Cardiovascular Safety of Combination Therapies for Type 2 Diabetes Mellitus

2 型糖尿病联合疗法的心血管安全性

• 批准号: 9294107
• 负责人: James S Floyd
• 金额: $ 15.92万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9294107
• 关键词: Address; Adrenergic Agents; Adrenergic beta-Antagonists; Adverse drug effect; Adverse effects; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Area; Blood Platelets; Blood Vessels; Calibration; Cardiovascular Agents; Cardiovascular Diseases; Cardiovascular system; Case-Control Studies; Cerebral Ischemia; Cessation of life; Clinical Trials; Cohort Studies; Combined Modality Therapy; Data; Data Quality; Diabetes Mellitus; Epidemiologic Methods; Epidemiology; Event; Generations; Glucose; Goals; Health; Hospitalization; Hypoglycemia; Impairment; Insulin; Internist; Interview; Ischemic Preconditioning; Knowledge; Link; Long-Acting Insulin; Marketing; Medical Records; Mentors; Meta-Analysis; Metformin; Methods; Modification; Myocardial; Myocardial Infarction; Myocardial Ischemia; Non-Insulin-Dependent Diabetes Mellitus; Observational Study; Oral; Outcome; Patients; Persons; Pharmaceutical Preparations; Pharmacoepidemiology; Physiological; Population; Population Study; Primary Prevention; Public Health; Randomized Clinical Trials; Recording of previous events; Records; Recurrence; Research; Research Personnel; Research Proposals; Residual state; Risk; Risk Estimate; Safety; Secondary Prevention; Selection Bias; Stress; Stroke; Sulfonylurea Compounds; Supervision; Survivors; System; Time; Tolbutamide; Training; Treatment Protocols; United States; United States Food and Drug Administration; Universities; Work; active method; analytical method; base; cardiovascular disorder prevention; cardiovascular disorder risk; cardiovascular risk factor; career; clinical decision-making; design; diabetes mellitus therapy; diabetic patient; disorder risk; epidemiology study; experience; follow-up; health care delivery; health data; hormone therapy; improved; interest; mortality; population based; programs; public health relevance; randomized trial; safety study; secondary analysis; skills

DESCRIPTION (provided by applicant): This K08 proposal will develop the career of Dr. James Floyd, a general internist with training and interests in cardiovascular disease epidemiology and pharmacoepidemiology. His goals are: 1) to evaluate the cardiovascular effects of various combinations of diabetes therapies; and 2) to become a successful independent investigator studying cardiovascular drug safety. These goals will be accomplished through an intensive mentored research experience in the design and conduct of cardiovascular drug safety studies and training in the use of several epidemiologic methods that can be used to address confounding and other forms of bias common in observational studies. These activities will take place under the supervision of primary mentor Dr. Bruce Psaty and co-mentors Dr. Barbara McKnight and Dr. Miguel Hernan, all of whom are accomplished investigators with expertise in cardiovascular disease, epidemiologic methods, and the design and conduct of drug safety studies. Insulin and oral glucose-lowering drugs are leading causes of hospitalizations for adverse drug effects in the U.S., and about 40% of persons with type 2 diabetes mellitus (DM) on insulin therapy use oral agents in combination. Concerns about the cardiovascular safety of oral diabetes therapies first emerged over forty years ago, when the first-generation sulfonylurea tolbutamide was found to increase the risk of cardiovascular death in the University Group Diabetes Program clinical trial. Sulfonylureas may cause adverse cardiovascular events as a consequence of hypoglycemia and through direct myocardial effects. We hypothesize that among persons with type 2 DM using long-acting insulin, the use of sulfonylureas compared with the use of long- acting insulin alone increases the risk of cardiovascular disease and death. In the setting of Group Health Cooperative, a large integrated healthcare delivery system, we have previously used electronic prescription records and health data obtained from medical records to conduct population-based studies of the cardiovascular safety of other classes of medications. Leveraging existing data from these studies, we propose to evaluate the cardiovascular safety of sulfonylureas and other glucose-lowering therapies in two linked epidemiologic studies: (1) an MI case-control study of long-acting insulin users with type 2 DM and no prior history of MI; and (2) an inception cohort study of survivors from the MI case group of the first study. Restriction to subjects without prevalent cardiovascular disease, adjustment for key potential confounding factors, analytic methods such as propensity score calibration, and sensitivity analyses will be used to address residual confounding, the most serious threat to the validity of these studies. Causal inference methods will be used to address time-varying selection bias that can occur in the cohort study. These studies may improve cardiovascular disease prevention for patients with type 2 DM, and this work will lead to proposals for other cardiovascular drug safety studies and launch the career of Dr. Floyd as a leading investigator in this area.

