang S., Zhang L., Wu Y., Ma J. Clinical patterns of metabolic syndrome in first-hospitalized major depressive disorder patients: comparison of antidepressant-exposed and drug-naïve groups. Neuropsychiatr Dis Treat. 2024; 20: 2159–68. https://doi.org/10.2147/NDT.S494619.

28. Khasanova A.K., Dobrodeeva V.S., Shnayder N.A., et al. Blood and urinary biomarkers of antipsychotic-induced metabolic syndrome. Metabolites. 2022; 12 (8): 726. https://doi.org/10.3390/metabo12080726.

29. Shnayder N.A., Nasyrova R.F., Pekarets N.A., et al. Circulating microRNAs are promising biomarkers for assessing the risk of antipsychotic-induced metabolic syndrome (review): part 1. Safety and Risk of Pharmacotherapy. 2025; 13 (3): 344–56 (in Russ.). https://doi.org/10.30895/2312-7821-2025-478.

30. Shnayder N.A., Grechkina V.V., Khasanova A.K., et al. Therapeutic and toxic effects of valproic acid metabolites. Metabolites. 2023; 13 (1): 134. https://doi.org/10.3390/metabo13010134.

31. Harris J.A., Murphy J.A. Lacosamide and epilepsy. CNS Neurosci Ther. 2011; 17 (6): 678–82. https://doi.org/10.1111/j.1755-5949.2010.00198.x.

32. Kim B.M., Ryu S.Y., Han M.A., Choi S.W. Loss of significant association between high-sensitivity C-reactive protein (hs-CRP) and metabolic syndrome after adjustment for waist circumference found in 2022 Korea National Health and Nutrition Examination Survey data. J Physiol Anthropol. 2025; 44 (1): 16. https://doi.org/10.1186/s40101-025-00396-5.

33. Devaraj S., Singh U., Jialal I. Human C-reactive protein and the metabolic syndrome. Curr Opin Lipidol. 2009; 20 (3): 182–9. https://doi.org/10.1097/MOL.0b013e32832ac03e.

34. Basta-Kaim A., Budziszewska B., Lasoń W. Effects of antiepileptic drugs on immune system. Przegl Lek. 2008; 65 (11): 799–802 (in Polish).

35. Dambach H., Hinkerohe D., Prochnow N., et al. Glia and epilepsy: experimental investigation of antiepileptic drugs in an astroglia/microglia co-culture model of inflammation. Epilepsia. 2014; 55 (1): 184–92. https://doi.org/10.1111/epi.12473.

36. Sheth R.D., Montouris G. Metabolic effects of AEDs: impact on body weight, lipids and glucose metabolism. Int Rev Neurobiol. 2008; 83: 329–46. https://doi.org/.1016/S0074-7742(08)00019-6.

37. Asadi-Pooya A.A., Sperling M.R. Antiseizure medications. 3rd ed. Oxford Academic; 2022: 193–6. https://doi.org/10.1093/med/9780197541210.003.0015.

38. Shnayder N.A., Grechkina V.V., Trefilova V.V., et al. Valproate-induced metabolic syndrome. Biomedicines 2023; 11 (5): 1499. https://doi.org/10.3390/biomedicines11051499.

39. Tien N., Wu T.Y., Lin C.L., et al. Association of epilepsy, anti-epileptic drugs (AEDs), and type 2 diabetes mellitus (T2DM): a population-based cohort retrospective study, impact of AEDs on T2DM-related molecular pathway, and via peroxisome proliferator-activated receptor γ transactivation. Front Endocrinol. 2023; 14: 1156952. https://doi.org/10.3389/fendo.2023.1156952.

40. Dmitrenko D.V. Personalized medicine in neurology. Personalized Psychiatry and Neurology. 2025; 5 (2): 1.