Which Anticonvulsant Mood Stabilizer Upped Diabetes Risk?

Some anticonvulsant mood stabilizers may increase the risk for developing type 2 diabetes (T2D), an observational study indicated.

Among adults who initiated an anticonvulsant mood stabilizer, treatment with valproate was tied with a 1.17% higher adjusted risk difference for developing T2D over 5 years compared with lamotrigine (Lamictal), in an intention-to-treat analysis (95% CI 0.66-1.76), reported Jenny W. Sun, PhD, of Harvard Medical School in Boston, and colleagues.

This difference translated to a number needed to harm of 87 patients starting valproate (rather than lamotrigine) for one T2D case within 5 years, they wrote in JAMA Network Open.

In a per-protocol analysis of patients who adhered to treatment, the point estimate of T2D risk for valproate versus lamotrigine was slightly higher (1.99%, 95% CI -0.64 to 5.31).

As for two other anticonvulsant mood stabilizers — carbamazepine (Tegretol) and oxcarbazepine (Trileptal, Oxtellar XR) — these agents didn’t have the significantly higher 5-year T2D risk difference compared with lamotrigine:

• Carbamazepine: 0.49% (95% CI -0.57 to 1.51)
• Oxcarbazepine: 0.27% (95% CI -0.47 to 0.96)

“These findings highlight that at the population level, the choice of which anticonvulsant mood stabilizer to initiate could have meaningful associations with the incidence of type 2 diabetes,” Sun’s group wrote. They pointed out that in the early 2010s, roughly 5% of adults and 1% of adolescents in the U.S. were treated with an anticonvulsant medication.

“Patients and clinicians concerned about the potential metabolic adverse effects of treatment should consider initiating lamotrigine, which was associated with the lowest risk of type 2 diabetes,” they suggested.

While the risk of T2D development was relatively unknown with these agents, there has been some other established metabolic risks seen with anticonvulsant mood stabilizers. Weight gain is a common adverse effect for some of these agents, with valproate and carbamazepine in particular. Of note, lamotrigine is one agent that isn’t associated with substantial weight gain.

When researchers looked solely at pediatric patients, the diabetes risk difference wasn’t apparent. Likewise compared with lamotrigine, initiation with either carbamazepine, oxcarbazepine, or valproate was not linked with a significantly higher 5-year risk difference for T2D:

• Carbamazepine: 0.04 (95% CI -0.42 to 0.64)
• Oxcarbazepine: 0.29% (95% CI -0.12 to 0.69)
• Valproate: 0.18% (95% CI -0.09 to 0.49)

“Although the comparative safety of mood stabilizer treatment was generally in the same direction for children, risk differences were small and underpowered,” Sun’s group pointed out.

For their study, the researchers used data from IBM MarketScan, which included commercially insured patients who initiated treatment with an anticonvulsant mood stabilizer between 2010 and 2019.

This included 274,206 ages 20 to 65 (adults) and 74,005 ages 10 to 19 years (children). Some exclusion criteria included having a diagnosis of type 1, type 2, secondary or gestational diabetes and anticonvulsant medication use the year prior.

Among adult patients, there were 26,641 carbamazepine initiators, 132,739 lamotrigine initiators, 24,226 oxcarbazepine initiators, and 90,600 valproate initiators. As for kids, there were 2,532 carbamazepine initiators, 36,394 lamotrigine initiators, 12,434 oxcarbazepine initiators, and 22,645 valproate initiators.

The most common medical diagnoses among this cohort included bipolar disorder, depression, anxiety, migraines, and neuropathic pain.

As for future studies, Sun’s group said that a “sufficiently large” randomized clinical trial would likely never come to fruition. Although it would “provide the relevant evidence,” a trial like that would be “too long and costly to conduct,” they said.