SGLT-2抑制剂——恩格列净的心血管保护作用及机制研究进展

摘要/Abstract

摘要： 心血管疾病是2型糖尿病患者死亡的首要原因。糖尿病患者心血管并发症的发病率、死亡率均高，严重降低患者的生活质量，增加了家庭经济负担。近年有研究证实，降低2型糖尿病患者主要心血管事件的降糖药物有2类，分别为钠-葡萄糖协同转运蛋白2(sodium-glucose co-transporter-2，SGLT-2)抑制剂及胰高血糖素祥肽-1(glucagon-like peptide，GLP-1)受体激动制。SGLT-2抑制剂是一种新型口服降糖药，恩格列净为美国FDA第一个批准的用于降低心血管危险因素的SGLT-2抑制剂。临床研究已证实恩格列净的心脏和肾脏保护作用。本研究就恩格列净的心血管保护作用及机制研究进展做一综述，以期为恩格列净的临床使用提供理论依据。

关键词: font-size:medium, ">SGLT-2抑制剂, 恩格列净, 心血管保护作用；2型糖尿病

Abstract: Cardiovascular disease is the leading cause of death in patients with type 2 diabetes. The incidence and mortality rate of cardiovascular complications in diabetic patients are pretty high, which seriously reduces the quality of life of patients, increases the family financial burden. Recent studies have shown that there are 2 kinds of hypoglycemic drugs that can reduce the major cardiovascular events of type 2 diabetes mellitus, called SGLT-2 inhibitors and GLP-1 receptor agonists. SGLT-2 inhibitors,new oral hypoglycemic drugs,are selective inhibitors. A series of clinical studies have confirmed the protective effect to the heart and renal of empagliflozin. This paper reviews the research progress of the cardiovascular protective effect and mechanism of empagliflozin, to provide a theoretical foundation for the use of clinical medicine.

Key words: SGLT-2 inhibitor, Empagliflozin, Cardiovascular protective effect;Type 2 diabetes

中图分类号:

周佩, 唐湘宇, 邓云霞, 张轶炜, 邓豪. SGLT-2抑制剂——恩格列净的心血管保护作用及机制研究进展[J]. 中国医药导刊, 2021, 23(11): 823-827.

ZHOU Pei, TANG Xiangyu, DENG Yunxia, ZHANG Yiwei, DENG Hao. Research Progress on the Cardiovascular Protective Effects and Mechanism of SGLT-2 Inhibitor— Empagliflozin[J]. CHINESE JOURNAL OF MEDICINAL GUIDE, 2021, 23(11): 823-827.

