朱琛颖1 王书琦2 韩薇1
1同济大学附属东方医院，上海200120；
2山西白求恩医院，太原030032
通信作者：韩薇，Email：dr.hanwei@foxmail.com
【摘要】心力衰竭（心衰）是各种心脏疾病的严重表现或晚期阶段，死亡率和再住院率居高不下。现有研究证据表明，钠‑葡萄糖共转运蛋白2(sodium‑glucose cotransporter 2 inhibitors，SGLT2)抑制剂可以显著降低心衰患者的心血管死亡和再住院率。但其在心衰中的作用机制目前尚不明确。本文将从SGLT2抑制剂在心衰中作用的证据出发，对其在心衰中的作用机制和潜在获益进行梳理。
【关键词】心力衰竭；钠‑葡萄糖共转运蛋白2抑制剂；心脏保护机制
我国心力衰竭（心衰）患病率持续升高，心衰患者的高死亡率、高住院率带来巨大的公共卫生负担［1］。根据《中国心血管健康与疾病报告2019概要》，≥35岁成年人中，心衰患病率为1.3%，较2000年增加44.0%［2］。对于新发因心衰住院的患者，5年死亡风险高达40%~50%［3］。长久以来，医学界对心衰治疗药物的探索未曾停歇。钠-葡萄糖共转运蛋白2(sodium-glucose cotransporter 2，SGLT2)抑制剂在多项大型临床试验中证实除了降低血糖的作用外，可以显著降低心衰患者的心血管死亡率和再住院率，已成为心血管药物治疗领域的一大热点，但是对于SGLT2抑制剂治疗心衰获益的相关机制目前尚未完全明确。本文从SGLT2抑制剂的心衰获益证据出发，对其可能的作用机制进行综述。
自2015年起，在2型糖尿病(type 2 diabetes mellitus，T2DM)药物的心血管结局研究(cardiovascular outcome trial，CVOT)中发现，恩格列净(EMPA-REG OUTCOME)［4］、卡格列净(CANVAS program)［5］和达格列净(DECLARE-TIMI 58)［6］在降低因心衰住院风险方面表现出一致性获益，进而开启了SGLT2抑制剂在心衰治疗领域的探索。2019年公布的DAPA-HF研究［7］是首个在射血分数降低的心力衰竭(heart failure with reduced ejection fraction，HFrEF)患者中应用SGLT2抑制剂治疗的心衰结局研究，该研究结果显示，不论合并或不合并 T2DM，达格列净在标准治疗的基础上可使HFrEF患者心血管死亡或心衰恶化的风险降低26%。2020年公布的EMPEOR-Reduced研究［8］也证实，恩格列净可显著降低HFrEF患者心血管死亡或因心衰住院风险。2021年SOLOIST-WHF研究［9］在T2DM患者中证明，索格列净可使全射血分数范围心衰患者心血管死亡、因心衰住院和心衰急诊就诊的复合终点事件风险降低33%。EMPEROR-Preserved研究［10］则是第一项在射血分数轻度降低的心力衰竭(heart failure with mildly reduced ejection fraction，HFmrEF)和射血分数保留的心力衰竭(heart failure with preserved ejection fraction，HFpEF)患者中达成主要终点的研究，结果显示恩格列净可显著降低HFmrEF和HFpEF患者心血管死亡或因心衰住院的风险。2022年DELIVER研究［11］结果的公布又为SGLT2抑制剂在HFmrEF和HFpEF的治疗获益增添了新证据。在丰富循证证据的推动下，2021年欧洲心脏病学会(European Society of Cardiology，ESC)急慢性心衰诊断和治疗指南首次将SGLT2抑制剂纳入HFrEF基石用药，并推荐包括SGLT2抑制剂在内的四类药物，即血管紧张素转换酶抑制剂(angiotensin-converting enzyme inhibitor，ACEI)/血管紧张素受体脑啡肽酶抑制剂(angiotensin receptor neprilysin inhibitor，ARNI)、β受体阻滞剂、醛固酮受体拮抗剂(mineralocorticoid receptor antagonists，MRA)、和SGLT2抑制剂的“新四联疗法”，作为所有HFrEF患者的一线治疗药物以降低死亡率［12］。2022年美国心脏协会(American Heart Association，AHA)/美国心脏病学会(American College of Cardiology，ACC)/美国心力衰竭协会(Heart Failure Association of America，HFSA)心衰管理指南强调应尽快给予HFrEF患者“新四联”治疗，在HFmrEF和HFpEF药物治疗方面，对SGLT2抑制剂予以2a类推荐，推荐级别优于MRA、ARB和ARNI［13］。
