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      轉(zhuǎn)化醫(yī)學(xué)在新型降糖藥物鈉葡萄糖協(xié)同轉(zhuǎn)運(yùn)蛋白2抑制劑中的應(yīng)用

      2018-01-16 13:47:43劉瑤霞四川省醫(yī)學(xué)科學(xué)院四川省人民醫(yī)院四川成都610072
      關(guān)鍵詞:恩格尿糖達(dá)格

      劉瑤霞,張 敏,陳 平 (四川省醫(yī)學(xué)科學(xué)院·四川省人民醫(yī)院,四川成都610072)

      0 引言

      1996年,《The Lancet》雜志上首次出現(xiàn)“轉(zhuǎn)化醫(yī)學(xué)(translational medicine)”一詞[1],其包括“從病床旁到實(shí)驗(yàn)臺(tái)”和“從實(shí)驗(yàn)臺(tái)到病床旁”兩個(gè)方面,是連接基礎(chǔ)研究和臨床應(yīng)用的橋梁。藥品研發(fā)中,轉(zhuǎn)化醫(yī)學(xué)的運(yùn)用包括:①臨床需求推動(dòng)基礎(chǔ)研究,從基礎(chǔ)研究中篩選符合臨床需求的藥物分子;②在臨床應(yīng)用中進(jìn)一步評(píng)估藥品療效及風(fēng)險(xiǎn)。本文從轉(zhuǎn)化醫(yī)學(xué)的角度,解讀鈉葡萄糖協(xié)同轉(zhuǎn)運(yùn)蛋白2抑制劑(sodium glucose co?transporter 2 inhibitors,SGLT2i)從臨床需求出發(fā)到藥品研發(fā),再由基礎(chǔ)研究回到臨床運(yùn)用的轉(zhuǎn)化過(guò)程。

      1 臨床需求是尋找新型降糖藥物的驅(qū)動(dòng)力

      糖尿?。╠iabetes mellitus,DM)以高血糖為主要臨床特征,可引發(fā)大血管、神經(jīng)系統(tǒng)、腎臟等多種并發(fā)癥,嚴(yán)重危害人體健康。目前血糖控制仍然是治療糖尿病,控制并發(fā)癥的基礎(chǔ)。盡管降糖藥物的種類不斷增多,雙胍類、磺脲類及非磺脲類胰島素促泌劑、噻唑烷二酮類、α葡糖苷酶抑制劑、二肽基肽酶4(DPP4)抑制劑、腸促胰島素類似物與腸促胰島素受體激動(dòng)劑(GLP?1)、胰島素及胰島素類似物等陸續(xù)進(jìn)入臨床治療,但在很大比例的患者中血糖仍然控制欠佳。為了控制血糖,延緩并發(fā)癥,通常需要增加降糖藥物劑量、種類以及最終使用胰島素[2]。因此,需要新型、有效降糖藥物來(lái)治療糖尿病。

      降糖藥物已經(jīng)針對(duì)多種組織器官,包括胰腺、肝臟、肌肉細(xì)胞、脂肪組織、腸道和攝食中樞。雖然腎臟在葡萄糖穩(wěn)態(tài)中發(fā)揮了重要作用,但既往尚無(wú)作用于腎臟的降糖藥物。腎臟調(diào)節(jié)血糖的機(jī)制為腎小管通過(guò)重吸收經(jīng)腎小球?yàn)V過(guò)的葡萄糖,保持血糖穩(wěn)態(tài)。通過(guò)對(duì)糖尿病患者尿糖排泄觀察發(fā)現(xiàn),其腎小管葡萄糖重吸收能力較正常人增加,尿糖排泄減少,血糖升高[3]。因此,抑制腎小管葡萄糖的再吸收,使葡萄糖從尿液中排出成為潛在的治療糖尿病的新方法。

      2 基礎(chǔ)研究的靈感與藥物遴選

      2.1 腎小管重吸收尿糖的基礎(chǔ)研究 正常生理?xiàng)l件下,人體每天有160~180 g葡萄糖流經(jīng)腎臟,幾乎全部被近端小管重吸收。隨著血漿葡萄糖濃度增加,其濾過(guò)量以及重吸收量也隨之增加。當(dāng)健康成年人血糖濃度超過(guò)11 mmol/L,葡糖糖腎臟濾過(guò)量超過(guò)重吸收最大閾值時(shí),就會(huì)出現(xiàn)糖尿現(xiàn)象[4-5]。 研究[5]發(fā)現(xiàn),鈉葡萄糖協(xié)同轉(zhuǎn)運(yùn)蛋白(sodium?glucose co?trans?porter,SGLT)在葡萄糖的主動(dòng)重吸收中起主要作用,其包含SGLT1和SGLT2兩種。SGLT2在腎臟近端小管大量表達(dá),負(fù)責(zé)約90%葡萄糖的再吸收;抑制SGLT2可以阻止葡萄糖在腎臟的重吸收,對(duì)降糖有顯著作用。SGLT1在腎小管僅有少量表達(dá),負(fù)責(zé)吸收10%未被SGLT2重吸收的葡萄糖;其還在腸道中大量表達(dá),在葡萄糖、半乳糖吸收中具有關(guān)鍵作用。因此,會(huì)同時(shí)阻止葡萄糖、半乳糖在腸道的吸收,這可能會(huì)導(dǎo)致腹瀉[6]。

