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

描述(申请人提供)：他汀类药物是预防心血管疾病的主要治疗方法。然而，新出现的数据表明，开始服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果的数据，显示出温和但高度显著的影响(汇总相对风险：1.13；95%可信区间1.03-1.24，p=0.007)，似乎不是药物或剂量特有的，也不容易根据传统的危险因素进行预测。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效应表明应该考虑多种途径。在JUPITER的试验中，17,802名看似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，这为研究这一问题提供了一个独特的机会。随机分配瑞舒伐他汀的Jupiter患者患糖尿病的相对风险为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记物。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。在这项研究计划的第一阶段，我们将通过测量具有代表性的木星参与者样本(400人被分配给瑞舒伐他汀，400人被分配给安慰剂)从基线到一年的生物标记物水平的变化来评估他汀类药物对这些途径的影响。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记物与临床2型糖尿病的关系。病例受试者(n=540)将是Jupiter参与者，他们在基线时没有临床或生化(空腹血糖和126 mg/dL)糖尿病，但在随访期间出现临床或生化(空腹血糖和126 mg/dL)糖尿病。次队列(n=2,000)将是从亲代木星种群中随机选择的样本。生物标记物将根据可信的生物途径和第一阶段产生的数据在病理生理学组中进行评估。通常的人口学、临床和行为风险因素的数据将被用来评估潜在的混淆和效果修正。这些分析将利用来自17802名初级预防患者的独特血库，该血库来自不同种族的患者(5000名非高加索人参与者)，其中包括6801名妇女，因此将提供一种以前所未有的方式评估他汀类药物治疗和糖尿病风险的具有成本效益的方法。如果得到资助，这项申请产生的结果将进一步提供一种识别2型糖尿病风险最高的人的方法，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。 公共卫生相关性：HMG-CoA还原酶抑制剂(他汀类药物)对心血管的益处是明确的。然而，最近发表的几项关于他汀类药物用于心血管疾病预防的大型随机临床试验的数据引起了人们对2型糖尿病风险适度增加的担忧。这种影响似乎不是药物或剂量所特有的，也不容易根据传统的风险因素进行预测。在评估罗舒伐他汀(JUPITER)试验的他汀类药物预防和干预试验的合理性范围内对他汀类药物引起的糖尿病进行的前瞻性评估的结果将阐明他汀类药物对与糖尿病发生有关的多个代谢途径的影响，并将提供一种识别药物相关糖尿病风险最高的个人的方法，随着他汀类药物治疗适应症的扩大，这一问题可能会变得越来越重要。

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. 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.