1.抗炎和抗氧化应激。炎症是心衰的主要病理生理机制之一［14］。SGLT2抑制剂（恩格列净、卡格列净和达格列净）可以减弱或改善T2DM患者的炎症特征［15,16,17］。核苷酸结合寡聚化结构域样受体蛋白3(nucleotide-binding domain-like receptor protein 3，NLRP3)炎症小体是一种多蛋白复合体，可诱导白细胞介素-1β(interleukin-1β，IL-1β)和IL-18的成熟，引起炎症反应，进而影响心衰进展［18］。研究显示，达格列净可以减轻T2DM小鼠左心室功能障碍的发展，并抑制NLRP3炎症小体的激活［19］；在血糖正常的HFrEF和HFpEF大鼠模型中，恩格列净可影响NLRP3炎症小体信号转导，从而减轻收缩或舒张功能障碍［20］。另外，氧化应激可诱导心肌重构、心肌细胞凋亡，最终导致心脏结构破坏、泵功能障碍，在心衰发生、发展过程中同样发挥重要作用［21］。在HFpEF中，炎症/氧化应激介导的内皮功能障碍也可能损害心肌细胞功能［22］。体外研究显示，恩格列净治疗可显著降低人HFpEF心肌中的炎症和氧化应激，改善内皮功能，逆转NO-sGC-cGMP-PKG通路及其下游靶点的病理性抑制［23］。
2.改善心肌纤维化。心肌纤维化是导致心衰进展的常见机制之一，可导致心肌重构、心室顺应性降低和心功能受损［24］。体外模型证实，SGLT2抑制剂显著减弱转化生长因子-β(transforming growth factor-β，TGF-β)诱导的人成纤维细胞活化，减少细胞外基质重构［25］。此外，在动物模型中进行的实验（包括心肌梗死和心肌病）也证明，SGLT2抑制剂通过抑制胶原合成和肌成纤维细胞分化发挥抗心肌纤维化作用［26,27］。
3.降低心肌Na+浓度。心衰的特征是Na+内流和外流间失衡导致的细胞Na+超负荷。其中，钠氢交换蛋白(Na+/H+exchange，NHE)活性上调可导致心肌细胞胞质中Na+浓度增加、Ca2+超载，线粒体中Ca2+浓度降低，加快心衰进程［28］。在分离的兔心肌细胞中首次报告SGLT2抑制剂可能对NHE1起抑制作用［29］，随后在鼠心肌细胞［30］和人心房组织［31］中得到了证实。在高脂饮食诱导的鼠心功能不全模型中，达格列净通过NHE1改善心脏炎症来缓解心功能不全和心肌重构［32］。然而，在健康大鼠心肌细胞进行的研究中，SGLT2抑制剂通过抑制NHE1影响细胞内Na+受到质疑［33］，这有待更进一步研究进行证实。晚期Na+电流也是心衰中Na+超负荷的主要因素，已在许多心脏疾病模型中证实抑制该电流具有心脏保护作用［34］。恩格列净可抑制鼠心衰心肌细胞中的晚期Na+电流，其原因与SGLT2抑制剂与心脏Na+通道亚型Nav1.5结合有关［35］。
4.抑制钠水重吸收。SGLT2抑制剂除直接抑制近端小管Na+和葡萄糖的重吸收外，还可减少水的重吸收。通过使用数学模型，结合水、电解质排泄的临床数据进一步分析，SGLT2抑制剂引起的渗透性利尿主要减少组织间液容量，对血容量的影响较小，这点区别于袢利尿剂，因此可在不减少动脉充盈和器官灌注的情况下更好地改善充血［36］。此外，EMBRACE-HF试验［37］结果显示，恩格列净可迅速降低心衰患者肺动脉压力（反映血流动力学状态的改变），且随着时间的推移效果更加明显，这一作用与袢利尿剂的使用无关。
5.抑制交感神经。研究发现，使用SGLT2抑制剂后血压和血容量降低，但未检测到心率增加，这可能与交感神经系统活性降低相关［38］。其作用机制目前尚不明确，可能包括：(1) SGLT2抑制剂上调酮体（主要是β-羟丁酸），阻断游离脂肪酸受体-3依赖性交感神经元激活；(2) SGLT2抑制剂诱导肾上腺G蛋白偶联受体激酶-2抑制，一方面恢复/增强交感神经抑制性α2-肾上腺素能受体功能以减少肾上腺儿茶酚胺分泌，另一方面下调酪氨酸羟化酶以减少肾上腺儿茶酚胺生物合成［39］。
6. 改善代谢。(1)控制血糖：糖尿病是心衰的独立危险因素［40］，有数据显示，糖尿病患者中心衰的患病率约为9%~22%，为普通人群的4倍［41］。糖尿病可导致血管（微血管和大血管）病变引起心肌缺血，并可直接对心肌（心肌细胞和间质）产生有害作用［42］。SGLT2抑制剂通过抑制肾小管上的SGLT2，以非胰岛素依赖的方式，减少葡萄糖的重吸收，促进尿葡萄糖排泄，达到降糖效果［43］。虽然SGLT2抑制剂是有效的降糖药物，但EMPA-REG OUTCOME研究事后分析［44］显示，恩格列净在不同基线糖化血红蛋白(HbA1c)水平，以及不同HbA1c下降幅度患者中的心衰获益无差异，提示降糖不能完全解释其心血管获益。