摘要
背景
在2型糖尿病患者中，鈉-葡萄糖協(xié)同轉(zhuǎn)運(yùn)蛋白2（SGLT2）抑制劑可降低因心力衰竭首次住院的風(fēng)險(xiǎn)，其機(jī)制可能與葡萄糖無(wú)關(guān)。我們需要更多關(guān)于SGLT2在射血分?jǐn)?shù)降低的心力衰竭（不論是否患2型糖尿?。┗颊咧兴a(chǎn)生效應(yīng)的數(shù)據(jù)。
方法
在這項(xiàng)3期、安慰劑對(duì)照試驗(yàn)中，我們將4,744例射血分?jǐn)?shù)≤40%的紐約心臟學(xué)會(huì)（New York Heart Association）心功能分級(jí)Ⅱ、Ⅲ或Ⅳ級(jí)心力衰竭患者隨機(jī)分組，分別接受推薦治療+達(dá)格列凈（劑量為每日1次，每次10 mg）或推薦治療+安慰劑。主要結(jié)局是由心力衰竭惡化（因心力衰竭住院或者因心力衰竭緊急就診并接受靜脈給藥治療）或心血管原因死亡構(gòu)成的復(fù)合結(jié)局。
結(jié)果
在中位18.2個(gè)月期間，達(dá)格列凈組2,373例患者中的386例（16.3%）和安慰劑組2,371例患者中的502例（21.2%）發(fā)生了主要結(jié)局（風(fēng)險(xiǎn)比，0.74；95% CI，0.65～0.85；P＜0.001）。達(dá)格列凈組237例患者（10.0%）和安慰劑組326例患者（13.7%）發(fā)生了首次心力衰竭惡化事件（風(fēng)險(xiǎn)比，0.70；95% CI，0.59～0.83）。達(dá)格列凈組227例患者（9.6%）和安慰劑組273例患者（11.5%）因心血管原因死亡（風(fēng)險(xiǎn)比，0.82；95% CI，0.69～0.98）；兩組分別有276例患者（11.6%）和329例患者（13.9%）死亡（風(fēng)險(xiǎn)比，0.83；95% CI，0.71～0.97）。糖尿病患者的觀察結(jié)果與非糖尿病患者的觀察結(jié)果相似。與血容量不足、腎功能障礙和低血糖相關(guān)的不良事件發(fā)生率無(wú)組間差異。
結(jié)論
在射血分?jǐn)?shù)降低的心力衰竭患者中，不論患者是否患糖尿病，與接受安慰劑治療的患者相比，在接受達(dá)格列凈治療的患者中，心力衰竭惡化或心血管原因死亡的風(fēng)險(xiǎn)均較低（由阿斯利康資助；DAPA-HF在ClinicalTrials.gov注冊(cè)號(hào)為NCT03036124）。
在2型糖尿病患者中開(kāi)展的大型臨床試驗(yàn)表明，鈉-葡萄糖協(xié)同轉(zhuǎn)運(yùn)蛋白2（SGLT2）抑制劑可降低因心力衰竭住院的風(fēng)險(xiǎn)1-4。這些試驗(yàn)中的大多數(shù)患者在基線時(shí)無(wú)心力衰竭，因此使用SGLT2抑制劑的益處基本上反映了對(duì)新發(fā)心力衰竭的預(yù)防。心力衰竭住院的風(fēng)險(xiǎn)降低在隨機(jī)分組后早期即可觀察到，因此提出了以下可能性：其作用機(jī)制不同于解釋降糖治療的心血管益處時(shí)通常假設(shè)的作用機(jī)制5-9。SGLT2抑制劑除了具有利尿作用及相關(guān)的血流動(dòng)力學(xué)作用之外，研究者還提出其對(duì)于心肌代謝、離子轉(zhuǎn)運(yùn)蛋白、纖維化、脂肪因子和血管功能有作用5-9。這些作用及腎功能保護(hù)作用也將有利于已確診的心力衰竭患者，包括尚未對(duì)SGLT2抑制劑進(jìn)行過(guò)試驗(yàn)的未患糖尿病的患者4,10,11。我們?cè)O(shè)計(jì)了DAPA-HF（達(dá)格列凈和心力衰竭不良結(jié)局的預(yù)防[Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure]）試驗(yàn)，目的是在射血分?jǐn)?shù)降低的心力衰竭患者（不論是否患糖尿病）中前瞻性地評(píng)估SGLT2抑制劑達(dá)格列凈的療效和安全性12,13。
方法
試驗(yàn)設(shè)計(jì)和監(jiān)管
執(zhí)行委員會(huì)與申辦方阿斯利康公司合作設(shè)計(jì)并監(jiān)管本試驗(yàn)的實(shí)施和分析12,13。我們按照試驗(yàn)方案和統(tǒng)計(jì)學(xué)分析計(jì)劃實(shí)施并報(bào)告了本試驗(yàn)，試驗(yàn)方案和統(tǒng)計(jì)學(xué)分析計(jì)劃與本文全文可在NEJM.org獲取。本試驗(yàn)在各研究中心獲得了倫理委員會(huì)批準(zhǔn)。試驗(yàn)中患者的安全性由獨(dú)立的數(shù)據(jù)和安全監(jiān)察委員會(huì)監(jiān)管。申辦方所做的分析由格拉斯哥大學(xué)（University of Glasgow）的獨(dú)立學(xué)術(shù)小組進(jìn)行了重復(fù)。本文初稿由可無(wú)限制查看數(shù)據(jù)的第一作者撰寫(xiě)，并由所有作者審閱和修改。所有作者決定投稿，并保證數(shù)據(jù)的準(zhǔn)確性和完整性，以及試驗(yàn)對(duì)方案的忠實(shí)度。
患者
患者納入標(biāo)準(zhǔn)包括：年齡至少18歲，射血分?jǐn)?shù)≤40%，紐約心臟學(xué)會(huì)（NYHA）心功能分級(jí)為Ⅱ、Ⅲ或Ⅳ級(jí)。本試驗(yàn)還要求患者的N末端B型鈉尿肽前體（NT-proBNP）血漿水平至少為600 pg/mL（如果患者在之前12個(gè)月內(nèi)曾因心力衰竭住院的話，則要求≥400 pg/mL）。對(duì)于基線心電圖顯示有心房顫動(dòng)或心房撲動(dòng)的患者，不論患者是否曾因心力衰竭住院，本試驗(yàn)均要求患者的NT-proBNP水平至少為900 pg/mL。
