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[摘要] 糖尿病与心血管疾病关系密切,治疗糖尿病的药物对心血管预后也有不同的影响。SGLT2抑制剂达格列净是治疗2型糖尿病的新药,目前有较多研究显示其能明显降低心血管风险事件的发生,特别是能明显改善糖尿病伴心力衰竭患者的临床症状、减少住院率和死亡率,还能改善心肌缺血、抑制心肌重塑、降低血压、减轻体重,对血脂、尿酸等均有不同程度的影响。达格列净对心血管系统作用是多方面的,获益也是多方面的,有望成为治疗糖尿病伴心血管疾病的理想药物。
[关键词] SGLT2抑制剂;达格列净;心血管;2型糖尿病
[中图分类号] R541.6 [文献标识码] A [文章编号] 1673-9701(2021)24-0188-05
Progress in application of SGLT2 inhibitor Dapagliflozin in cardiovascular diseases
SHENG Xiaosheng1 CAO Congcong1 JIANG Lizhen1 WU Lijuan2 WANG Xiaobing3
1.Department of Cardiology,Jinhua People′s Hospital in Zhejiang Province, Jinhua 321000, China; 2.Xinshi Street Community Service Centre, Jinhua 321000, China; 3.Department of Medical Sciences, Jinhua Polytechnic, Jinghua 321000, China
[Abstract] Diabetes is closely related to cardiovascular disease, and the drugs for treating diabetes also have different effects on cardiovascular prognosis. SGLT2 inhibitor dapagliflozin is a new drug for the treatment of type 2 diabetes mellitus. There are many studies showing that it can significantly reduce the occurrence of cardiovascular risk events. In particular, it can significantly improve the clinical symptoms, reduce hospitalization rate and mortality of patients with diabetes and heart failure. Dapagliflozin can not only decrease myocardial ischemia and prevent myocardial remodeling but also lower blood pressure or reduce body weight.It has varying degrees influence on blood lipids and serum uric acid. Dapagliflozin has many effects and benefits on cardiovascular system. It is expected to be an ideal drug for the treatment of diabetes mellitus with cardiovascular disease.
[Key words] SGLT2 inhibitor; Dapagliflozin; Cardiovascular; Type 2 diabetes
1980年以來,全球2型糖尿病的发病率和患病率增长了3倍,并且在不断升级。糖尿病和心血管疾病关系密切,其中冠状动脉疾病(Coronary artery disease,CAD),心力衰竭(Heart failure,HF)和中风是2型糖尿病患者死亡和致残的主要原因。有报道糖尿病患者70%~80%死于心血管并发症[1]。因而联合治疗2型糖尿病和心血管疾病,合理使用对糖尿病和心血管均获益的药物治疗变得越来越重要。
