SGLT-2抑制剂对2型糖尿病患者血浆浓度及风险标志物氧化三甲胺肾脏清除率的影响。
完整摘要 · 中文译文
背景：钠-葡萄糖协同转运蛋白2（SGLT-2）抑制剂因其在血糖控制方面的有效性，以及对心血管疾病和死亡率的有益作用，已成为治疗2型糖尿病（T2D）的关键药物类别，并适用于许多其他临床适应证。因此，近期EMMY试验的一项二次分析结果出乎意料：在该试验中，接受恩格列净治疗的急性心肌梗死患者与安慰剂组相比，血清氧化三甲胺（TMAO）水平更高，而此前研究已将血液中高浓度的TMAO与不良心血管结局和死亡率相关联。鉴于此，我们研究的目的是在T2D患者环境中探讨SGLT-2抑制剂恩格列净和达格列净对血浆浓度和肾脏清除率（ClR）的影响。 方法：来自两项前瞻性、随机、安慰剂对照、双盲、交叉试验的T2D患者（恩格列净N = 69，NCT02471963；达格列净N = 54，NCT02383238）在基线和每次接受SGLT-2抑制剂或安慰剂治疗后采集的血浆和24小时尿液样本，通过液相色谱-串联质谱法（LC-MS/MS）测定TMAO。 结果：在接受SGLT-2抑制剂治疗后，总共123名患者中，TMAO血浆水平比安慰剂组高11.5%（p = 0.006），TMAO的ClR降低10.3%（p = 0.048），而其尿液排泄量无相关变化（p = 0.521）。在达格列净试验中，治疗后TMAO血浆浓度高23.4%（p = 0.021），TMAO的ClR低22.6%（p = 0.025）。 与安慰剂相比，达格列净组的TMAO血浆浓度有所增加。恩格列净组观察到类似趋势，但未达到统计学显著性。 结论：使用SGLT-2抑制剂与TMAO血浆浓度轻度升高相关。结合既往试验数据，目前的研究结果提示SGLT-2抑制剂可能存在类别效应。该效应是否影响SGLT-2抑制剂的总体临床获益，需进一步研究探讨。 试验注册：http://www. CLINICALTRIALS：gov：NCT02471963（2015年6月15日注册，回顾性注册）和NCT02383238。
完整摘要 · 英文原文
BACKGROUND: Sodium-glucose cotransporter-2 (SGLT-2) inhibitors have become a key drug class in the treatment of Type 2 diabetes (T2D) due to their effectiveness in blood sugar control, but also for many other clinical indications because of beneficial effects on cardiovascular diseases and mortality. Therefore, the findings of a secondary analysis of the recent EMMY trial, in which acute myocardial infarction patients treated with empagliflozin had higher trimethylamine-N-oxide (TMAO) serum levels compared to placebo, were unexpected, as high TMAO concentrations in blood have previously been linked to adverse cardiovascular and mortality outcomes. In light of this, the aim of our study was to explore the effects of the SGLT-2 inhibitors empagliflozin and dapagliflozin on plasma concentrations and renal clearance (ClR) in a T2D patient setting. METHODS: Plasma and 24-h urine samples from two prospective, randomised, placebo-controlled, double-blind, cross-over trials with T2D patients (empagliflozin N = 69, NCT02471963; dapagliflozin N = 54, NCT02383238), taken at baseline and after each treatment with either SGLT-2 inhibitor or placebo, were measured for TMAO via LC-MS/MS. RESULTS: After treatment with an SGLT-2 inhibitor, in the total of 123 patients, TMAO plasma levels were 11.5% higher compared to placebo (p = 0.006) and ClR of TMAO was reduced by 10.3% (p = 0.048) without any relevant change in its urinary excretion (p = 0.521). In the dapagliflozin trial, TMAO plasma concentration was 23.4% higher (p = 0.021), and ClR of TMAO was 22.6% lower (p = 0.025) after treatment with dapagliflozin compared to placebo. For empagliflozin, a similar trend was observed, but did not reach statistical significance. CONCLUSION: Treatment with an SGLT-2 inhibitor was associated with a modest increase in plasma concentration of TMAO. Together with data from a previous trial, the present findings suggest a possible class effect of SGLT-2 inhibitors. Whether this effect impacts the overall clinical benefits of SGLT-2 inhibitors needs to be subject to further investigations. TRIAL REGISTRATION: http://www. CLINICALTRIALS: gov: NCT02471963 (registered 15th June 2015, retrospectively registered) and NCT02383238.