      抑制SGLT2受體,降低腎臟葡萄糖再吸收,增加尿液葡萄糖排出量,從而降低血糖濃度,這成為治療T2DM的一種新型療法。科學(xué)家們?cè)?jīng)擔(dān)心,這種增加尿糖排泄的方法可能會(huì)因尿糖滲透性利尿作用,出現(xiàn)容量丟失,甚至脫水。但是,觀察家族性糖尿綜合征患者(編碼SGLT2的基因突變)發(fā)現(xiàn),這類患者即使每天尿糖達(dá)50 g,也無(wú)低血容量癥狀[7],長(zhǎng)期壽命不受影響。這使得 SGLT2抑制劑(SGLT2i)作為T2DM治療靶點(diǎn)的研究更加深入。

      2.2 抑制尿糖重吸收藥物的研發(fā)與篩選 早在19世紀(jì)初,研究者就發(fā)現(xiàn)使用根皮苷(一種從蘋果樹皮中分離出來(lái)的天然存在的葡萄糖苷)可以使狗出現(xiàn)尿糖、體質(zhì)量減輕和多尿的現(xiàn)象[8]。 之后研究[9]發(fā)現(xiàn),根皮苷通過(guò)非選擇性抑制腎臟鈉葡萄糖協(xié)同轉(zhuǎn)運(yùn)蛋白SGLT2,從而發(fā)揮尿糖和降低高血糖的作用。這種降糖作用不依賴胰島素,不引起低血糖[10]。但由于根皮苷非選擇性抑制SGLT2,其對(duì)SGLT1也有很強(qiáng)的抑制作用,腸吸收能力很弱,在體內(nèi)非常容易被β?糖苷酶水解,口服生物利用度差,所以并不適合作為降血糖劑[11]。因此科學(xué)家的注意力主要集中在合成選擇性更高、生物利用度更高的葡糖苷類似物(SGLT2抑制劑)上。新研發(fā)的葡糖苷類似物包括早期的O?葡萄糖苷和現(xiàn)在的C?葡萄糖苷。

      在早期藥物的遴選中,葡糖苷類似物O?葡萄糖苷類,如 T?1095和舍格列凈(sergliflozin)、瑞莫列凈(remoliflozin),由于其非選擇性抑制SGLT2以及生物利用度的原因,研究被終止。新研發(fā)的C?葡萄糖苷類,選擇性及生物利用度高。世界各大藥品研發(fā)公司均有藥品上市或者進(jìn)入臨床,主要代表藥物有達(dá)格列凈(dapagliflozin)、坎格列凈(canagliflozin)、恩格列凈(empagliflozin),伊格列凈脯氨酸片(ipragliflozinl?pro?line)、埃格列凈(ertugliflozin)、魯格列凈(luseoglifloz?in)等。

      經(jīng)過(guò)Ⅰ、Ⅱ、Ⅲ期臨床試驗(yàn),驗(yàn)證有效性、安全性等指標(biāo)后,陸續(xù)有多種SGLT2i獲批上市。目前經(jīng)FDA批準(zhǔn)上市的藥物有坎格列凈、達(dá)格列凈、恩格列凈、埃格列凈,以及埃格列凈/二甲雙胍、埃格列凈/西格列汀的復(fù)方制劑。 luseogliflozin(TS?071),伊格列凈脯氨酸片已在日本上市。目前批準(zhǔn)在我國(guó)上市的SGLT2i有坎格列凈、達(dá)格列凈、恩格列凈。由于SGLT2i的藥理作用依賴一定水平的 eGFR[4],因此使用達(dá)格列凈、恩格列凈治療時(shí),需要患者eGFR≥60 mL/(min·1.73 m2),坎格列凈需要患者eGFR≥45 mL/(min·1.73m2)。 SGLT2i可單獨(dú)使用及與其他降糖藥物聯(lián)合使用。

      3 臨床應(yīng)用SGLT2i評(píng)估降糖療效及降糖外獲益

      3.1 SGLT2i的降糖療效 一系列臨床試驗(yàn)[4,12-13]表明,SGLT2i具有良好的降糖作用,可有效降低HbA1c 平均 0.5% ~1.0%。 多藥物等效性研究[14-16]顯示,SGLT2降糖效果不劣于磺脲類。不僅如此,SGLT2i與其他降糖藥物聯(lián)用,包括二甲雙胍[17-19]、二甲雙胍+磺脲類[20]、吡格列酮[21-22]、DPP4[23-25],以及與胰島素聯(lián)用[26-28]的藥物研究發(fā)現(xiàn),降糖有效且耐受良好。 還有研究[29-30]顯示 SGLT2i與二甲雙胍聯(lián)用,降糖效果明顯優(yōu)于安慰劑,且不劣于格列美脲。