达格列净是一种钠-葡萄糖协同转运蛋白 2抑制剂(sodium-glucose cotransporter 2 inhibitor,SGLT2i),通过抑制肾小管的SGLT2受体,减少肾小管对葡萄糖的重吸收,增加尿液中葡萄糖的排泄,从而降低血浆中葡萄糖的水平。虽然SGLT2i是一种治疗糖尿病药物,但近来较多研究发现,SGLT2抑制剂能降低心血管风险事件发生,在大型临床试验(EMPA-REG OUTCOME,CANVAS Program和 DECLARE-TIMI 58)中,SGLT2 抑制剂已显示可改善长期临床结果,包括T2DM(2型糖尿病,type 2 diabetes mellitus)的全因死亡率,心血管死亡和心力衰竭住院治疗[2-3],因而本文就达格列净在心血管获益方面作一讨论。
1 达格列净在糖尿病伴心力衰竭中的应用
在糖尿病伴心力衰竭治疗方面,杨光全等[4]研究发现,在慢性心力衰竭合并2型糖尿病患者服用达格列净6个月后明左室舒张功能得到明显改善。Mikhail 等[5]报道SGLT2抑制剂达格列净治疗糖尿病伴慢性心衰患者可以明显改善心衰患者临床症状,改善生化质量,减少住院率和死亡率。Fumitaka Soga[6]也研究发现达格列净用于治疗2型糖尿病合并慢性心力衰竭患者,能明显降低左房容量指数和左室质量指数,改善心衰患者的左室舒张功能。Ye等[7]在小鼠模型中,单独使用达格列净和联合应用达格列净和沙格列汀进行对照,结果发现。与对照组相比,达格列净单独治疗和联合治疗组均显示左室收缩功能,左室舒张末期和收缩末期容积显着改善。而且,与单独使用达格列净的组相比,联合治疗组显示出左室舒张末期和收缩末期容积的改善更大。一项大型随机临床试验DAPA-HF研究[8]达格列净是否能改善心力衰竭患者的长期心血管预后,结果提示不管是在2型糖尿病患者中,还是在非糖尿病患者中,达格列净都能改善射血分数,能明显降低心血管功能死亡和心力衰竭事件,该研究揭示了SGLT2抑制剂改善因为心血管预后的潜在机制是独立于降糖作用之外。另外,SGLT2i 作为二甲双胍治疗的联合药物疗法,在长达两年的治疗中与非 SGLT2i 组合相比,可显著改善预后,在长期治疗中,SGLT2i 治疗中 HbA1c 与基线相比变化的改善明显大于非 SGLT2i 组合。这些患者的复杂心血管结果的发生率也较低,包括心肌梗死或其他心血管原因导致的死亡以及因心力衰竭而住院,在使用SGLT2i之前,其他抗高血糖药均未显示出良好的心血管特征,说明达格列净与二甲双胍合用治疗糖尿病,对心力衰竭有具有明显益处[2,9]。Wang等[10]研究提示,新确诊的接受 SGLT2i 治疗的 T2DM 患者的心房利钠肽水平降低,这可能有益于心血管系统。在实验性糖尿病性心肌病模型中,SGLT2 抑制剂可改善心脏的收缩和舒张功能,体内左心室压力-体积环分析表明,SGLT2 抑制剂改善了收缩末期和舒张末期压力之间的关系[11-12]。此外,SGLT2 抑制剂在糖尿病心肌病患者中显示出降低了心力衰竭住院的风险,表明 SGLT2 抑制剂在 T2DM 患者中对改善糖尿病心肌病患者心功能起关键作用[13]。达格列净在心力衰竭中应用以及研究较多,证据也比较充分,以上的研究结果也说明,SGLT2 抑制剂达格列净对于糖尿病合并心力衰竭具有明显的有益作用。 2 达格列净在糖尿病伴冠心病心肌缺血中的应用
在糖尿病伴冠心病心肌缺血患者中用达格列净治疗,也有研究者发现达格列净能改善糖尿病伴缺血性心肌病患者的内皮功能[14]。这些作者认为,SGLT2 抑制剂通过刺激线粒体的生物发生来减少线粒体的损伤,从而导致心肌摄取的正常化以及葡萄糖和脂肪酸的氧化。此外,Tanajak 等比较了达格列净与维格列汀对糖尿病前期大鼠缺血再灌注损伤后的心脏保护作用,结果表明达格列净比维格列汀在改善左室功能障碍和梗塞面积方面具有更大的疗效[11]。达格列净和维格列汀联合治疗在减轻左室功能障碍和梗塞面积方面显示出最大的疗效。临床试验表明,与使用其他降糖药相比,在患有T2DM和高心血管风险特征的患者中,SGLT2i 的使用与心血管疾病死亡率降低相关[15]。荟萃分析还显示,SGLT2 抑制剂在降低已确诊的动脉粥样硬化性心血管疾病(ASCVD,Atherosclerotic cardiovascular disease)患者的心肌梗死、脑卒中和心血管死亡的风险方面具有临床优势[16],说明达格列净有改善冠心病心肌缺血作用,对于糖尿病伴冠心病患者,包括心肌梗死患者,使用达格列净均能明显获益。
