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.

詞 匯

cotransporter n.協同轉運蛋白,協同轉運體

glycosuric adj.糖尿的,糖尿病的

tubular adj.管子構成的;有管狀部分的;管狀的

colocalize v.共同定位，共同處于，共同確定地點

glucuresis n.經尿排糖

sequestration n.封存，扣押，隔離，沒收

depletion n.竭盡，耗盡，排除

tyrosine n.酪氨酸

hydroxylase n.羥基酶，羥化酶

pathobiological adj.病理學的

salutary adj.有益的

podocyte n.足細胞，足狀突細胞

mesangial adj.腎小球膜的

halt n. & v. 停止，暫定，跛，躊躇，小站；使停止，停下，使終止，猶豫

convolute n. & adj. & v. 盤旋面；盤繞的，迂曲的，回旋型的；旋，盤旋，盤繞起來

macula densa n.致密斑

elegant adj.雅致的，優美的，文雅的，精確的，簡練的，上等的

注 釋

1.osmotically inactive sodium 指“滲透性上非活性鈉”。鈉離子在溶液中時，具有自由運動特性，稱作滲透性活性鈉（osmotically active sodium），但當結合到其他物質如皮下結締組織中時，即失去自由運動特性，稱作滲透性上非活性鈉。有學者認為皮下組織中滲透性上非活性鈉的儲存與血鈉及血容量調節有關，從而影響血壓。

2.tubuloglomerular feedback 指“管-球反饋”。當近曲小管致密斑處鈉含量增高時，通過管-球反饋收縮腎小球的入球小動脈，腎小球內壓降低和濾過減少，從而減少鈉的濾過和排出。人體腎臟除存在管-球反饋機制外，還存在一種“連接管-球反饋”（connecting tubuloglomerular feedback），其可抑制管-球反饋，擴張入球小動脈，增加腎小球內壓和濾過，促進鈉的排出。正常情況下，管-球反饋與連接管-球反饋之間呈動態平衡，腎臟疾病情況下，管-球反饋變得不敏感或受抑制，腎小球處于持續高內壓和超濾狀態，從而導致腎損傷及腎功能不斷惡化。一些藥物如SGLT2i 通過恢復管-球反饋的敏感性，適度收縮入球小動脈，降低腎小球內壓，從而穩定或延緩腎功能不全的進展。

參考譯文

第99 課 糖鈉協轉運蛋白2 抑制劑對心-腎系統的多效作用

糖鈉協轉運蛋白2 抑制劑（sodium-glucose cotran sporter-2 inhibitors，SGLT2i）, 包括恩格列凈、達格列凈和坎格列凈，現在已廣為批準用于降糖治療。雖然SGLT2i 最初只是考慮用作降糖藥，但其作用遠超于此，目前正在研究用于治療心力衰竭和慢性腎病，甚至非糖尿病患者。鑒于其獨特的糖尿機制，SGLT2i 也降低體重。也許更重要的是其滲透性利尿和利鈉作用促進血容量減少，降低收縮壓和舒張壓分別達4～6和1～2 mmHg，這成為心血管和腎臟獲益的基礎。

SGLT2i 介導的降糖和代謝作用

正常成人生理狀態下，每天有近180 g 葡萄糖經腎小球濾過而經腎小管完全重吸收。2 型糖尿病患者，當血糖濃度超過近20 mg/L（11.1 mmol/L）的閾值時，尿液中可檢測到葡萄糖。

在腎臟，腎小管糖的重吸收伴隨著鈉的吸收，鈉隨電化學梯度從鈉濃度較高的腎小球濾過液中進入濃度較低的腎小管上皮細胞中。這一梯度通過腎小管上皮細胞基底外側的Na+/K+ATPase 得以維持。通過鈉- 糖協轉運蛋白1 和2（SGLT1/2），葡萄糖偶聯鈉離子進入細胞。SGLT2 是一種高容量/低親和力的轉運蛋白，與SGLT1 相比表達濃度較高，后者是一種低容量/ 高親和力的轉運蛋白。SGLT2，而非STLT1，與腎鈉/氫交換蛋白NHE3 共處，主要參與近曲小管鈉離子的重吸收，SGLT2i 通過與NHE3 的交互作用而抑制重吸收而促進排鈉。

SGLT2i 對心血管系統的影響

SGLT2i 介導的尿鈉和尿糖排泄降低心臟前負荷、減輕肺淤血和周圍水腫。在2 型糖尿病患者心血管與腎臟預后試驗中這些作用在降低心力衰竭住院率方面起主要作用。尿量在開始治療后12 周內恢復正常。SGLT2i 的排鈉作用隨著時間推移而減弱，這同其他利尿劑一樣，通過代償機制達到穩態，可能是SGLT2i 引起的排糖作用（與其他以排鈉為主作用的利尿劑比較）降低間質容量的比例大于血管內容量。這與滲透性上非活性鈉的外周隔離導致更多不含電解質水被清除有關。

