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. 2023 May 16;100(20):e2071-e2082.
doi: 10.1212/WNL.0000000000207222. Epub 2023 Mar 24.

Association of Long-term Antiseizure Medication Use and Incident Type 2 Diabetes Mellitus

Wei-En Johnny Tseng  1 , Chun-Wei Chang  1 , Jawl-Shan Hwang  1 , Po-Chuan Ko  1 , Chun-Jing Liu  1 , Siew-Na Lim  2
Affiliations

Association of Long-term Antiseizure Medication Use and Incident Type 2 Diabetes Mellitus

Wei-En Johnny Tseng et al. Neurology. .

Abstract

Background and objectives: Diabetes mellitus (DM) contributes significantly to metabolic syndrome and cardiovascular events, and it may be a comorbidity of epilepsy. The objective of this study was to investigate whether long-term antiseizure medication (ASM) use is associated with the risk of developing type 2 diabetes.

Methods: We analyzed data from the Chang Gung Research Database. Patients aged ≥45 years who received ASM treatment from January 2001 to May 2019 were identified. Patients with DM-associated diseases and short-term ASM use were excluded. The patients were classified into nonenzyme interaction, enzyme-inducing, enzyme-inhibiting, and mixed ASM groups. The rate of incident diabetes associated with individual ASM was further analyzed. Propensity score weighting was performed to balance between-group differences. Analyses were conducted with Cox proportional regression models and stabilized inverse probability of treatment weighting (IPTW). Hazard ratios (HRs) were calculated at 3, 4, 6, and 9 years after the index date and the end of follow-up.

Results: A total of 5,103 patients were analyzed, of whom 474 took nonenzyme interaction ASMs, 1,156 took enzyme-inducing ASMs, 336 took enzyme-inhibiting ASMs, and 3,137 took mixed ASMs. During follow-up (39,248 person-years), 663 patients developed new-onset DM, and the prevalence was 13.0%. The incidence of DM plateaued at 6-9 years after ASM initiation. Enzyme-inhibiting ASMs were significantly associated with a higher HR starting at the third year and then throughout the study period. The HRs were 1.93 (95% CI 1.33-2.80), 1.85 (95% CI 1.24-2.75), and 2.08 (95% CI 1.43-3.03) in unadjusted, adjusted, and stabilized IPTW models, respectively, at the end of follow-up. The dosing of ASM did not increase the risk of DM, and none of the individual ASM analyses reached statistical significance.

Discussion: The long-term use of enzyme-inhibiting ASMs was associated with an increased risk of incident DM, and the risk increased with the duration of treatment. These findings may guide the choice of drugs in those requiring long-term ASM therapy, particularly in high-risk individuals.

Classification of evidence: This study provides Class IV evidence that enzyme-inhibiting ASMs were associated with an increased risk of developing DM compared with nonenzyme interaction ASMs.

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Conflict of interest statement

The authors report no disclosures relevant to the manuscript. Go to Neurology.org/N for full disclosures.

Figures

Figure 1
Figure 1. Flowchart of the Study Cohorts
ASM = antiseizure medication; DM = diabetes mellitus; TSH = thyroid-stimulating hormone.
Figure 2
Figure 2. Cumulative Incidence of DM by ASM Groups (A) and by Individual ASMs (B)
ASM = antiseizure medication; DM = diabetes mellitus.
Figure 3
Figure 3. Relative Defined Daily Dose of ASM in Patients With or Without DM Occurrence
ASM = antiseizure medication; DM = diabetes mellitus.
See this image and copyright information in PMC

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