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

描述（由申请人提供）：这是一个K08职业发展奖的申请卡洛斯阿尔瓦雷斯，助理教授和临床药剂师在得克萨斯理工大学健康科学中心药学院。他的长期职业目标是成为2型糖尿病和慢性肾病患者治疗药物的药物流行病学方面的国际知名专家和独立研究者。此K 08申请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）大型复杂国家数据库的分析。这个职业发展奖也将支持阿尔瓦雷斯博士的独立之路。为了实现这一目标，阿尔瓦雷斯博士组建了一个多学科的指导和咨询团队，在校外资助的临床研究方面具有丰富的经验。慢性肾脏病（CKD）是2型糖尿病（T2DM）的常见和众所周知的并发症。这种并发症通常会限制医疗服务提供者处方二甲双胍，二甲双胍是一种降糖药物，已知在T2DM患者中具有发病率和死亡率获益。FDA在T2DM和CKD患者中使用任意血清肌酐临界点标记的二甲双胍禁忌症没有证据，通常需要处方医生启动或将患者转换为不良事件特征更差或与心脏结局不良相关的其他降糖药物。其他国家的指南不支持FDA禁忌症，并允许二甲双胍用于轻度至中度CKD患者（通过估计的肾小球滤过率测量）。这项建议也没有证据。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尚不清楚。Alvarez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。在目标1中，他将确定二甲双胍在T2DM和CKD患者中的使用模式。他将分析来自芬奇托管的国家VA数据库的复杂管理和临床数据。目标1中确定的模式将告知他应在目标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物不良事件的相关性。具体而言，他将研究乳酸酸中毒的住院事件和低血糖的初级住院或急诊就诊。在目标3中，Alvarez博士将评估二甲双胍与微血管和大血管结局发展之间的关系。评估的微血管结局将是增殖性糖尿病视网膜病变和肾脏疾病进展。大血管结局将测量为非致死性卒中、急性心肌梗死、非创伤性下肢截肢和心血管疾病死亡的复合终点。他还将比较使用二甲双胍和其他降糖药物的患者的血糖控制情况。目标2和目标3将使用创新技术，如组合高维倾向评分和工具变量建模，以减少观察性研究中经常遇到的偏倚。该研究将成为R01或等同应用的基础，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.