Durability of Early Combination Therapy vs Conventional Therapy in New Onset T2DM

 描述(申请人提供)：高血糖是糖尿病微血管并发症发展的主要危险因素。美国食品和药物管理局建议将2型糖尿病患者的糖化血红蛋白降至“尽可能接近正常水平，同时避免低血糖”的水平(即糖化血红蛋白6.0-6.5%)。实现这一目标的最佳药物疗法一直没有确定。我们已经证明，与逐步添加二甲双胍、磺脲类药物和胰岛素(传统疗法)相比，新诊断的T2 DM患者开始服用纠正T2 DM已知病理生理缺陷的药物(三联疗法)后，HbA1c的下降幅度更大，并且HbA1c的下降持续了36个月。与体重减轻3.1公斤的接受三联疗法的受试者相比，接受传统疗法的受试者体重显著增加(3.7公斤)，低血糖事件的发生率更高(7.4倍)。此外，与传统疗法相比，三联疗法显著提高了胰岛素敏感性和β细胞功能。在这项资助中，我们建议继续跟踪所有目前活跃的受试者36个月，以获得关于三联疗法与传统疗法相比的长期疗效、持久性、安全性和作用机制的信息。

 DESCRIPTION (provided by applicant): Hyperglycemia is the major risk factor for the development of diabetic microvascular complications. The ADA recommends lowering the A1c in T2DM individuals to levels (i.e. HbA1c <6.0-6.5%) "as close to normal as possible while avoiding hypoglycemia". The optimal pharmacologic therapy which achieves this goal never has been determined. We have demonstrated that starting newly diagnosed T2DM individuals on a combination of agents (metformin, pioglitazone, exenatide) which correct known pathophysiologic defects in T2DM (Triple Therapy) produces a greater decrease in HbA1c compared to stepwise addition of metformin, sulfonylurea and insulin (Conventional Therapy) and that the decrease in HbA1c was maintained for 36 months of follow-up. Subjects receiving Conventional Therapy experienced significant weight gain (3.7 kg) and a higher rate (7.4-fold increase) of hypoglycemic events compared to subjects receiving Triple Therapy who lost 3.1 kg of body weight. Moreover, Triple Therapy produced profound increases in insulin sensitivity and beta cell function compared to Conventional Therapy. In this grant, we propose to continue to follow-all currently active subjects for an additional 36 months to obtain information about the long term efficacy, durability, safety, and mechanism of action of Triple Therapy compared to Conventional Therapy.