Restricted accessResearch articleFirst published online 2016-8-8
Pharmacological Agents Targeting γ-Secretase Increase Risk of Cancer and Cognitive Decline in Alzheimer’s Disease Patients: A Systematic Review and Meta-Analysis
Background: Drugs targeting γ-secretase in Alzheimer’s disease (AD) have failed to demonstrate efficacy in clinical trials.
Objective: To perform a meta-analysis of randomized controlled trials (RCTs) to evaluate the efficacy and safety of drugs targeting γ-secretase in AD.
Methods: Ten trials were identified involving 5,227 patients using electronic databases and manual review of reference lists. RCTs of at least two weeks duration involving a drug targeting γ-secretase were eligible. The main outcomes examined were adverse events and cognitive measures (ADAS-cog, MMSE, ADCS-ADL, and CDR-sb). A sub-group analysis was performed, excluding the γ-secretase modulator tarenflurbil, to evaluate the safety and efficacy of γ-secretase inhibitors only.
Results: There was an increased risk of adverse events (Odds Ratio (OR) 1.38, 95% CI 1.09–1.73; p = 0.01), serious adverse events (OR 1.50, 95% CI 1.22–1.84; p < 0.001), and skin cancers (OR 4.77, 95% CI 2.83–8.06; p < 0.001). There was significantly increased risk of infections (OR 1.36, 95% CI 1.13–1.63; p < 0.001) in the subgroup analysis excluding tarenflurbil. Pooled results also revealed a worsening in ADAS-cog (difference in means 1.33, 95% CI 0.58–2.08; p < 0.001) and MMSE (difference in means –0.66, 95% CI –0.96 to 0.35; p < 0.001), but not ADCS-ADL or CDR-sb.
Conclusion: The use of γ-secretase inhibitors is associated with significantly increased risk of serious adverse events including skin cancers, and worsening in cognitive indicators. This evidence indicates that γ-secretase may not be an appropriate target for clinical treatment of AD.
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