【导语】2013年第73届美国糖尿病协会科学年会(ADA2013)于6月21日~25日在美国芝加哥隆重举办。与往年相比，本届ADA年会的一个最大变化是增加了主席口头报告专场（President's Oral Session）。25日专场上公布的几项研究结果在与会听众中激起了激烈讨论：对新发2型糖尿病患者治疗方案探索结果显示，二甲双胍+吡格列酮+艾塞那肽三联降糖方案优于传统阶梯降糖方案。

背景：尽管在UKPDS研究中，二甲双胍、磺脲类和基础胰岛素的阶梯降糖方案减少了微血管并发症，但HbA1c水平升高至＞8.5%且65%的患者在10.5年后才接受胰岛素治疗。在美国和其他国家，最常见的治疗建议依然是二甲双胍+磺脲类+胰岛素联合降糖方案。

目标：对比三联降糖方案（基于病理生理学的疗法）和二甲双胍逐步加用磺脲类和基础胰岛素的阶梯降糖方案（治疗失败的疗法）起始治疗新发2型糖尿病(T2DM)的有效性和安全性。

研究设计：147例新发2型糖尿病患者（年龄= 45±1; BMI=36±0.5;Hb A1c = 8.6±0.1%; 糖尿病病程= 5.6±0.5 个月）随机分为2组，71例患者接受起始三联降糖方案：二甲双胍（1000mg/d渐增至45mg/d）+吡格列酮（15mg/d渐增至45mg/d）+艾塞那肽（5μg渐增至10μg，2次/d）；76例患者接受阶梯降糖方案：二甲双胍（1000mg/d渐增至2000mg/d），然后加用格列吡嗪（5mg/d渐增至20mg/d）和基础胰岛素以使HbA1c水平＜6.5%。

结果：6个月时，三联降糖方案组患者的HbA1c水平从8.6%降至6.1%。24个月时，HbA1c水平仍维持在6.1%。而阶梯降糖方案组患者的HbA1c水平在6个月时降至6.1%，但24个月时又升至6.6%（P＜0.01）。三联降糖方案组HbA1c水平达标（＜6.5%）的患者多于阶梯降糖方案组（46% 比 22%，P<0.0001）。除了显著降低HbA1c水平之外，三联降糖方案的低血糖发生率较阶梯降糖方案组降低13.6倍，且平均体重降低1.2kg，而阶梯降糖组患者的平均体重增加了3.6kg（P=0.02）。

结论：对新发2型糖尿病患者，阶梯降糖方案仅降低血糖水平，不能纠正其潜在的病理生理学缺陷，而三联降糖方案针对主要代谢缺陷（胰岛素抵抗和β细胞功能障碍），能更有效、安全地治疗高血糖。

【研究摘要】

Initial Triple Combination Therapy is Superior to Stepwise Add-On Conventional Therapy in Newly Diagnosed T2DM

Muhammad A. Abdul-Ghani MD, PhD   University of Texas Health Science Center at San Antonio

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.