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）

• 批准号: 8286969
• 负责人: Aruna Das Pradhan
• 金额: $ 61.19万
• 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: 2010-08-14 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8286969
• 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; 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; 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; 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

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. PUBLIC HEALTH RELEVANCE: The cardiovascular benefit of HMG-CoA reductace inhibitors (statins) is unequivocal. However, recently published data deriving from several large randomized clinical trials of statin initiation for cardiovascular disease prevention have raised concern regarding a modest increase in risk of type 2 diabetes. This effect does not appear to be drug or dose specific, nor easily predicted on the basis of traditional risk factors. Findings from this prospective evaluation of statin-induced diabetes within the Justification for the Use of Statins in Prevention: and Intervention trial Evaluating Rosuvastatin (JUPITER) trial will clarify the impact of statins on multiple metabolic pathways implicated in diabetogenesis and will offer a method of identifying individuals at greatest risk for drug-associated diabetes, an issue likely to take on increasing importance as indications for statin therapy expand.

描述（由申请人提供）：用于预防心血管疾病的他汀类药物治疗是治疗的主要手段。但是，新兴的数据表明他汀类药物的启动还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已经收集了有关糖尿病预后的数据，并证明了适度但非常重要的影响（摘要相对风险：1.13; 95％CI 1.03-1.24，p = 0.007）似乎不是药物或剂量特异性，也不容易根据传统风险因素进行预测。他汀类药物诱导的糖尿病的机制目前尚不清楚，但是这些药物的多效作用表明应该考虑多种途径。木星试验在rosuvastatin（每天20毫克）或安慰剂中发起了17,802名显然健康的非糖尿病男性和女性，提供了一个独特的机会来检查这个问题。与木星中随机分配与余地蛋白蛋白的随机分配相关的糖尿病的相对风险为1.26（1.05-1.51; p = 0.02）。我们采用两种互补的前瞻性方法，建议全面评估一系列反映他汀类药物诱导的糖尿病的合理机制的生物标志物。这些将包括：1）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/铁超负荷，5）5）脂质代谢，6）生长因子活性，7）凋亡，8）炎症，8）炎症，9）9）12）内皮动作障碍，10）分支机构抗蛋白抗蛋白酸性蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白含有蛋白质蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白蛋白含量是弥补的，纽扣骨内分泌调节。在该研究计划的第一阶段，我们将通过在木星参与者的代表性样本中测量从基线到1年的生物标志物水平的变化来评估他汀类药物对这些途径的影响（分配给Rosuvastatin的400个和分配给安慰剂的400个）。在第二阶段，利用前瞻性病例 - 霍特方法，我们还将评估与临床2型糖尿病的生物标志物关系。病例受试者（n = 540）将是基线的木星参与者，他们没有临床或生化（禁食等离子体葡萄糖<126 mg/dl）糖尿病，他们在随访期间患有临床或生化（禁食等离子体葡萄糖> 126 mg/dl）糖尿病。子体位（n = 2,000）将是父木星种群的随机选择样本。将根据合理的生物学途径以及在第一阶段产生的数据中评估生物标志物在病理生理组中进行评估。关于常规人口，临床和行为风险因素的数据将用于评估潜在的混杂和影响修改。这些分析将利用17,802名初级预防患者队列的独特血库，这些患者在种族上多样化（> 5000名非可口可乐参与者），其中包括6,801名女性，因此将提供一种以固定方式评估他汀类药物治疗和糖尿病风险的成本效益方法。如果获得资助，则从本申请中产生的发现还应提供一种识别最大风险2型糖尿病风险的方法，这一问题可能会增加重要性，因为他汀类药物治疗的指示继续扩大。 公共卫生相关性：HMG-COA还原抑制剂（他汀类药物）的心血管益处是明确的。但是，最近发布的数据来自几项针对预防心血管疾病的他汀类药物启动的大型随机临床试验，这引起了人们对2型糖尿病风险的适度增加的关注。这种作用似乎不是药物或剂量特定的，也不是根据传统危险因素进行预测的。从这种对他汀类药物使用毒素的理由中对他汀类毒素诱发的糖尿病的预期评估的结果以及评估rosuvastatin（jupiter）试验的干预试验将阐明他汀类药物对糖尿病发生涉及多种代谢途径的影响，并将为识别药物症状的依赖的型号的识别，并可能会增加持续性的持续性，并可能会增加持续性的静态疗法。