参考文献

参考文献
     [1]吴易航, 张宇辉, 张健. SGLT2i恩格列净对2型糖尿病患者心脏保护作用的研究进展[J].心血管病学进展, 2020,41(8): 787-789, 829.
     [2]DeFronzo RA, Norton L, Abdul-Ghani M. Renal, metabolic and cardiovascular considerations of SGLT2 inhibition[J].Nat Rev Nephrol,2017,13(1): 11-26.
     [3]Grempler R, Augustin R, Froehner S, et al.Functional characterisation of human SGLT-5 as a novel kidney-specific sodium-dependent sugar transporter[J].FEBS Lett,2012,586(3): 248-253.
     [4]Lin X, Ma L, Fitzgerald RL, et al.Human sodium/inositol cotransporter 2 (SMIT2) transports inositols but not glucose in L6 cells[J].Arch Biochem Biophys, 2009, 481(2): 197-201.
     [5]洪庆霞, 梅文柳, 刘文雅,等.钠-葡萄糖协同转运蛋白功能与作用研究进展[J].中南药学，2021，19(9): 1757-1765.
     [6]Qiu M, Ding LL, Zhou HR. Comparative efficacy of five SGLT2i on cardiorenal events: anetwork meta-analysis based on ten CVOTs[J].Am J Cardiovasc Drugs,2021:1-13.
     [7]Zinman B, Wanner C, Lachin JM, et al.Empagliflozin, cardiovascular outcomes, and mortality in type 2 Diabetes[J].N Engl J Med, 2015, 373(22): 2117-2128.
     [8]Wiviott SD, Raz I, Bonaca MP, et al.Dapagliflozin and cardiovascular outcomes in type 2 diabetes[J].N Engl J Med,2019,380(4): 347-357.
     [9]Neal B, Perkovic V, Matthews DR, et al.Rationale, design and baseline characteristics of the canagliflozin cardiovascular assessment study-renal (CANVAS-R): a randomized, placebo-controlled trial[J].Diabetes Obes Metab,2017,19(3): 387-393.
     [10]Michael NE, Mohammed Q, Sheryl WL, et al.Empagliflozin effects on pulmonary artery pressure in patients with heart failure: results from the EMBRACE-HF trial[J].Circulation,2021, 143(17):1673-1686.
     [11]Zannad F, Ferreira JP, Pocock SJ, et al.SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials[J].Lancet,2020, 396(10254): 819-829.
     [12]Kosiborod M, Birkeland KI, Cavender MA, et al.Rates of myocardial infarction and stroke in patients initiating treatment with SGLT2-inhibitors versus other glucose-lowering agents in real-world clinical practice: results from the CVD-REAL study[J].Diabetes Obes Metab, 2018, 20(8): 1983-1987.
     [13]Kosiborod M, Lam C, Kohsaka S, et al.Cardiovascular events associated with SGLT-2 inhibitors versus other glucose-lowering drugs: the CVD-REAL 2 study[J].J Am Coll Cardiol,2018,71(23): 2628-2639.
     [14]Kosiborod M, Cavender MA, Fu AZ, et al.Lower risk of heart failure and death in patients initiated on sodium-glucose cotransporter-2 inhibitors versus other glucose-lowering drugs: the CVD-REAL study (comparative effectiveness of cardiovascular outcomes in new users of sodium-glucose cotransporter-2 inhibitors)[J].Circulation,2017,136(3):249-259.
     [15]Usman MS, Siddiqi TJ, Memon MM, et al.Sodium-glucose co-transporter 2 inhibitors and cardiovascular outcomes: a systematic review and meta-analysis[J].Eur J Prev Cardiol,2018,25(5):495-502.
     [16]Packer M, Anker SD, Butler J, et al.Cardiovascular and renal outcomes with empagliflozin in heart failure[J].N Engl J Med,2020,383(15):1413-1424.
     [17]Santos-Gallego CG, Vargas-Delgado AP, Requena-Ibanez JA, et al.Randomized trial of empagliflozin in nondiabetic patients with heart failure and reduced ejection fraction[J].J Am Coll Cardiol, 2021, 77(3): 243-255.
     [18]Zannad F, Ferreira JP, Pocock SJ, et al.Cardiac and kidney benefits of empagliflozin in heart failure across the spectrum of kidney function: insights from EMPEROR-reduced[J].Circulation,2021,143(4): 310-321.
     [19]Heerspink H, Stefansson BV, Chertow GM, et al.Rationale and protocol of the dapagliflozin and prevention of adverse outcomes in chronic kidney disease (DAPA-CKD) randomized controlled trial[J].Nephrol Dial Transplant,2020,35(2):274-282.
     [20]田丽,王琼英,孙润民,等.SGLT2i对2型糖尿病合并高血压患者24 h动态血压影响的荟萃分析[J].中华心血管病杂志,2021,49(10):1000-1011.
