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: 8013621
• 负责人: Daniel Hal Solomon
• 金额: $ 20.57万
• 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 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8013621
• 关键词: Acute-Phase Proteins; Adrenal Cortex Hormones; Age; Animal Model; Antimalarials; Atherosclerosis; Attention; Blood Glucose; Body Composition; Body mass index; Cardiovascular Diseases; 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关节炎（RA）的疼痛和残疾的能力现在将注意力集中在减少RA相关合并症的影响上。 RA中最常见的死亡原因是心血管疾病（CV）疾病，心肌梗塞和中风的风险在RA中大约翻了一番。 RA中简历风险的决定因素包括传统的简历风险因素以及定义RA的炎症过程的各个方面。 RA相关的炎症可能通过直接影响内皮以及对胰岛素代谢的间接影响加速了动脉粥样硬化。几项研究报告说，RA患者胰岛素抵抗的患病率增加。但是，尚不清楚RA​​的炎症是否引起胰岛素抵抗。下丘脑垂体轴的皮质类固醇和异常也可能导致异常的葡萄糖代谢。很少有信息可以指导RA中糖尿病前胰岛素抵抗状态的管理。 羟氯喹（HCQ）是RA早期常用药物，可能在改善胰岛素抵抗中发挥作用。先前的几项试验表明，HCQ在糖尿病患者中降低血糖水平的能力，一项大量的流行病学研究发现，使用HCQ的受试者不太可能患上糖尿病。在动物模型中，抗疟疾通过减慢胰岛素代谢来降低血糖。 由于CV疾病，RA和胰岛素抵抗的主要合并症可能是CV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剂。我们提出以下试验试验：目标1：测试HCQ是否改善了具有RA的非糖尿病受试者的胰岛素抵抗。我们将对患有RA的受试者进行双盲随机对照试验，以检验HCQ提高胰岛素敏感性的假设。 AIM 2将使用试验的日期来确定RA中胰岛素抵抗的决定因素。我们假设RA将与胰岛素抵抗的风险增加有关，并且RA中胰岛素抵抗增加的独立危险因素包括更高的BMI，急性相应物升高，脂肪与肌肉比率更高，体育活动较小。 公共卫生相关性： 如果这项研究证明了HCQ对随机受试者中胰岛素抵抗的有益作用，则可以提供有力的证据，表明HCQ超出了RA和SLE疾病活动。目前，许多患者在许多患者中停止了HCQ，因为他们“加强”对更具侵略性的DMARD治疗，或者在某些患有RA携带不良预后的患者中可能永远不会尝试HCQ。如果HCQ提高了胰岛素敏感性，则可能会在RA患者长期继续进行HCQ。同样，将强烈考虑更大的临床终点研究。

项目成果

Effect of hydroxychloroquine on insulin sensitivity and lipid parameters in rheumatoid arthritis patients without diabetes mellitus: a randomized, blinded crossover trial.

• DOI: 10.1002/acr.22285
• 发表时间: 2014-08
• 期刊: ARTHRITIS CARE & RESEARCH
• 影响因子: 4.7
• 作者: Solomon, Daniel H.;Garg, Rajesh;Lu, Bing;Todd, Derrick J.;Mercer, Emileigh;Norton, Tabatha;Massarotti, Elena
• 通讯作者: Massarotti, Elena