Mechanisms of Statin-Induced DM in JUPITER (Rosuvasatin for CVD Prevention)

JUPITER 中他汀类药物诱发 DM 的机制（用于预防 CVD 的瑞舒伐他汀）

基本信息

批准号：
8507268
负责人：
Aruna Das Pradhan
金额：
$ 23.78万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-14 至 2014-12-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8507268
关键词：
3-hydroxy-3-methylglutaryl-coenzyme A Accounting Adipocytes Aliquot Apolipoproteins A Apolipoproteins B Apoptosis BAX gene Behavioral Beta Cell Biochemical Biological Assay Biological Markers Blood Banks Blood Vessels Blood specimen Branched-Chain Amino Acids Budgets C-reactive protein Cardiovascular Diseases Cardiovascular system Caucasians Caucasoid Race Cell physiology Cells Cessation of life Clinic Visits Clinical Clinical Trials Collaborations Conduct Clinical Trials Conflict (Psychology)Coronary heart disease Data Data Analyses Databases Development Diabetes Mellitus Diagnosis Dose Dyslipidemias E-Selectin Endocrine Enrollment Epidemiologic Studies Evaluation Event Ferritin Fibrinogen Functional disorder Funding Future Glucose Glycosylated hemoglobin A Goals Growth Factor Hepatic High Density Lipoproteins Homeostasis Hospitalization Impaired fasting glycaemia Individual Inflammation Insulin Insulin Resistance Insulin-Like Growth Factor I Insulin-Like Growth-Factor Binding Protein 1 Interleukin-18 Interleukin-6 Intervention Trial Investigation Iron Overload Isoleucine Knowledge LDL Cholesterol Lipoproteins Laboratories Leptin Leucine Link Lipids Measures Metabolic Pathway Metabolic syndrome Metabolism Methods Modeling Modification Natriuretic Peptides Non-Insulin-Dependent Diabetes Mellitus Obesity Osteocalcin Outcome P-Selectin Parents Participant Pathway interactions Patients Peptides Pharmaceutical Preparations Phase Physicians Placebos Plasma Plasminogen Activator Inhibitor 1 Population Prevention Preventive Intervention Primary Prevention Publishing Random Allocation Randomized Randomized Clinical Trials Regulation Relative Risks Research Risk Risk Factors Sampling Secondary Prevention Series Signal Transduction Specimen Statistical Methods Stroke System Time Time Study Unstable angina Validation Valine Vascular Diseases Woman adiponectin base bone cardiovascular disorder prevention clinical risk clinically relevant cohort cost cost effective diabetes risk fasting plasma glucose follow-up hazard indexing inhibitor/antagonist interest lipid metabolism men non-diabetic novel osteopontin programs prospective public health relevance resistin rosuvastatin sample collection

项目摘要

DESCRIPTION (provided by applicant): Statin therapy for cardiovascular disease prevention is a mainstay of treatment. However, emerging data suggest that statin initiation is also accompanied by a modest increase in risk of clinical diabetes. Six large randomized clinical trials have collected data on diabetes outcomes and demonstrate a modest but highly significant effect (summary relative risk: 1.13; 95% CI 1.03-1.24, p=0.007) that does not appear to be drug or dose specific, nor easily predicted on the basis of traditional risk factors. The mechanisms of statin-induced diabetes are currently unknown, but the pleiotropic effects of these agents suggest multiple pathways should be considered. The JUPITER trial in which 17,802 apparently healthy non-diabetic men and women were initiated on rosuvastatin (20 mg per day) or placebo offers a unique opportunity in which to examine this issue. The relative risk of diabetes associated with random allocation to rosuvastatin in JUPITER was 1.26 (1.05-1.51; p=0.02). Employing two complementary prospective approaches, we propose to comprehensively evaluate a series of biomarkers reflecting twelve plausible mechanisms of statin-induced diabetes. These will include biomarkers of: 1) insulin resistance, 2) 2-cell function, 3) adipocyte signaling, 4) hepatic dysfunction/iron overload, 5) lipid metabolism, 6) growth factor activity, 7) apoptosis, 8) inflammation, 9) endothelial dysfunction, 10) branched chain amino acid metabolism, 11) natriuretic peptide activity and 12) osteo-endocrine regulation. In Phase One of this research program, we will evaluate statin effects on these pathways by measuring change in biomarker levels from baseline to 1-year in a representative sample of JUPITER participants (400 allocated to rosuvastatin and 400 allocated to placebo). In Phase Two, utilizing a prospective case-cohort approach, we will also assess biomarker relationships with clinical type 2 diabetes. Case subjects (n=540) will be JUPITER participants who were free of clinical or biochemical (fasting plasma glucose < 126 mg/dL) diabetes at baseline who develop clinical or biochemical (fasting plasma glucose > 126 mg/dL) diabetes during follow-up. The subcohort (n=2,000) will be a randomly selected sample of the parent JUPITER population. Biomarkers will be assessed in pathophysiologic groups based upon plausible biologic pathways as well as data generated in Phase One. Data on usual demographic, clinical and behavioral risk factors will be used to evaluate potential confounding and effect modification. These analyses will take advantage of a unique blood bank from a cohort of 17,802 primary prevention patients that is ethnically diverse (>5000 non-Caucasian participants) and includes 6,801 women and will thus provide a cost-efficient method to evaluate statin therapy and diabetes risk in an unprecedented manner. If funded, the findings generated from this application should additionally provide a method for identifying those at greatest risk of type 2 diabetes, an issue that is likely to increase in importance as indications for statin therapy continue to broaden.

