ADA2013：三联疗法对新发T2DM疗效优于药物叠加的传统疗法

英国糖尿病前瞻性研究（UKPDS）发现，对糖尿病患者逐步叠加二甲双胍、磺酰脲类和基础胰岛素药物治疗可减少微血管并发症，但患者的糖化血红蛋白（A1c）会逐渐升高至8.5%以上，且10.5年后，近65%的患者仍需要接受胰岛素治疗。迄今，“二甲双胍+磺酰脲类+胰岛素”仍是美国及其他国家治疗指南中采用最为频繁的疗法。Muhammad A. Abdul-Ghani等人对此进行了研究，并于2013年6年25日在美国糖尿病学会2013年会公布了研究结果。

这项研究的目的在于，对比新发T2DM的两种初始疗法的有效性和安全性：三联疗法（基于病理生理学的手段）vs 按顺序叠加二甲双胍、磺酰脲类和基础胰岛素（在前一种药物失败的基础上叠加后一种药物）。

研究共招募147名新诊断出来的T2DM患者（年龄=45±1；BMI=36±0.5；A1c = 8.6±0.1%；糖尿病病程= 5.6±0.5月），随机分配接受三联疗法（n=71）和传统疗法（n=76）。三联疗法为二甲双胍（1000→2000 mg/d）+吡格列酮（15→45 mg/d）+艾塞那肽（5→10 μg BID）；传统疗法为，先用二甲双胍（剂量逐步增加，1000→2000 mg/d），随后叠加格列吡嗪（5→20 mg/d），最后叠加基础胰岛素，将A1c维持在6.5%以下。

结果发现，6个月后，接受三联疗法的患者A1c水平从8.6%降低至6.1%，24个月后维持在6.1%稳定水平。传统治疗的患者治疗6个月后，A1c水平也降低至6.1%，但到24个月时，又上升至6.6%（p < 0.01）。传统治疗组中未达到A1c<6.5%治疗目标的患者较多（传统46% vs 三联22%，p<0.0001）。除低水平A1c外，三联治疗组低血糖的发生率比传统治疗组低13.6倍。研究结束时，三联治疗组患者平均体重降低了1.2kg，而传统治疗组平均体重增加了3.6kg（p=0.02）。

核心代谢缺陷（胰岛素抵抗和β细胞功能缺陷）可引起低血糖。本次研究证明，T2DM治疗中，与只降低血糖浓度而不纠正潜在病理生理学紊乱的疗法相比，靶向核心代谢缺陷的抗糖尿病疗法更为安全有效。

原文：

Background: In UKPDS stepwise addition of metformin sulfonylurea and basal insulin reduced microvascular complications but A1c rose progressively to > 8.5% and ~65% of individuals required insulin therapy after 10.5 years. Yet metformin add SU add insulin remains the most frequently employed therapeutic recommendation in the US and other countries.

Aim: To compare the efficacy and safety of initiating therapy in new onset T2DM with triple therapy (pathophysiologic-based approach) versus metformin followed by sequential addition of sulfonylurea and basal insulin (treat to fail approach).

Research Design: 147 newly diagnosed T2DM (age = 45±1; BMI=36±0.5; A1c = 8.6±0.1%; diabetes duration = 5.6±0.5 mo) were randomized to receive initial combination therapy with metformin (1000→2000 mg/d) + pioglitazone (15→45 mg/d) + exenatide (5→10 μg BID) (Triple Therapy n=71) or escalating dose of metformin (1000→2000 mg/d) followed by sequential addition of glipizide (5→20 mg/d) and then basal insulin to maintain A1c < 6.5% (Conventional Therapy n = 76).

Results: In subjects receiving Triple Therapy A1c decreased from 8.6 to 6.1% at 6 mo and remained stable at 6.1% at 24 mo. With Conventional Therapy A1c declined to 6.1% at 6 mo and then increased to 6.6% at 24 mo (p < 0.01). More subjects in Conventional Arm failed to achieve the treatment A1c goal <6.5% (46 vs 22% p<0.0001). Despite significantly lower A1c Triple Therapy subjects had a 13.6-fold lower rate of hypoglycemia compared to subjects receiving Conventional Therapy. Lastly Triple Therapy subjects had mean weight loss of 1.2 kg versus 3.6 kg weight gain (p=0.02) in subjects on Conventional Therapy.

Conclusion: Antidiabetic therapy targeting the core metabolic defects (insulin resistance and beta cell dysfunction) responsible for hyperglycemia is more effective and safer than therapy simply aimed at lowering the plasma glucose conc without correcting the underlying pathophysiologic disturbances present in T2DM.

编辑： 高飞    来源：丁香园