      3.2 SGLT2i對(duì)體質(zhì)量的影響 臨床試驗(yàn)研究[31]顯示,SGLT2i通??墒贵w質(zhì)量減輕2~5 kg。輕度的體質(zhì)量減輕可能是由于尿糖的滲透性利尿作用。但體脂成分分析顯示,使用SGLT2抑制劑的患者體質(zhì)量減輕由身體脂肪組織減少所致[32]。

      3.3 SGLT2i對(duì)血壓的影響 SGLT2i臨床實(shí)驗(yàn)研究一致發(fā)現(xiàn)其具有降低血壓的作用[33-36]。 研究[33]發(fā)現(xiàn),單藥治療時(shí),達(dá)格列凈、坎格列凈、恩格列凈可使血壓降低3~5 mmHg;與其他降糖藥物聯(lián)用時(shí),其也可發(fā)揮類似的降壓作用。一項(xiàng)納入20例肥胖2型糖尿病患者的研究[37]顯示使用 SGLT2i后,在用藥早期,血壓降低與滲透性利尿血容量減少有關(guān),6個(gè)月后,降壓作用與尿鈉排泄增加有關(guān)。

      3.4 SGLT2i對(duì)心血管事件的影響 EMPA?REG OUTCOME研究[38]顯示,在伴有心血管疾病的T2DM患者中,恩格列凈組心血管死亡、非致死性心梗和非致死性腦卒中的風(fēng)險(xiǎn)較對(duì)照組降低14%,全因死亡風(fēng)險(xiǎn)下降了32%,心衰引起的住院發(fā)生率下降了35%,心血管死亡風(fēng)險(xiǎn)下降38%。2018年發(fā)表的CANVAS研究[39]顯示,坎格列凈也存在心血管獲益,與安慰劑相比,可使心血管疾病死亡及心衰住院風(fēng)險(xiǎn)降低(16.3 vs 20.8/1000 人?年)。 CVD?REAL 2 研究[40]對(duì)六個(gè)國(guó)家的數(shù)據(jù)進(jìn)行了匯總分析,結(jié)果顯示,與其他降糖藥相比,SGLT2抑制劑可降低全因死亡或心衰住院復(fù)合結(jié)局風(fēng)險(xiǎn),約40%,全因死亡風(fēng)險(xiǎn)降低49%,心衰住院風(fēng)險(xiǎn)降低36%,心肌梗死風(fēng)險(xiǎn)降低19%;卒中風(fēng)險(xiǎn)降低32%。

      3.5 SGLT2i對(duì)血尿酸的影響 大型薈萃分析[41](>12 000例患者)顯示,恩格列凈可使血尿酸水平降低。恩格列凈10 mg組血尿酸平均降低32.7 μmol/L(-10.4%);25 mg 組平均降低 36.3 μmol/L(-11.2%),而安慰劑對(duì)照組血尿酸水平升高3.0 μmol/L(+0.9%)。

      3.6 臨床應(yīng)用中觀察SGLT2i對(duì)腎功能的影響 一項(xiàng)納入22 843名2型糖尿病患者的meta分析[42]顯示,SGLT2i對(duì)總體人群以及慢性腎臟疾?。╟hronic kidney disease,CKD)人群的腎小球?yàn)V過(guò)率(eGFR)沒(méi)有影響。短期使用SGLT2i,eGFR有所下降;長(zhǎng)期使用SGLT2i,eGFR保持穩(wěn)定。尿蛋白肌酐比(尿ACR)在總體2型糖尿病人群中,沒(méi)有明顯變化,但在合并CKD患者中明顯下降。但也有Mate分析[43]顯示,SGLT2i與安慰劑比較,血肌酐升高,與其他降糖藥物(二甲雙胍、DPP4抑制劑)比較,血肌酐變化沒(méi)有明顯差異。還有薈萃分析[44]發(fā)現(xiàn),合并心血管高風(fēng)險(xiǎn)的T2DM患者使用SGLT2i具有腎臟保護(hù)作用,其保護(hù)機(jī)制可能為減少腎小球?yàn)V過(guò)、炎癥和氧化應(yīng)激反應(yīng)等。

      4 臨床應(yīng)用SGLT2i,評(píng)估不良反應(yīng)及風(fēng)險(xiǎn)