(2) 降尿酸：高尿酸血症常见于心衰患者，超过一半的住院慢性心衰患者尿酸水平升高。既往研究发现，尿酸水平升高不仅是心衰的危险因素，还与疾病的严重程度和不良预后相关［45］。SGLT2抑制剂引起尿糖增加，尿糖通过竞争GLUT9转运蛋白，减少了尿酸的再吸收，从而降低血浆尿酸水平［46］；对EMPA-REG OUTCOME的事后分析显示，血浆尿酸与心衰住院率和心血管死亡相关，在恩格列净降低心衰或心血管死亡率的原因中，尿酸水平下降约占25%［47］。(3) 改善脂肪代谢：正常心脏具有“代谢灵活性”，可根据情况切换不同底物作为能量来源，以保持ATP的产生；衰竭的心脏由于线粒体氧化能力下降面临能量供应不足，葡萄糖和脂肪酸氧化减少，酮体氧化增加［48］。酮体除了为心衰患者提供辅助燃料外，还可能发挥改善内皮功能、减轻氧化应激、改善线粒体功能、抗炎和减轻心脏重构等作用［49］。SGLT2抑制剂降低血糖，从而降低胰岛素并提高胰高血糖素水平，促进脂肪分解，释放游离脂肪酸；并可通过上调肝脏、肾脏和肠道中的酮体生成相关酶和酮体转运蛋白增加血液和组织中β-羟基丁酸水平［50］。在非糖尿病猪中诱导心衰，恩格列净可将心肌燃料利用从葡萄糖转向酮体、游离脂肪酸和支链氨基酸，从而改善心肌能量，增强左心室收缩功能，并改善左心室重构［51］。此外，在阿霉素诱导的心衰小鼠中，SGLT2抑制剂可导致血酮水平升高，并显示出对心脏的保护作用［52］。另外，心衰患者心外膜脂肪组织(epicardial adipose tissue，EAT)质量增加，在慢性炎症性疾病（尤其是导致HFpEF）状况下，心外膜成为脂肪生成紊乱的场所，导致促炎性脂肪因子分泌，引起心房和心室纤维化［53］；并与HFmrEF和HFpEF患者不良预后相关［54］。分析SGLT2抑制剂治疗对EAT体积的影响发现，达格列净治疗可能改善糖尿病患者全身代谢参数并减少EAT体积，可能有助于降低心血管事件的风险［55］；EMPA-TROPISM研究［56］中，恩格列净治疗也减少了不伴糖尿病的HFrEF患者EAT体积。
7.其他。研究表明，SGLT2抑制剂可以短期升高促红细胞生成素水平［57］，促红细胞生成素水平升高除改善心肌细胞线粒体功能、血管生成、细胞增殖和炎症外，还可通过提高血细胞比容从而增加组织供氧来保护心肌［58］。通过对EMPA-REG OUTCOME研究分析表明，恩格列净降低糖尿病患者心血管死亡风险的获益约50%归因于其诱导的血细胞比容和血红蛋白的增加［59］。
1.肾脏保护作用。心衰通过增加肾静脉压和减少心输出量引起灌注不足而导致肾功能不全，慢性肾脏病(chronic kidney disease，CKD)可通过增加水钠潴留、炎症、肾素-血管紧张素-醛固酮系统活化和加速动脉粥样硬化而导致心衰恶化［60］。SGLT2抑制剂作用于近端肾小管，抑制Na+和葡萄糖的重吸收，使转运至致密斑的Na+和葡萄糖增多，通过管球反馈机制收缩肾小球入球小动脉，使肾小球高灌注、高压力、高滤过得以缓解［61］，从而起到肾脏保护作用。CREDENCE研究［62］证实卡格列净具有降糖以外的肾脏保护作用，可延缓蛋白尿进展、减少肾脏终点事件的发生。DAPA-CKD研究［63］和EMPA-KIDNEY研究［64］则证明，达格列净或恩格列净能显著降低CKD患者心肾复合终点事件的发生率。
2.肝脏保护作用。非酒精性脂肪性肝病(non-alcoholic fatty liver disease，NAFLD)是全球慢性肝病最常见的病因，分为两种亚型：非酒精性单纯脂肪肝、非酒精性脂肪性肝炎(nonalcoholic steatohepatitis，NASH)。NASH可进展为肝纤维化、肝硬化甚至肝细胞癌［65］。NAFLD与新发心衰风险增加之间存在强关联，且这种风险的大小随着NAFLD的严重程度而增加［66］。现有研究表明，SGLT2抑制剂能减轻NAFLD进展。在T2DM 合并NAFLD的患者，使用伊格列净治疗72周可改善患者肝纤维化［70］。小规模研究也表明，达格列净治疗可降低NAFLD患者的肝酶水平、肝脂肪含量或肝硬度值［68,69］。内质网应激和自噬被认为是NAFLD/NASH发生和进展的重要机制，均参与调节肝细胞凋亡［70］。在高脂饮食喂养的apoE(-/-)小鼠中，恩格列净治疗5周可通过促进自噬、减少内质网应激和抑制肝细胞凋亡，减轻NAFLD进展［71］。
