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

基本信息

批准号：
8580532
负责人：
James S Floyd
金额：
$ 12.98万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8580532
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 Electronics Epidemiologic Methods Epidemiologic Studies Epidemiology Event Generations Glucose Goals Health Hospitalization Hypoglycemia Insulin Internist Interview Ischemic Preconditioning Knowledge Lead Learning Link Long-Acting Insulin 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 Primary Prevention Public Health Randomized Clinical Trials Recording of previous events 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 adrenergic base cardiovascular disorder prevention cardiovascular disorder risk cardiovascular risk factor career clinical decision-making design diabetes mellitus therapy diabetic patient experience follow-up health care delivery health record hormone therapy improved interest mortality population based post-market programs public health relevance randomized trial safety study skills

项目摘要

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）：该K08提案将发展詹姆斯·弗洛伊德（James Floyd）博士的职业生涯，詹姆斯·弗洛伊德（James Floyd）是一名对心血管疾病流行病学和药物ePidemiology的培训和兴趣。他的目标是：1）评估糖尿病疗法各种组合的心血管效应； 2）成为一名成功研究心血管药物安全的独立研究者。这些目标将通过在设计和进行心血管药物安全研究和进行培训方面的大量指导研究经验来实现，用于使用几种流行病学方法，可用于解决观察性研究中常见的混杂和其他形式的偏见。这些活动将在主要导师Bruce Psaty博士和联席会员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，流行病学方法以及药物安全研究的设计和行为方面具有专业知识的研究人员。在美国，胰岛素和口服降糖药物是导致不良药物作用的住院原因，大约40％的2型糖尿病患者（DM）结合了胰岛素治疗使用口服剂。对口腔糖尿病疗法的心血管安全性的担忧首先出现了40年前，当时第一代Sulfonylurea tolbutamide被发现增加了大学组糖尿病计划临床试验中心血管死亡的风险。磺酰脲可能导致低血糖症和直接心肌作用导致心血管不良事件。我们假设在使用长效胰岛素的2型DM型人中，与单独使用长作用胰岛素相比，使用磺酰尿素的使用会增加心血管疾病和死亡的风险。在一个大型综合医疗保健提供系统的集团健康合作社的设置中，我们以前使用了从医疗记录获得的电子处方记录和健康数据来进行基于人群的其他类别药物的心血管安全研究。利用这些研究中的现有数据，我们建议评估两种相关的流行病学研究中磺酰尿和其他降糖疗法的心血管安全性：（1）MI病例对照研究的长效胰岛素使用2型胰岛素的长效胰岛素研究，具有2型DM和MI MI的先前历史；（2）第一研究的MI病例组的成立队列研究。限制对没有普遍的心血管疾病的受试者，对关键潜在混杂因素的调整，诸如倾向得分校准等分析方法和灵敏度分析等分析方法将用于解决残留混杂，这是对这些研究有效性的最严重威胁。因果推理方法将用于解决队列研究中可能发生的时变选择偏见。这些研究可以改善2型DM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研究提出建议，并启动Floyd博士作为该领域的主要研究人员的职业。