      4.1 SGLT2i與泌尿道感染、生殖道感染風(fēng)險(xiǎn) 由于尿糖濃度增加,泌尿生殖系感染率的增加是SGLT2i最常見的不良反應(yīng)[45-51]。 系統(tǒng)評(píng)價(jià)顯示,與安慰劑相比,SGLT2i尿路及生殖道感染更常見,OR值分別為 1.34 和 3.50[45]。 薈萃分析[46-47]顯示,女性患者生殖道感染(外陰陰道炎)的發(fā)生率高于男性(龜頭炎)。 同時(shí),大量的臨床研究[41,48-49]也發(fā)現(xiàn),使用SGLT2i出現(xiàn)的生殖道及泌尿道的感染,程度均較輕,標(biāo)準(zhǔn)抗感染治療有效,極少需要停用SGLT2i。

      4.2 SGLT2i與血容量減少風(fēng)險(xiǎn) SGLT2i導(dǎo)致的尿糖滲透性利尿作用,對(duì)于易感人群存在容量丟失、低血壓的潛在風(fēng)險(xiǎn)。實(shí)驗(yàn)[52]發(fā)現(xiàn)達(dá)格列凈組低血壓發(fā)生率為0.8%,安慰劑組為 0.4%,兩組均未出現(xiàn)脫水及低血容量。8個(gè)臨床研究薈萃[53]發(fā)現(xiàn),容量丟失整體發(fā)生率為坎格列凈 100 mg組 2.3%,300 mg組3.4%,對(duì)照組為 1.5%。 亞組分析發(fā)現(xiàn),使用坎格列凈治療組中,75歲及以上老年患者、eGFR <60 mL/(min·1.73 m2)的患者,以及使用袢利尿劑的患者容量丟失的風(fēng)險(xiǎn)增加[46]。因此對(duì)血壓下降存在風(fēng)險(xiǎn)的患者(例如心血管疾病、低血壓病史、高齡的患者)需要進(jìn)行容量狀態(tài)的監(jiān)測(cè)[54-55]。

      4.3 SGLT2i與低血糖風(fēng)險(xiǎn) 系統(tǒng)評(píng)價(jià)顯示,SGLT2i不增 加 低 血 糖 風(fēng) 險(xiǎn)[56]。 但 較 多 研 究[57-59]顯 示SGLT2與磺脲類降糖藥或胰島素一起使用時(shí)低血糖風(fēng)險(xiǎn)增加。因此,當(dāng)SGLT2i與胰島素或胰島素促泌劑聯(lián)用時(shí),需考慮減少胰島素或胰島素促泌劑的劑量,以降低低血糖的發(fā)生率。

      4.4 SGLT2i與骨折風(fēng)險(xiǎn) 有研究[60]發(fā)現(xiàn)在中度腎損害[eGFR 為 30~60 mL/(min·1.73 m2)]的患者中使用達(dá)格列凈,對(duì)照組骨折發(fā)生率增加,但對(duì)于骨的形成和吸收、以及骨密度并無(wú)影響。一項(xiàng)使用坎格列凈的研究[61]中,治療超過(guò)26周后,治療組骨折事件發(fā)生率增加,但未見有臨床意義的骨密度改變。薈萃分析[62]顯示,在2型糖尿病患者中使用恩格列凈10 mg qd及5 mg qd治療,與安慰劑組比較,骨折發(fā)生率沒(méi)有增加。

      4.5 SGLT2i與腫瘤風(fēng)險(xiǎn) 臨床數(shù)據(jù)[63]顯示,達(dá)格列凈組與對(duì)照組所導(dǎo)致的膀胱癌及乳腺癌發(fā)生率相似(1.4%vs 1.3%)。 但也有學(xué)者[33]報(bào)道,達(dá)格列凈與吡格列酮聯(lián)用時(shí),膀胱癌的發(fā)生率要略高于對(duì)照組。對(duì)于坎格列凈的研究[64]顯示,乳腺癌及膀胱癌的發(fā)生率與對(duì)照組相似。對(duì)于恩格列凈,歐洲藥品局評(píng)估報(bào)告[65]指出,惡性黑色素瘤和泌尿道惡性腫瘤的風(fēng)險(xiǎn)尚不能排除,但還需更長(zhǎng)時(shí)間的研究來(lái)評(píng)估這種風(fēng)險(xiǎn)程度。

      4.6 SGLT2i與血栓、酮癥酸中毒、截肢風(fēng)險(xiǎn) 由于滲透性利尿作用,血容量的減少,血液濃縮,理論上會(huì)增加靜脈血栓栓塞(venous thromboembolism,VET)的風(fēng)險(xiǎn)。但臨床研究[61]發(fā)現(xiàn),達(dá)格列凈與對(duì)照組相比,VET事件的發(fā)生率相近;坎格列凈的Ⅲ期臨床研究[64]中,10 mg劑量組、25 mg劑量組、對(duì)照組 VET事件的發(fā)生率相似,分別為0.2%、0.3%和 0.2%。 使用SGLT2抑制劑出現(xiàn)的酮癥酸中毒非常罕見[66-67]。偶發(fā)的酮癥酸中毒事件,可能由使用SGLT2抑制劑治療的同時(shí),患者合并重大疾病、食物及液體攝入減少,以及胰島素使用劑量減少等所致[68]。2017年發(fā)布的CANVAS研究[39]結(jié)果顯示,坎格列凈組腳趾、足及腿部截肢風(fēng)險(xiǎn)增加(3.4例/1000人?年 vs 6.3例/1000 人?年)。