     [21]Mancia G, Cannon CP, Tikkanen I,et al.根据基础降压用药分析恩格列净在2型糖尿病合并高血压患者中的降压作用[J].中华高血压杂志,2016,24(10): 999.
     [22]Inzucchi SE, Zinman B, Fitchett D, et al.How does empagliflozin reduce cardiovascular mortality? insights from a mediation analysis of the EMPA-REG OUTCOME trial[J].Diabetes Care, 2018, 41(2): 356-363.
     [23]Mazer CD, Hare G, Connelly PW, et al.Effect of empagliflozin on erythropoietin levels, iron stores, and red blood cell morphology in patients with type 2 diabetes mellitus and coronary artery disease[J].Circulation, 2020, 141(8): 704-707.
     [24]包丽雯, 刘荣宸, 严芳英, 等.钠-葡萄糖共转运体2抑制剂治疗心血管疾病的研究进展[J].中华心血管病杂志, 2020, (4): 339-343.
     [25]Liu Y, Wu M, Xu B, et al.Empagliflozin alleviates atherosclerosis progression by inhibiting inflammation and sympathetic activity in a normoglycemic mouse model[J].J Inflamm Res, 2021, 14: 2277-2287.
     [26]Andreadou I, Efentakis P, Balafas E, et al.Empagliflozin limits myocardial infarction in vivo and cell death in vitro: role of STAT3, mitochondria, and redox aspects[J].Front Physiol, 2017, 8: 1077.
     [27]Monami M, Nardini C, Mannucci E. Efficacy and safety of sodium glucose co-transport-2 inhibitors in type 2 diabetes: a meta-analysis of randomized clinical trials[J].Diabetes Obes Metab, 2014, 16(5): 457-466.
     [28]Eid RA, Alkhateeb MA, El-Kott AF, et al.A high-fat diet rich in corn oil induces cardiac fibrosis in rats by activating JAK2/STAT3 and subsequent activation of ANG Ⅱ/TGF-1β/Smad3 pathway: the role of ROS and IL-6 trans-signaling[J].J Food Biochem, 2019, 43(8): e12952.
     [29]Daud E, Ertracht O, Bandel N, et al.The impact of empagliflozin on cardiac physiology and fibrosis early after myocardial infarction in non-diabetic rats[J].Cardiovasc Diabetol, 2021, 20(1): 132.
     [30]Quagliariello V, De Laurentiis M, Rea D, et al.The SGLT-2 inhibitor empagliflozin improves myocardial strain, reduces cardiac fibrosis and pro-inflammatory cytokines in non-diabetic mice treated with doxorubicin[J].Cardiovasc Diabetol, 2021,20(1): 150.
     [31]Uthman L, Baartscheer A, Bleijlevens B, et al.Class effects of SGLT2 inhibitors in mouse cardiomyocytes and hearts: inhibition of Na+/H+ exchanger, lowering of cytosolic Na+ and vasodilation[J].Diabetologia, 2018, 61(3): 722-726.
     [32]Lee M, Brooksbank K, Wetherall K, et al.Effect of empagliflozin on left ventricular volumes in patients with type 2 diabetes, or prediabetes, and heart failure with reduced ejection fraction (SUGAR-DM-HF)[J].Circulation, 2021, 143(6): 516-525.
     [33]Al Jobori H, Daniele G, Adams J, et al.Determinants of the increase in ketone concentration during SGLT2 inhibition in NGT, IFG and T2DM patients[J].Diabetes Obes Metab, 2017, 19(6): 809-813.
     [34]Fitchett D, Inzucchi SE, Wanner C, et al.Relationship between hypoglycaemia, cardiovascular outcomes, and empagliflozin treatment in the EMPA-REG OUTCOME trial[J].Eur Heart J, 2020, 41(2): 209-217.
     [35]仲恒, 王丹, 段滨红. 恩格列净使用剂量对2型糖尿病治疗效果和不良反应的影响研究[J].糖尿病新世界, 2020, 23(21): 6-8.
     [36]Deol H, Lekkakou L, Viswanath AK, et al.Combination therapy with GLP-1 analogues and SGLT-2 inhibitors in the management of diabesity: the real world experience[J].Endocrine, 2017, 55(1): 173-178.
     [37]Ojima A, Matsui T, Nishino Y, et al.Empagliflozin, an inhibitor of sodium-glucose cotransporter 2 exerts anti-inflammatory and antifibrotic effects on experimental diabetic nephropathy partly by suppressing AGEs-receptor axis[J].Horm Metab Res, 2015, 47(9): 686-92.
     [38]Sanajou D, Ghorbani HA, Argani H, et al.AGE-RAGE axis blockade in diabetic nephropathy: Current status and future directions[J].Eur J Pharmacol, 2018, 833: 158-164.
