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。……