描述（由申请人提供）：本 K08 提案将发展 James Floyd 博士的职业生涯，James Floyd 是一位普通内科医生，接受过心血管疾病流行病学和药物流行病学培训并对其感兴趣。他的目标是：1）评估各种糖尿病疗法组合对心血管的影响； 2) 成为研究心血管药物安全性的成功独立研究者。这些目标将通过在设计和进行心血管药物安全性研究方面的深入指导研究经验以及使用多种流行病学方法的培训来实现，这些方法可用于解决观察性研究中常见的混杂因素和其他形式的偏见。这些活动将在主要导师 Bruce Psaty 博士以及联合导师 Barbara McKnight 博士和 Miguel Hernan 博士的监督下进行，他们都是在心血管疾病、流行病学方法以及设计和实施研究方面具有专业知识的资深研究人员。药物安全性研究。 在美国，胰岛素和口服降糖药物是因药物不良反应而住院的主要原因，约 40% 接受胰岛素治疗的 2 型糖尿病 (DM) 患者联合使用口服药物。人们对口服糖尿病疗法的心血管安全性的担忧首次出现在四十多年前，当时大学团体糖尿病计划临床试验中发现第一代磺酰脲类甲苯磺丁脲会增加心血管死亡的风险。磺酰脲类药物可能因低血糖和直接心肌效应而导致不良心血管事件。我们假设，在使用长效胰岛素的 2 型糖尿病患者中，与单独使用长效胰岛素相比，使用磺脲类药物会增加心血管疾病和死亡的风险。在大型综合医疗服务系统 Group Health Cooperative 的背景下，我们之前曾使用电子处方记录和从病历中获得的健康数据对其他类别药物的心血管安全性进行基于人群的研究。利用这些研究的现有数据，我们建议在两项相关的流行病学研究中评估磺酰脲类和其他降糖疗法的心血管安全性：(1) 一项针对患有 2 型糖尿病且既往无糖尿病史的长效胰岛素使用者的 MI 病例对照研究心肌梗死史； (2) 对第一项研究的心肌梗死病例组幸存者进行初始队列研究。限制没有普遍心血管疾病的受试者，调整关键的潜在混杂因素，使用倾向评分校准等分析方法和敏感性分析来解决残余混杂因素，这是对这些研究有效性最严重的威胁。因果推理方法将用于解决队列研究中可能出现的随时间变化的选择偏差。这些研究可能会改善 2 型糖尿病患者的心血管疾病预防，这项工作将为其他心血管药物安全性研究提出建议，并开启弗洛伊德博士作为该领域主要研究者的职业生涯。

项目成果

β-blockers for secondary prevention in stable coronary artery disease: can observational studies provide valid answers?

β受体阻滞剂用于稳定型冠状动脉疾病的二级预防：观察性研究能否提供有效的答案？

• 发表时间: 2014-11
• 作者: Floyd; James S
• 通讯作者: James S

The Application of Genomics in Diabetes: Barriers to Discovery and Implementation.

基因组学在糖尿病中的应用：发现和实施的障碍。

• 发表时间: 2016-11
• 影响因子: 16.2
• 作者: Floyd, James S;Psaty, Bruce M
• 通讯作者: Psaty, Bruce M