3.呼吸系统保护作用。阻塞性睡眠呼吸暂停(obstructive sleep apnea，OSA)是一种与睡眠相关的呼吸障碍，与心衰的发生和发展相关［72］。多项研究表明，SGLT2抑制剂与改善OSA相关。一项纳入36名T2DM合并OSA患者的小型病例对照研究结果显示，达格列净治疗组患者呼吸暂停-低通气指数显著改善，最低动脉血氧饱和度上升，Epworth嗜睡量表评分降低［73］。另一项针对OSA患者的小型回顾性研究显示，SGLT2抑制剂治疗与显著降低的呼吸暂停-低通气指数相关［74］。除此之外，在VERTIS CV研究［75］中，艾托格列净使T2DM合并动脉粥样硬化性心血管疾病患者OSA发病率降低近一半。对9项大型SGLT2抑制剂的随机对照试验进行荟萃分析显示，与安慰剂相比，SGLT2抑制剂降低OSA风险，并且与慢性阻塞性肺病、哮喘、肺水肿等11种呼吸系统疾病的风险降低有关［76］。
SGLT2抑制剂在短时间内完成了从合并T2DM到不合并T2DM心衰、从HFrEF到HFpEF的临床研究循证之路，实现了从降糖药物跨界到心衰治疗药物的转变。现有证据表明SGLT2抑制剂对心衰的获益涉及多种机制，可能是多种机制共同作用的结果，其中部分机制尚未明确或存在一定争议；如何综合考虑这些机制以更好地解释观察到的临床获益值得探究。期待更进一步的机制研究和大规模临床试验为SGLT2抑制剂在心衰治疗中的作用提供更全面的循证依据，也为未来潜在的心衰治疗提供新思路。
参考文献
[1]中国老年医学学会心电及心功能分会, 中国医师协会心血管内科分会, 中国心衰中心联盟专家委员会. 慢性心力衰竭加重患者的综合管理中国专家共识2022 [J]. 中国循环杂志, 2022, 37 (3): 215-225. DOI: 10.3969/j.issn.1000-3614.2022.03.003 .
[2]中国心血管健康与疾病报告编写组. 中国心血管健康与疾病报告2019概要 [J]. 中国循环杂志, 2020, 35 (9): 833-854. DOI: 10.3969/j.issn.1000-3614.2020.09.001 .
[3]Butler J , Anker SD , Filippatos G , et al. Sodium glucose co-transporter inhibitors and heart failure outcomes across different patient populations [J]. Eur Heart J, 2021, 42 (48): 4887-4890. DOI: 10.1093/eurheartj/ehab704 .
[4]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. DOI: 10.1056/NEJMoa1504720 .
[5]Neal B , Perkovic V , Mahaffey KW , et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes [J]. N Engl J Med, 2017, 377 (7): 644-657. DOI: 10.1056/NEJMoa1611925 .
[6]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. DOI: 10.1056/NEJMoa1812389 .
[7]McMurray JJV , Solomon SD , Inzucchi SE , et al. Dapagliflozin in patients with heart failure and reduced ejection fraction [J]. N Engl J Med, 2019, 381 (21): 1995-2008. DOI: 10.1056/NEJMoa1911303 .
[8]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. DOI: 10.1056/NEJMoa2022190 .
[9]Bhatt DL , Szarek M , Steg PG , et al. Sotagliflozin in patients with diabetes and recent worsening heart failure [J]. N Engl J Med, 2021, 384 (2): 117-128. DOI: 10.1056/NEJMoa2030183 .
[10]Anker SD , Butler J , Filippatos G , et al. Empagliflozin in heart failure with a preserved ejection fraction [J]. N Engl J Med, 2021, 385 (16): 1451-1461. DOI: 10.1056/NEJMoa2107038 .