      目前已對(duì)SGLT2i進(jìn)行了眾多的臨床試驗(yàn)研究,獲取了大量相關(guān)療效及風(fēng)險(xiǎn)的數(shù)據(jù),這些研究結(jié)果也增進(jìn)藥物使用說(shuō)明書及臨床指南的修訂。由于SGLT2i對(duì)血容量及血壓的影響,在處方信息中,達(dá)格列凈、坎格列凈以及恩格列凈未被推薦用于低血壓風(fēng)險(xiǎn)(例如存在容量丟失或使用袢利尿劑)的患者。對(duì)于這些患者,需先糾正容量,方可起始使用SGLT2i。達(dá)格列凈的產(chǎn)品特性概要(summary of product char?acteristics,SPC)建議:正在服用利尿劑,存在血容量不足或中、重度腎臟損害的患者禁用此藥,并對(duì)正在服藥的患者加強(qiáng)監(jiān)測(cè)。對(duì)于卡格列凈,根據(jù)CANVAS研究結(jié)果,2017年7月FDA說(shuō)明書已經(jīng)增加下肢截肢風(fēng)險(xiǎn)的警告。由于SGLT2i的心血管獲益,在2型糖尿病的藥物治療中,2018年ADA[70]標(biāo)準(zhǔn)納入了最新心血管終點(diǎn)試驗(yàn)(cardiovascular outcomes trials,CVOT)結(jié)果證據(jù),指出糖尿病合并動(dòng)脈粥樣硬化性心血管疾病(atherosclerotic cardiovascular disease,ASCVD)患者首先采取生活方式干預(yù)和二甲雙胍治療,在考慮藥物特異性和患者因素后,可聯(lián)合一種被確認(rèn)可降低主要心血管不良事件和(或)心血管死亡率的降糖藥物,包括恩格列凈、坎格列凈。由此,降糖治療路徑作了相應(yīng)的改動(dòng)。

      綜上所述,SGLT2抑制劑是一種作用于腎臟,通過(guò)抑制腎小管SGLT2受體,從而抑制腎小管重吸收葡萄糖,促進(jìn)尿糖排泄的新型降糖藥物。其源于臨床需求而進(jìn)行藥品研發(fā),通過(guò)層層篩選,后廣泛應(yīng)用于臨床。大量臨床試驗(yàn)研究結(jié)果顯示,其降糖療效確切,同時(shí)具有減輕體質(zhì)量,降低血壓、心血管獲益等,并且低血糖風(fēng)險(xiǎn)低。SGLT2抑制劑的研發(fā)及臨床應(yīng)用是轉(zhuǎn)化醫(yī)學(xué)在糖尿病藥物治療領(lǐng)域的典型體現(xiàn)。

      [1]Geraghty J.Adenomatous polyposis coli and translational medicine[J].Lancet,1996,348(9025):422.

      [2]Dandona P,Chaudhuri A.Sodium?glucose co?transporter 2 inhibitors for type 2 diabetes mellitus:An overview for the primary care physician[J].Int J Clin Pract,2017,71(5):e12937.

      [3]DeFronzo RA,Davidson JA,Del Prato S.The role of the kidneys in glucose homeostasis:a new path towards normalizing glycaemia[J].Diabetes Obes Metab,2012,14(1):5-14.

      [4]紀(jì)立農(nóng),郭立新,郭曉蕙,等.鈉?葡萄糖共轉(zhuǎn)運(yùn)蛋白2(SGLT2)抑制劑臨床合理應(yīng)用中國(guó)專家建議[J].中國(guó)糖尿病雜志,2016,24(10):865-870.

      [5]Wright EM,Loo DD,Hirayama BA.Biology of human sodium glucose transporters[J].Physiol Rev,2011,91(2):733-794.

      [6]Wright EM,Loo DD,Hirayama BA.Biology of human sodium glucose transporters[J].Physiol Rev,2011,91(2): 733-794.

      [7]Patel AK,F(xiàn)onseca V.Turning glucosuriain to a therapy: Efficacy and safety with SGLT2 inhibitors[J].Curr Diab Rep,2010,10(2) :101-107.

      [8]Rossetti L,Smith D,Shulman GI,et al.Correction of hyperglycemia with phlorizin normalizes tissue sensitivity to insulin in diabetic rats[J].J Clin Invest,1987,79(5):1510-1515.

      [9]Ehrenkranz JR,Lewis NG,Kahn CR,et al.Phlorizin: a review[J].Diabetes Metab Res Rev,2005,21(1):31-38.

      [10]Rossetti L,Shulman GI,Zawalich W,et al.Effect of chronic hyperglycemia on in vivo insulin secretion in partially pancreatectomized rats[J].J Clin Invest,1987,80(4):1037-1044.

