The multiple pleiotropic effects of sodium- glucose cotransporter 2 inhibitors on cardiorenal system

Sodium-glucose cotransporter-2 inhibitors（SGLT2i）, including empagliflozin, dapagliflozin, and canagliflozin, are now widely approved antihyperglycemic herapies. Although initially considered to be only glucose-lowering agents, the effects of SGLT2i have expanded far beyond that, and their use is now being studied in the treatment of heart failure and chronic kidney disease, even in patients without diabetes. Because of their unique glycosuric mechanism, SGLT2i also reduce weight. Perhaps more important are the osmotic diuretic and natriuretic effects contributing to plasma volume contraction, and decreases in systolic and diastolic blood pressures by 4 to 6 and 1 to 2 mm Hg,respectively,which may underlie cardiovascular and kidney benefits.

Glucose-lowering and Metabolic Effects Mediated by SGLT2i

Under physiological conditions in normal adults,approximately 180 g of glucose are filtered by the renal glomeruli and reabsorbed completely by the renal tubules each day. In patients with type 2 diabetes mellitus （T2DM）,glucose can be detected in the urine when blood glucose concentration exceeds a threshold of approximately 200 mg/dl（11.1 mmol/L）.

In the kidneys, tubular glucose reabsorption is coupled with sodium （Na+） that follows the electrochemical gradient of a higher Na+ concentration in the glomerular filtrate to a lower intracellular concentration in epithelial tubular cells.This gradient is maintained through the basolateral Na+/K+ATPase of the epithelial tubular cell. Glucose enters the cell coupled with Na+through sodium-glucose cotransporters 1 and 2（SGLT1/2）. SGLT2 are high-capacity/low-affinity transporters and are expressed in higher concentrations as compared with SGLT1, which are low-capacity/high-affinity transporters. SGLT2, but not SGLT1, colocalize with the renal Na+/ hydrogen exchanger NHE3, which is largely responsible for Na+reabsorption in the proximal tubule,and SGLT2i appear to cross react with NHE3 and thereby inhibit reabsorption and augment natriuresis.

Effects of SGLT2i on the Cardiovascular System

SGLT2i-mediated natriuresis and glucosuria lower cardiac pre-load and reduce pulmonary congestion and systemic edema. These effects appear to play a role in the reduction of hospitalizations for HF observed in the cardiovascular and kidney outcomes trials in patients with T2DM. Urinary output returns to normal within 12 weeks after treatment is begun.As is the case with other diuretic agents, the natriuresis induced by SGLT2i is attenuated over time through compensatory mechanisms and achievement of a stable state. It is possible that SGLT2i-mediated glucuresis （compared with other diuretic agents whose actions are primarily natriuretic）results in greater proportional reductions of interstitial compared with intravascular volume. This may occur as a consequence of greater electrolyte-free water clearance by peripheral sequestration of osmotically inactive sodium1.

SGLT2i have been shown to significantly reduce the Na+content of the skin. An increased（cutaneous）tissue Na+content has been correlated with left ventricular hypertrophy. The SGLT2i induced Na+depletion may improve left ventricular remodeling and ejection fraction. SGLT2i also reduce cardiac afterload by lowering arterial pressure by 3 to 5 mm Hg without increasing heart rate, and have been shown to reduce arterial stiffness. The reduction of blood pressure is preserved, even in patients with reduced glomerular filtration rate, suggesting that SGLT2i may reduce the sympathetic nervous system overdrive of HF. Studies carried out both in vitro and in vivo have shown that norepinephrine up-regulates expression of sodium-glucose cotransporter-2, thereby enhancing Na+ and glucose reabsorption by the proximal tubule,while, conversely, SGLT2i reduces tyrosine hydroxylase and noradrenaline in the kidney and heart thereby contributing to the natriuresis and glucuresis.