[11]Solomon SD , McMurray JJV , Claggett B , et al. Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction [J]. N Engl J Med, 2022, 387 (12): 1089-1098. DOI: 10.1056/NEJMoa2206286 .
[12]McDonagh TA , Metra M , Adamo M , et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure [J]. Eur Heart J, 2021, 42 (36): 3599-3726. DOI: 10.1093/eurheartj/ehab368 .
[13]Heidenreich PA , Bozkurt B , Aguilar D , et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines [J]. J Am Coll Cardiol, 2022, 79 (17): e263-e421. DOI: 10.1016/j.jacc.2021.12.012 .
[14]Nikolic M , Zivkovic V , Jovic JJ , et al. SGLT2 inhibitors: a focus on cardiac benefits and potential mechanisms [J]. Heart Fail Rev, 2022, 27 (3): 935-949. DOI: 10.1007/s10741-021-10079-9 .
[15]Iannantuoni F , MdM A , Diaz-Morales N , et al. The SGLT2 inhibitor empagliflozin ameliorates the inflammatory profile in type 2 diabetic patients and promotes an antioxidant response in leukocytes [J]. J Clin Med, 2019, 8 (11): 1814. DOI: 10.3390/jcm8111814 .
[16]Heerspink HJL , Perco P , Mulder S , et al. Canagliflozin reduces inflammation and fibrosis biomarkers: a potential mechanism of action for beneficial effects of SGLT2 inhibitors in diabetic kidney disease [J]. Diabetologia, 2019, 62 (7): 1154-1166. DOI: 10.1007/s00125-019-4859-4 .
[17]Leng W , Wu M , Pan H , et al. The SGLT2 inhibitor dapagliflozin attenuates the activity of ROS-NLRP3 inflammasome axis in steatohepatitis with diabetes mellitus [J]. Ann Transl Med, 2019, 7 (18): 429. DOI: 10.21037/atm.2019.09.03 .
[18]Sano S , Oshima K , Wang Y , et al. Tet2-mediated clonal hematopoiesis accelerates heart failure through a mechanism involving the IL-1beta/NLRP3 inflammasome [J]. J Am Coll Cardiol, 2018, 71 (8): 875-886. DOI: 10.1016/j.jacc.2017.12.037 .
[19]Ye Y , Bajaj M , Yang HC , et al. SGLT-2 inhibition with dapagliflozin reduces the activation of the Nlrp3/ASC inflammasome and attenuates the development of diabetic cardiomyopathy in mice with type 2 diabetes. Further augmentation of the effects with saxagliptin, a DPP4 inhibitor [J]. Cardiovasc Drugs Ther, 2017, 31 (2): 119-132. DOI: 10.1007/s10557-017-6725-2 .
[20]Byrne NJ , Matsumura N , Maayah ZH , et al. Empagliflozin blunts worsening cardiac dysfunction associated with reduced NLRP3 (nucleotide-binding domain-like receptor protein 3) inflammasome activation in heart failure [J]. Circ Heart Fail, 2020, 13 (1): e006277. DOI: 10.1161/CIRCHEARTFAILURE.119.006277 .
[21]张媛, 范谦, 杨新春. 氧化应激与心力衰竭 [J]. 中华老年心脑血管病杂志, 2006, 8 (8): 572-573. DOI: 10.3969/j.issn.1009-0126.2006.08.028 .
[22]Cappetta D , De Angelis A , Ciuffreda LP , et al. Amelioration of diastolic dysfunction by dapagliflozin in a non-diabetic model involves coronary endothelium [J]. Pharmacol Res, 2020, 157104781. DOI: 10.1016/j.phrs.2020.104781 .
[23]Kolijn D , Pabel S , Tian Y , et al. Empagliflozin improves endothelial and cardiomyocyte function in human heart failure with preserved ejection fraction via reduced pro-inflammatory-oxidative pathways and protein kinase Galpha oxidation [J]. Cardiovasc Res, 2021, 117 (2): 495-507. DOI: 10.1093/cvr/cvaa123 .
[24]Fedak PW , Verma S , Weisel RD , et al. Cardiac remodeling and failure From molecules to man (Part II) [J]. Cardiovasc Pathol, 2005, 14 (2): 49-60. DOI: 10.1016/j.carpath.2005.01.005 .
[25]Kang S , Verma S , Hassanabad AF , et al. Direct effects of empagliflozin on extracellular matrix remodelling in human cardiac myofibroblasts: novel translational clues to explain EMPA-REG OUTCOME results [J]. Can J Cardiol, 2020, 36 (4): 543-553. DOI: 10.1016/j.cjca.2019.08.033 .