除非患者有禁忌證或治療導(dǎo)致了無(wú)法接受的副作用，否則要求患者接受標(biāo)準(zhǔn)的心力衰竭器械治療（植入式心律轉(zhuǎn)復(fù)除顫器、心臟再同步治療或者兩者）和標(biāo)準(zhǔn)的藥物治療（包括血管緊張素轉(zhuǎn)化酶抑制劑、血管緊張素受體阻滯劑或者沙庫(kù)巴曲-纈沙坦聯(lián)合β受體阻滯劑治療）。此外，我們鼓勵(lì)患者使用鹽皮質(zhì)激素受體拮抗劑。本試驗(yàn)按照指南建議對(duì)藥物劑量進(jìn)行個(gè)體化調(diào)整。2型糖尿病患者繼續(xù)接受降糖治療，但可以根據(jù)需要調(diào)整劑量。具體而言，為了減小低血糖風(fēng)險(xiǎn)（例如對(duì)于糖化血紅蛋白水平＜7%的患者），可以降低胰島素和磺酰脲類(lèi)藥物劑量。
排除標(biāo)準(zhǔn)包括近期接受過(guò)SGLT2抑制劑治療或有與SGLT2抑制劑相關(guān)的無(wú)法接受的副作用，患1型糖尿病，有低血壓癥狀或收縮壓低于95 mmHg，估計(jì)腎小球?yàn)V過(guò)率（eGFR）低于30 mL/（min·1.73 m2）（或腎功能迅速下降）。
試驗(yàn)程序
所有患者均提供了書(shū)面知情同意并進(jìn)入14日篩選期，我們?cè)谶@一期間核實(shí)納入和排除標(biāo)準(zhǔn)，并收集基線數(shù)據(jù)。篩選完成后，我們利用平衡區(qū)組（確保兩種治療方案的比例接近1∶1），按照隱蔽固定隨機(jī)化計(jì)劃將患者隨機(jī)分組，分別接受達(dá)格列凈（劑量為每日1次，每次10 mg）或匹配安慰劑治療。研究者使用交互式語(yǔ)音或網(wǎng)絡(luò)應(yīng)答系統(tǒng)進(jìn)行治療分組。根據(jù)篩選時(shí)確認(rèn)的2型糖尿病診斷（即確診或者糖化血紅蛋白水平≥6.5%［≥48 mmol/M]）對(duì)隨機(jī)化進(jìn)行分層。
我們?cè)陔S機(jī)分組后14日和60日對(duì)患者進(jìn)行了評(píng)價(jià)，重點(diǎn)評(píng)估心力衰竭和血容量狀況、不良事件，以及腎功能和鉀水平。其他試驗(yàn)訪視安排在4個(gè)月時(shí)，以及之后每4個(gè)月1次（補(bǔ)充附錄圖S1，補(bǔ)充附錄可在NEJM.org獲?。Ｍ暾?jì)劃表見(jiàn)試驗(yàn)方案。如果患者懷孕或發(fā)生糖尿病酮癥酸中毒，則將達(dá)格列凈或安慰劑停藥。如果出現(xiàn)eGFR急性非預(yù)期下降、血容量不足或低血壓（或者為了避免這些情況），允許降低藥物劑量（降至每日5 mg達(dá)格列凈或安慰劑）或暫時(shí)停藥；可能的情況下，之后可再次增加劑量或重新開(kāi)始用藥。
結(jié)局
主要結(jié)局是由心力衰竭惡化或心血管原因死亡構(gòu)成的復(fù)合結(jié)局。心力衰竭惡化指的是因心力衰竭而發(fā)生計(jì)劃外住院，或者因心力衰竭緊急就診并接受靜脈給藥治療。
關(guān)鍵次要結(jié)局是由因心力衰竭住院或心血管原因死亡構(gòu)成的復(fù)合結(jié)局。其他次要結(jié)局包括因心力衰竭住院的總次數(shù)（包括重復(fù)入院）和心血管原因死亡；堪薩斯城心肌病問(wèn)卷（Kansas City Cardiomyopathy Questionnaire）癥狀總分從基線至8個(gè)月時(shí)的變化，該問(wèn)卷的評(píng)分范圍為0～100分，評(píng)分較高表示癥狀較少，≥5分的變化被認(rèn)為有臨床意義14；由腎功能惡化（定義為eGFR持續(xù)降低≥50%）、終末期腎病（定義為eGFR持續(xù)[≥28日]＜15 mL/[min·1.73 m2]、持續(xù)透析或腎移植）或腎臟原因死亡構(gòu)成的復(fù)合結(jié)局，以及全因死亡12。所有結(jié)局均由臨床事件委員會(huì)成員按照預(yù)設(shè)標(biāo)準(zhǔn)（定義列在補(bǔ)充附錄內(nèi)）進(jìn)行裁定，臨床事件委員會(huì)成員不知曉試驗(yàn)分組情況15。
預(yù)設(shè)的安全性分析包括嚴(yán)重不良事件、與停止試驗(yàn)治療相關(guān)的不良事件、關(guān)注的不良事件（即血容量不足、腎臟事件、嚴(yán)重低血糖事件、骨折、糖尿病酮癥酸中毒和截肢）、診斷為富尼埃壞疽和值得關(guān)注的實(shí)驗(yàn)室檢查結(jié)果。考慮到之前已廣泛收集關(guān)于達(dá)格列凈的安全性數(shù)據(jù)，因此本試驗(yàn)未常規(guī)收集其他不良事件數(shù)據(jù)3。
統(tǒng)計(jì)學(xué)分析
我們計(jì)算得出，844起主要結(jié)局事件將為本試驗(yàn)提供90%的統(tǒng)計(jì)學(xué)功效，在0.05的雙側(cè)α水平檢測(cè)出達(dá)格列凈和安慰劑之間0.80的風(fēng)險(xiǎn)比。在安慰劑組中，事件的預(yù)期年發(fā)生率為11%，根據(jù)18個(gè)月的預(yù)期納入期和約24個(gè)月的平均隨訪期，我們估計(jì)納入約4,500例患者將提供所需數(shù)量的主要事件。我們利用封閉檢驗(yàn)程序（closed testing procedure），對(duì)主要和次要結(jié)局進(jìn)行了預(yù)設(shè)的分級(jí)檢驗(yàn)。針對(duì)主要和次要結(jié)局的多重比較，考慮到一次期中療效分析，我們?cè)?.0499的雙側(cè)α水平控制了Ⅰ型錯(cuò)誤。
根據(jù)意向治療原則，我們?cè)谥饕痛我Y(jié)局分析中納入了被隨機(jī)分組的所有患者。使用平均值和標(biāo)準(zhǔn)差、中位數(shù)和四分位距或者百分比總結(jié)了基線特征。我們使用重復(fù)測(cè)量的混合模型分析了縱向指標(biāo)（如糖化血紅蛋白水平和體重），并且估算了治療組之間的最小二乘均值差異以及95%置信區(qū)間。我們利用Kaplan-Meier估計(jì)值和Cox比例風(fēng)險(xiǎn)模型評(píng)價(jià)了至事件發(fā)生時(shí)間數(shù)據(jù)，上述模型根據(jù)糖尿病分層，并將心力衰竭住院史和治療分組作為固定效應(yīng)；對(duì)于腎臟結(jié)局，模型中納入了基線eGFR，而非心力衰竭住院史。我們應(yīng)用Cox模型計(jì)算了風(fēng)險(xiǎn)比、95%置信區(qū)間和雙側(cè)P值，并應(yīng)用半?yún)?shù)比例比率模型（proportional-rates model）計(jì)算了全部（包括復(fù)發(fā)）事件16。