      [11]Chao EC,Henry RR.SGLT2 inhibition??a novel strategy for diabetes treatment[J].Nat Rev Drug Discov,2010,9(7):551-559.

      [12]Stenl?f K,Cefalu WT,Kim KA,et al.Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise[J].Diabetes Obes Metab,2013,15(4):372-382.

      [13]Roden M,Weng J,Eilbracht J,et al.Empagliflozin monotherapy with sitagliptin as an active comparator in patients with type 2 diabetes:a randomised,double?blind,placebo?controlled,phase 3 trial.Lancet Diabetes Endocrinol,2013,1(3):208-219.

      [14]Ridderstr?le M,Andersen KR,Zeller C,et al.Comparison of empagliflozin and glimepiride as add?on to metformin in patients with type 2 diabetes: a 104?week randomised,active?controlled,double?blind,phase 3 trial[J].Lancet Diabetes Endocrinol,2014,2(9):691-700.

      [15]Nauck MA,del Prato S,Meier JJ,et al.Dapagliflozin versus glipizide as add?on therapy in patients with type 2 diabetes who have inadequate glycemic controlwith metformin: a randomized,52?week,double?blind,active?controlled noninferiority trial[J].Diabetes Care,2011,34(9): 2015-2022.

      [16]Cefalu WT,Leiter LA,Yoon KH,et al.Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA?SU):52 week results from a randomised,double?blind,phase 3 non?inferiority trial[J].Lancet,2013,382(9896):941-950.

      [17]Del Prato S,Nauck M,Durán?Garcia S,et al.Long?term glycaemic response and tolerability of dapagliflozin versus a sulphonylurea as add?on therapy to metformin in patients with type 2 diabetes: 4?year data[J].Diabetes Obes Metab,2015,17(6):581-590.

      [18]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.

      [19]Schumm?Draeger PM,Burgess L,Korányi L,et al.Twice?daily dapagliflozin co?administered with metformin in type 2 diabetes: a 16?week randomized,placebo?controlled clinical trial[J].DiabetesObes Metab,2015,17(1):42-51.

      [20]Matthaei S,Bowering K,Rohwedder K,et al.Dapagliflozin improves glycemic control and reduces body weight as add?on therapy to metformin plus sulfonylurea: a 24?week randomized,double?blind clinical trial[J].Diabetes Care,2015,38(3):365-372.

      [21]Kovacs CS,Seshiah V,Swallow R,et al.Empagliflozin improves glycaemic and weight control as add?on therapy to pioglitazone or pioglitazone plus metformin in patients with type 2 diabetes: a 24?week,randomized,placebo?controlled trial[J].Diabetes Obes Metab,2014,16(2):147-158.

      [22]Rosenstock J,Vico M,Wei L,et al.Effects of dapagliflozin,an SGLT2 inhibitor,on HbA(1c),body weight,and hypoglycemia risk in patientswith type 2 diabetesinadequately controlled on pioglitazone monotherapy[J].Diabetes Care,2012,35(7):1473-1478.

      [23]DeFronzo RA,Lewin A,Patel S,et al.Combination of empagliflozin and linagliptin as second?line therapy in subjects with type 2 diabetes inadequately controlled on metformin [J].Diabetes Care,2015,38(3):384-393.

      [24]Jabbour SA,Hardy E,Sugg J,et al.Dapagliflozin is effective as add?on therapy to sitagliptin with or without metformin: a 24?week,multicenter,randomized,double?blind,placebo?controlled study[J].Diabetes Care,2014,37(3):740-750.

      [25]Lewin A,DeFronzo RA,Patel S,et al.Erratum.Initial combination of empagliflozin and linagliptin in subjects with type 2 diabetes[J].Diabetes Care,2015,38(6):1173.

      [26]Neal B,Perkovic V,de Zeeuw D,et al.Efficacy and safety of canagliflozin,an inhibitor of sodium?glucose cotransporter 2,when used in conjunction with insulin therapy in patients with type 2 diabetes[J].Diabetes Care,2015,38(3):403-411.

      [27]Rosenstock J,Jelaska A,Zeller C,et al.Impact of empagliflozin added on to basal insulin in type 2 diabetes inadequately controlled on basal insulin: a 78?week randomized,double?blind,placebo?controlled trial[J].Diabetes Obes Metab,2015,17(10):936-948.

      [28]Rosenstock J,Jelaska A,F(xiàn)rappin G,et al.Improved glucose control with weight loss,lower insulin doses,and no increased hypoglycemia with empagliflozin added to titrated multiple daily injections of insulin in obese inadequately controlled type 2 diabetes[J].Diabetes Care,2014,37(7):1815-1823.

      [29]Bailey CJ,Gross JL,Pieters A,et al.Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised,double?blind,placebo?controlled trial[J].Lancet,2010,375(9733):2223-2233.

