Safety and Effectiveness of Metformin Therapy in Patients with Type 2 Diabetes an

描述（由申请人提供）：这是一份申请K08职业发展奖的申请，申请人是德克萨斯理工大学健康科学中心药学院的助理教授兼临床药剂师Carlos Alvarez。他的长期职业目标是成为国际知名的2型糖尿病和慢性肾脏疾病治疗药物流行病学专家和独立研究者。这个K08应用程序的职业发展目标是支持以下方面的培训：目标1)药物流行病学，目标2)卫生服务研究，目标3)大型、复杂的国家数据库分析。这项职业发展奖也将支持阿尔瓦雷斯博士走向独立。为了实现这一目标，Alvarez博士组建了一个多学科指导和咨询团队，在外部资助的临床研究方面具有丰富的经验。慢性肾脏疾病（CKD）是2型糖尿病（T2DM）常见且众所周知的并发症。这种并发症通常限制了医生开二甲双胍的处方，二甲双胍是一种已知对2型糖尿病患者具有发病率和死亡率益处的降糖药。FDA标记的T2DM和CKD患者使用任意血清肌酐切割点使用二甲双胍的禁忌症没有证据基础，通常需要处方者启动或转换患者使用其他不良事件概况或与不良心脏结局相关的降糖药。其他国家的指南没有批准FDA的禁忌症，并允许通过估计肾小球滤过率来测量轻度至中度CKD患者使用二甲双胍。这一建议也没有证据依据。因此，二甲双胍在T2DM和CKD患者中的安全性和有效性在很大程度上是未知的。阿尔瓦雷斯博士的研究将通过三个具体的研究目标来确定安全性和有效性。在目的1中，他将确定T2DM和CKD患者使用二甲双胍的模式。他将分析由VINCI托管的国家VA数据库中复杂的行政和临床数据。在目标1中确定的模式将告诉他应该在目标2和3中进一步测试的变量。目的2将检查二甲双胍和其他降糖药不良事件的关联。具体来说，他将研究乳酸性酸中毒的住院事件和低血糖的初级住院或急诊就诊情况。在Aim 3中，Alvarez博士将评估二甲双胍与微血管和大血管预后发展之间的关系。评估的微血管结果将是增殖性糖尿病视网膜病变的发展和肾脏疾病的进展。大血管结局将以非致死性中风、急性心肌梗死、非创伤性下肢截肢和心血管疾病死亡的综合结果来衡量。他还将比较服用二甲双胍和其他降糖药的患者的血糖控制情况。目标2和目标3将使用高维倾向评分和工具变量建模相结合的创新技术来减少观察性研究中经常遇到的偏差。该研究将构成R01或同等应用的基础，以比较VA系统和英国治疗的2型糖尿病和慢性肾脏疾病患者的二甲双胍使用模式、安全性和有效性。

DESCRIPTION (provided by applicant): This is an application for a K08 Career Development Award for Carlos Alvarez, an Assistant Professor and clinical pharmacist at Texas Tech University Health Sciences Center School of Pharmacy. His long-term career goal is to be an internationally known expert and independent investigator in the pharmacoepidemiology of therapeutic agents used in patients with type 2 diabetes and chronic kidney disease. The career development aims of this K08 application are to support training in: Aim 1) pharmacoepidemiology, Aim 2) health services research, and Aim 3) analysis of large, complex national databases. This career development award will also support Dr. Alvarez's path to independence. To achieve this goal, Dr. Alvarez has assembled a multidisciplinary mentoring and advisory team with significant experience in extramurally funded clinical research. Chronic kidney disease (CKD) is a common and well known complication of type 2 diabetes (T2DM). This complication often restricts providers from prescribing metformin, a glucose-lowering agent with known morbidity and mortality benefits in patients with T2DM. This FDA labeled contraindication for metformin using arbitrary serum creatinine cut-points in patients with T2DM and CKD is not evidence based and often necessitates prescribers to initiate or switch patients to other glucose-lowering agents with worse adverse event profiles or that have been associated with poor cardiac outcomes. Guidance in other countries do not endorse the FDA contraindication and allows for metformin use in patients with mild to moderate CKD as measured by estimated glomerular filtration rate. This recommendation is also not based in evidence. Thus, the safety and effectiveness of metformin in patients with T2DM and CKD is largely unknown. Dr. Alvarez's research will focus on determining the safety and effectiveness through three specific research aims. In Aim 1 he will determine patterns of metformin use in patients with T2DM and CKD. He will analyze complex administrative and clinical data from the national VA database hosted by VINCI. Patterns identified in Aim 1 will inform him of the variables that should be further tested in Aims 2 and 3. Aim 2 will examine associations of adverse events for metformin and other glucose-lowering agents. Specifically, he will study incident hospitalizations for lactic acidosis and primary hospitalizations or emergency department visits for hypoglycemia. In Aim 3, Dr. Alvarez will assess the relationship between metformin and the development of microvascular and macrovascular outcomes. Microvascular outcomes assessed will be the development of proliferative diabetic retinopathy and progression of kidney disease. Macrovascular outcomes will be measured as a composite of non-fatal stroke, acute myocardial infarction, non-traumatic lower extremity amputation and cardiovascular disease death. He will also compare glycemic control between patients prescribed metformin and those on other glucose-lowering agents. Innovative techniques such as combination high-dimensional propensity score and instrumental variable modeling will be used in Aims 2 and 3 to reduce bias often encountered in observational research. The research will form the basis for an R01 or equivalent application to compare metformin usage patterns, safety and effectiveness in patients with type 2 diabetes and chronic kidney disease between those treated in the VA system and the United Kingdom.