我們應(yīng)用協(xié)方差秩分析方法（rank analysis of covariance method）分析了堪薩斯城心肌病問(wèn)卷癥狀總分（將其作為基于秩的復(fù)合結(jié)局，并包括8個(gè)月時(shí)的患者生存狀態(tài)和生存患者的評(píng)分從基線至8個(gè)月的變化），并且應(yīng)用相應(yīng)贏率估算了療效大小17。我們?cè)?4個(gè)預(yù)設(shè)亞組中評(píng)估了療效的一致性。我們?cè)诒浑S機(jī)分組并接受了至少1劑達(dá)格列凈或安慰劑治療的患者中進(jìn)行了安全性分析。我們利用Fisher精確檢驗(yàn)比較了不良事件發(fā)生率。所有分析均采用Stata軟件15版（StataCorp）和R 3.5.1版（R Foundation for Statistical Computing）進(jìn)行。
結(jié)果
患者
從2017年2月15日至2018年8月17日，我們?cè)?0個(gè)國(guó)家410個(gè)中心將共計(jì)4,744例患者隨機(jī)分組，分別接受達(dá)格列凈或匹配安慰劑治療（圖1）。基線時(shí)，各組的患者特征和心力衰竭治療情況平衡（表1）。篩選時(shí)，各組均有42%的患者有2型糖尿病病史，各組均有另外3%的患者被新診斷為糖尿病。
圖1. 患者納入和隨訪
隨機(jī)分組的所有患者均被納入主要分析。未接受達(dá)格列凈或安慰劑治療的患者被排除出安全性分析。
表1. 患者的基線特征*
* 加減值為均值±SD。兩組的所有變量均無(wú)顯著差異。由于舍入，百分比總計(jì)可能不是100。ACE表示血管緊張素轉(zhuǎn)換酶，ARB表示血管緊張素受體阻滯劑，DPP-4表示二肽基肽酶4，GFR表示腎小球?yàn)V過(guò)率，GLP-1表示胰高血糖素樣肽1，IQR表示四分位距，NT-proBNP表示N末端B型鈉尿肽前體，NYHA表示紐約心臟學(xué)會(huì)。
? 體質(zhì)指數(shù)為體重（kg）除以身高（m）的平方。
? 人種是由研究者報(bào)告。
§ 達(dá)格列凈組另外82例患者和安慰劑組另外74例患者患糖尿病，但之前未診斷出，糖尿病的定義為根據(jù)篩選和隨機(jī)分組時(shí)中央實(shí)驗(yàn)室的測(cè)定結(jié)果，糖化血紅蛋白水平≥6.5%（≥48 mmol/M）。
? 此類(lèi)別包括植入式心律轉(zhuǎn)復(fù)除顫器或者使用除顫器的心臟再同步治療。
‖ 此類(lèi)別包括使用或不使用除顫器的心臟再同步治療。
** 表中僅列出基線時(shí)有糖尿病病史的患者的降糖藥物治療。
249例患者因死亡之外的其他原因停用達(dá)格列凈，258例患者因死亡之外的其他原因停用安慰劑（10.5% vs. 10.9%，P=0.71）。在末次評(píng)估時(shí)，在仍服用達(dá)格列凈的患者中，2,039例患者（98.1%）繼續(xù)接受每日10 mg劑量；1,993例患者（98.2%）繼續(xù)接受同等劑量安慰劑。試驗(yàn)結(jié)束時(shí)，達(dá)格列凈組并無(wú)任何患者的生存狀態(tài)不明，安慰劑組2例患者的生存狀態(tài)不明。中位隨訪持續(xù)時(shí)間為18.2個(gè)月（范圍，0～27.8）。
結(jié)局
達(dá)格列凈組386例患者（16.3%）和安慰劑組502例患者（21.2%）發(fā)生了由心力衰竭惡化（因心力衰竭住院治療或者因心力衰竭緊急就診并接受靜脈給藥治療）或心血管原因死亡構(gòu)成的主要復(fù)合結(jié)局（風(fēng)險(xiǎn)比，0.74；95% CI，0.65～0.85；P＜0.001）（表2和圖2A）。
表2. 主要和次要心血管結(jié)局及特別關(guān)注的不良事件*
* 加減值為均值±SD。NA表示不適用，原因是僅報(bào)告了被納入分層檢驗(yàn)策略的療效結(jié)局的P值。
? 主要結(jié)局是由心力衰竭惡化（因心力衰竭住院或者因心力衰竭緊急就診并接受靜脈給藥治療）或心血管原因死亡構(gòu)成的復(fù)合結(jié)局。
? 我們利用半?yún)?shù)比例比率模型分析了因心力衰竭住院和心血管原因死亡的總數(shù)，在該模型中，療效被報(bào)告為率比。
§ KCCQ癥狀總分范圍為0～100分，較高評(píng)分表示癥狀及與心力衰竭相關(guān)的生理限制較少。療效顯示為贏率，數(shù)值大于1表示優(yōu)效性。
? 腎功能惡化指的是由估計(jì)GFR持續(xù)降低≥50%至少28日、終末期腎病或腎臟原因死亡構(gòu)成的復(fù)合結(jié)局。終末期腎病的定義為估計(jì)GFR＜15 mL/（min·1.73 m2）的持續(xù)時(shí)間至少28日、長(zhǎng)期透析治療（持續(xù)＞28日）或腎移植。據(jù)報(bào)告，達(dá)格列凈組23例患者（1.0%）和安慰劑組46例患者（1.9%）發(fā)生了嚴(yán)重不良事件急性腎損傷（P=0.007）。
‖安全性人群包括被隨機(jī)分組并接受至少1劑達(dá)格列凈或安慰劑治療的所有患者。
** 嚴(yán)重低血糖的定義為需要他人協(xié)助才能主動(dòng)攝入碳水化合物（糖類(lèi)）或接受胰高血糖素治療，或者采取其他糾正措施。所有病例均發(fā)生于基線時(shí)患糖尿病的患者。
?? 所有糖尿病酮癥酸中毒均發(fā)生于基線時(shí)患糖尿病的患者。
?? 實(shí)驗(yàn)室和其他指標(biāo)的組間差異均被報(bào)告為療效。
§§ 表中僅列出了糖尿病患者的糖化血紅蛋白值。
圖2. 心血管結(jié)局
主要結(jié)局為由心血管原因死亡、因心力衰竭住院或因心力衰竭緊急就診并接受靜脈給藥治療構(gòu)成的復(fù)合結(jié)局（圖A）。我們利用Kaplan-Meier方法估算了主要結(jié)局、因心力衰竭住院（圖B）、心血管原因死亡（圖C）和全因死亡（圖D）的累積發(fā)生率；利用Cox回歸模型估算了風(fēng)險(xiǎn)比和95%置信區(qū)間，該模型根據(jù)糖尿病狀態(tài)分層，并將心力衰竭住院史和治療分組作為解釋變量。這些分析納入了被隨機(jī)分組的所有患者。我們?cè)?4個(gè)月時(shí)（當(dāng)時(shí)不到10%的患者仍有風(fēng)險(xiǎn)）將圖截尾。各圖中的插圖顯示放大的y軸上的相同數(shù)據(jù)。