An updated meta-analysis including the CREDENCE trial indicated that SGLT2i reduce the risk of hospitalization for HF by 32%, cardiovascular death by 17% and all-cause death by 15%. A secondary analysis of the CANVAS program found similar reductions in heart failure with reduced ejection fraction（HFrEF）（HR:0.69）and heart failure with preserved ejection fraction （HFpEF） （HR: 0.83）. In the DECLARE-TIMI 58 trial, similar reductions in hospitalization for HF were observed in patients with reduced as well as with preserved ejection fraction（HFrEF: HR: 0.64; and HFpEF: HR: 0.76）. However,the reduction of cardiovascular death was limited to patients with HFrEF （HFrEF: HR: 0.55; and HFpEF:HR:1.08）.Although the pathobiological mechanisms of these salutary effects are still under study, it is of interest that a mechanistic trial in 97 patients with T2DM and atherosclerotic cardiovascular disease,reported by Verma et al. demonstrated that 3 months of treatment with empagliflozin, compared with placebo,significantly reduced left ventricular mass, as measured by magnetic resonance imaging. Serial measurements of biomarker concentrations reflecting different pathobiological mechanisms may add further insight into the mode of action. When compared with placebo, the SGTL2i canagliflozin has been shown to delay the rise in N-terminal pro-B-type natriuretic peptide and high-sensitivity troponin I over 2 years.

A meta-analysis of the 3 SGLT2i cardiovascular outcomes trials found modest reductions for MACE and reported that this effect was confined to patients with established atherosclerotic cardiovascular disease（HR:0.86; P ＜0.001）whereas no effect was observed in those who had multiple cardiovascular risk factors but no known atherosclerotic cardiovascular disease.However, in CREDENCE, a consistent reduction of MACE was seen both in patients with established atherosclerotic cardiovascular disease （secondary prevention）and those with only multiple cardiovascular risk factors（primary prevention）.

Effects of SGLT2i on kidney function

T2DM results in multiple metabolic and hemodynamic changes that promote structural changes in the kidneys, affecting primarily the microcirculation.In the early stage of diabetic kidney disease, glomerular hyperfiltration is observed, which is associated with an increase of single-glomerular filtration rate to adapt to a reduced number of nephrons, systemic arterial hypertension, or increased metabolic demand.Hemodynamic changes through contraction of afferent and/or vasodilation of efferent glomerular arterioles exert mechanical（shear and tensile）stress on the glomerular capillaries, basement membrane, podocytes, and the proximal tubular epithelium, ultimately causing renal hypertrophy and expansion of the mesangial matrix.These changes activate further harmful pathways promoting inflammation,and glomerular fibrosis causing progressive reduction of glomerular filtration rate,progressive albuminuria, and ultimately, end-stage kidney disease.

The protective effects of SGLT2i on the kidney are believed to be mediated by a number of both hemodynamic and nonhemodynamic mechanisms（Central Illustration）. The improvements of cardiac function by SGLT2i may contribute to their favorable effects on the kidneys halting the "vicious cardiorenal circle".Activation of the tubuloglomerular feedback2has been hypothesized to be mainly responsible. The action of SGLT2i in the proximal convoluted tubule results in increased concentrations of Na+at the macula densa.Primarily driven through adenosine-mediated signal cascades, this causes vasoconstriction of the afferent arterioles and thereby lowers the intraglomerular pressure and consequently reduces hyperfiltration and related damage.An elegant study recently confirmed the SGLT2i-mediated restoration of the tubuloglomerular feedback, demonstrating afferent arteriolar vasoconstriction after administration of empagliflozin in a diabetes mouse model. A recent secondary analysis from the EMPA-REG Outcome trial reported that empagliflozin reduced the incidence of a composite renal outcome irrespective of baseline medication but the magnitude of the observed reductions tended to be larger in patients treated with angiotensin-converting enzyme inhibitors/angiotensin receptor blocker. After causing reduction of eGFR in the range of 3 to 5 mL/min/1.73 m2over the first few weeks of SGLT2i,eGFR then stabilizes and SGTL2i preserves and delays the progression of CKD.

