Effectiveness of Immediate vs. Delayed Use of Metformin in New-Onset T2 Diabetes

描述(由申请人提供)：本申请涉及广泛的挑战领域(05)比较有效性和具体挑战主题05-DK-101*为新发现的2型糖尿病患者选择最佳的初始治疗方案。2007年对2型糖尿病的初始药物治疗建议进行了修改--从磺脲类药物改为二甲双胍作为初始单一疗法，从建议进行医学营养治疗(MNT)和改变生活方式的初步试验，改为建议在糖尿病初步诊断时立即开始药物治疗和MNT。UKPDS和两项观察性研究的结果表明，与磺脲类药物相比，二甲双胍单一疗法可能会降低心血管并发症的风险；采用研究的结果表明，与磺脲格列本脲相比，二甲双胍单一疗法的疗效持久性更长。二甲双胍似乎对低密度脂蛋白-胆固醇水平也有一定的相对好处，而且通常不会导致低血糖。来自糖尿病预防计划的证据表明，二甲双胍在防止从糖耐量受损到糖尿病的进展方面是有效的，这表明如果立即开始治疗，一旦超过2型糖尿病的诊断门槛，它也可能有效地减缓胰腺功能的恶化。最近对ACORD、ADVANCE和VADT试验的建议也表明，在预防2型糖尿病的微血管和大血管并发症方面，早期血糖控制可能比晚些时候更有效。这些指南的作者承认这些指南是“基于共识的”，并明确表示需要更好的证据，特别是关于较长期结果的证据。它们还没有在临床实践中被广泛采用，也不清楚它们是否会影响不同的、真实世界的患者群体的结果。毫无疑问，不同的医生、不同的系统和不同的时间采用不同的方法，这就提供了一个“自然实验”的机会来研究早期应用二甲双胍是否比先前的方法更能延缓糖尿病的恶化和并发症的发生。我们建议研究立即开始二甲双胍单一治疗与延迟开始二甲双胍治疗或早/晚开始磺脲类单一治疗对于不同结果的比较效果。使用HMO研究网络糖尿病联盟4个大型卫生系统成员的电子病历数据，我们将创建一个新诊断的2型糖尿病患者的大量队列，平均随访时间为3.5年。在纵向分析中，我们将检验与其他策略相比，及时使用二甲双胍是否与以下方面有关：1.单一治疗(从最初发现糖尿病到单一治疗失败)的更持久的血糖控制2.在首次诊断后1年和2年内体重增加较少3.严重低血糖发生率的差异4.更好的低密度脂蛋白控制或较低强度的降脂治疗5.血压控制不同或降压治疗强度较低6.心血管疾病终点的发生率差异(急性心肌梗死、中风或冠心病的联合终点，颈动脉或外周血运重建)7.微血管并发症发生率的差异(新发糖尿病视网膜病变、微量蛋白尿或估计的肾小球滤过率下降率)。我们认识到观察性方法固有的混淆风险。我们可以从EMR记录中获得许多临床和人口统计学的混杂因素，所有的比较都将使用倾向分数进行调整，以便在首次发现糖尿病时或之前测量这些变量。作为对这些分析的补充，我们将进行工具变量分析，使用医生处方实践作为工具变量。最近的研究表明，二甲双胍是糖尿病初始治疗的最佳口服药物，在糖尿病首次被发现时立即服用二甲双胍，而不是等到血糖达到稍微更高的目标水平，可以延缓糖尿病的进展，并预防心脏病、中风和肾脏疾病等并发症。这项研究对来自4个大型医疗保健系统的近40,000名新诊断的糖尿病患者进行了非常早期的二甲双胍治疗与更传统的治疗方法的比较。如果显示出早期使用二甲双胍的优势，这项研究的发现可能会极大地改变美国治疗2型糖尿病的方式，并减轻这种非常常见的疾病引发的并发症的负担。

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (05) Comparative Effectiveness and Specific Challenge Topic 05-DK-101* Selecting the Optimal Initial Treatment Regimen for Patients With Newly Discovered Type 2 Diabetes. Recommendations for initial pharmacotherapy in type 2 diabetes were modified in 2007 - to change from sulfonylureas to metformin as initial monotherapy, and from recommending an initial trial of medical nutrition therapy (MNT) and lifestyle change to recommending prompt initiation of pharmacotherapy along with MNT at initial diagnosis of diabetes. Findings from UKPDS and from two observational studies suggest that metformin monotherapy may lower risk for cardiovascular complications relative to sulfonylureas; findings from the ADOPT Study indicate that durability of monotherapy effectiveness is longer with metformin than with the sulfonylurea glyburide. Metformin also appears to have a modest relative benefit on LDL- cholesterol levels and usually does not cause hypoglycemia. Evidence from the Diabetes Prevention Program demonstrates that metformin is effective in preventing progression from impaired glucose tolerance to diabetes, suggesting that it may also be effective in slowing deterioration of pancreatic function once the diagnostic threshold for type 2 diabetes has been crossed if started immediately. Recent recommendations in response to the ACORD, ADVANCE, and VADT trials also suggest that early glycemic control may be more effective than later in preventing both microvascular and macrovascular complications of type 2 diabetes. These guidelines are acknowledged by their authors to be "consensus-based" and the need for better evidence, especially