Comparison of empagliflozin and glimepiride as add-on to metformin in patients with type 2 diabetes: a 104-week randomised, active-controlled, double-blind, phase 3 trial
Comparison of empagliflozin and glimepiride as add-on to metformin in patients with type 2 diabetes: a 104-week randomised, active-controlled, double-blind, phase 3 trial
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DOI：
10.1016/s2213-8587(14)70120-2
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发表时间：
2014-09-01
影响因子：
44.5
通讯作者：
Broedl, Uli C.
中科院分区：
文献类型：
--
作者：
Ridderstrale, Martin;Andersen, Knut Robert;Broedl, Uli C.
背景 二甲双胍是 2 型糖尿病患者推荐的一线药物治疗。对于最佳二线药物治疗尚未达成共识。我们比较了钠葡萄糖协同转运蛋白 2 抑制剂恩格列净和磺酰脲类格列美脲作为二甲双胍辅助治疗 2 型糖尿病患者的疗效和安全性。 方法 在这项双盲 3 期试验中，尽管接受二甲双胍治疗以及饮食和运动咨询，但 HbA(1c) 浓度为 7-10% 的 2 型糖尿病患者（年龄 >= 18 岁）被随机分配到 1 组：计算机生成的随机序列与恩格列净（25 mg，每日一次，口服）或格列美脲（1-4 mg，每日一次，口服）分层的 1 比率，按 HbA(1c)、估计肾小球滤过率 (eGFR) 和区域分层，作为二甲双胍的附加疗法，持续 104 周。患者和研究人员对治疗分配情况不知情。主要终点是第 52 周和第 104 周时 HbA1c 水平相对于基线的变化。主要终点的差异首先进行非劣效性测试（基于 0.3% 的裕度）。如果显示非劣效性，则在第 104 周时对主要终点的差异进行优效性测试。对完整分析组进行了分析，即接受至少一剂研究药物治疗且具有基线 HbA(1c) 值的患者。本研究已在 ClinicalTrials.gov 注册，编号为 NCT01167881。 104 周的延长正在进行中。 结果 2010 年 8 月至 2011 年 6 月期间，1549 名患者被随机分配接受恩格列净 (n=769) 或格列美脲 (n=780) 治疗；恩格列净组中有四名患者没有接受指定的治疗。恩格列净在两个时间点均不劣于格列美脲。第 104 周时，恩格列净与格列美脲相比，HbA(1c) 相对于基线变化的调整后平均差异为 -0.11%（95% CI -0.19 至 -0.02；优越性 p=0.0153）。 661 名（86%）接受恩格列净治疗的患者和 673 名（86%）接受格列美脲治疗的患者报告了不良事件。恩格列净组有 72 名患者（9%）报告了严重不良事件，格列美脲组有 68 名患者（9%）报告了严重不良事件。恩格列净组有 119 名患者（16%）报告了严重不良事件，格列美脲组有 89 名患者（11%）报告了严重不良事件。已确认的低血糖不良事件（血浆葡萄糖
Background Metformin is the recommended first-line pharmacotherapy for patients with type 2 diabetes. There is no consensus on the optimum second-line pharmacotherapy. We compared the efficacy and safety of the sodium glucose cotransporter 2 inhibitor empagliflozin and the sulfonylurea glimepiride as add-on to metformin in patients with type 2 diabetes.Methods In this double-blind phase 3 trial, patients (aged >= 18 years) with type 2 diabetes and HbA(1c) concentrations of 7-10%, despite metformin treatment and diet and exercise counselling, were randomly assigned in a 1: 1 ratio with a computer-generated random sequence, stratified by HbA(1c), estimated glomerular filtration rate (eGFR), and region, to empagliflozin (25 mg once daily, orally) or glimepiride (1-4 mg once daily, orally) as add-on to metformin for 104 weeks. Patients and investigators were masked to treatment assignment. The primary endpoint was change from baseline in HbA 1c levels at weeks 52 and 104. Differences in the primary endpoint were first tested for non-inferiority (based on a margin of 0.3%). If non-inferiority was shown, differences in the primary endpoint at week 104 were then tested for superiority. Analysis was done on the full-analysis set-ie, patients who were treated with at least one dose of study drug and had a baseline HbA(1c) value. This study is registered with ClinicalTrials.gov, number NCT01167881. A 104-week extension is ongoing.Findings Between August, 2010, and June, 2011, 1549 patients were randomly assigned to receive empagliflozin (n=769) or glimepiride (n=780); four patients in the empagliflozin group did not receive the assigned treatment. Empagliflozin was non-inferior to glimepiride at both timepoints. At week 104, adjusted mean difference in change from baseline in HbA(1c) with empagliflozin versus glimepiride was -0.11% (95% CI -0.19 to -0.02; p=0.0153 for superiority). Adverse events were reported in 661 (86%) patients treated with empagliflozin and 673 (86%) patients treated with glimepiride. Severe adverse events were reported in 72 (9%) patients in the empagliflozin group and 68 (9%) in the glimepiride group. Serious adverse events were reported in 119 (16%) patients in the empagliflozin group and 89 (11%) in the glimepiride group. Confirmed hypoglycaemic adverse events (plasma glucose