[26]Tian J , Zhang M , Suo M , et al. Dapagliflozin alleviates cardiac fibrosis through suppressing EndMT and fibroblast activation via AMPKalpha/TGF-beta/Smad signalling in type 2 diabetic rats [J]. J Cell Mol Med, 2021, 25 (16): 7642-7659. DOI: 10.1111/jcmm.16601 .
[27]Lee TM , Chang NC , Lin SZ . Dapagliflozin, a selective SGLT2 Inhibitor, attenuated cardiac fibrosis by regulating the macrophage polarization via STAT3 signaling in infarcted rat hearts [J]. Free Radic Biol Med, 2017, 104: 298-310. DOI: 10.1016/j.freeradbiomed.2017.01.035 .
[28]Clancy CE , Chen-Izu Y , Bers DM , et al. Deranged sodium to sudden death [J]. J Physiol, 2015, 593 (6): 1331-1345. DOI: 10.1113/jphysiol.2014.281204 .
[29]Baartscheer A , Schumacher CA , Wust RC , et al. Empagliflozin decreases myocardial cytoplasmic Na(+) through inhibition of the cardiac Na(+)/H(+) exchanger in rats and rabbits [J]. Diabetologia, 2017, 60 (3): 568-573. DOI: 10.1007/s00125-016-4134-x .
[30]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. DOI: 10.1007/s00125-017-4509-7 .
[31]Trum M , Riechel J , Lebek S , et al. Empagliflozin inhibits Na(+)/H(+) exchanger activity in human atrial cardiomyocytes [J]. ESC Heart Fail, 2020, 7 (6): 4429-4437. DOI: 10.1002/ehf2.13024 .
[32]Lin K , Yang N , Luo W , et al. Direct cardio-protection of dapagliflozin against obesity-related cardiomyopathy via NHE1/MAPK signaling [J]. Acta Pharmacol Sin, 2022, 43 (10): 2624-2635. DOI: 10.1038/s41401-022-00885-8 .
[33]Chung YJ , Park KC , Tokar S , et al. Off-target effects of sodium-glucose co-transporter 2 blockers: empagliflozin does not inhibit Na+/H+exchanger-1 or lower [Na+]i in the heart [J]. Cardiovasc Res, 2021, 117 (14): 2794-2806. DOI: 10.1093/cvr/cvaa323 .
[34]Trum M , Riechel J , Wagner S . Cardioprotection by SGLT2 Inhibitors-does it all come down to Na(+)[J]? Int J Mol Sci, 2021, 22 (15): 7976. DOI: 10.3390/ijms22157976 .
[35]Philippaert K , Kalyaanamoorthy S , Fatehi M , et al. Cardiac late sodium channel current is a molecular target for the sodium/glucose cotransporter 2 inhibitor empagliflozin [J]. Circulation, 2021, 143 (22): 2188-2204. DOI: 10.1161/CIRCULATIONAHA.121.053350 .
[36]Hallow KM , Helmlinger G , Greasley PJ , et al. Why do SGLT2 inhibitors reduce heart failure hospitalization? A differential volume regulation hypothesis [J]. Diabetes Obes Metab, 2018, 20 (3): 479-487. DOI: 10.1111/dom.13126 .
[37]Nassif ME , Qintar M , Windsor SL , 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. DOI: 10.1161/CIRCULATIONAHA.120.052503 .
[38]Scheen AJ . Effect of SGLT2 inhibitors on the sympathetic nervous system and blood pressure [J]. Curr Cardiol Rep, 2019, 21 (8): 70. DOI: 10.1007/s11886-019-1165-1 .
[39]Lymperopoulos A , Borges JI , Cora N , et al. Sympatholytic mechanisms for the beneficial cardiovascular effects of SGLT2 inhibitors: A research hypothesis for dapagliflozin′s effects in the adrenal gland [J]. Int J Mol Sci, 2021, 22 (14): 7684. DOI: 10.3390/ijms22147684 .
[40]Dhingra R , Vasan RS . Diabetes and the risk of heart failure [J]. Heart Fail Clin, 2012, 8 (1): 125-33. DOI: 10.1016/j.hfc.2011.08.008 .
[41]Dunlay SM , Givertz MM , Aguilar D , et al. Type 2 diabetes mellitus and heart failure: A Scientific Statement From the American Heart Association and the Heart Failure Society of America: This statement does not represent an update of the 2017 ACC/AHA/HFSA heart failure guideline update [J]. Circulation, 2019, 140 (7): e294-e324. DOI: 10.1161/CIR.0000000000000691 .