3 达格列净在抑制心肌重塑中的作用
但对于心肌重塑方面的获益,目前临床和基础研究均比较少,而目前研究表明SGLT2抑制剂能从多方面抑制机体炎症反应,Ye等[7]在动物研究中发现,达格列净具有抗炎,抗纤维化和改善糖尿病心肌病心衰功能,降低IL-1β(白介素-1β),IL-6(白介素-6)等炎症指标。在心肌缺血模型中,达格列净通过增加M2巨噬细胞的活化来抑制成纤维细胞的分化,减少胶原合成,不仅抑制了心脏收缩压和舒张压功能恶化,还具有明显的心脏抗纤维化作用。病理实验研究表明,SGLT2 抑制剂防止了缺血性心肌损伤后左室重构和纤维化区域的扩大[11-12]。实验数据表明,SGLT2 抑制剂可减少血浆容量,从而大大减轻了压力超负荷引起的心脏纤维化和重塑[17],从达格列净抑制心肌重塑指标以及病理组织学改变,达格列净具有一定的抑制心肌重塑作用。
4 达格列净对交感神经系统的作用
实验和临床研究表明,SGLT2 抑制剂未激活肾素血管紧张素系统[18-19]。SGLT2 抑制剂的降压作用在EMPA-REG OUTCOME 试驗中也未引起心律的补偿性增加,表明 SGLT2 抑制剂治疗后无进一步的交感神经系统激活[20-21]。目前达格列净对交感神经系统研究尚不够多,机制也不够明确,尚需更多深入研究。
5 达格列净对血压的影响
SGLT2 通过竞争性阻断肾脏近曲小管中的 SGLT2 受体而影响高血糖症和降低血压(BP)[22],阻止过滤后的葡萄糖和钠的再吸收,从而导致糖尿和利尿[23]。由于渗透性利尿和利尿钠的生理作用,SGLT2i 可减少前负荷和后负荷,引起体积收缩,并降低血压(1至2 mmHg)[23-24],这提供了心脏肾脏保护。也有研究表明达格列净可降低收缩压(-2.6 至-6.4 mmHg),但无明确的剂量关系。对于高血压控制不佳和已有心血管疾病的患者,达格列净可以减轻体重以及收缩压,而不会影响心血管安全性,这是由于达格列净改善了心血管的危险因素[25-26]。达格列净对心血管疾病和高血压的老年患者以及有心血管病史的患者均显示出有益的作用,而与心血管风险的程度无关。这些有利的影响是 SGLT2 抑制心血管危险因素的结果。
6 达格列净对体重的影响
在患有心血管疾病的 T2DM 老年患者中,达格列净改善血糖控制并促进体重减轻。这些患者对它的耐受性良好,并且不会增加低血糖的风险[27]。达格列净有渗透性利尿作用,因而其降低体重可能与利尿有关系。
7 达格列净对氧化应激的影响
达格列净可降低氧化应激, 从而导致其心血管效应。在连续血糖监测设备上新诊断为 T2DM 的患者中,达格列净显示出降低的血糖波动,而血糖升高没有增加。它可以降低氧化应激,如血浆 8-PGF2α水平(氧化应激的生物标志物)显著降低,降低的葡萄糖波动和氧化应激都可以使心血管系统受益[28]。此外, Leng等研究结果表明,SGLT2抑制剂达格列净可以通过抑制糖尿病动脉粥样硬化中的NLRP3炎性体来减轻动脉粥样硬化病变的形成并增加病变的稳定性,这种作用可能是由于它通过活性氧-NLRP3-caspase-1(ROS-NLRP3-caspase-1)途径对巨噬细胞分泌白介素-1β的抑制作用[29]。Terami等[30]达格列净能显著降低db/db小鼠肾脏巨噬细胞浸润及炎症和氧化应激基因表达,抑制高糖诱导的mProx24细胞炎性细胞因子基因表达和氧化应激。这表明达格列净可通过改善高血糖、抑制炎症和氧化应激来改善糖尿病肾病。
8 达格列净对血脂的影响
达格列净对2型糖尿病患者的血脂水平变化很小,非高密度脂蛋白胆固醇、低密度脂蛋白和高密度脂蛋白胆固醇水平略有升高,对甘油三酯水平的影响不确切,需要更多的数据来了解达格列净对血脂水平的影响[29,31]。
9 达格列净对降低尿酸的作用
达格列净具有一定的降尿酸作用,Hao等[32]研究发现可以改善血糖控制不佳的住院T2DM患者的血糖控制,并降低血尿酸水平,考虑到与高尿酸血症相关的不良反应,与其他口服降糖药相比,达格列净被认为可为住院的T2DM患者提供更多益处。Xin等[33]通过Meta分析认为与安慰剂对比,2型糖尿病患者使用SGLT2抑制剂能够显著降低血尿酸水平,提示SGLT2抑制剂可能对糖尿病高尿酸血症患者有益。
