Metformin for Preventing Frailty in High Risk Older Adults

摘要 虚弱是一种老年综合症，会导致老年人的健康状况不佳，如跌倒、残疾、 住院、收容和死亡。由于美国老龄化人口的急剧增长和 与虚弱相关的医疗费用(估计每年超过180亿美元)，虚弱是一种主要的健康 护理问题。几乎没有关于潜在的药物干预措施的研究，这些干预措施会延迟或 减少虚弱的发生率。因此，这项研究的主要目的是测试二甲双胍作为一种新的干预措施 预防虚弱。我们认为糖尿病/胰岛素抵抗和炎症是导致 脆弱，使用二甲双胍来调节糖尿病/胰岛素抵抗和炎症将防止 和/或改善虚弱的进程。 测试二甲双胍预防脆弱的理由如下： 1)胰岛素抵抗与虚弱的发病机制有关，我们自己的研究表明 糖尿病是居住在社区的老年人虚弱发作或恶化的重要预测因子； 2)几项研究表明，体弱的老年人(与非体弱的人相比)处于慢性状态 低度“无菌”炎症，表现为血浆炎症浓度升高 标记物； 3)除了虚弱外，炎症在胰岛素抵抗的发病机制中也起着关键作用； 4)二甲双胍兼具胰岛素增敏和抗炎作用； 5)我们分析了2415名患有糖尿病的成年退伍军人的临床管理数据，结果显示 与患者相比，服用二甲双胍作为单一疗法的患者虚弱的风险降低了34% 服用磺脲类药物。 我们假设二甲双胍将导致炎症和胰岛素抵抗的减轻。 年龄较大的糖耐量异常受试者，这些变化将因此防止发病和/或 这一老年人亚群中虚弱程度的发展。 我们建议研究葡萄糖耐量异常的受试者，这一人群约有三分之一 老年人，最有可能受益于二甲双胍。据我们所知，这项研究将是第一次 研究一项针对涉及虚弱病因的中央机制的潜在干预。我们会 还要评估潜在的分子机制(胰岛素信号、AMPK信号等)。作为潜在的蜂窝 由二甲双胍缓解的脆性缺陷。因为与脆弱(两者)相关的巨大成本 个人和经济)，一种即使在老年人亚群体中也能预防或延缓虚弱的治疗方法， 会对我们的社会产生重大的积极影响。

ABSTRACT Frailty is a geriatric syndrome which leads to poor health outcomes in older adults, such as falls, disability, hospitalization, institutionalization, and death. Due to the dramatic growth in the U.S. aging population and the health care costs associated with frailty (estimated at more than $18 billion per year), frailty is a major health care problem. There has been little research into potential pharmacologic interventions that would delay or reduce the incidence of frailty. Thus, the major goal of this study is to test metformin as a novel intervention for the prevention of frailty. We propose that diabetes/insulin resistance and inflammation are major contributors to frailty, and that the use of metformin to modulate diabetes/insulin resistance and inflammation will prevent and/or ameliorate the progression of frailty. The rationale for testing metformin for frailty prevention is based on the following: 1) Insulin resistance has been linked to the pathogenesis of frailty and our own research shows that diabetes is a significant predictor of frailty onset or worsening in community-dwelling older adults; 2) Several studies have shown that frail older subjects (compared with non-frail) are under a state of chronic low grade “sterile” inflammation, as evidenced by increase plasma concentration of inflammatory markers; 3) In addition to frailty, inflammation also plays a key role in the pathogenesis of insulin resistance; 4) Metformin has both insulin sensitizing and anti-inflammatory properties, and; 5) Our analyzed clinical administrative data from 2,415 adult veterans with diabetes shows that those who were taking metformin as monotherapy were at 34% reduced risk of becoming frail compared to patients taking sulfonylureas. We hypothesize that metformin will lead to reduced inflammation and insulin resistance present in older glucose-intolerant subjects and that these changes will consequently prevent the onset and/or progression of frailty in this sub-population of older adults. We propose to study glucose intolerant subjects, a population which encompasses approximately one-third of older adults, and is most likely to benefit from metformin. To our knowledge, this research will be the first to study a potential intervention targeted toward a central mechanism involved in the etiology of frailty. We will also assess potential molecular mechanisms (insulin signaling, AMPK signaling, etc.) as potential cellular defects in frailty that are alleviated by metformin. Because of the enormous costs associated with frailty (both personal and economic), a treatment that prevents or delays frailty, even in a sub-population of older adults, would have a major positive impact in our society.