Background

Dapagliflozin is a sodium-glucose cotransporter-2 inhibitor approved for the treatment of type 2 diabetes. We aimed to assess the efficacy and safety of dapagliflozin as an add-on to adjustable insulin in patients with inadequately controlled type 1 diabetes.

Methods

DEPICT-1 was a double-blind, randomised, parallel-controlled, three-arm, phase 3, multicentre study done at 143 sites in 17 countries. Eligible patients were aged 18–75 years and had inadequately controlled type 1 diabetes (HbA_1c between ≥7·7% and ≤11·0% [≥61·0 mmol/mol and ≤97·0 mmol/mol]) and had been prescribed insulin for at least 12 months before enrolment. After an 8 week lead-in period to optimise diabetes management, patients were randomly assigned (1:1:1) using an interactive voice response system to dapagliflozin 5 mg or 10 mg once daily, given orally, or matched placebo. Randomisation was stratified by current use of continuous glucose monitoring, method of insulin administration, and baseline HbA_1c. The primary efficacy outcome was the change from baseline in HbA_1c after 24 weeks of treatment in the full analysis set, which consisted of all randomly assigned patients who received at least one dose of study drug. An additional 55 patients who were incorrectly and non-randomly allocated to only dapagliflozin treatment groups were included in the safety analysis set. This study was registered with ClinicalTrials.gov, number NCT02268214; data collection for the present analysis was completed on Jan 4, 2017, and a 28 week extension phase is ongoing.

Findings

Between Nov 11, 2014, and April 16, 2016, 833 patients were assigned to treatment groups and included in safety analyses (dapagliflozin 5 mg [n=277] vs dapagliflozin 10 mg [n=296] vs placebo [n=260]; 778 of these patients were randomly assigned and included in the full analysis set for efficacy analyses (259 vs 259 vs 260; difference due to randomisation error affecting 55 patients). Mean baseline HbA_1c was 8·53% (70 mmol/mol; SD 0·67% [7·3 mmol/mol]). At week 24, both doses of dapagliflozin significantly reduced HbA_1c compared with placebo (mean difference from baseline to week 24 for dapagliflozin 5 mg vs placebo was −0·42% [95% CI −0·56 to −0·28; p<0·0001] and for dapagliflozin 10 mg vs placebo was −0·45% [−0·58 to −0·31; p<0·0001]). Among patients in the dapagliflozin 5 mg (n=277), dapagliflozin 10 mg (n=296), and placebo (n=260) groups, the most common adverse events were nasopharyngitis (38 [14%] vs 36 [12%] vs 39 [15%]), urinary tract infection (19 [7%] vs 11 [4%] vs 13 [5%]), upper respiratory tract infection (15 [5%] vs 15 [5%] vs 11 [4%]), and headache (12 [4%] vs 17 [6%] vs 11 [4%]). Hypoglycaemia occurred in 220 (79%), 235 (79%), and 207 (80%) patients in the dapagliflozin 5 mg, dapagliflozin 10 mg, and placebo groups, respectively; severe hypoglycaemia occurred in 21 (8%), 19 (6%), and 19 (7%) patients, respectively. Adjudicated definite diabetic ketoacidosis occurred in four (1%) patients in the dapagliflozin 5 mg group, five (2%) in the dapagliflozin 10 mg group, and three (1%) in the placebo group.

Interpretation

Our results suggest that dapagliflozin is a promising adjunct treatment to insulin to improve glycaemic control in patients with inadequately controlled type 1 diabetes.

Funding

AstraZeneca and Bristol-Myers Squibb.

中文翻译：

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达格列净在控制不充分的1型糖尿病（DEPICT-1）患者中的疗效和安全性：多中心，双盲，3期，随机对照试验的24周结果

背景

达格列净是一种批准用于治疗2型糖尿病的钠-葡萄糖共转运蛋白2抑制剂。我们旨在评估dapagliflozin作为1型糖尿病控制不足的患者中可调节胰岛素的补充剂的疗效和安全性。

方法

DEPICT-1是一项在17个国家/地区的143个地点进行的双盲，随机，平行对照，三臂，三期，多中心研究。符合条件的患者年龄在18-75岁之间，并没有充分控制1型糖尿病（HbA _1c在≥7·7％和≤11·0％[≥61·0 mmol / mol和≤97·0 mmol / mol]之间），并且患有入院前至少12个月服用胰岛素。经过为期8周的优化糖尿病管理的导入期后，使用交互式语音应答系统将患者随机分配（1：1：1），以口服dapagliflozin 5 mg或10 mg每天一次，口服或配套安慰剂。随机化通过当前使用的连续血糖监测，胰岛素给药方法和基线HbA _1c进行分层。主要疗效结果是HbA相对于基线的变化完整分析集中治疗24周后的_1c，包括所有接受至少一种剂量研究药物的随机分配患者。安全分析集还包括另外55名错误且非随机分配给dapagliflozin治疗组的患者。该研究已在ClinicalTrials.gov上注册，编号NCT02268214 ; 本分析的数据收集于2017年1月4日完成，并且为期28周的扩展阶段正在进行中。

发现

在2014年11月11日至2016年4月16日之间，将833例患者分为治疗组并纳入安全性分析（达格列净5 mg [n = 277]与达格列净10 mg [n = 296] vs安慰剂[n = 260]；这些患者中有778名被随机分配并纳入完整的分析集以进行功效分析（259 vs 259 vs 260；由于随机误差影响55位患者而造成的差异），平均基线HbA _1c为8·53％（70 mmol / mol； SD） 0·67％[7·3 mmol / mol]。在第24周时，两种剂量的dapagliflozin与安慰剂相比均显着降低HbA _1c（对于5 mg dapagliflozin，从基线到第24周的平均差异与安慰剂为-0·42％[95％CI -0·56至-0·28；p <0·0001]，相对于安慰剂，达格列净10 mg相对于安慰剂为−0·45％[−0·58至-0·31；p <0·0001]）。dapagliflozin 5 mg（n = 277），dapagliflozin 10 mg（n = 296）和安慰剂（n = 260）组的患者中，最常见的不良反应是鼻咽炎（38 [14％] vs 36 [12％] vs 39 [15％]），尿路感染（19 [7％] vs 11 [4％] vs 13 [5％]），上呼吸道感染（15 [5％] vs 15 [5％] vs 11 [ 4％]）和头痛（12 [4％] vs 17 [6％] vs11 [4％]）。达格列净5毫克，达格列净10毫克和安慰剂组分别发生220（79％），235（79％）和207（80％）患者的低血糖；严重低血糖症分别发生在21（8％），19（6％）和19（7％）患者中。达格列净5 mg组中有4例（1％）患者确诊为糖尿病性酮症酸中毒，达格列净10 mg组中有5例（2％）患者，安慰剂组有3例（1％）患者。

解释

我们的结果表明，达格列净是一种有前途的胰岛素辅助疗法，可改善控制不充分的1型糖尿病患者的血糖控制。

资金

阿斯利康和百时美施贵宝。