      [30]Cefalu WT,Leiter LA,Yoon KH,et al.Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA?SU): 52 week results from a randomised,double?blind,phase 3 non?inferiority trial[J].Lancet,2013,382(9896):941-950.

      [31]DeFronzo RA,Davidson JA,Del Prato S.The role of the kidneys in glucose homeostasis: a new path towards normalizing glycaemia[J].Diabetes Obes Metab,2012,14(1):5-14.

      [32]Bolinder J,Ljunggren ?,Johansson L,et al.Dapagliflozin maintains glycaemic control while reducing weight and body fat mass over 2 years in patients with type 2 diabetes mellitus inadequately controlled on metformin[J].Diabetes Obes Metab,2014,16(2):159-169.

      [33]Weir MR,Januszewicz A,Gilbert RE,et al.Effect of canagliflozin on blood pressure and adverse events related to osmotic diuresis and reduced intravascular volume in patients with type 2 diabetes mellitus[J].J Clin Hypertens(Greenwich),2014,16(12):875-882.

      [34]Sj?str?m CD,Johansson P,Ptaszynska A,et al.Dapagliflozin lowers blood pressure in hypertensive and non?hypertensive patients with type 2 diabetes[J].Diab Vasc Dis Res,2015,12(5):352-358.

      [35]Tikkanen I,Narko K,Zeller C,et al.Empagliflozin reduces blood pressure in patients with type 2 diabetes and hypertension[J].Diabetes Care,2015,38(3):420-428.

      [36]Amin NB,Wang X,Mitchell JR,et al.Blood pressure?lowering effect of the sodium glucose co?transporter?2 inhibitor ertugliflozin,assessed via ambulatory blood pressure monitoring in patients with type 2 diabetes and hypertension[J].Diabetes Obes Metab,2015,17(8):805-808.

      [37]Kawasoe S,Maruguchi Y,Kajiya S,et al.Mechanism of the blood pressure?lowering effect of sodium?glucose cotransporter 2 inhibitors in obese patients with type 2 diabetes[J].BMC Pharmacol Toxicol,2017,18(1):23.

      [38]Ceriello A,Genovese S,Mannucci E,et al.Understanding EMPA?REG OUTCOME[J].Lancet Diabetes Endocrinol,2015,3(12):929-930.

      [39]CANVAS Suggests Canagliflozin Reduces CV Death,Heart Failure Hospitalization Risk.ACC.org.Mar 11,2018.https://www.acc.org/latest?in?cardiology/articles/2018/03/07/15/08/sun?445pm?canvas?canagliflozin?for?prevention?of?hf?in?type?2?diabetes?acc?2018

      [40]CVD?REAL 2: SGLT?2 InhibitorsAssociated With Lower Cardiovascular Risk Versus Other Glucose?Lowering Drugs.ACC.org.Mar 11,2018.http://www.acc.org/latest?in?cardiology/articles/2018 /03/07/15 /08 /sun?445pm?cvd?real?2?lower?risk?of?cv?events?and?death?associated?with?sglt?2?inhibitors?acc?2018

      [41]Kohler S,Salsali A,Hantel S,et al.Safety and tolerability of empagliflozin in patients with type 2 diabetes[J].Clin Ther,2016,38(6):1299-1313.

      [42]Xu L,Li Y,Lang J,et al.Effects of sodium?glucose co?transporter 2(SGLT2) inhibition on renal function and albuminuria in patients with type 2 diabetes: a systematic review and meta?analysis[J].Peer J,2017,5:e3405.

      [43]Storgaard H,Gluud LL,Bennett C,et al.Benefits and harms of sodium?glucose co?transporter 2 inhibitors in patients with type 2 diabetes: a systematic review and meta?analysis[J].PLoS One,2016,11(11):e0166125.

      [44]Kawanami D,Matoba K,Takeda Y,et al.SGLT2 inhibitors as a therapeutic option for diabetic nephropathy[J].Int J Mol Sci,2017,18(5): 1083.

      [45]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.

      [46]BoehringerIngelheim Pharmaceuticals,Inc.JARDIANCE ?(empagliflozin) tablets,for oral use.Updated March 18,2016.http://www. accessdata.fda.gov/drugsatfda docs/label/2016/204629s005lbl.pdf.Accessed March 23,2016.

      [47]Janssen Pharmaceuticals,Inc.INVOKANA (canagliflozin) tablets,for oral use[J].Revised March 2016.http://www.accessdata.fda.gov/drugsatfda docs/label/2016/204042s011lbl.pdf.Accessed 1,April 2016.

      [48]Johnsson KM,Ptaszynska A,Schmitz B,et al.Vulvovaginitis and balanitis in patients with diabetes treated with dapagliflozin[J].J Diabetes Complicat,2013,27(5):479-484.

      [49]Johnsson KM,Ptaszynska A,Schmitz B,et al.Urinary tract infections in patients with diabetes treated with dapagliflozin[J].J Diabetes Complicat,2013,27(5):473-478.