综上,达格列净是一种高度选择性的 SGLT2抑制剂,它通过阻断近端肾小管 S1 段中表达的 SGLT2 受体来降低肾脏对葡萄糖的吸收,从而控制血糖水平。综上临床试验显示达格列净可降低 HbA1c,体重,血压和血清尿酸。SGLT2 例如达格列净影响内脏脂肪和血糖水平,它们都是代谢综合征的组成部分,并且与心血管的进展有关。达格列净可减少氧化应激,并可延缓动脉粥样硬化,SGLT2 抑制剂还可能降低心房利钠肽水平。因而达格列净对心血管系统作用是多方面的,获益也是多方面的,有望成为治疗糖尿病伴心血管疾病的理想药物,但达格列净发挥其心脏保护和肾保护作用的作用机制尚不清楚,需要进一步研究。它在一般人群中是安全且耐受良好的,包括老年患者和具有高风险心血管因素或先前存在的心血管疾病的人群。但有报道达格列净具有较高的生殖器感染和泌尿系统感染发生率[33-35],未来需要更多的临床研究来完善评价达格列净的临床效果。 [參考文献]
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(收稿日期:2021-01-16)
[关键词] SGLT2抑制剂;达格列净;心血管;2型糖尿病
[中图分类号] R541.6 [文献标识码] A [文章编号] 1673-9701(2021)24-0188-05
Progress in application of SGLT2 inhibitor Dapagliflozin in cardiovascular diseases
SHENG Xiaosheng1 CAO Congcong1 JIANG Lizhen1 WU Lijuan2 WANG Xiaobing3
1.Department of Cardiology,Jinhua People′s Hospital in Zhejiang Province, Jinhua 321000, China; 2.Xinshi Street Community Service Centre, Jinhua 321000, China; 3.Department of Medical Sciences, Jinhua Polytechnic, Jinghua 321000, China
[Abstract] Diabetes is closely related to cardiovascular disease, and the drugs for treating diabetes also have different effects on cardiovascular prognosis. SGLT2 inhibitor dapagliflozin is a new drug for the treatment of type 2 diabetes mellitus. There are many studies showing that it can significantly reduce the occurrence of cardiovascular risk events. In particular, it can significantly improve the clinical symptoms, reduce hospitalization rate and mortality of patients with diabetes and heart failure. Dapagliflozin can not only decrease myocardial ischemia and prevent myocardial remodeling but also lower blood pressure or reduce body weight.It has varying degrees influence on blood lipids and serum uric acid. Dapagliflozin has many effects and benefits on cardiovascular system. It is expected to be an ideal drug for the treatment of diabetes mellitus with cardiovascular disease.
