Exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy (DURATION-8): a 28 week, multicentre, double-blind, phase 3, randomised controlled trial
Exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy (DURATION-8): a 28 week, multicentre, double-blind, phase 3, randomised controlled trial
复制标题
DOI：
10.1016/s2213-8587(16)30267-4
复制
发表时间：
2016-12-01
影响因子：
44.5
通讯作者：
Jabbour, Serge A.
中科院分区：
文献类型：
--
作者：
Frias, Juan P.;Guja, Cristian;Jabbour, Serge A.
背景胰高血糖素样肽-1（GLP-1）受体激动剂和钠-葡萄糖协同转运蛋白-2（SGLT-2）抑制剂通过不同的机制降低血糖和体重，并改善心血管风险因素。我们的目的是比较的有效性和安全性共同启动的GLP-1受体激动剂艾塞那肽和SGLT 2抑制剂达格列净与艾塞那肽或达格列净单独在2型糖尿病患者控制不充分的metformin.Methods DURATION-8是一个28周，多中心，双盲，随机，活性对照的3期试验在109个网站在6个国家。通过交互式语音和网络应答系统，将二甲双胍单药治疗稳定（≥ 1500 mg/天）但血糖控制不佳（HbA（1c）8-12% [64-108 mmol/mol]）的2型糖尿病成人（年龄≥ 18岁）随机分配（1：1：1）接受艾塞那肽2 mg每周一次皮下注射+达格列净10 mg每日一次口服片剂、艾塞那肽+达格列净匹配口服安慰剂或达格列净+艾塞那肽匹配安慰剂注射。根据基线HbA（1c）（≥ 9.0% [= 75 mmol/mol]）对随机化进行分层。主要终点是HbA（1c）从基线至第28周的变化。次要终点是第2周和第28周空腹血糖和第28周餐后2小时血糖较基线的变化; HbA（1c）低于7.0%的患者比例（< 53 mmol/mol）;第28周时体重变化;第28周时体重减轻5%或更多的患者比例;以及第28周时收缩压的变化。研究结果在2014年9月4日至2015年10月15日期间，我们将695名患者随机分配至艾塞那肽联合达格列净组（n=231）、艾塞那肽单药组（n = 231; n=1未治疗）或达格列净单药组（n=233）。ClinicalTrials.gov意向治疗人群包括685名参与者（平均HbA（1c）9.3%[SD 1.1]; 78 mmol/mol [12]），其中611名（88%）完成了研究。28周后，艾塞那肽+达格列净组基线HbA（1c）的变化为-2.0%（95% CI-2，1至-1，8），艾塞那肽组为-1，6%（-1，8至-1，4），达格列净组为-1，4%（-1，6至-1，2）。与艾塞那肽单药治疗（-0.4%[95% CI-0.6至-0.1]; p=0.004）或达格列净单药治疗（-0.6%[-0.8至-0.3]; p < 0.001）相比，艾塞那肽加达格列净显著降低了HbA 1c自基线至第28周。艾塞那肽+达格列净在所有次要疗效终点方面均显著上级任一单药，空腹血糖和餐后血糖降低幅度更大，HbA 1c低于7.0%的患者更多（< 53 mmol/mol），体重减轻更大，体重减轻5%或以上的患者比例更大，收缩压下降幅度较大的（任何组中均为p = 5%的患者）是腹泻、注射部位结节、恶心和尿路感染。未报告严重低血糖或轻微低血糖发作。解释在二甲双胍单药治疗控制不佳的2型糖尿病患者中，同时开始艾塞那肽和达格列净治疗可改善各种血糖指标和心血管风险因素。双重治疗方案耐受性良好，具有该组合的预期安全性特征。来自正在进行的研究（AWARD-10; NCT 02597049）的其他数据将进一步为这些药物类别的联合使用提供信息。
Background Glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose co-transporter-2 (SGLT2) inhibitors reduce glycaemia and weight, and improve cardiovascular risk factors via different mechanisms. We aimed to compare the efficacy and safety of co-initiation of the GLP-1 receptor agonist exenatide and the SGLT2 inhibitor dapagliflozin with exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled by metformin.Methods DURATION-8 was a 28 week, multicentre, double-blind, randomised, active-controlled phase 3 trial done at 109 sites in six countries. Adults (aged >= 18 years) with type 2 diabetes and inadequate glycaemic control (HbA(1c) 8-12% [64-108 mmol/mol]) despite stable metformin monotherapy (>= 1500 mg/day) were randomly assigned (1:1:1), via an interactive voice and web-response system, to receive once-weekly exenatide 2 mg by subcutaneous injection plus once-daily dapagliflozin 10 mg oral tablets, exenatide with dapagliflozin-matched oral placebo, or dapagliflozin with exenatide-matched placebo injections. Randomisation was stratified by baseline HbA(1c) (= 9.0% [= 75 mmol/mol]). The primary endpoint was change in HbA(1c) from baseline to week 28. Secondary endpoints were the change from baseline in fasting plasma glucose at week 2 and week 28, and 2 h postprandial glucose at week 28; the proportion of patients with an HbA(1c) less than 7,0% (< 53 mmol/mol) at week 28; change in weight at week 28; the proportion of patients with weight loss of 5% or more at week 28; and change in systolic blood pressure at week 28. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02229396.Findings Between Sept 4, 2014, and Oct 15, 2015, we randomly assigned 695 patients to receive exenatide plus dapagliflozin (n=231), exenatide alone (n=231; n=1 untreated), or dapagliflozin alone (n=233). The intention-to-treat population comprised 685 participants (mean HbA(1c) 9,3% [SD 1,1]; 78 mmol/mol [12]), of whom 611 (88%) completed the study. After 28 weeks, the change in baseline HbA(1c) was -2, 0% (95% CI-2, 1 to -1, 8) in the exenatide plus dapagliflozin group, -1, 6% (-1, 8 to -1, 4) in the exenatide group, and -1, 4% (-1, 6 to-1, 2) in the dapagliflozin group. Exenatide plus dapagliflozin significantly reduced HbA 1c from baseline to week 28 compared with exenatide alone (-0, 4% [95% CI-0,6 to-0,1]; p=0.004) or dapagliflozin alone (-0,6% [-0,8 to -0,3]; p < 0.001). Exenatide plus dapagliflozin was significantly superior to either drug alone for all secondary efficacy endpoints, with greater reductions in fasting plasma and postprandial glucose, more patients with an HbA 1c less than 7,0% (< 53 mmol/mol), greater weight loss, a greater proportion of patients with weight loss of 5% or more, and greater reductions in systolic blood pressure (all p = 5% of patients in any group) were diarrhoea, injection-site nodules, nausea, and urinary tract infections. No episodes of major hypoglycaemia or minor hypoglycaemia were reported.Interpretation Co-initiation of exenatide and dapagliflozin improved various glycaemic measures and cardiovascular risk factors in patients with type 2 diabetes inadequately controlled by metformin monotherapy. The dual treatment regimen was well tolerated, with the expected safety profile for this combination. Additional data from an ongoing study (AWARD-10; NCT02597049) will further inform the use of these drug classes in combination.