復(fù)合結(jié)局全部3個(gè)構(gòu)成部分的事件發(fā)生率均顯示達(dá)格列凈的療效較好；在心力衰竭惡化事件中，發(fā)生數(shù)量最多的是因心力衰竭住院。在接受達(dá)格列凈治療的患者中，231例（9.7%）因心力衰竭住院，而在接受安慰劑治療的患者中，318例患者（13.4%）因心力衰竭住院（風(fēng)險(xiǎn)比，0.70；95% CI，0.59～0.83）（圖2B）。達(dá)格列凈組227例患者（9.6%）和安慰劑組273例患者（11.5%）因心血管原因死亡（風(fēng)險(xiǎn)比，0.82；95% CI，0.69～0.98）（圖2C）。在本試驗(yàn)期間，每預(yù)防1起主要事件，需要接受達(dá)格列凈治療的患者數(shù)量為21例（95% CI，15～38）。
在達(dá)格列凈組中，由因心力衰竭住院或心血管原因死亡構(gòu)成的次要復(fù)合結(jié)局的發(fā)生率低于安慰劑組（風(fēng)險(xiǎn)比，0.75；95% CI，0.65～0.85；P＜0.001）（表2）。達(dá)格列凈組共發(fā)生了567起首次和復(fù)發(fā)性事件（發(fā)生于382例患者的340例因心力衰竭住院和227例心血管原因死亡），安慰劑組共發(fā)生了742起首次和復(fù)發(fā)性事件（發(fā)生于495例患者的469例因心力衰竭住院和273例心血管原因死亡），率比為0.75（95% CI，0.65～0.88；P＜0.001）。
在基線至第8個(gè)月之間，達(dá)格列凈組的堪薩斯城心肌病問(wèn)卷癥狀總分增幅（表示癥狀較少）超過(guò)安慰劑組（表2）。在達(dá)格列凈組中，總分增加至少5分（最小重要差異）的患者超過(guò)安慰劑組（58.3% vs. 50.9%；比值比，1.15；95% CI，1.08～1.23），顯著惡化的患者少于安慰劑組（25.3% vs. 32.9%；比值比，0.84；95% CI，0.78～0.90；對(duì)于兩項(xiàng)比較，P＜0.001）。各組的預(yù)設(shè)腎臟復(fù)合結(jié)局發(fā)生率無(wú)差異（表2）。
達(dá)格列凈組276例患者（11.6%）和安慰劑組329例患者（13.9%）死亡（風(fēng)險(xiǎn)比，0.83；95% CI，0.71～0.97）（圖2D）。對(duì)死亡和因心力衰竭住院所做的分析見(jiàn)圖S2。
達(dá)格列凈對(duì)主要結(jié)局產(chǎn)生的效應(yīng)在各預(yù)設(shè)亞組（包括基線時(shí)無(wú)糖尿病的患者）中總體一致，但NYHA心功能分級(jí)Ⅲ級(jí)或Ⅳ級(jí)患者的獲益似乎小于NYHA心功能分級(jí)Ⅱ級(jí)患者。我們對(duì)基線時(shí)服用沙庫(kù)巴曲-纈沙坦的患者進(jìn)行了一項(xiàng)事后亞組分析，結(jié)果顯示達(dá)格列凈與安慰劑相比，主要結(jié)局的風(fēng)險(xiǎn)比為0.75（95% CI，0.50～1.13），而在未服用沙庫(kù)巴曲-纈沙坦的患者中，這一風(fēng)險(xiǎn)比為0.74（95% CI，0.65～0.86）。
圖3. 各預(yù)設(shè)亞組的主要復(fù)合結(jié)局
圖中顯示的是試驗(yàn)方案預(yù)設(shè)的各亞組的主要結(jié)局（由因心力衰竭住院、因心力衰竭緊急就診并接受靜脈給藥治療或心血管原因死亡構(gòu)成的復(fù)合結(jié)局）。人種是由研究者報(bào)告。體質(zhì)指數(shù)為體重（kg）除以身高（m）的平方。ECG表示心電圖，eGFR表示估計(jì)腎小球?yàn)V過(guò)率，LVEF表示左心室射血分?jǐn)?shù)，MRA表示鹽皮質(zhì)激素受體拮抗劑，NT-proBNP表示N末端B型鈉尿肽前體，NYHA表示紐約心臟學(xué)會(huì)。
糖化血紅蛋白、血細(xì)胞比容、肌酐、NT-proBNP、收縮壓和體重從基線至8個(gè)月時(shí)的變化見(jiàn)表2。
安全性
由于未接受達(dá)格列凈或安慰劑治療，共有8例患者（達(dá)格列凈組5例和安慰劑組3例）被排除出安全性分析（表2）。達(dá)格列凈組29例患者（1.2%）和安慰劑組40例患者（1.7%）發(fā)生了與血容量不足相關(guān)的嚴(yán)重不良事件（P=0.23）。達(dá)格列凈組38例患者（1.6%）和安慰劑組65例患者（2.7%）發(fā)生了嚴(yán)重腎臟不良事件（P=0.009）。不良事件很少導(dǎo)致患者停止治療。所有嚴(yán)重不良事件均列在表S1內(nèi)，達(dá)格列凈組并無(wú)任何事件的發(fā)生率顯著高于安慰劑組。
討論
這是一項(xiàng)對(duì)左心室射血分?jǐn)?shù)降低的心力衰竭患者開(kāi)展的隨機(jī)、安慰劑對(duì)照試驗(yàn)，結(jié)果顯示與安慰劑組相比，在達(dá)格列凈組中，由心力衰竭惡化（因心力衰竭住院或者因心力衰竭緊急就診并接受靜脈給藥治療）或心血管原因死亡構(gòu)成的主要復(fù)合結(jié)局的風(fēng)險(xiǎn)較低。在復(fù)合結(jié)局的3個(gè)構(gòu)成部分中，每個(gè)的發(fā)生率均為達(dá)格列凈組低于安慰劑組；因心力衰竭住院和心血管原因死亡的總數(shù)也是達(dá)格列凈組少于安慰劑組。根據(jù)堪薩斯城心肌病問(wèn)卷評(píng)分，達(dá)格列凈導(dǎo)致的心力衰竭癥狀較少。顯著且有臨床意義的益處在隨機(jī)分組后的早期即可觀察到，并且在因心力衰竭接受其他推薦治療的患者中也可觀察到。
達(dá)格列凈在未患2型糖尿病的患者中（該人群在所有患者中占55%）與在糖尿病患者中同樣有效。這證明了SGLT2抑制劑在未患糖尿病的患者中產(chǎn)生的心血管益處，因此支持之前提出的以下觀點(diǎn)：此類(lèi)治療具有降糖之外的其他有益作用4-11。因此，我們的研究結(jié)果可能將達(dá)格列凈的治療作用擴(kuò)大到糖尿病患者之外。