SGLT2i 明顯降低皮膚的鈉離子含量，（皮膚）組織鈉離子含量的增加與左心室肥大相關聯。SGLT2i 引起的鈉離子消耗可以改善左心室重構和射血分數。SGLT2i 也能通過降低血壓3～5 mmHg 而降低心臟后負荷，但又不增加心率，尚能降低動脈硬度。即使腎小球濾過率降低的患者，血壓仍然降低，提示SGLT2i 能降低心力衰竭時的交感神經過度興奮。體外和體內研究均顯示去甲腎上腺素上調鈉-糖協轉運蛋白2 的表達，從而促進近端小管鈉離子和葡萄糖的重吸收，反過來，SGLT2i 減少腎臟和心臟的酪氨酸羥化酶和去甲腎上腺素，從而促進排鈉和排糖。

包括CREDENCE 試驗在內的最新Meta 分析提示，SGLT2i 減少心力衰竭住院風險達32%、心血管死亡達17%和所有死亡達15%。CANVAS 項目的二次分析發現類似的心力衰竭風險降低，收縮功能不全和舒張功能不全的風險分別為0.69 和0.83。在DECLARE-TIME58 試驗中，觀察到收縮功能不全和舒張功能不全患者類似的心力衰竭住院風險降低，分別為0.64 和0.76。然而，心血管死亡風險降低只見于收縮功能不全而非舒張功能不全患者，分別為0.55 和1.08。雖然這些有益作用的病理學機制尚在研究中，令人感興趣的是Verma 等報道的97 例糖尿病合并動脈粥樣硬化心血管病患者參與的機理試驗證實，相比安慰劑組，3 個月的恩格列凈治療能顯著降低由磁共振顯像測得的左心室質量。系列測定反映不同病理生物學機制的生物標志物濃度有助于進一步了解作用方式。與對照組比較，SGTL2i 坎格列凈能延緩N 末端腦鈉肽前體和超敏肌鈣蛋白I 升高達2 年之久。

3 項SGLT2i 心血管預后試驗的Meta 分析發現主要心血管不良事件中度下降，報告指出這一效應只限于已有動脈粥樣硬化心血管疾病者，而對那些有多種心血管危險因素而無動脈粥樣硬化疾病者無效。然而，CREDENCE 試驗中，持續的心血管主要不良事件下降同時見于那些確診動脈粥樣硬化心血管疾病者和只有心血管危險因素者（一級預防）。

SGLT2i 對腎臟功能的影響

2 型糖尿病引起的多方面代謝和血流動力學變化促進腎臟的結構變化，主要影響微循環。在糖尿病性腎病早期，觀察到腎小球高濾過情況，這是由單一腎濾過增加來適應腎單位數量的減少、高血壓或代謝需求。通過收縮入球小動脈和（或）舒張出球小動脈的血流動力學變化，對腎小球毛細血管、基底膜、足細胞和近端小管產生機械應力，最終導致腎肥大和腎小球膜基質的擴展。這些變化進一步激活有害通路，促進炎癥和腎小球纖維化導致腎小球濾過率進行性下降，白蛋白尿進行性加重，最終為終末期腎病。

SGLT2i 對腎臟的保護作用認為與一系列血流動力學和非血流動力學介導的機制相關。SGLT2i 改善心功能源于其對腎臟的有益作用，阻止“心-腎惡性循環”。推測管-球反饋的激活是主要原因。SGLT2i 在近曲小管的作用增加致密斑的鈉離子濃度。這主要通過腺苷介導的信號級聯驅使，引起入球小動脈收縮，從而降低腎小球內壓，達到降低超濾和相關的損傷。最近一項研究證實SGLT2i 介導的管-球反饋恢復，論證了糖尿病小鼠模型使用恩格列凈后入球小動脈收縮。新近的EMPA-REG 預后試驗二次分析報告，恩格列凈降低腎臟復合終點發生率而不受基線藥物影響，但觀察到那些接受血管緊張素轉換酶抑制劑/血管緊張素受體阻斷劑治療者降幅較大。在SGLT2i 應用最初幾周導致eGFR 降低3～5 mL·min-·11.73 m-2后，eGFR 趨向穩定，SGTL2i 保存和延緩慢性腎病的進展。

通過促進尿糖排出的SGLT2i 降糖作用機制需要有適度保留的腎功能（即eGFR≥45 mL·min-·11.73 m-2）。因此，當前美國食品藥品監督管理局批準SGLT2i 只能用于eGFR≥45 mL·min-·11.73 m-2的患者。值得關注的是這一限制只涉及這些藥物的降糖作用。鑒于DAPA-HF 試驗中非糖尿病患者的有利結果，SGLT2i 對心腎的有益療效有可能獨立于降糖作用。

至今發表的涉及糖尿病患者的每項GLT2i 預后試驗顯示，由持續eGFR 惡化、終末期腎病和腎性死亡組成的復合終點顯著降低30%～47%。盡管顯著的腎臟保護作用不受基礎eGFR 影響，3 項SGLT2i 心血管預后試驗的薈萃分析顯示，eGFR 保存較好者（如eGFR＞90 mL·min-1·1.73 m-2）保護作用更大。鑒于這類藥的直接血流動力學作用，糖尿病伴早期腎功能不全，即高濾過狀態者，比晚期腎功能不全者獲益更大。EMPA-REG 預后試驗的二次分析顯示，心力衰竭病史并不改變對腎臟預后的治療效果。來自3 項SGLT2i 心血管預后試驗討論的亞組分析也表明慢性糖尿病性腎病患者的心血管和腎臟事件呈持續下降。