[Key words] SGLT2 inhibitor; Dapagliflozin; Cardiovascular; Type 2 diabetes
1980年以來,全球2型糖尿病的发病率和患病率增长了3倍,并且在不断升级。糖尿病和心血管疾病关系密切,其中冠状动脉疾病(Coronary artery disease,CAD),心力衰竭(Heart failure,HF)和中风是2型糖尿病患者死亡和致残的主要原因。有报道糖尿病患者70%~80%死于心血管并发症[1]。因而联合治疗2型糖尿病和心血管疾病,合理使用对糖尿病和心血管均获益的药物治疗变得越来越重要。
达格列净是一种钠-葡萄糖协同转运蛋白 2抑制剂(sodium-glucose cotransporter 2 inhibitor,SGLT2i),通过抑制肾小管的SGLT2受体,减少肾小管对葡萄糖的重吸收,增加尿液中葡萄糖的排泄,从而降低血浆中葡萄糖的水平。虽然SGLT2i是一种治疗糖尿病药物,但近来较多研究发现,SGLT2抑制剂能降低心血管风险事件发生,在大型临床试验(EMPA-REG OUTCOME,CANVAS Program和 DECLARE-TIMI 58)中,SGLT2 抑制剂已显示可改善长期临床结果,包括T2DM(2型糖尿病,type 2 diabetes mellitus)的全因死亡率,心血管死亡和心力衰竭住院治疗[2-3],因而本文就达格列净在心血管获益方面作一讨论。
1 达格列净在糖尿病伴心力衰竭中的应用
在糖尿病伴心力衰竭治疗方面,杨光全等[4]研究发现,在慢性心力衰竭合并2型糖尿病患者服用达格列净6个月后明左室舒张功能得到明显改善。Mikhail 等[5]报道SGLT2抑制剂达格列净治疗糖尿病伴慢性心衰患者可以明显改善心衰患者临床症状,改善生化质量,减少住院率和死亡率。Fumitaka Soga[6]也研究发现达格列净用于治疗2型糖尿病合并慢性心力衰竭患者,能明显降低左房容量指数和左室质量指数,改善心衰患者的左室舒张功能。Ye等[7]在小鼠模型中,单独使用达格列净和联合应用达格列净和沙格列汀进行对照,结果发现。与对照组相比,达格列净单独治疗和联合治疗组均显示左室收缩功能,左室舒张末期和收缩末期容积显着改善。而且,与单独使用达格列净的组相比,联合治疗组显示出左室舒张末期和收缩末期容积的改善更大。一项大型随机临床试验DAPA-HF研究[8]达格列净是否能改善心力衰竭患者的长期心血管预后,结果提示不管是在2型糖尿病患者中,还是在非糖尿病患者中,达格列净都能改善射血分数,能明显降低心血管功能死亡和心力衰竭事件,该研究揭示了SGLT2抑制剂改善因为心血管预后的潜在机制是独立于降糖作用之外。另外,SGLT2i 作为二甲双胍治疗的联合药物疗法,在长达两年的治疗中与非 SGLT2i 组合相比,可显著改善预后,在长期治疗中,SGLT2i 治疗中 HbA1c 与基线相比变化的改善明显大于非 SGLT2i 组合。这些患者的复杂心血管结果的发生率也较低,包括心肌梗死或其他心血管原因导致的死亡以及因心力衰竭而住院,在使用SGLT2i之前,其他抗高血糖药均未显示出良好的心血管特征,说明达格列净与二甲双胍合用治疗糖尿病,对心力衰竭有具有明显益处[2,9]。Wang等[10]研究提示,新确诊的接受 SGLT2i 治疗的 T2DM 患者的心房利钠肽水平降低,这可能有益于心血管系统。在实验性糖尿病性心肌病模型中,SGLT2 抑制剂可改善心脏的收缩和舒张功能,体内左心室压力-体积环分析表明,SGLT2 抑制剂改善了收缩末期和舒张末期压力之间的关系[11-12]。此外,SGLT2 抑制剂在糖尿病心肌病患者中显示出降低了心力衰竭住院的风险,表明 SGLT2 抑制剂在 T2DM 患者中对改善糖尿病心肌病患者心功能起关键作用[13]。达格列净在心力衰竭中应用以及研究较多,证据也比较充分,以上的研究结果也说明,SGLT2 抑制剂达格列净对于糖尿病合并心力衰竭具有明显的有益作用。 2 达格列净在糖尿病伴冠心病心肌缺血中的应用