在其他預(yù)設(shè)的亞組中，主要結(jié)局風(fēng)險(xiǎn)的降低情況總體一致，但一項(xiàng)比較提示可能存在異質(zhì)性，NYHA心功能分級(jí)Ⅲ級(jí)或Ⅳ級(jí)患者的獲益小于NYHA心功能分級(jí)Ⅱ級(jí)患者。然而，在也反映疾病處于較晚期的其他亞組（例如射血分?jǐn)?shù)降幅較大、腎功能較差和NT-proBNP水平升高）中，觀察結(jié)果與NYHA心功能分級(jí)亞組的觀察結(jié)果并不一致。
我們的試驗(yàn)人群與之前SGLT2抑制劑試驗(yàn)中的患者不同，因?yàn)楸驹囼?yàn)中患者的心力衰竭住院和心血管原因死亡風(fēng)險(xiǎn)遠(yuǎn)高于之前試驗(yàn)中的許多患者。本試驗(yàn)中的大部分患者已經(jīng)在接受髓袢利尿藥和鹽皮質(zhì)激素受體拮抗劑治療，我們并不知曉達(dá)格列凈可否產(chǎn)生在其他患者人群中觀察到的初始利尿作用。此外因?yàn)楸驹囼?yàn)有許多患者患慢性腎臟疾病，因此我們并不知曉上述作用是否會(huì)導(dǎo)致血容量不足和腎功能惡化。結(jié)果表明，以上兩項(xiàng)不良反應(yīng)均不常見(jiàn)（發(fā)生率均＜8%，無(wú)組間差異），而且嚴(yán)重腎臟不良事件總體而言罕見(jiàn)，且達(dá)格列凈組的發(fā)生率顯著低于安慰劑組?？傮w而言，因不良反應(yīng)停用達(dá)格列凈或安慰劑的患者很少（兩組均＜5%）。嚴(yán)重低血糖和糖尿病酮癥酸中毒均罕見(jiàn)，且兩種不良事件均僅發(fā)生于糖尿病患者。
本試驗(yàn)有一些局限性。我們使用了特殊的納入和排除標(biāo)準(zhǔn)，因此可能限制了研究結(jié)果的普遍適用性。本試驗(yàn)中黑色人種患者所占的比例不到5%，此外有多種合并癥的高齡患者相對(duì)較少。基線時(shí)應(yīng)用沙庫(kù)巴曲-纈沙坦的患者較少，而在降低因心力衰竭住院和心血管原因死亡的發(fā)生率方面，沙庫(kù)巴曲-纈沙坦比腎素-血管緊張素系統(tǒng)阻滯劑單藥治療更有效18。然而，目前推測(cè)SGLT2抑制和腦啡肽酶抑制的作用機(jī)制不同，而且在一項(xiàng)事后亞組分析中，達(dá)格列凈在接受沙庫(kù)巴曲-纈沙坦治療的患者和未接受上述治療的患者中產(chǎn)生相似益處19,20。
在射血分?jǐn)?shù)降低的心力衰竭患者中，不論患者是否患糖尿病，接受SGLT2抑制劑達(dá)格列凈治療的患者發(fā)生心力衰竭惡化或心血管原因死亡的風(fēng)險(xiǎn)均低于接受安慰劑治療的患者，并且癥狀評(píng)分優(yōu)于接受安慰劑治療的患者。
Supported by AstraZeneca.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
Dr. McMurray reports receiving fees (all fees listed paid to Glasgow University) for serving on a steering committee from Bayer, fees for serving on a steering committee, fees for serving on an end-point committee, and travel support from Cardiorentis, fees for serving on a steering committee and travel support from Amgen, fees for serving on a steering committee and travel support from Oxford University–Bayer, fees for serving as principal investigator of a trial and travel support from Theracos, fees for serving on a steering committee and travel support from AbbVie, fees for serving on a steering committee from DalCor Pharmaceuticals, fees for serving on a data and safety monitoring committee from Pfizer, fees for serving on a data and safety monitoring committee from Merck, fees for serving on an executive committee, fees for serving as co-principal investigator of a trial, fees for serving on a steering committee, fees for serving on an executive committee, travel support, and advisory board fees from Novartis, fees for serving as co-principal investigator for a trial, fees for serving on a steering committee, and travel support from GlaxoSmithKline, fees for serving on a steering committee from Bristol-Myers Squibb, and fees for serving on a steering committee, fees for serving on an end-point adjudication committee, and travel support from Vifor Pharma–Fresenius; Dr. Solomon, receiving grant support and consulting fees (all fees listed paid to Brigham and Women’s Hospital) from Alnylam