[42]Park JJ . Epidemiology, pathophysiology, diagnosis and treatment of heart failure in diabetes [J]. Diabetes Metab J, 2021, 45 (2): 146-157. DOI: 10.4093/dmj.2020.0282 .
[43]Joshi SS , Singh T , Newby DE , et al. Sodium-glucose co-transporter 2 inhibitor therapy: mechanisms of action in heart failure [J]. Heart, 2021, 107 (13):1032-1038. DOI: 10.1136/heartjnl-2020-318060 .
[44]Inzucchi SE , Kosiborod M , Fitchett D , et al. Improvement in cardiovascular outcomes with empagliflozin is independent of glycemic control [J]. Circulation, 2018, 138 (17): 1904-1907. DOI: 10.1161/CIRCULATIONAHA.118.035759 .
[45]Lee SJ , Oh BK , Sung KC . Uric acid and cardiometabolic diseases [J]. Clin Hypertens, 2020, 26: 13. DOI: 10.1186/s40885-020-00146-y .
[46]Lytvyn Y , Skrtic M , Yang GK , et al. Glycosuria-mediated urinary uric acid excretion in patients with uncomplicated type 1 diabetes mellitus [J]. Am J Physiol Renal Physiol, 2015, 308 (2):F77-83. DOI: 10.1152/ajprenal.00555.2014 .
[47]Verma S , Ji Q , Bhatt DL , et al. Association between uric acid levels and cardio-renal outcomes and death in patients with type 2 diabetes: a subanalysis of EMPA-REG OUTCOME [J]. Diabetes Obes Metab, 2020, 22 (7): 1207-1214. DOI: 10.1111/dom.13991 .
[48]Lopaschuk GD , Karwi QG , Tian R , et al. Cardiac energy metabolism in heart failure [J]. Circ Res, 2021, 128 (10): 1487-1513. DOI: 10.1161/CIRCRESAHA.121.318241 .
[49]Yurista SR , Chong CR , Badimon JJ , et al. Therapeutic potential of ketone bodies for patients with cardiovascular disease: JACC State-of-the-Art Review [J]. J Am Coll Cardiol, 2021, 77 (13): 1660-1669. DOI: 10.1016/j.jacc.2020.12.065 .
[50]Kim JH , Lee M , Kim SH , et al. Sodium-glucose cotransporter 2 inhibitors regulate ketone body metabolism via inter-organ crosstalk [J]. Diabetes Obes Metab, 2019, 21 (4): 801-811. DOI: 10.1111/dom.13577 .
[51]Santos-Gallego CG , Requena-Ibanez JA , San Antonio R , et al. Empagliflozin ameliorates adverse left ventricular remodeling in nondiabetic heart failure by enhancing myocardial energetics [J]. J Am Coll Cardiol, 2019, 73 (15): 1931-1944. DOI: 10.1016/j.jacc.2019.01.056 .
[52]Oh CM , Cho S , Jang JY , et al. Cardioprotective potential of an SGLT2 inhibitor against doxorubicin-induced heart failure[J]. Korean Circ J, 2019, 49 (12):1183-1195. DOI: 10.4070/kcj.2019.0180 .
[53]Packer M . Epicardial adipose tissue may mediate deleterious effects of obesity and inflammation on the myocardium [J]. J Am Coll Cardiol, 2018, 71 (20): 2360-2372. DOI: 10.1016/j.jacc.2018.03.509 .
[54]Van Woerden G , Van Veldhuisen DJ , Manintveld OC , et al. Epicardial adipose tissue and outcome in heart failure with mid-range and preserved ejection fraction [J]. Circ Heart Fail, 2022, 15 (3): e009238. DOI: 10.1161/CIRCHEARTFAILURE.121.009238 .
[55]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. DOI: 10.1186/s12933-017-0658-8 .
[56]Requena-Ibanez JA , Santos-Gallego CG , Rodriguez-Cordero A , et al. Mechanistic insights of empagliflozin in nondiabetic patients with HFrEF: from the EMPA-TROPISM study [J]. JACC Heart Fail, 2021, 9 (8): 578-589. DOI: 10.1016/j.jchf.2021.04.014 .
[57]Sano M , Goto S . Possible mechanism of hematocrit elevation by sodium glucose cotransporter 2 inhibitors and associated beneficial renal and cardiovascular effects [J]. Circulation, 2019, 139 (17): 1985-1987. DOI: 10.1161/CIRCULATIONAHA.118.038881 .
[58]Mazer CD HG , 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. DOI: 10.1161/CIRCULATIONAHA.119.044235 .
[59]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. DOI: 10.2337/dc17-1096 .
[60]Imran H , Nester W , Elgendy IY , et al. Role of sodium glucose co-transporter 2 inhibitors in patients with heart failure: an elusive mechanism [J]. Ann Med, 2020, 52 (5): 178-190. DOI: 10.1080/07853890.2020.1767298 .
