Cardiovascular Safety of Combination Therapies for Type 2 Diabetes Mellitus

描述(由申请人提供)：这份K08提案将发展詹姆斯·弗洛伊德博士的职业生涯，他是一名普通内科医生，接受过心血管疾病流行病学和药物流行病学方面的培训，并对此感兴趣。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的独立调查者。这些目标将通过在设计和实施心血管药物安全性研究方面的密集指导研究经验以及在使用几种可用于解决观察性研究中常见的混淆和其他形式的偏见的流行病学方法方面的培训来实现。这些活动将在主要导师布鲁斯·帕萨蒂博士以及共同导师芭芭拉·麦克奈特博士和米格尔·埃尔南博士的监督下进行，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实施方面具有专业知识的资深研究人员。在美国，胰岛素和口服降糖药物是导致药物不良反应而住院的主要原因，接受胰岛素治疗的2型糖尿病(DM)患者中约有40%联合使用口服药物。对口服糖尿病治疗的心血管安全性的担忧最早出现在40多年前，当时第一代磺脲类药物甲苯丁胺在大学小组糖尿病计划临床试验中被发现增加了心血管死亡的风险。磺脲类药物可能由于低血糖和直接的心肌影响而导致不良的心血管事件。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。在团体健康合作社这一大型综合医疗保健提供系统的背景下，我们以前曾使用电子处方记录和从医疗记录中获得的健康数据来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脲类药物和其他降糖疗法的心血管安全性：(1)对患有2型糖尿病且无心肌梗死病史的长效胰岛素使用者进行的心肌梗死病例对照研究；(2)第一项研究的心肌梗死病例组幸存者的初始队列研究。对没有普遍心血管疾病的受试者的限制，对关键潜在混杂因素的调整，倾向分数校准等分析方法，以及敏感性分析，将被用来解决残留混杂，这是这些研究有效性最严重的威胁。因果推断方法将被用来解决队列研究中可能发生的时变选择偏差。这些研究可能会改善2型糖尿病患者的心血管疾病预防，这项工作将导致对其他心血管药物安全性研究的建议，并开启弗洛伊德博士作为该领域领先研究者的职业生涯。

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.