描述（由申请人提供）：预防心血管疾病的他汀类药物治疗是主要治疗方法。然而，新出现的数据表明，开始使用他汀类药物也伴随着临床糖尿病风险的适度增加。六项大型随机临床试验收集了有关糖尿病结局的数据，并证明了适度但非常显着的效果（总体相对风险：1.13；95% CI 1.03-1.24，p = 0.007），该效果似乎不具有药物或剂量特异性，也不容易根据传统的风险因素进行预测。他汀类药物诱发糖尿病的机制目前尚不清楚，但这些药物的多效作用表明应考虑多种途径。 JUPITER 试验中，17,802 名表面健康的非糖尿病男性和女性开始服用瑞舒伐他汀（每天 20 毫克）或安慰剂，为研究这一问题提供了独特的机会。 JUPITER 中与瑞舒伐他汀随机分配相关的糖尿病相对风险为 1.26 (1.05-1.51；p=0.02)。采用两种互补的前瞻性方法，我们建议全面评估一系列反映他汀类药物诱发糖尿病的十二种可能机制的生物标志物。这些将包括以下生物标志物：1) 胰岛素抵抗，2) 2-细胞功能，3) 脂肪细胞信号传导，4) 肝功能障碍/铁超载，5) 脂质代谢，6) 生长因子活性，7) 细胞凋亡，8) 炎症， 9）内皮功能障碍，10）支链氨基酸代谢，11）利钠肽活性和12）骨内分泌调节。在该研究计划的第一阶段，我们将通过测量 JUPITER 参与者代表性样本（400 名分配给瑞舒伐他汀，400 名分配给安慰剂）的生物标志物水平从基线到 1 年的变化来评估他汀类药物对这些途径的影响。在第二阶段，我们还将利用前瞻性病例队列方法评估生物标志物与临床 2 型糖尿病的关系。病例受试者 (n=540) 为 JUPITER 参与者，他们在基线时没有临床或生化（空腹血糖 < 126 mg/dL）糖尿病，但在随访期间出现临床或生化（空腹血糖 > 126 mg/dL）糖尿病。向上。子队列 (n=2,000) 将是从母体 JUPITER 群体中随机选择的样本。将根据合理的生物学途径以及第一阶段生成的数据在病理生理学组中评估生物标志物。有关常见人口统计、临床和行为风险因素的数据将用于评估潜在的混杂因素和效应修改。这些分析将利用来自 17,802 名初级预防患者的独特血库，这些患者属于不同种族（超过 5000 名非白人参与者），其中包括 6,801 名女性，因此将提供一种经济高效的方法来评估他汀类药物治疗和糖尿病风险以前所未有的方式。如果获得资助，该申请的研究结果还将提供一种识别 2 型糖尿病风险最高人群的方法，随着他汀类药物治疗适应症的不断扩大，这一问题可能会变得越来越重要。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial.

DOI：
10.1016/s0140-6736(12)61190-8
发表时间：
2012-08-11
期刊：
LANCET
影响因子：
168.9
作者：
Ridker, Paul M.;Pradhan, Aruna;MacFadyen, Jean G.;Libby, Peter;Glynn, Robert J.
通讯作者：
Glynn, Robert J.