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

描述（由申请人提供）：他汀类药物治疗是心血管疾病预防的主要治疗方法。然而，新出现的数据表明，他汀类药物的开始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糖尿病结局的数据，并证明了适度但高度显著的效果（总相对危险度：1.13;95% CI: 1.03-1.24, p=0.007），这似乎不是药物或剂量特异性的，也不容易根据传统的危险因素预测。他汀类药物诱导糖尿病的机制目前尚不清楚，但这些药物的多效性表明应考虑多种途径。JUPITER试验中，17802名明显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一个独特的机会。JUPITER随机分配瑞舒伐他汀与糖尿病相关的相对风险为1.26 （1.05-1.51;p=0.02）。采用两种互补的前瞻性方法，我们建议综合评估一系列反映他汀类药物诱导糖尿病的12种可能机制的生物标志物。这些生物标志物包括：1)胰岛素抵抗，2)2细胞功能，3)脂肪细胞信号，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。在该研究项目的第一阶段，我们将评估他汀类药物对这些途径的影响，通过测量具有代表性的JUPITER参与者样本（400人分配给瑞舒伐他汀组，400人分配给安慰剂组）从基线到1年的生物标志物水平变化。在第二阶段，利用前瞻性病例队列方法，我们还将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）将是在基线时无临床或生化（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）糖尿病的JUPITER参与者。亚队列（n= 2000）将从母体JUPITER人群中随机选择样本。生物标志物将根据合理的生物学途径以及第一阶段产生的数据在病理生理组中进行评估。通常的人口统计学、临床和行为危险因素的数据将用于评估潜在的混淆和效果修正。这些分析将利用一个独特的血库，该血库来自17,802名不同种族的初级预防患者（bb50 000名非高加索参与者），包括6,801名女性，因此将以前所未有的方式提供一种成本效益的方法来评估他汀类药物治疗和糖尿病风险。如果获得资助，该应用产生的研究结果将额外提供一种识别2型糖尿病高危人群的方法，随着他汀类药物治疗适应症的不断扩大，这一问题的重要性可能会增加。

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.