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.

项目摘要/摘要 与年龄相关的黄斑变性（AMD）是严重视力丧失和法律失明的主要原因 美国50岁以上的人。在高级阶段，患者失去了任何脉络膜的视力 新血管形成或地理萎缩。尽管在过去的十年中取得了巨大进展 新血管AMD的治疗，目前尚无治疗方法来减慢或逆转干燥或非血管 形式，其中drusen（由脂质和蛋白质组成的沉积物）在中央的钥匙细胞下积聚 黄斑的一部分，导致进一步的功能障碍，可能会易于高级并发症 疾病，视力降低和中央Scotomata。干燥的AMD通常可以不可避免地这样 随着这些并发症的风险增加，该drusen量每年增加。 二甲双胍是一种用于其降血糖作用的通用口服药物，但也发现它具有 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 - 所有过程均与AMD发病机理核心。值得注意的是，药物 已经发现有无数的抗染色作用，最近已广泛测试抗衰老 非糖尿病患者的终点。当前的研究建议确定二甲双胍是否可以减少 drusen积累在AMD中的进展。参加研究的非糖尿病患者将被随机分为 安慰剂或每日口服二甲双胍。在24个月的过程中，这两个小组将通过 几项措施。在AIM 1中，AMD将通过多模式成像进行评估，包括光学连贯性 断层扫描，眼底自动荧光和眼底摄影。 drusen体积的立方根 基线对18和24个月将是评估口服影响的主要结果指标 二甲双胍；还将比较新的脉络膜新生血管形成和地理萎缩的发生率。在 AIM 2，最校正的早期治疗糖尿病性视网膜病变研究视力和其他视觉 两组之间将比较心理物理测试。这将确定对视觉性能的影响 独立于Drusen的解剖变化。在AIM 3中，与生活质量有关的主观视觉功能， 将使用国家眼科研究所的视觉功能问卷和低亮度评估 问卷。该措施在AMD患者中尤其重要，因为该疾病极大地影响 患者的生活质量恶化。当前的计划赠款将为临床试验做准备， 可以评估这种廉价的药物以治疗AMD。因此，目前的高回报研究 有可能实现一种具有成本效益的治疗，该治疗可以在全球范围内迅速采用 损失和失明。