在糖尿病伴冠心病心肌缺血患者中用达格列净治疗,也有研究者发现达格列净能改善糖尿病伴缺血性心肌病患者的内皮功能[14]。这些作者认为,SGLT2 抑制剂通过刺激线粒体的生物发生来减少线粒体的损伤,从而导致心肌摄取的正常化以及葡萄糖和脂肪酸的氧化。此外,Tanajak 等比较了达格列净与维格列汀对糖尿病前期大鼠缺血再灌注损伤后的心脏保护作用,结果表明达格列净比维格列汀在改善左室功能障碍和梗塞面积方面具有更大的疗效[11]。达格列净和维格列汀联合治疗在减轻左室功能障碍和梗塞面积方面显示出最大的疗效。临床试验表明,与使用其他降糖药相比,在患有T2DM和高心血管风险特征的患者中,SGLT2i 的使用与心血管疾病死亡率降低相关[15]。荟萃分析还显示,SGLT2 抑制剂在降低已确诊的动脉粥样硬化性心血管疾病(ASCVD,Atherosclerotic cardiovascular disease)患者的心肌梗死、脑卒中和心血管死亡的风险方面具有临床优势[16],说明达格列净有改善冠心病心肌缺血作用,对于糖尿病伴冠心病患者,包括心肌梗死患者,使用达格列净均能明显获益。
3 达格列净在抑制心肌重塑中的作用
但对于心肌重塑方面的获益,目前临床和基础研究均比较少,而目前研究表明SGLT2抑制剂能从多方面抑制机体炎症反应,Ye等[7]在动物研究中发现,达格列净具有抗炎,抗纤维化和改善糖尿病心肌病心衰功能,降低IL-1β(白介素-1β),IL-6(白介素-6)等炎症指标。在心肌缺血模型中,达格列净通过增加M2巨噬细胞的活化来抑制成纤维细胞的分化,减少胶原合成,不仅抑制了心脏收缩压和舒张压功能恶化,还具有明显的心脏抗纤维化作用。病理实验研究表明,SGLT2 抑制剂防止了缺血性心肌损伤后左室重构和纤维化区域的扩大[11-12]。实验数据表明,SGLT2 抑制剂可减少血浆容量,从而大大减轻了压力超负荷引起的心脏纤维化和重塑[17],从达格列净抑制心肌重塑指标以及病理组织学改变,达格列净具有一定的抑制心肌重塑作用。
4 达格列净对交感神经系统的作用
实验和临床研究表明,SGLT2 抑制剂未激活肾素血管紧张素系统[18-19]。SGLT2 抑制剂的降压作用在EMPA-REG OUTCOME 试驗中也未引起心律的补偿性增加,表明 SGLT2 抑制剂治疗后无进一步的交感神经系统激活[20-21]。目前达格列净对交感神经系统研究尚不够多,机制也不够明确,尚需更多深入研究。
5 达格列净对血压的影响
SGLT2 通过竞争性阻断肾脏近曲小管中的 SGLT2 受体而影响高血糖症和降低血压(BP)[22],阻止过滤后的葡萄糖和钠的再吸收,从而导致糖尿和利尿[23]。由于渗透性利尿和利尿钠的生理作用,SGLT2i 可减少前负荷和后负荷,引起体积收缩,并降低血压(1至2 mmHg)[23-24],这提供了心脏肾脏保护。也有研究表明达格列净可降低收缩压(-2.6 至-6.4 mmHg),但无明确的剂量关系。对于高血压控制不佳和已有心血管疾病的患者,达格列净可以减轻体重以及收缩压,而不会影响心血管安全性,这是由于达格列净改善了心血管的危险因素[25-26]。达格列净对心血管疾病和高血压的老年患者以及有心血管病史的患者均显示出有益的作用,而与心血管风险的程度无关。这些有利的影响是 SGLT2 抑制心血管危险因素的结果。