The glucose-lowering mechanism of action of SGLT2i, which enhances urinary glucose excretion,requires kidney function that is at least moderately well preserved （i.e.,an eGFR ≥45 mL/min/1.73 m2）.As a consequence, SGLT2i are currently approved by the U.S. Food and Drug Administration only in patients with an eGFR ≥45 mL/min/1.73 m2. It is important to note that this limitation concerns only the glucose-lowering effectiveness of these drugs. It is likely that the salutary effects of SGLT2i on cardiorenal events occur independently of the glucose-lowering effect, given the favorable results observed in the DAPA-HF trial in patients without T2DM.

Each of the SGLT2i outcome trials in patients with T2DM published to date have shown robust reductions by 30%to 47%in the composite of sustained worsening of eGFR, end-stage kidney disease, or death of renal cause. Although significant renal protections were seen irrespective of baseline levels of eGFR, a meta-analysis of the 3 SGLT2i cardiovascular outcomes trials suggested greater protective effects in patients with more preserved eGFR （i.e., eGFR ＞90 mL/min/1.73 m2）.Given the presumed direct renal hemodynamic effects of this drug class, it is tempting to speculate that T2DM patients in an early stage of kidney involvement, that is,with hyperfiltration, derive greater benefit than those with later changes. A secondary analysis from the EMPA-REG OUTCOME trial revealed that a history of HF did not modify the treatment effect on kidney outcomes. Subgroup analyses from the 3 SGLT2i cardiovascular outcomes trials discussed, also showed consistent reductions in cardiovascular and kidney events in patients with chronic diabetic kidney disease.

词 汇

cotransporter n.协同转运蛋白,协同转运体

glycosuric adj.糖尿的,糖尿病的

tubular adj.管子构成的;有管状部分的;管状的

colocalize v.共同定位，共同处于，共同确定地点

glucuresis n.经尿排糖

sequestration n.封存，扣押，隔离，没收

depletion n.竭尽，耗尽，排除

tyrosine n.酪氨酸

hydroxylase n.羟基酶，羟化酶

pathobiological adj.病理学的

salutary adj.有益的

podocyte n.足细胞，足状突细胞

mesangial adj.肾小球膜的

halt n. & v. 停止，暂定，跛，踌躇，小站；使停止，停下，使终止，犹豫

convolute n. & adj. & v. 盘旋面；盘绕的，迂曲的，回旋型的；旋，盘旋，盘绕起来

macula densa n.致密斑

elegant adj.雅致的，优美的，文雅的，精确的，简练的，上等的

注 释

1.osmotically inactive sodium 指“渗透性上非活性钠”。钠离子在溶液中时，具有自由运动特性，称作渗透性活性钠（osmotically active sodium），但当结合到其他物质如皮下结缔组织中时，即失去自由运动特性，称作渗透性上非活性钠。有学者认为皮下组织中渗透性上非活性钠的储存与血钠及血容量调节有关，从而影响血压。

2.tubuloglomerular feedback 指“管-球反馈”。当近曲小管致密斑处钠含量增高时，通过管-球反馈收缩肾小球的入球小动脉，肾小球内压降低和滤过减少，从而减少钠的滤过和排出。人体肾脏除存在管-球反馈机制外，还存在一种“连接管-球反馈”（connecting tubuloglomerular feedback），其可抑制管-球反馈，扩张入球小动脉，增加肾小球内压和滤过，促进钠的排出。正常情况下，管-球反馈与连接管-球反馈之间呈动态平衡，肾脏疾病情况下，管-球反馈变得不敏感或受抑制，肾小球处于持续高内压和超滤状态，从而导致肾损伤及肾功能不断恶化。一些药物如SGLT2i 通过恢复管-球反馈的敏感性，适度收缩入球小动脉，降低肾小球内压，从而稳定或延缓肾功能不全的进展。

