Hydroxychloroquine to Improve Insulin Sensitivity in Rheumatoid Arthritis

羟氯喹可改善类风湿关节炎的胰岛素敏感性

• 批准号: 7774466
• 负责人: Daniel Hal Solomon
• 金额: $ 17.36万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7774466
• 关键词: Acute-Phase Proteins; Adrenal Cortex Hormones; Age; Animal Model; Antimalarials; Atherosclerosis; Attention; Blood Glucose; Body Composition; Body mass index; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Clinical; Comorbidity; Data; Diabetes Mellitus; Disease; Disease-Modifying Second-Line Drugs; Double-Blind Method; Endothelium; Epidemiologic Studies; Fatty acid glycerol esters; Gender; Hydroxychloroquine; Hyperglycemia; Inflammation; Inflammatory; Insulin; Insulin Resistance; Intervention; Intervention Studies; Medicine; Metabolism; Methotrexate; Muscle; Myocardial Infarction; Pain management; Paper; Patients; Persons; Physical activity; Play; Prevalence; Principal Investigator; Process; Publishing; Randomized; Randomized Controlled Trials; Recruitment Activity; Reporting; Rheumatoid Arthritis; Risk; Risk Factors; Role; Stroke; Systemic Lupus Erythematosus; Testing; Therapeutic; Translating; Translations; Work; cardiovascular disorder risk; cardiovascular risk factor; cohort; diabetic; disability; dosage; glucose metabolism; hypothalamic pituitary axis; improved; insulin sensitivity; non-diabetic; outcome forecast; pilot trial; public health relevance; randomized placebo controlled trial

DESCRIPTION (provided by applicant): Our ability to better control the pain and disability of rheumatoid arthritis (RA) now focuses attention on reducing the impact of RA-associated comorbidities. The most common cause of death in RA is cardiovascular (CV) disease, and the risk of myocardial infarction and stroke are approximately doubled in RA. The determinants of CV risk in RA include traditional CV risk factors as well as aspects of the inflammatory process defining RA. It is likely that RA-associated inflammation accelerates atherosclerosis through direct effects on the endothelium as well as indirect effects on insulin metabolism. Several studies report an increased prevalence of insulin resistance among persons with RA. However, it is not clear whether the inflammation of RA causes insulin resistance. Corticosteroids and abnormalities in the hypothalamic-pituitary axis may also contribute to abnormal glucose metabolism. Little information is available to guide management of a pre-diabetic insulin resistance state in RA. Hydroxychloroquine (HCQ), a commonly used medicine early in RA, may play a role in improving insulin resistance. Several previous trials demonstrated the ability of HCQ to reduce blood glucose levels in diabetics, and a large epidemiologic study found that subjects with RA using HCQ were less likely to develop diabetes. In animal models, anti-malarials lower blood glucose through slowing insulin metabolism. With CV disease a major comorbidity in RA and insulin resistance possibly a major determinant of CV risk, intervention studies need to begin to translate prior work into clinical therapeutics. We propose the following pilot trial: Aim 1: To test whether HCQ improves insulin resistance in non-diabetic subjects with RA. We will conduct a double-blind randomized controlled trial in subjects with RA to test the hypothesis that HCQ improves insulin sensitivity. Aim 2 will use date from the trial to identify determinants of insulin resistance in RA. We hypothesize that RA will be associated with an increased risk of insulin resistance and that independent risk factors for increased insulin resistance in RA include higher BMI, elevated acute phase reactants, greater fat to muscle ratio, and less physical activity. PUBLIC HEALTH RELEVANCE: If this study demonstrates a beneficial effect of HCQ on insulin resistance among the randomized subjects, this would provide strong evidence that HCQ has benefits beyond RA and SLE disease activity. Currently, HCQ is stopped in many patients as they "step-up" to more aggressive DMARD treatments, or HCQ may never be tried in some patients who present with RA carrying with poor prognosis. If HCQ improves insulin sensitivity, there may be rationale for continuing HCQ chronically in patients with RA. As well, a larger clinical endpoint study would be strongly considered.

描述（由申请人提供）：我们更好地控制类风湿性关节炎 (RA) 疼痛和残疾的能力现在集中于减少 RA 相关合并症的影响。 RA 中最常见的死亡原因是心血管 (CV) 疾病，并且 RA 中心肌梗塞和中风的风险大约增加一倍。 RA 中心血管风险的决定因素包括传统的心血管风险因素以及定义 RA 的炎症过程的各个方面。 RA 相关炎症很可能通过对内皮的直接影响以及对胰岛素代谢的间接影响而加速动脉粥样硬化。几项研究报告称，类风湿性关节炎患者的胰岛素抵抗患病率有所增加。然而，尚不清楚RA​​炎症是否会导致胰岛素抵抗。皮质类固醇和下丘脑-垂体轴异常也可能导致葡萄糖代谢异常。可用于指导 RA 糖尿病前期胰岛素抵抗状态管理的信息很少。 羟氯喹（HCQ）是 RA 早期常用的药物，可能在改善胰岛素抵抗方面发挥作用。之前的几项试验证明了 HCQ 能够降低糖尿病患者的血糖水平，一项大型流行病学研究发现，使用 HCQ 的 RA 受试者患糖尿病的可能性较小。在动物模型中，抗疟疾药物通过减缓胰岛素代谢来降低血糖。 由于心血管疾病是 RA 的主要合并症，而胰岛素抵抗可能是心血管风险的主要决定因素，因此干预研究需要开始将先前的工作转化为临床治疗。我们建议进行以下试点试验： 目标 1：测试 HCQ 是否可以改善患有 RA 的非糖尿病受试者的胰岛素抵抗。我们将对 RA 受试者进行双盲随机对照试验，以检验 HCQ 改善胰岛素敏感性的假设。目标 2 将使用试验数据来确定 RA 中胰岛素抵抗的决定因素。我们假设 RA 与胰岛素抵抗风险增加有关，并且 RA 胰岛素抵抗增加的独立危险因素包括较高的 BMI、升高的急性期反应物、较高的脂肪与肌肉比率和较少的体力活动。 公共卫生相关性： 如果这项研究证明 HCQ 对随机受试者的胰岛素抵抗有有益作用，这将提供强有力的证据，证明 HCQ 的益处超出 RA 和 SLE 疾病活动范围。目前，许多患者在“升级”至更积极的 DMARD 治疗时停止了 HCQ，或者在一些预后不良的 RA 患者中可能永远不会尝试 HCQ。如果 HCQ 可以改善胰岛素敏感性，那么 RA 患者长期持续使用 HCQ 可能是合理的。此外，还将强烈考虑进行更大规模的临床终点研究。