6 达格列净对体重的影响
在患有心血管疾病的 T2DM 老年患者中,达格列净改善血糖控制并促进体重减轻。这些患者对它的耐受性良好,并且不会增加低血糖的风险[27]。达格列净有渗透性利尿作用,因而其降低体重可能与利尿有关系。
7 达格列净对氧化应激的影响
达格列净可降低氧化应激, 从而导致其心血管效应。在连续血糖监测设备上新诊断为 T2DM 的患者中,达格列净显示出降低的血糖波动,而血糖升高没有增加。它可以降低氧化应激,如血浆 8-PGF2α水平(氧化应激的生物标志物)显著降低,降低的葡萄糖波动和氧化应激都可以使心血管系统受益[28]。此外, Leng等研究结果表明,SGLT2抑制剂达格列净可以通过抑制糖尿病动脉粥样硬化中的NLRP3炎性体来减轻动脉粥样硬化病变的形成并增加病变的稳定性,这种作用可能是由于它通过活性氧-NLRP3-caspase-1(ROS-NLRP3-caspase-1)途径对巨噬细胞分泌白介素-1β的抑制作用[29]。Terami等[30]达格列净能显著降低db/db小鼠肾脏巨噬细胞浸润及炎症和氧化应激基因表达,抑制高糖诱导的mProx24细胞炎性细胞因子基因表达和氧化应激。这表明达格列净可通过改善高血糖、抑制炎症和氧化应激来改善糖尿病肾病。
8 达格列净对血脂的影响
达格列净对2型糖尿病患者的血脂水平变化很小,非高密度脂蛋白胆固醇、低密度脂蛋白和高密度脂蛋白胆固醇水平略有升高,对甘油三酯水平的影响不确切,需要更多的数据来了解达格列净对血脂水平的影响[29,31]。
9 达格列净对降低尿酸的作用
达格列净具有一定的降尿酸作用,Hao等[32]研究发现可以改善血糖控制不佳的住院T2DM患者的血糖控制,并降低血尿酸水平,考虑到与高尿酸血症相关的不良反应,与其他口服降糖药相比,达格列净被认为可为住院的T2DM患者提供更多益处。Xin等[33]通过Meta分析认为与安慰剂对比,2型糖尿病患者使用SGLT2抑制剂能够显著降低血尿酸水平,提示SGLT2抑制剂可能对糖尿病高尿酸血症患者有益。
综上,达格列净是一种高度选择性的 SGLT2抑制剂,它通过阻断近端肾小管 S1 段中表达的 SGLT2 受体来降低肾脏对葡萄糖的吸收,从而控制血糖水平。综上临床试验显示达格列净可降低 HbA1c,体重,血压和血清尿酸。SGLT2 例如达格列净影响内脏脂肪和血糖水平,它们都是代谢综合征的组成部分,并且与心血管的进展有关。达格列净可减少氧化应激,并可延缓动脉粥样硬化,SGLT2 抑制剂还可能降低心房利钠肽水平。因而达格列净对心血管系统作用是多方面的,获益也是多方面的,有望成为治疗糖尿病伴心血管疾病的理想药物,但达格列净发挥其心脏保护和肾保护作用的作用机制尚不清楚,需要进一步研究。它在一般人群中是安全且耐受良好的,包括老年患者和具有高风险心血管因素或先前存在的心血管疾病的人群。但有报道达格列净具有较高的生殖器感染和泌尿系统感染发生率[33-35],未来需要更多的临床研究来完善评价达格列净的临床效果。 [參考文献]
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(收稿日期:2021-01-16)