Pharmaceuticals, Amgen, AstraZeneca, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, MyoKardia, Novartis, Theracos, Bayer, and Cytokinetics, grant support from Bellerophon Therapeutics, Celladon, Ionis Pharmaceuticals, Lonestar Heart, Mesoblast, Sanofi Pasteur, and Eidos Therapeutics, consulting fees from Akros Pharma, Corvia Medical, Ironwood Pharma, Merck, Roche, Takeda Pharmaceutical, Quantum Genomics, AOBiome, Cardiac Dimensions, Tenaya Therapeutics, and Daiichi Sankyo, and fees for serving on a data and safety monitoring board from Janssen; Dr. Inzucchi, receiving advisory fees from AstraZeneca and Zafgen, lecture fees, consulting fees, fees for serving as a clinical-trial publications committee member, reimbursement for medical writing, and travel support from Boehringer Ingelheim, fees for serving on a steering committee and travel support from Sanofi–Lexicon, lecture fees, consulting fees, and travel support from Merck, and advisory fees and travel support from vTv Therapeutics and Abbott–Alere; Dr. K?ber, receiving lecture fees from Novartis and Bristol-Myers Squibb; Dr. Kosiborod, receiving grant support, honoraria, and research support from AstraZeneca, grant support and honoraria from Boehringer Ingelheim, and honoraria from Sanofi, Amgen, Novo Nordisk, Merck (Diabetes), Eisai, Janssen, Bayer, GlaxoSmithKline, Glytec, Intarcia Therapeutics, Novartis, Applied Therapeutics, Amarin, and Eli Lilly; Dr. Ponikowski, receiving consulting fees, fees for serving on a speakers bureau, and fees (paid to himself and to his institution) for serving as an investigator and steering or executive committee member for clinical trials from Boehringer Ingelheim, lecture fees from Pfizer, fees (paid to himself and to his institution) for serving as an investigator and steering or executive committee member for clinical trials from Amgen, grant support (paid to his institution), fees for serving on a speakers bureau, consulting fees, and fees (paid to himself and to his institution) for serving as an investigator and steering or executive committee member for clinical trials from Vifor Pharma, fees for serving on a speakers bureau and consulting fees from Servier, fees for serving on a speakers bureau, consulting fees, and fees (paid to himself and to his institution) for serving as an investigator and steering or executive committee member for clinical trials from Bayer, fees for serving on a speakers bureau, consulting fees, and fees (paid to himself and to his institution) for serving as an investigator and steering or executive committee member for clinical trials from Bristol-Myers Squibb, fees for serving on a speakers bureau and consulting fees from Respicardia, fees for serving on a speakers bureau from Berlin-Chemie, fees for serving on a