Ji Shiliang, Zhao Xingxing, Zhu Ruifang, Dong Yongchao, Huang Lifeng, Zhang Taiquan
Department of pharmacy, Suzhou Science & Technology Town Hospital, Gusu School, Nanjing Medical University, Suzhou, China.
Department of Neonatology, The Affiliated Suzhou Hospital of Nanjing Medical University (Suzhou Municipal Hospital), Gusu School, Nanjing Medical University, Suzhou, China.
Ther Adv Chronic Dis. 2022 Jul 9;13:20406223221109454. doi: 10.1177/20406223221109454. eCollection 2022.
AMPK has attracted widespread interest as a potential therapeutic target for age-related diseases, given its key role in controlling energy homeostasis. Metformin (Met) has historically been used to treat Type 2 diabetes and has been shown to counteract age-related diseases. However, studies regarding the relationship between Met and a variety of age-related classifications of cognitive decline have reported mixed findings.
To assess the potential effect of Met on the onset of dementia and discuss the possible biological mechanisms involved.
This study was registered in the PROSPERO database (CRD420201251468). PubMed, Embase, and Cochrane Library were searched from inception to 25 May 2021, for population-based cohort studies. Effect estimates with 95% confidence intervals (CIs) were pooled using the random-effects model. Meta-regression and subgroup analyses were performed to explore sources of heterogeneity and the stability of the results.
Fourteen population-based cohort studies (17 individual comparisons) involving 396,332 participants were identified. Meta-analysis showed that Met exposure was significantly associated with reduced risk of all subtypes of dementias [relative risk (RR) = 0.79, 95% CI = 0.68-0.91; < 0.001]. Conversely, no significant reduction in risk was observed for those who received Met monotherapy at the onset of vascular dementia (VD), Parkinson's disease (PD), and Alzheimer's disease (AD). The effect was more prominent in patients who had long-term Met exposure (⩾4 years) (RR = 0.38, 95% CI = 0.32-0.46; < 0.001), while no such significant effect was found with short-term Met exposure (1-2 years) (RR = 1.20, 95% CI = 0.87-1.66; < 0.001). Moreover, no association was observed for Met exposure in participants of European descent (RR = 1.01, 95% CI = 0.66-1.54; = 0.003) compared with those from other countries.
Based on the evidence from population-based cohort studies, our findings suggest that the AMPK activator, Met, is a potential geroprotective agent for dementias, particularly among long-term Met users. Due to the significant heterogeneity among the included studies, we should interpret the results with caution.
鉴于AMPK在控制能量平衡中的关键作用，它作为与年龄相关疾病的潜在治疗靶点已引起广泛关注。二甲双胍（Met）一直以来被用于治疗2型糖尿病，并且已被证明可对抗与年龄相关的疾病。然而，关于Met与各种年龄相关认知衰退分类之间关系的研究报告结果不一。
评估Met对痴呆症发病的潜在影响，并探讨其中可能涉及的生物学机制。
本研究已在国际前瞻性系统评价注册库（PROSPERO数据库，注册号：CRD420201251468）登记。从数据库建库至2021年5月25日，检索了PubMed、Embase和Cochrane图书馆，查找基于人群的队列研究。使用随机效应模型汇总95%置信区间（CI）的效应估计值。进行Meta回归和亚组分析以探索异质性来源和结果的稳定性。
共纳入14项基于人群的队列研究（17项个体比较），涉及396,332名参与者。Meta分析表明，Met暴露与所有痴呆症亚型风险降低显著相关[相对风险（RR）=0.79，95%CI=0.68-0.91；P<0.001]。相反，在血管性痴呆（VD）、帕金森病（PD）和阿尔茨海默病（AD）发病时接受Met单药治疗的患者中，未观察到风险显著降低。长期Met暴露（⩾4年）的患者效果更显著（RR=0.38，95%CI=0.32-0.46；P<0.001），而短期Met暴露（1-2年）则未发现显著效果（RR=1.20，95%CI=0.87-1.66；P<0.001）。此外，与其他国家的参与者相比，欧洲血统参与者的Met暴露未观察到相关性（RR=1.01，95%CI=0.66-1.54；P=0.003）。
基于基于人群的队列研究证据，我们的研究结果表明，AMPK激活剂Met是痴呆症的潜在老年保护剂，尤其是在长期使用Met的人群中。由于纳入研究之间存在显著异质性，我们应谨慎解释结果。
