Evaluating the safety of investigational anti-Alzheimer’s drugs: a comprehensive meta-analysis in the past to current decade

Evaluating the safety of investigational anti-Alzheimer’s drugs: a comprehensive meta-analysis in the past to current decade Avaliação da segurança de medicamentos experimentais para Alzheimer: uma meta-análise abrangente das últimas décadas até o período atual Neelufar Shama Shaik Scient Institute of Pharmacy, India http://orcid.org/0000-0002-5607-3466 Harika Balya Fujairah University, UAE http://orcid.org/0000-0002-8229-0405 Srinivasan Ramamurthy Fujairah University, UAE http://orcid.org/0000-0002-8434-151X Balaji Pandiyan Vels Institute of Science, Technology and Advanced Studies (VISTAS), India http://orcid.org/0000-0001-5317-1661 Joel Mart Elias Vels Institute of Science, Technology and Advanced Studies (VISTAS), India http://orcid.org/0009-0000-9560-674X Suvarnalakshmi Gunturu The Oxford College of Pharmacy, India http://orcid.org/0009-0002-4377-6784

ABSTRACT. Alzheimer’s disease is a progressive illness that results in the degeneration of neurons with considerable burden. The pharmacological treatments for Alzheimer’s disease include cholinesterase inhibitors, monoclonal antibodies, NMDA receptor antagonists despite having different adverse drug reactions (ADR) alongside the health benefits. Limited data exists for the complete safety evaluation across different classes of anti-Alzheimer’s drugs. Objective: The meta-analysis evaluated the severity, frequency and variability of ADR as a result of Alzheimer’s drugs to determine relative safety across various classes. Methods: This meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines with studies derived from the United States National Library of Medicine (PubMed), Embase, Scopus and ClinicalTrials.gov that focus on randomized controlled trials (RCTs) and observational studies which detailed ADRs of anti-Alzheimer’s drugs. Jeffrey’s Amazing Statistics Program (JASP) software was used to conduct heterogeneity assessment (I2), risk ratio (RR) and publication bias analysis in addition to meta-regression. Results: 31 studies were utilized. The studies with cholinesterase inhibitors exhibited more gastrointestinal ADRs and monoclonal antibodies exhibited amyloid-related imaging abnormalities (ARIA-H and E). The BACE1 inhibitors showed liver toxicity that led to increased patient drug discontinuation. A random-effects model was used for the analysis due to heterogeneity (I2>50%). The meta-regression analysis indicated drug class as a predictor for the type of ADR. Conclusion: The research demonstrates considerable variations in the safety of Alzheimer’s drugs that need tailored treatment supported by post-approval monitoring systems. The literature needs extended investigations of safety evaluation as well as practical treatment investigations in actual clinical settings. Unlike conventional reviews focusing solely on currently approved therapies, this study provides a cross-generational analysis of adverse drug reactions across both historical and investigational anti-Alzheimer’s agents, offering insights into mechanism-related safety patterns that may inform the development and clinical use of emerging therapies.
RESUMO. A doença de Alzheimer é uma enfermidade progressiva que resulta em degeneração de neurônios, com carga considerável. Os tratamentos farmacológicos para a doença de Alzheimer incluem inibidores da colinesterase, anticorpos monoclonais e antagonistas do receptor NMDA, embora apresentem diferentes reações adversas a medicamentos (RAM) em paralelo aos benefícios à saúde. Existem dados limitados para uma avaliação completa de segurança entre as diferentes classes de medicamentos anti-Alzheimer. Objetivo: A meta-análise avaliou a gravidade, a frequência e a variabilidade das RAM decorrentes do uso de medicamentos para Alzheimer, a fim de determinar a segurança relativa entre as diversas classes. Métodos: Esta meta-análise seguiu as diretrizes PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses), com estudos obtidos na United States National Library of Medicine (PubMed), Embase, Scopus e ClinicalTrials.gov, focados em ensaios clínicos randomizados (ECR) e estudos observacionais que detalhavam as RAM de medicamentos anti-Alzheimer. O software Jeffrey’s Amazing Statistics Program (JASP) foi utilizado para realizar a avaliação de heterogeneidade (I2), razão de risco (RR) e análise de viés de publicação, além da metarregressão. Resultados: Foram utilizados 31 estudos. Os estudos com inibidores da colinesterase apresentaram mais RAM gastrointestinais, e os anticorpos monoclonais apresentaram anormalidades de imagem relacionadas à amiloide (ARIA-H e ARIA-E). Os inibidores de BACE1 mostraram toxicidade hepática, o que levou a um aumento da descontinuação do medicamento pelos pacientes. Devido à heterogeneidade (I2>50%), foi utilizado um modelo de efeitos aleatórios para a análise. A metarregressão indicou a classe de fármacos como preditora do tipo de RAM. Conclusão: A pesquisa demonstra variações consideráveis na segurança dos medicamentos para Alzheimer, o que exige tratamentos individualizados apoiados por sistemas de monitoramento pós-aprovação. A literatura requer investigações mais extensas de avaliação de segurança, bem como estudos práticos de tratamento em cenários clínicos reais. Diferentemente das revisões convencionais, que se concentram apenas nas terapias atualmente aprovadas, este estudo fornece uma análise transgeracional das reações adversas a medicamentos tanto em fármacos históricos quanto em agentes experimentais anti-Alzheimer, oferecendo insights sobre padrões de segurança relacionados ao mecanismo que podem orientar o desenvolvimento e o uso clínico de novos tratamentos.
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