speakers bureau, consulting fees, and fees (paid to himself and to his institution) for serving as an investigator and steering or executive committee member for clinical trials from Cibiem, fees for serving on a speakers bureau, consulting fees, and fees (paid to himself and to his institution) for serving as an investigator and steering or executive committee member for clinical trials from Novartis, and fees for serving on a speakers bureau, consulting fees, and fees (paid to himself and to his institution) for serving as an investigator and steering or executive committee member for clinical trials from RenalGuard; Dr. Sabatine, receiving grant support (paid to Brigham and Women’s Hospital) and consulting fees from Amgen, AstraZeneca, Intarcia Therapeutics, Janssen Research and Development, the Medicines Company, MedImmune, Merck, and Novartis, receiving consulting fees from Anthos Therapeutics, Bristol-Myers Squibb, CVS Caremark, DalCor Pharmaceuticals, Dyrnamix, Esperion, IFM Therapeutics, and Ionis Pharmaceuticals, receiving grant support (paid to Brigham and Woman’s Hospital) from Bayer, Daiichi Sankyo, Eisai, GlaxoSmithKline, Pfizer, Poxel, Quark Pharmaceuticals, and Takeda Pharmaceutical, and serving as a member of the TIMI Study Group, which receives grant support (paid to Brigham and Women’s Hospital) from Abbott, Aralez Pharmaceuticals, Roche, and Zora Biosciences; Dr. Anand, receiving fees for serving as United States national leader of a trial from AstraZeneca, fees for serving on a steering committee from ARCA Biopharma, Amgen, LivaNova, and Novartis, fees for serving on an end-point committee from Boehringer Ingelheim, fees for serving as chair of a data and safety monitoring board from Boston Scientific, and advisory board fees from Zensun; Dr. Bělohlávek, receiving advisory board fees from Novartis and Pfizer and lecture fees from Getginge; Dr. B?hm, receiving lecture fees from Amgen, Bayer, Servier, Medtronic, Boehringer Ingelheim, Vifor Pharma, and Bristol-Myers Squibb, grant support and lecture fees from AstraZeneca, and grant support from Deutsche Forschungsgemeinschaft; Dr. Chiang, receiving honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo, MSD, Novartis, Pfizer, and Sanofi; Dr. de Boer, receiving grant support (paid to University Medical Center Groningen [UMCG]), consulting fees, and lecture fees from AstraZeneca, grant support (paid to UMCG) from Bristol-Myers Squibb, grant support (paid to UMCG) and consulting fees from Abbott, grant support (paid to UMCG) and lecture fees from Roche, and consulting fees from MandalMed and being a minority shareholder in scPharmaceuticals; Dr. Desai, receiving consulting fees from Abbott, Biofourmis, Boston Scientific, Boehringer Ingelheim, DalCor Pharmaceuticals, and