达格列净治疗二甲双胍血糖控制不佳的 2 型糖尿病患者的效果：一项随机、双盲、安慰剂对照试验。

Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial.

机构信息

Life and Health Sciences, Aston University, Birmingham, UK.

出版信息

Lancet. 2010 Jun 26;375(9733):2223-33. doi: 10.1016/S0140-6736(10)60407-2.

DOI:10.1016/S0140-6736(10)60407-2

PMID:20609968

Abstract

BACKGROUND

Correction of hyperglycaemia and prevention of glucotoxicity are important objectives in the management of type 2 diabetes. Dapagliflozin, a selective sodium-glucose cotransporter-2 inhibitor, reduces renal glucose reabsorption in an insulin-independent manner. We assessed the efficacy and safety of dapagliflozin in patients who have inadequate glycaemic control with metformin.

METHODS

In this phase 3, multicentre, double-blind, parallel-group, placebo-controlled trial, 546 adults with type 2 diabetes who were receiving daily metformin (>/=1500 mg per day) and had inadequate glycaemic control were randomly assigned to receive one of three doses of dapagliflozin (2.5 mg, n=137; 5 mg, n=137; or 10 mg, n=135) or placebo (n=137) orally once daily. Randomisation was computer generated and stratified by site, implemented with a central, telephone-based interactive voice response system. Patients continued to receive their pre-study metformin dosing. The primary outcome was change from baseline in haemoglobin A(1c)(HbA(1c)) at 24 weeks. All randomised patients who received at least one dose of double-blind study medication and who had both a baseline and at least one post-baseline measurement (last observation carried forward) were included in the analysis. Data were analysed by use of ANCOVA models. This trial is registered with ClinicalTrials.gov, number NCT00528879.

FINDINGS

534 patients were included in analysis of the primary endpoint (dapagliflozin 2.5 mg, n=135; dapagliflozin 5 mg, n=133; dapagliflozin 10 mg, n=132; placebo, n=134). At week 24, mean HbA(1c) had decreased by -0.30% (95% CI -0.44 to -0.16) in the placebo group, compared with -0.67% (-0.81 to -0.53, p=0.0002) in the dapagliflozin 2.5 mg group, -0.70% (-0.85 to -0.56, p<0.0001) in the dapagliflozin 5 mg group, and -0.84% (-0.98 to -0.70, p<0.0001) in the dapagliflozin 10 mg group. Symptoms of hypoglycaemia occurred in similar proportions of patients in the dapagliflozin (2-4%) and placebo groups (3%). Signs, symptoms, and other reports suggestive of genital infections were more frequent in the dapagliflozin groups (2.5 mg, 11 patients [8%]; 5 mg, 18 [13%]; 10 mg, 12 [9%]) than in the placebo group (seven [5%]). 17 patients had serious adverse events (four in each of the dapagliflozin groups and five in the placebo group).

INTERPRETATION

Addition of dapagliflozin to metformin provides a new therapeutic option for treatment of type 2 diabetes in patients who have inadequate glycaemic control with metformin alone.

FUNDING

Bristol-Myers Squibb and AstraZeneca.

摘要

背景

纠正高血糖和预防糖毒性是 2 型糖尿病治疗的重要目标。达格列净是一种选择性钠-葡萄糖协同转运蛋白 2 抑制剂，以胰岛素非依赖的方式减少肾脏对葡萄糖的重吸收。我们评估了达格列净在二甲双胍血糖控制不佳的患者中的疗效和安全性。

方法

在这项 3 期、多中心、双盲、平行组、安慰剂对照试验中，546 名正在接受每日二甲双胍（>/=1500mg/天）治疗且血糖控制不佳的 2 型糖尿病患者被随机分配接受三种剂量的达格列净（2.5mg，n=137；5mg，n=137；或 10mg，n=135）或安慰剂（n=137）口服，每日一次。随机分配由计算机生成，并按地点分层，通过中央电话互动语音应答系统实施。患者继续接受研究前的二甲双胍剂量。主要终点是 24 周时血红蛋白 A1c（HbA1c）的变化。所有接受至少一剂双盲研究药物且基线和至少一次基线后测量（最后观察值结转）的随机患者均纳入分析。数据分析采用协方差分析模型。这项试验在 ClinicalTrials.gov 注册，编号为 NCT00528879。

结果

534 名患者被纳入主要终点分析（达格列净 2.5mg，n=135；达格列净 5mg，n=133；达格列净 10mg，n=132；安慰剂，n=134）。在第 24 周时，安慰剂组的平均 HbA1c 下降了 0.30%（95%CI-0.44 至-0.16），而达格列净 2.5mg 组下降了 0.67%（-0.81 至-0.53，p=0.0002），达格列净 5mg 组下降了 0.70%（-0.85 至-0.56，p<0.0001），达格列净 10mg 组下降了 0.84%（-0.98 至-0.70，p<0.0001）。低血糖症状在达格列净组（2-4%）和安慰剂组（3%）中发生的患者比例相似。达格列净组（2.5mg，11 例[8%]；5mg，18 例[13%]；10mg，12 例[9%]）比安慰剂组（7 例[5%]）更频繁出现生殖器感染的迹象、症状和其他提示。17 名患者发生严重不良事件（达格列净组各 4 例，安慰剂组 5 例）。