Oral metformin for non-neovascular age-related macular degeneration

口服二甲双胍治疗非新生血管性年龄相关性黄斑变性

• 批准号: 10040399
• 负责人: Jay Michael Stewart
• 金额: $ 23.65万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10040399
• 关键词: Address; Adopted; Affect; Age; Age related macular degeneration; American; Anatomy; Area; Blindness; Blood; Cell physiology; Cells; Central Scotomas; Choroidal Neovascularization; Chronic; Cicatrix; Clinical; Clinical Trials; Complement; Data; Deposition; Development; Diabetic Retinopathy; Disease; Drusen; Early treatment; Elderly; Enrollment; Extravasation; Exudative age-related macular degeneration; FRAP1 gene; Functional disorder; Fundus; Fundus photography; Grant; Hypoglycemia; Hypoglycemic Agents; Incidence; Inflammation; Interruption; Intervention; Investigation; Legal Blindness; Lesion; Lipids; Liquid substance; Masks; Measures; Metformin; Mitochondria; Multimodal Imaging; Mutation; National Eye Institute; Nonexudative age-related macular degeneration; Optical Coherence Tomography; Oral; Outcome; Outcome Measure; Oxidative Stress; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Performance; Persons; Pharmaceutical Preparations; Pharmacology; Phase; Placebos; Plant Roots; Preparation; Process; Production; Proteins; Quality of life; Questionnaires; Randomized; Reactive Oxygen Species; Reading; Research; Retina; Risk; Specific qualifier value; Stress; Structure of retinal pigment epithelium; Testing; Therapeutic Trials; Time; United States; Vision; Visual; Visual Acuity; Visual Psychophysics; advanced disease; anti aging; base; cost effective; diabetes management; effective therapy; experience; geographic atrophy; hepatic gluconeogenesis; high reward; high risk; improved; luminance; macula; mitochondrial dysfunction; non-diabetic; novel therapeutics; placebo group; prevent; primary outcome; prospective; secondary endpoint; senescence; vision development; visual performance

Project Summary/Abstract Age-related macular degeneration (AMD) is the leading cause of severe vision loss and legal blindness in persons over age 50 in the United States. In its advanced stages, patients lose vision from either choroidal neovascularization or geographic atrophy. Although great progress has been made during the past decade in the treatment of neovascular AMD, currently no therapy exists to slow or reverse the dry or non-neovascular form, in which drusen (deposits consisting of lipid and protein) accumulate beneath key cells in the central portion of the macula, leading to further dysfunction that can predispose to the complications of advanced disease, with reduced visual acuity and central scotomata. Dry AMD generally progresses inexorably such that drusen volume increases each year, with increasing risk of these complications and worse vision. Metformin is a generic oral medication used for its hypoglycemic effects but which also has been found to have numerous other cellular actions, including reducing oxidative stress and reactive oxygen species production, inflammation, and mitochondrial stress -- all processes central to the pathogenesis of AMD. Notably, the drug has been found to have myriad anti-senescence effects and has recently been tested extensively for anti-aging endpoints in non-diabetic patients. The current study proposes to determine whether metformin can reduce the progression of drusen accumulation in AMD. Non-diabetic patients enrolled in the study will be randomized to either placebo or daily oral metformin. Over the course of 24 months, the two groups will be compared by several measures. In Aim 1, AMD will be assessed with multimodal imaging, including optical coherence tomography, fundus autofluorescence, and fundus photography. The cube root of the drusen volume at baseline versus 18 and 24 months will be the primary outcome measure for assessing the effect of oral metformin; incidence of new choroidal neovascularization and geographic atrophy will also be compared. In Aim 2, best-corrected Early Treatment of Diabetic Retinopathy Study visual acuity and other visual psychophysical tests will be compared between the two groups. This will identify effects on visual performance independent of anatomic changes in drusen. In Aim 3, subjective visual function, as it relates to quality of life, will be assessed using the National Eye Institute Visual Function Questionnaire and the Low Luminance Questionnaire. This measure is particularly relevant in patients with AMD, as the disease dramatically impacts patients' quality of life for the worse. The current planning grant will enable preparations for a clinical trial that can evaluate this inexpensive medication for the treatment of AMD. Therefore, the present high-reward study has the potential to enable a cost-effective treatment that could be rapidly adopted worldwide to prevent vision loss and blindness.

项目概要/摘要 年龄相关性黄斑变性（AMD）是严重视力丧失和法定失明的主要原因 美国50岁以上的人。在晚期阶段，患者会因任一脉络膜而丧失视力 新血管形成或地图样萎缩。尽管在过去的十年中已经取得了巨大的进步 新生血管性 AMD 的治疗，目前尚无疗法可以减缓或逆转干性或非新生血管性 AMD 形式，其中玻璃膜疣（由脂质和蛋白质组成的沉积物）积聚在中央关键细胞下方 黄斑的一部分，导致进一步的功能障碍，可能导致晚期并发症 疾病，伴有视力下降和中央暗点。干性 AMD 通常会不可避免地发展，例如 玻璃疣体积逐年增加，这些并发症和视力恶化的风险也随之增加。 二甲双胍是一种通用口服药物，具有降血糖作用，但也被发现具有 许多其他细胞作用，包括减少氧化应激和活性氧的产生， 炎症和线粒体应激——所有这些过程都是 AMD 发病机制的核心。值得注意的是，该药 已被发现具有多种抗衰老作用，并且最近已进行了广泛的抗衰老测试 非糖尿病患者的终点。目前的研究旨在确定二甲双胍是否可以减少 AMD 中玻璃膜疣积累的进展。参加该研究的非糖尿病患者将被随机分组 安慰剂或每日口服二甲双胍。在 24 个月的过程中，将通过以下方式对两组进行比较： 几项措施。在目标 1 中，AMD 将通过多模态成像进行评估，包括光学相干性 断层扫描、眼底自发荧光和眼底摄影。玻璃膜疣体积的立方根 基线与 18 个月和 24 个月的比较将是评估口服药物效果的主要结果指标。 二甲双胍；还将比较新脉络膜新生血管和地图样萎缩的发生率。在 目标 2，糖尿病视网膜病变的最佳矫正早期治疗研究视力和其他视力 将比较两组之间的心理物理测试。这将确定对视觉表现的影响 与玻璃疣的解剖学变化无关。在目标 3 中，主观视觉功能与生活质量相关， 将使用国家眼科研究所视觉功能问卷和低亮度进行评估 调查问卷。这项措施对于 AMD 患者尤其重要，因为这种疾病会极大地影响 患者的生活质量每况愈下。目前的规划拨款将用于临床试验的准备工作 可以评估这种廉价药物治疗 AMD 的效果。因此，目前的高回报研究 有潜力实现一种具有成本效益的治疗方法，可在全世界范围内迅速采用，以预防视力障碍 损失和失明。