Comparison of Rates of Type 2 Diabetes in Adults and Children Treated With Anticonvulsant Mood Stabilizers

JAMA Netw Open. 2022 Apr 1;5(4):e226484. doi: 10.1001/jamanetworkopen.2022.6484.


Importance: Anticonvulsant mood stabilizer treatment is associated with an increased risk of weight gain, but little is known about the risk of developing type 2 diabetes (T2D).

Objective: To evaluate the comparative safety of anticonvulsant mood stabilizers on risk of T2D in adults and children by emulating a target trial.

Design, setting, and participants: This observational cohort study used data from IBM MarketScan (2010-2019), with a 5-year follow-up period. The nationwide sample of US commercially insured patients included children (aged 10-19 years) and adults (aged 20-65 years) who initiated anticonvulsant mood stabilizer treatment. Data were analyzed from August 2020 to May 2021.

Exposures: Initiation and continuation of carbamazepine, lamotrigine, oxcarbazepine, or valproate.

Main outcomes and measures: Onset of T2D during follow-up. Weighted pooled logistic regression was used to estimate the association of initiation and continuation of carbamazepine, lamotrigine, oxcarbazepine, or valproate with the risk of developing T2D. Inverse probability weights were used to control for confounding and loss to follow-up by measured baseline and time-varying covariates.

Results: The analysis included 274 206 adults (159 428 women [58%]; mean [SD] age, 39.9 [13.2] years) and 74 005 children (38 672 girls [52%]; mean [SD] age, 15.6 [2.6] years) who initiated an anticonvulsant mood stabilizer. In adults, initiation of valproate was associated with an increased risk of developing T2D compared with initiation of lamotrigine (5-year risk difference [RD], 1.17%; 95% CI, 0.66% to 1.76%). The number needed to harm was 87 patients initiating valproate for 1 patient to develop T2D within 5 years compared with initiation of lamotrigine. Point estimates were similar when evaluating the association of treatment continuation (5-year RD, 1.99%; 95% CI, -0.64% to 5.31%). The estimated association was smaller and more variable comparing carbamazepine and oxcarbazepine to lamotrigine. In children, RDs were much smaller and more variable (5-year RD for initiation of oxcarbazepine vs lamotrigine, 0.29%; 95% CI, -0.12% to 0.69%; 5-year RD for initiation of valproate vs lamotrigine, 0.18%; 95% CI, -0.09% to 0.49%).

Conclusions and relevance: In this cohort study, valproate was associated with the highest risk of developing T2D in adults. The comparative safety was generally similar in children, but estimates were small and variable. In the absence of randomized trials, emulating target trials within health care databases can generate the age-specific drug safety data needed to inform treatment decision-making.

Publication types

  • Observational Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Anticonvulsants* / adverse effects
  • Carbamazepine / adverse effects
  • Child
  • Cohort Studies
  • Diabetes Mellitus, Type 2* / drug therapy
  • Diabetes Mellitus, Type 2* / epidemiology
  • Female
  • Humans
  • Lamotrigine / therapeutic use
  • Middle Aged
  • Oxcarbazepine / therapeutic use
  • Valproic Acid / adverse effects
  • Young Adult


  • Anticonvulsants
  • Carbamazepine
  • Valproic Acid
  • Lamotrigine
  • Oxcarbazepine