Efficacy and Safety of Glycogen Synthase Kinase 3 Inhibitors for Alzheimer's Disease: A Systematic Review and Meta-Analysis.

BACKGROUND

The efficacy and safety of glycogen synthase kinase 3 (GSK-3) inhibitors in patients with Alzheimer's disease (AD) is unknown.

OBJECTIVE

A systematic review and meta-analysis of randomized controlled trials (RCTs) to test GSK-3 inhibitors on AD patients.

METHODS

We included RCTs of GSK-3 inhibitors in AD patients and subjects with mild cognitive impairment (MCI), using cognitive function scores as a primary measure.

RESULTS

Five RCTs (three RCTs using lithium and two RCTs using tideglusib) with 568 patients were included. There was no significant difference in cognitive function scores between the GSK-3 inhibitors and placebo groups [standardized mean difference (SMD) = -0.25, p = 0.11, I2 = 55% ]. However, significant heterogeneity remained. A sensitivity analysis revealed that the lithium subgroup was more effective on cognitive function scores than placebo for AD and MCI (lithium subgroup: SMD = -0.41, p = 0.04; tideglusib subgroup: SMD = -0.02, p = 0.89). Moreover, a meta-regression analysis showed that the effect size of GSK-3 inhibitors on cognitive function scores was associated with study duration (coefficient, -0.0116). For safety outcomes, tideglusib was associated with a higher incidence of increased aspartate aminotransferase than placebo. There were no significant differences in other secondary outcomes between treatments.

CONCLUSION

Our results suggested that GSK-3 inhibitors were ineffective in treating AD and MCI; however, several studies included in the present meta-analysis were small, and future studies using a larger sample size are needed.