Wilding J P H, Woo V, Rohwedder K, Sugg J, Parikh S
Diabetes and Endocrinology Research Group, Department of Obesity & Endocrinology, Clinical Sciences Centre, University Hospital Aintree, Liverpool, UK.
Diabetes Obes Metab. 2014 Feb;16(2):124-36. doi: 10.1111/dom.12187. Epub 2013 Aug 29.
Dapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), has been shown to improve glycaemic control, stabilize insulin dosing and mitigate insulin-associated weight gain over 48 weeks in patients whose type 2 diabetes mellitus (T2DM) was inadequately controlled despite high doses of insulin. Here the efficacy and safety of dapagliflozin therapy after a total of 104 weeks are evaluated in this population.
This was a 24-week, randomized, placebo-controlled, double-blinded, multicentre trial followed by two site- and patient-blinded extension periods of 24 and 56 weeks (NCT00673231), respectively. A total of 808 patients, whose T2DM was inadequately controlled on insulin ≥30 IU/day, with or without up to two oral antidiabetic drugs, were randomly assigned to receive placebo or 2.5, 5 or 10 mg/day of dapagliflozin for 104 weeks. At 48 weeks, patients on dapagliflozin 5 mg were switched to 10 mg. Outcomes over 104 weeks included change from baseline in HbA1c, insulin dose and body weight; analyses used observed cases and included data after insulin up-titration. Adverse events (AEs) were evaluated throughout 104 weeks.
Five hundred and thirteen patients (63.6%) completed the study. Mean HbA1c changes from baseline at 104 weeks were -0.4% in the placebo group and -0.6 to -0.8% in the dapagliflozin groups. In the placebo group, mean insulin dose increased by 18.3 IU/day and weight increased by 1.8 kg at 104 weeks, whereas in the dapagliflozin groups, insulin dose was stable and weight decreased by 0.9-1.4 kg. AEs, including hypoglycaemia, were balanced across groups. Proportions of patients with events suggestive of genital infection and of urinary tract infection (UTI) were higher with dapagliflozin versus placebo (genital infection 7.4-14.3% vs. 3.0%; UTI 8.4-13.8% vs. 5.6%) but most occurred in the first 24 weeks and most were single episodes that responded to routine management.
Dapagliflozin improved glycaemic control, stabilized insulin dosing and reduced weight without increasing major hypoglycaemic episodes over 104 weeks in patients whose T2DM was inadequately controlled on insulin. However, rates of genital infection and of UTI were elevated with dapagliflozin therapy.
达格列净是一种钠-葡萄糖协同转运蛋白2（SGLT2）的选择性抑制剂，已被证明在2型糖尿病（T2DM）患者中，即使使用高剂量胰岛素血糖控制仍不佳的情况下，可在48周内改善血糖控制、稳定胰岛素剂量并减轻胰岛素相关体重增加。在此，对该人群在总共104周的达格列净治疗后的疗效和安全性进行评估。
这是一项为期24周的随机、安慰剂对照、双盲、多中心试验，随后分别有两个为期24周和56周的单中心、患者盲法延长期（NCT00673231）。总共808例T2DM患者，胰岛素剂量≥30 IU/天，无论是否联用至多两种口服抗糖尿病药物，随机分配接受安慰剂或2.5、5或10 mg/天的达格列净治疗104周。在48周时，服用5 mg达格列净的患者换用10 mg。104周的结局指标包括糖化血红蛋白（HbA1c）、胰岛素剂量和体重相对于基线的变化；分析采用实际观察病例，并纳入胰岛素剂量上调后的的数据。在整个104周期间评估不良事件（AE）。
513例患者（63.6%）完成了研究。安慰剂组在104周时HbA1c相对于基线的平均变化为-0.4%，达格列净组为-0.6%至-0.8%。在安慰剂组，104周时平均胰岛素剂量增加18.3 IU/天，体重增加1.8 kg，而在达格列净组，胰岛素剂量稳定，体重减轻0.9 - 1.4 kg。包括低血糖在内的不良事件在各组间均衡。与安慰剂相比，达格列净组提示生殖器感染和尿路感染（UTI）的患者比例更高（生殖器感染7.4 - 14.3%对3.0%；UTI 8.4 - 13.8%对5.6%），但大多数发生在最初24周内，且大多数为单次发作，对常规处理有反应。
对于胰岛素治疗血糖控制不佳的T2DM患者，达格列净在104周内改善了血糖控制、稳定了胰岛素剂量并减轻了体重，且未增加严重低血糖发作。然而，达格列净治疗使生殖器感染和UTI的发生率升高。