with respect to longer-term outcomes is clearly stated. They have not been widely adopted in clinical practice, and it is unknown whether they are impacting outcomes in diverse, real-world, patient populations. Undoubtedly, there has been variation in adoption across physicians, systems, and time, providing this "natural experiment" opportunity to study whether early initiation of metformin is superior to prior practice for delaying deterioration of diabetes and the onset of complications. We propose to examine the comparative effectiveness of immediate initiation of metformin monotherapy vs. delayed initiation of metformin or early/late initiation of sulfonylurea monotherapy for a variety of outcomes. Using electronic medical record data from 4 large health system members of the HMO Research Network Diabetes Consortium, we will create a large cohort of newly diagnosed type 2 diabetic patients with average follow-up of 3.5 years. In longitudinal analyses, we will examine whether prompt initiation of metformin (within 6 months of the earliest detection of diabetes) compared with other strategies is associated with: 1. Longer durability of glycemic control on monotherapy (from initial detection of diabetes to failure of monotherapy) 2. Less weight gain at 1 and 2 years post initial diagnosis 3. Differences in the incidence of severe hypoglycemia 4. Better LDL-cholesterol control or lower intensity of lipid-lowering therapy required 5. Differences in blood pressure control or lower intensity of anti-hypertensive therapy required 6. Differences in the incidence of cardiovascular disease endpoints (combined endpoint of acute myocardial infarction, stroke, or coronary, carotid or peripheral revascularization) 7. Differences in incidence of microvascular complications (new onset diabetic retinopathy, microalbuminuria, or rate of decline in estimated glomerular filtration rate). We recognize the risks of confounding inherent in observational approaches. Many clinical and demographic confounders are available to us from EMR records and all comparisons will be adjusted, using propensity scores, for these variables measured at or before initial detection of diabetes. As a complement to these analyses, we will conduct instrumental variable analyses, using physician prescribing practices as the instrumental variable. Recent studies suggest that metformin is the best oral medication for initial treatment of diabetes and that starting metformin immediately when diabetes is first detected, rather than waiting until blood sugars reach a somewhat higher target level, could delay progression of diabetes and prevent complications such as heart disease, stroke and kidney disease. This study compares very early treatment with metformin to more traditional approaches in a population of nearly 40,000 newly diagnosed diabetic patients from 4 large health care systems. If an advantage is shown for early use of metformin, the study's findings could dramatically change the way in which type 2 diabetes is treated in the U.S. and reduce the burden of complications from this very common condition.