      [50]Nyirjesy P,Sobel JD,F(xiàn)ung A,et al.Genital mycotic infections with canagliflozin,a sodium glucose co?transporter 2 inhibitor,in patients with type 2 diabetes mellitus: a pooled analysis of clinical studies[J].Curr Med Res Opin,2014,30(6):1109-1119.

      [51]Kohler S,Salsali A,Hantel S,et al.Safety and tolerability of empagliflozin in patients with type 2 diabetes[J].Clin Ther,2016,38(6):1299-1313.

      [52]European Medicines Agency.Forxiga (dapagliflozin).EMA assessment report.Procedure no.EMEA/H/C/002322.http://www.ema.europa.eu/docs/en GB/document library/EPAR ?Public assessment report/human/002322/WC500136024.pdf.Accessed September 17,2013.

      [53]Janssen Pharmaceuticals,Inc.INVOKANA (canagliflozin) tablets,for oral use[J].Revised March 2016.http://www.accessdata.fda.gov/drugsatf ?da docs/label/2016/204042s011lbl.pdf.Accessed 1,April 2016.

      [54]Janssen?Cilag International NV.Summary of product characteristics:canagliflozin.Updated 13 January 2016.http://www.ema.europa.eu/docs /en GB/document library/EPAR ?Product Information/human/002649/WC500156456.pdf.Accessed March 23,2016.

      [55]Boehringer Ingelheim International GmbH.Summary of product characteristics:empagliflozin.Updated December 7,2015.http://www.ema.europa.eu/docs/enGB/documentlibrary/EPAR ?Product Information /human/002677/WC500168592.pdf.Accessed March 23,2016.

      [56]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.

      [57]Rosenstock J,Jelaska A,Zeller C,et al.Impact of empagliflozin added on to basal insulin in type 2 diabetes inadequately controlled on basal insulin: a 78?week randomized,double?blind,placebo?controlled trial[J].Diabetes Obes Metab,2015,17(10):936-948.

      [58]Wilding JP,Charpentier G,Hollander P,et al.Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: a randomised trial[J].Int J Clin Pract,2013,67(12):1267-1282.

      [59]AstraZeneca AB.Summary of product characteristics: dapagliflozin.http://www.ema.europa.eu/docs/en GB/document library/EPAR?Product Information /human/004161/WC500198486.pdf.Accessed March 23,2016

      [60]Ljunggren ?,Bolinder J,Johansson L,et al.Dapagiflozin has no effect on markers of bone formation and resorption or bone mineral density in patients with inadequately controlled type 2 diabetes mellitus on metformin[J].Diabetes Obes Metab,2012,14 (11):990-999.

      [61]European MedicinesAgency.Forxiga(Dapagliflozin).EMA assessment report.Procedure no.EMEA/H/C/002322;2012[EB/OL].[2013?09?17].http://www.ema.europa.eu/docs/en GB/document library/EPAR?Public assessm?ent report/human/002322/WC500136024.pdf

      [62]Wanner C,Toto RD,Gerich J,et al.No increase in bone fractures with empagliflozin(EMPA)in a pooled analysis of more than 11 000 patients with type 2 diabetes(T2DM)[J].J Am Soc Nephrol,2013,24(3):452.

      [63]Ptaszynska A,Johnsson KM,Parikh SJ,et al.Safety profile of dapagliflozin for type 2 diabetes:pooled analysis of clinical studies for overall safety and rare events[J].Drug Saf,2014,37(10):815-829.

      [64]US Food and Drug Administration.FDA briefing document.NDA 204042.nvokana (Canagliflozin)tablets;2013[EB/OL].[2014-03- 31].http://www.fda.gov/downloads/Advisory Committees/Committees Meeting Mater? ials/Drugs/Endocrin ?ologicand Metabolic Drugs Advisory?Committee/UCM 334550.pdf

      [65]European Medicines Agency.AssessmentReport: Jardiance(empaglifl ?ozin).March 20,2014.http://www.ema.europa.eu/docs/en GB/document library/EPAR ?Public assessment report/human/002677/WC500168594 pdf.Accessed March 17,2016.

      [66]Perkins BA,Cherney DZ,Partridge H,et al.Sodium?glucose cotransporter 2 inhibition and glycemic control in type 1 diabetes:results of an 8?week open?label proof?of?concept trial[J].Diabetes Care,2014,37(5):1480-1483.

      [67]Taylor SI,Blau JE,Rother KI.SGLT2 inhibitors may predispose to ketoacidosis[J].J Clin Endocrinol Metab,2015,100 (8):2849-2852.

      [68]US Food and Drug Administration.FDA drug safety communication:FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood.Issued May 15,2015.http://www.fda.gov/Drugs/Drug Safety/ucm475463.htm.Accessed March

      [69]American Diabetes Association.Classification and diagnosis of diabetes: standards of medical care in diabetes?2018[J].Diabetes Care,2018,41(Suppl 1):S13-S27.

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