参考译文

第99 课 糖钠协转运蛋白2 抑制剂对心-肾系统的多效作用

糖钠协转运蛋白2 抑制剂（sodium-glucose cotran sporter-2 inhibitors，SGLT2i）, 包括恩格列净、达格列净和坎格列净，现在已广为批准用于降糖治疗。虽然SGLT2i 最初只是考虑用作降糖药，但其作用远超于此，目前正在研究用于治疗心力衰竭和慢性肾病，甚至非糖尿病患者。鉴于其独特的糖尿机制，SGLT2i 也降低体重。也许更重要的是其渗透性利尿和利钠作用促进血容量减少，降低收缩压和舒张压分别达4～6和1～2 mmHg，这成为心血管和肾脏获益的基础。

SGLT2i 介导的降糖和代谢作用

正常成人生理状态下，每天有近180 g 葡萄糖经肾小球滤过而经肾小管完全重吸收。2 型糖尿病患者，当血糖浓度超过近20 mg/L（11.1 mmol/L）的阈值时，尿液中可检测到葡萄糖。

在肾脏，肾小管糖的重吸收伴随着钠的吸收，钠随电化学梯度从钠浓度较高的肾小球滤过液中进入浓度较低的肾小管上皮细胞中。这一梯度通过肾小管上皮细胞基底外侧的Na+/K+ATPase 得以维持。通过钠- 糖协转运蛋白1 和2（SGLT1/2），葡萄糖偶联钠离子进入细胞。SGLT2 是一种高容量/低亲和力的转运蛋白，与SGLT1 相比表达浓度较高，后者是一种低容量/ 高亲和力的转运蛋白。SGLT2，而非STLT1，与肾钠/氢交换蛋白NHE3 共处，主要参与近曲小管钠离子的重吸收，SGLT2i 通过与NHE3 的交互作用而抑制重吸收而促进排钠。

SGLT2i 对心血管系统的影响

SGLT2i 介导的尿钠和尿糖排泄降低心脏前负荷、减轻肺淤血和周围水肿。在2 型糖尿病患者心血管与肾脏预后试验中这些作用在降低心力衰竭住院率方面起主要作用。尿量在开始治疗后12 周内恢复正常。SGLT2i 的排钠作用随着时间推移而减弱，这同其他利尿剂一样，通过代偿机制达到稳态，可能是SGLT2i 引起的排糖作用（与其他以排钠为主作用的利尿剂比较）降低间质容量的比例大于血管内容量。这与渗透性上非活性钠的外周隔离导致更多不含电解质水被清除有关。

SGLT2i 明显降低皮肤的钠离子含量，（皮肤）组织钠离子含量的增加与左心室肥大相关联。SGLT2i 引起的钠离子消耗可以改善左心室重构和射血分数。SGLT2i 也能通过降低血压3～5 mmHg 而降低心脏后负荷，但又不增加心率，尚能降低动脉硬度。即使肾小球滤过率降低的患者，血压仍然降低，提示SGLT2i 能降低心力衰竭时的交感神经过度兴奋。体外和体内研究均显示去甲肾上腺素上调钠-糖协转运蛋白2 的表达，从而促进近端小管钠离子和葡萄糖的重吸收，反过来，SGLT2i 减少肾脏和心脏的酪氨酸羟化酶和去甲肾上腺素，从而促进排钠和排糖。

包括CREDENCE 试验在内的最新Meta 分析提示，SGLT2i 减少心力衰竭住院风险达32%、心血管死亡达17%和所有死亡达15%。CANVAS 项目的二次分析发现类似的心力衰竭风险降低，收缩功能不全和舒张功能不全的风险分别为0.69 和0.83。在DECLARE-TIME58 试验中，观察到收缩功能不全和舒张功能不全患者类似的心力衰竭住院风险降低，分别为0.64 和0.76。然而，心血管死亡风险降低只见于收缩功能不全而非舒张功能不全患者，分别为0.55 和1.08。虽然这些有益作用的病理学机制尚在研究中，令人感兴趣的是Verma 等报道的97 例糖尿病合并动脉粥样硬化心血管病患者参与的机理试验证实，相比安慰剂组，3 个月的恩格列净治疗能显著降低由磁共振显像测得的左心室质量。系列测定反映不同病理生物学机制的生物标志物浓度有助于进一步了解作用方式。与对照组比较，SGTL2i 坎格列净能延缓N 末端脑钠肽前体和超敏肌钙蛋白I 升高达2 年之久。

