Pharmacological Agents Targeting γ-Secretase Increase Risk of Cancer and Cognitive Decline in Alzheimer’s Disease Patients: A Systematic Review and Meta-Analysis
Affiliations: [a]
The Whiteley-Martin Research Centre, Discipline of Surgery, The University of Sydney, Nepean Hospital, Penrith, NSW, Australia
| [b]
Department of Psychology, The Ohio State University, Columbus, OH, USA
Correspondence:
[*]
Correspondence to: Professor Guy D. Eslick, The Whiteley-Martin Research Centre, Discipline of Surgery, The University of Sydney, Nepean Hospital, Level 3, Clinical Building, P.O. Box 63, Penrith, NSW 2751, Australia. Tel.: +61 2 47 341 373; Fax: +61 2 47 343 432; E-mail: guy.eslick@sydney.edu.au.
Abstract: 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.