Regeneron, grant support (paid to Brigham and Women’s Hospital) and consulting fees from Alnylam Pharmaceuticals and Novartis, and advisory board fees from Corvidia and Relypsa; Dr. Howlett, receiving grant support, consulting fees, and lecture fees from AstraZeneca, Boehringer Ingelheim, Novartis, and Servier, consulting fees and lecture fees from Novo Nordisk, consulting fees from Janssen, and grant support, consulting fees, lecture fees, and provision of drugs from Pfizer; Dr. Katova, receiving fees for serving as national coordinator of a trial from Novartis and AstraZeneca; Dr. Kitakaze, receiving grant support and lecture fees from Astellas Pharma, Sanofi, Pfizer, Ono Pharmaceutical, Novartis, and Mitsubishi Tanabe Pharma, lecture fees from Daiichi Sankyo, Bayer, Boehringer Ingelheim, Kowa Pharmaceutical, Sawai Pharmaceutical, MSD, Shionogi, Kureha, Taisho Toyama Pharmaceutical, Takeda Pharmaceutical, and Toa Eiyo, and manuscript fees from Japan Medical Data Center; Dr. Ljungman, receiving lecture fees and advisory board fees from AstraZeneca, lecture fees from Novartis, and advisory board fees from Pfizer; Dr. Merkely, receiving lecture fees from AstraZeneca, Sanofi Aventis, Servier, and Biotronik and grant support and lecture fees from Abbott and Medtronic; Dr. Nicolau, receiving consulting fees from Amgen, grant support from AstraZeneca, Bristol-Myers Squibb, CSL Behring, DalCor Pharmaceuticals, Janssen, Novo Nordisk, and Vifor Pharma, grant support and fees for serving as principal investigator from Bayer, lecture fees from Daiichi Sankyo, grant support and consulting fees from Novartis, grant support, fees for serving as principal investigator, and advisory board fees from Sanofi, and lecture fees and advisory board fees from Servier; Dr. O’Meara, receiving fees for serving on a clinical trial (paid to her institution), consulting fees, and lecture fees from AstraZeneca, Bayer, Amgen, and Novartis, consulting fees from Merck, fees for serving on a clinical trial (paid to her institution) from American Regent, and consulting fees and lecture fees from Pfizer and Boehringer Ingelheim; Dr. Petrie, receiving lecture fees from AstraZeneca, Novartis, and Eli Lilly, grant support, advisory board fees, and fees for serving on an end-point committee from Boehringer Ingelheim, advisory board fees, lecture fees, and fees for serving on an end-point committee from Novo Nordisk, advisory board fees from Napp Pharmaceuticals, and fees for serving on an end-point committee from Takeda Pharmaceutical and Bayer; Dr. Tereshchenko, receiving lecture fees from Servier, Pfizer, Novartis, and Boehringer Ingelheim; Dr. Verma, receiving grant support, lecture fees, and advisory board fees from AstraZeneca, Boehringer Ingelheim, Bayer, