Division of Diabetes, Metabolism, and Endocrinology, Department of Medicine, Toho University Graduate School of Medicine, 6-11-1 Omori-Nishi, Ota-ku, Tokyo, 143-8541, Japan.
Department of Nephrology, Tokyo Kyosai Hospital, Tokyo, Japan.
Cardiovasc Diabetol. 2017 Jul 6;16(1):84. doi: 10.1186/s12933-017-0564-0.
BACKGROUND: Recent studies reported that sodium glucose cotransporter 2 (SGLT2) inhibitors can potentially reduce the risk of cardiovascular mortality in patients with type 2 diabetes mellitus (T2DM). However, there is little or no information on the therapeutic effects of SGLT2 inhibitors on the progression of atherosclerosis. This dapagliflozin effectiveness on vascular endothelial function and glycemic control (DEFENCE) study was designed to determine the effects of dapagliflozin, a SGLT2 inhibitor, on endothelial function in patients with early-stage T2DM. METHODS: DEFENCE is a prospective, randomized, open-label, blinded-endpoint, parallel-group, comparative clinical trial. Between October 2015 and August 2016, 80 T2DM patients treated with 750 mg of metformin (hemoglobin A1c ≥6.0 and <8.0%, n = 80) were enrolled and randomized to receive either 1500 mg/day metformin (the metformin group, n = 40), or 750 mg/day metformin supplemented with 5 mg/day dapagliflozin (the dapagliflozin group, n = 40), for 16 weeks. The primary endpoint was a change in flow-mediated dilation (FMD) from baseline to the end of the 16-week treatment period. The secondary outcomes include changes in indexes of glycemic control, lipid metabolism, and oxidative stress, body composition, and safety evaluation. RESULTS: Although FMD tended to improve only in the dapagliflozin group, ΔFMD was comparable between the two groups. Analysis of patients with HbA1c >7.0% showed significant improvement of FMD in the dapagliflozin group than metformin group (P < 0.05). HbA1c, fasting plasma glucose, plasma glucagon, and body weight significantly decreased in both groups. Interestingly, urine 8-hydroxy-2'-deoxyguanosin, a biomarker of oxidative stress, was significantly lower in the dapagliflozin group than metformin group at 16 weeks (P < 0.001). CONCLUSIONS: Dapagliflozin add-on therapy to metformin for 16 weeks improved endothelial function, as assessed by FMD, in patients with inadequately controlled early-stage T2DM. Improvement in oxidative stress may contribute to the improvement in FMD. Trial registration University Hospital Medical Information Network Clinical Trial Registry (UMIN000018754).
背景：最近的研究表明，钠-葡萄糖共转运蛋白 2（SGLT2）抑制剂可能降低 2 型糖尿病（T2DM）患者的心血管死亡风险。然而，关于 SGLT2 抑制剂对动脉粥样硬化进展的治疗效果的信息很少或没有。本研究旨在评估 SGLT2 抑制剂达格列净对早期 T2DM 患者血管内皮功能和血糖控制的影响，即达格列净对血管内皮功能和血糖控制的疗效（DEFENCE）研究。
方法：DEFENCE 是一项前瞻性、随机、开放标签、盲终点、平行组、对照临床试验。2015 年 10 月至 2016 年 8 月，纳入 80 例接受 750mg 二甲双胍（糖化血红蛋白（HbA1c）≥6.0%且<8.0%，n=80）治疗的 T2DM 患者，随机分为二甲双胍 1500mg/d 组（n=40）或二甲双胍 750mg/d 加用达格列净 5mg/d 组（n=40），治疗 16 周。主要终点为 16 周治疗期间从基线到结束时的血流介导的舒张（FMD）的变化。次要结局包括血糖控制、脂质代谢和氧化应激、身体成分和安全性评估的指标的变化。
结果：尽管 FMD 仅在达格列净组有改善趋势，但两组间ΔFMD 无差异。对 HbA1c>7.0%的患者进行分析显示，达格列净组的 FMD 显著改善，优于二甲双胍组（P<0.05）。两组的 HbA1c、空腹血糖、血浆胰高血糖素和体重均显著下降。有趣的是，16 周时达格列净组尿液 8-羟基-2'-脱氧鸟苷（氧化应激的生物标志物）显著低于二甲双胍组（P<0.001）。
结论：达格列净联合二甲双胍治疗 16 周可改善早期 T2DM 患者的内皮功能，以 FMD 评估。氧化应激的改善可能有助于 FMD 的改善。
试验注册：大学医院医疗信息网临床试验注册（UMIN000018754）。
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