3 项SGLT2i 心血管预后试验的Meta 分析发现主要心血管不良事件中度下降，报告指出这一效应只限于已有动脉粥样硬化心血管疾病者，而对那些有多种心血管危险因素而无动脉粥样硬化疾病者无效。然而，CREDENCE 试验中，持续的心血管主要不良事件下降同时见于那些确诊动脉粥样硬化心血管疾病者和只有心血管危险因素者（一级预防）。

SGLT2i 对肾脏功能的影响

2 型糖尿病引起的多方面代谢和血流动力学变化促进肾脏的结构变化，主要影响微循环。在糖尿病性肾病早期，观察到肾小球高滤过情况，这是由单一肾滤过增加来适应肾单位数量的减少、高血压或代谢需求。通过收缩入球小动脉和（或）舒张出球小动脉的血流动力学变化，对肾小球毛细血管、基底膜、足细胞和近端小管产生机械应力，最终导致肾肥大和肾小球膜基质的扩展。这些变化进一步激活有害通路，促进炎症和肾小球纤维化导致肾小球滤过率进行性下降，白蛋白尿进行性加重，最终为终末期肾病。

SGLT2i 对肾脏的保护作用认为与一系列血流动力学和非血流动力学介导的机制相关。SGLT2i 改善心功能源于其对肾脏的有益作用，阻止“心-肾恶性循环”。推测管-球反馈的激活是主要原因。SGLT2i 在近曲小管的作用增加致密斑的钠离子浓度。这主要通过腺苷介导的信号级联驱使，引起入球小动脉收缩，从而降低肾小球内压，达到降低超滤和相关的损伤。最近一项研究证实SGLT2i 介导的管-球反馈恢复，论证了糖尿病小鼠模型使用恩格列净后入球小动脉收缩。新近的EMPA-REG 预后试验二次分析报告，恩格列净降低肾脏复合终点发生率而不受基线药物影响，但观察到那些接受血管紧张素转换酶抑制剂/血管紧张素受体阻断剂治疗者降幅较大。在SGLT2i 应用最初几周导致eGFR 降低3～5 mL·min-·11.73 m-2后，eGFR 趋向稳定，SGTL2i 保存和延缓慢性肾病的进展。

通过促进尿糖排出的SGLT2i 降糖作用机制需要有适度保留的肾功能（即eGFR≥45 mL·min-·11.73 m-2）。因此，当前美国食品药品监督管理局批准SGLT2i 只能用于eGFR≥45 mL·min-·11.73 m-2的患者。值得关注的是这一限制只涉及这些药物的降糖作用。鉴于DAPA-HF 试验中非糖尿病患者的有利结果，SGLT2i 对心肾的有益疗效有可能独立于降糖作用。

至今发表的涉及糖尿病患者的每项GLT2i 预后试验显示，由持续eGFR 恶化、终末期肾病和肾性死亡组成的复合终点显著降低30%～47%。尽管显著的肾脏保护作用不受基础eGFR 影响，3 项SGLT2i 心血管预后试验的荟萃分析显示，eGFR 保存较好者（如eGFR＞90 mL·min-1·1.73 m-2）保护作用更大。鉴于这类药的直接血流动力学作用，糖尿病伴早期肾功能不全，即高滤过状态者，比晚期肾功能不全者获益更大。EMPA-REG 预后试验的二次分析显示，心力衰竭病史并不改变对肾脏预后的治疗效果。来自3 项SGLT2i 心血管预后试验讨论的亚组分析也表明慢性糖尿病性肾病患者的心血管和肾脏事件呈持续下降。