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

 描述（由申请方提供）：高血压是糖尿病微血管并发症发生的主要风险因素。ADA建议将T2 DM患者的A1 c降低至“尽可能接近正常水平，同时避免低血糖”的水平（即HbA 1c <6.0-6.5%）。实现这一目标的最佳药物治疗从未被确定。我们已经证明，与逐步添加二甲双胍、磺脲类药物和胰岛素（常规治疗）相比，新诊断的T2 DM患者开始接受纠正T2 DM已知病理生理缺陷的药物（二甲双胍、吡格列酮、艾塞那肽）联合治疗（三联治疗）可使HbA 1c降低更大，并且HbA 1c降低可维持36个月随访。接受常规治疗的受试者体重显著增加（3.7 kg），低血糖事件发生率高于接受三联治疗的受试者（体重减轻3.1 kg）（增加7.4倍）。此外，与传统疗法相比，三联疗法产生了胰岛素敏感性和β细胞功能的显著增加。在这项资助中，我们建议继续对所有目前活跃的受试者进行额外36个月的随访，以获得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.