     [39]Xu L, Ota T. Emerging roles of SGLT2 inhibitors in obesity and insulin resistance: focus on fat browning and macrophage polarization[J].Adipocyte, 2018, 7(2): 121-128.
     [40]Hring HU, Merker L, Seewaldt-Becker E, et al.Empagliflozin as add-on to metformin in patients with type 2 diabetes: a 24-week, randomized, double-blind, placebo-controlled trial[J].Diabetes Care, 2014, 37(6): 1650-1659.
     [41]沈超, 徐珽, 苏娜. 恩格列净对2型糖尿病患者血脂影响的系统评价[J].中国药业, 2019, 28(10): 38-43.
     [42]Mosenzon O, Wiviott SD, Cahn A, et al.Effects of dapagliflozin on development and progression of kidney disease in patients with type 2 diabetes: an analysis from the DECLARE-TIMI 58 randomised trial[J].Lancet Diabetes Endocrinol, 2019, 7(8): 606-617.
     [43]Zelniker TA, Wiviott SD, Raz I, et al.SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials[J].Lancet, 2019, 393(10166): 31-39.
     [44]Neuen BL, Young T, Heerspink H, et al.SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis[J].Lancet Diabetes Endocrinol, 2019, 7(11): 845-854.
     [45]张慧芳, 王利杰, 张程远, 等.SGLT-2抑制剂对2型糖尿病患者的肾脏保护作用进展[J].实用医药杂志, 2021, 38(06): 558-563.
     [46]Cherney D, Zinman B, Inzucchi SE, et al.Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease: an exploratory analysis from the EMPA-REG OUTCOME randomised, placebo-controlled trial[J].Lancet Diabetes Endocrinol, 2017, 5(8): 610-621.
     [47]隋超, 陈亚镇, 赖贻旺. 血管紧张素转化酶抑制剂联合SGLT-2抑制剂治疗糖尿病肾病效果研究[J].临床军医杂志, 2018, 46(12): 1437-1440.
     [48]Ferrannini E, Mark M, Mayoux E. Response to comment on ferrannini et al.CV protection in the EMPA-REG OUTCOME trial: a"thrifty substrate"hypothesis[J].Diabetes Care, 2016, 39(12): e226.
     [49]Packer M. SGLT2 inhibitors produce cardiorenal benefits by promoting adaptive cellular reprogramming to induce a state of fasting mimicry: aparadigm shift in understanding their mechanism of action[J].Diabetes Care, 2020, 43(3): 508-511.
     [50]Sato T, Aizawa Y, Yuasa S, et al.The effect of dapagliflozin treatment on epicardial adipose tissue volume[J].Cardiovasc Diabetol,2018,17(1):6.
     [51]Woloshuk A, Lee M, Assmus M, et al.A case of ureteral fungal mass removal in a patient taking empagliflozin[J].CEN Case Rep, 2021, 10(4): 603-607.
     [52]Perlman A, Heyman SN, Stokar J, et al.Clinical spectrum and mechanism of acute kidney injury in patients with diabetes mellitus on SGLT-2 inhibitors[J].Isr Med Assoc J, 2018, 20(8): 513-516.
     [53]Vasilakou D, Karagiannis T, Athanasiadou E, et al.Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis[J].Ann Intern Med, 2013, 159(4): 262-274.
     [54]Thong KY, Yadagiri M, Barnes DJ, et al.Clinical risk factors predicting genital fungal infections with sodium-glucose cotransporter 2 inhibitor treatment: the ABCD nationwide dapagliflozin audit[J].Prim Care Diabetes, 2018, 12(1): 45-50.
     [55]Heerspink HJ, Perkins BA, Fitchett DH,et al.Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney effects, potential mechanisms, and clinical applications[J].Circulation, 2016, 134(10): 752-772.
     [56]Chowdhary M, Kabbani AA, Chhabra A. Canagliflozin-induced pancreatitis: a rare side effect of a new drug[J].Ther Clin Risk Manag, 2015, 11: 991-994.
     [57]Frent I, Bucsa C, Leucuta D,et al.An investigation on the association between sodium glucose co-transporter 2 inhibitors use and acute pancreatitis: A VigiBase study[J].Pharmacoepidemiol Drug Saf, 2021,30(10):1428-1440.
     [58]Dicembrini I, Nreu B, Mannucci E,et al.Sodium-glucose co-transporter-2 (SGLT-2) inhibitors and cancer: a meta-analysis of randomized controlled trials[J].Diabetes Obes Metab, 2019, 21(8): 1871-1877.
     [59]杨晶. 达格列净抑制乳腺癌细胞增殖的机制研究[D].南华大学,2020.
     [60]胡伟贤. 胡伟贤. 达格列净通过PI3K/AKT/mTOR信号通路抑制结直肠癌转移的机制研究[D].南方医科大学,2020.
     [61]葛均波, 霍勇, 高秀芳, 等.改善心血管和肾脏结局的新型抗高血糖药物临床应用中国专家建议[J].中国循环杂志, 2020, 35(3): 231-238.

快速检索引用检索图表检索高级检索