Mechanisms of Action of Hydroxychloroquine in Reducing Risk of Type 2 Diabetes

羟氯喹降低 2 型糖尿病风险的作用机制

• 批准号: 8140487
• 负责人: Frederico G. S. Toledo
• 金额: $ 18.73万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-08 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8140487
• 关键词: Adherence; Adverse effects; Affect; Antimalarials; Attenuated; Behavior Therapy; Beta Cell; Cell physiology; Clinical; Clinical Trials; Data; Development; Diabetes Mellitus; Diabetes prevention; Diet Modification; Disease; Drug effect disorder; Drug usage; Epidemic; Family history of; Feasibility Studies; Fright; Glucose; Half-Life; Human; Hydroxychloroquine; Insulin; Insulin Resistance; Intervention; Metabolism; Methodology; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Overweight; Patients; Pharmaceutical Preparations; Pharmacotherapy; Pilot Projects; Placebos; Prediabetes syndrome; Prevention; Public Health; Randomized; Retinal; Rheumatoid Arthritis; Risk; Safety; Sampling; Toxic effect; United States; Vascular Diseases; base; cost; design; diabetes risk; diabetic; double-blind placebo controlled trial; glucose metabolism; glucose tolerance; glycemic control; high risk; improved; indexing; insulin secretion; insulin sensitivity; intravenous glucose tolerance test; prevent; public health relevance

DESCRIPTION (provided by applicant): Mechanisms of Action of Hydroxychloroquine in Reducing Risk of Type 2 Diabetes. Diabetes is approaching epidemic proportions in the United States. Efforts to implement effective strategies for diabetes prevention have been limited by poor long-term adherence to lifestyle modifications and potential side effects and costs of pharmacologic interventions. We recently showed that long-term use of hydroxychloroquine (HCQ), an antimalarial used to treat rheumatoid arthritis is associated with an impressive 77% reduction in risk of diabetes when taken for more than 4 years. This protective association increases with greater duration of use. In patients with well established Type 2 diabetes mellitus (T2DM), HCQ has a positive effect on glycemic control. In spite of its efficacy and excellent safety profile, HCQ is not used to treat T2DM because of potential retinal toxicity, a very rare though feared side effect unrelated to vascular disease or T2DM. The precise mechanism(s) by which HCQ attenuates diabetes risk have not been determined. Here we propose a pilot and feasibility clinical trial of HCQ in subjects with pre-diabetes. In this pilot and feasibility clinical trial, we will study changes in beta-cell function (insulin secretion) and insulin sensitivity associated with short-term HCQ therapy compared with placebo using frequent sampling intravenous glucose tolerance testing (FSIGTT) methodology. We propose to 1) determine the short-term effects of HCQ (600 mg/d orally) on beta-cell function, insulin disposition index, and insulin sensitivity in subjects with pre-diabetes and 2) determine the change in insulin secretion, disposition index and sensitivity 3 months after HCQ cessation. Thirty overweight or obese pre- diabetic subjects with a family history of T2DM will be randomized to receive HCQ or placebo for 3 months. We will determine insulin secretion and insulin resistance using FSIGTT at baseline and 3 months in all subjects, and again after 3 month drug washout in the HCQ-treated subjects only. We hypothesize that insulin secretion and sensitivity will improve in subjects with pre-diabetes treated with HCQ for 3 months. Based on its long half-life and increasing effect on diabetes risk with prolonged exposure, we expect that the effects of HCQ on pre-diabetic subjects will persist, albeit marginally smaller, 3 months after drug cessation. Given HCQ's potential clinical utility as an alternative to current drugs used to delay or prevent the onset of T2DM, this pilot and feasibility study will provide preliminary data to assist in planning a T2DM prevention trial of HCQ in high-risk subjects. The rapidly increasing occurrence of Type 2 diabetes has become a pressing public health concern. Approaches to prevent this debilitating disease include diet and lifestyle modification as well as drug therapy. The current study attempts to document the ability of a relatively safe and inexpensive drug treatment to prevent diabetes in overweight people at high risk for developing the disease. PUBLIC HEALTH RELEVANCE: This pilot clinical trial of hydroxychloroquine compared with placebo in humans will examine the mechanism(s) of action of the drug in attenuating the risk of type 2 diabetes mellitus (T2DM) in patients with pre-diabetes. Results will be used to design a large-scale clinical trial to determine the effect of this drug in preventing or delaying the development of T2DM in subjects at high risk.

描述（由申请人提供）：羟氯喹降低 2 型糖尿病风险的作用机制。在美国，糖尿病已接近流行病的程度。由于生活方式改变的长期依从性差以及药物干预的潜在副作用和成本，实施有效的糖尿病预防策略的努力受到限制。我们最近发现，长期使用羟氯喹 (HCQ)（一种用于治疗类风湿关节炎的抗疟药）超过 4 年，可将患糖尿病的风险显着降低 77%。这种保护作用随着使用时间的延长而增强。对于已确诊的 2 型糖尿病 (T2DM) 患者，HCQ 对血糖控制具有积极作用。尽管 HCQ 具有功效和出色的安全性，但由于潜在的视网膜毒性，它不用于治疗 T2DM，这是一种与血管疾病或 T2DM 无关但非常罕见但令人担忧的副作用。 HCQ 降低糖尿病风险的确切机制尚未确定。在这里，我们建议在糖尿病前期受试者中进行 HCQ 的试点和可行性临床试验。在这项试点和可行性临床试验中，我们将使用频繁采样静脉内葡萄糖耐量测试 (FSIGTT) 方法，研究与安慰剂相比，与短期 HCQ 治疗相关的 β 细胞功能（胰岛素分泌）和胰岛素敏感性的变化。我们建议 1) 确定 HCQ（口服 600 mg/d）对糖尿病前期受试者的 β 细胞功能、胰岛素处置指数和胰岛素敏感性的短期影响，2) 确定 HCQ 停止后 3 个月胰岛素分泌、处置指数和敏感性的变化。 30 名具有 T2DM 家族史的超重或肥胖糖尿病前期受试者将随机接受 HCQ 或安慰剂 3 个月。我们将在所有受试者的基线和 3 个月时使用 FSIGTT 确定胰岛素分泌和胰岛素抵抗，并仅在接受 HCQ 治疗的受试者中在 3 个月药物清除后再次测定胰岛素分泌和胰岛素抵抗。我们假设接受 HCQ 治疗 3 个月的糖尿病前期受试者的胰岛素分泌和敏感性将会改善。由于其半衰期长，且随着长期暴露对糖尿病风险的影响不断增加，我们预计 HCQ 对糖尿病前期受试者的影响将在停药后 3 个月持续存在，尽管稍小一些。鉴于 HCQ 作为当前用于延迟或预防 T2DM 发病的药物的替代品的潜在临床效用，这项试点和可行性研究将提供初步数据，以协助规划 HCQ 在高危受试者中进行 T2DM 预防试验。 2 型糖尿病的发病率迅速增加已成为紧迫的公共卫生问题。预防这种使人衰弱的疾病的方法包括饮食和生活方式的改变以及药物治疗。目前的研究试图证明一种相对安全且廉价的药物治疗对于高风险超重人群预防糖尿病的能力。 公共健康相关性：这项在人体中进行的羟氯喹与安慰剂对照临床试验将探讨该药物在降低糖尿病前期患者患 2 型糖尿病 (T2DM) 风险方面的作用机制。结果将用于设计大规模临床试验，以确定该药物在预防或延缓高危受试者发生 T2DM 方面的效果。