[61]Anders HJ DJ , Thurau K . Nephron protection in diabetic kidney disease [J]. N Engl J Med, 2016, 375 (21): 2096-2098. DOI: 10.1056/NEJMcibr1608564 .
[62]Perkovic V , Jardine MJ , Neal B , et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy [J]. N Engl J Med, 2019, 380 (24): 2295-2306. DOI: 10.1056/NEJMoa1811744 .
[63]Heerspink HJL , Stefansson BV , Correa-Rotter R , et al. Dapagliflozin in patients with chronic kidney disease [J]. N Engl J Med, 2020, 383 (15): 1436-1446. DOI: 10.1056/NEJMoa2024816 .
[64]EMPA-KIDNEY Collaborative Group, Herrington WG , Staplin N , Wanner C , et al. Empagliflozin in patients with chronic kidney disease [J]. N Engl J Med, 2023, 388 (2): 117-127. DOI: 10.1056/NEJMoa2204233 .
[65]Loomba R , Friedman SL , Shulman GI . Mechanisms and disease consequences of nonalcoholic fatty liver disease [J]. Cell, 2021, 184 (10): 2537-2564. DOI: 10.1016/j.cell.2021.04.015 .
[66]Mantovani A , Byrne CD , Benfari G , et al. Risk of heart failure in patients with nonalcoholic fatty liver disease: JACC Review Topic of the Week [J]. J Am Coll Cardiol, 2022, 79 (2): 180-191. DOI: 10.1016/j.jacc.2021.11.007 .
[67]Takahashi H , Kessoku T , Kawanaka M , et al. Ipragliflozin improves the hepatic outcomes of patients with diabetes with NAFLD [J]. Hepatol Commun, 2022, 6 (1): 120-132. DOI: 10.1002/hep4.1696 .
[68]Choi DH , Jung CH , Mok JO , et al. Effect of dapagliflozin on alanine aminotransferase improvement in type 2 diabetes mellitus with non-alcoholic fatty liver disease [J]. Endocrinol Metab (Seoul), 2018, 33 (3): 387-394. DOI: 10.3803/EnM.2018.33.3.387 .
[69]Kurinami N , Sugiyama S , Yoshida A , et al. Dapagliflozin significantly reduced liver fat accumulation associated with a decrease in abdominal subcutaneous fat in patients with inadequately controlled type 2 diabetes mellitus [J]. Diabetes Res Clin Pract, 2018, 142: 254-263. DOI: 10.1016/j.diabres.2018.05.017 .
[70]Wu WKK , Zhang L , Chan MTV . Autophagy, NAFLD and NAFLD-related HCC [J]. Adv Exp Med Biol, 2018, 1061: 127-138. DOI: 10.1007/978-981-10-8684-7_10 .
[71]Nasiri-Ansari N , Nikolopoulou C , Papoutsi K , et al. Empagliflozin attenuates Non-Alcoholic fatty liver disease (NAFLD) in high fat diet fed apoE((-/-)) mice by activating autophagy and reducing ER stress and apoptosis [J]. Int J Mol Sci, 2021, 22 (2): 818. DOI: 10.3390/ijms22020818 .
[72]Khattak HK , Hayat F , Pamboukian SV , et al. Obstructive sleep apnea in heart failure: review of prevalence, treatment with continuous positive airway pressure, and prognosis [J]. Tex Heart Inst J, 2018, 45 (3): 151-161. DOI: 10.14503/THIJ-15-5678 .
[73]Tang Y , Sun Q , Bai XY , et al. Effect of dapagliflozin on obstructive sleep apnea in patients with type 2 diabetes: a preliminary study [J]. Nutr Diabetes, 2019, 9 (1): 32. DOI: 10.1038/s41387-019-0098-5 .
[74]Sawada K , Karashima S , Kometani M , et al. Effect of sodium glucose cotransporter 2 inhibitors on obstructive sleep apnea in patients with type 2 diabetes [J]. Endocr J, 2018, 65 (4): 461-467. DOI: 10.1507/endocrj.EJ17-0440 .
[75]Wojeck BS , Inzucchi SE , Neeland IJ , et al. Ertugliflozin and incident obstructive sleep apnea: an analysis from the VERTIS CV trial [J]. Sleep Breath, 2023, 27 (2): 669-672. DOI: 10.1007/s11325-022-02594-2 .
[76]Yin DG , Qiu M , Duan XY . Association between SGLT2is and cardiovascular and respiratory diseases: a meta-analysis of large trials [J]. Front Pharmacol, 2021, 12: 724405. DOI: 10.3389/fphar.2021.724405 .
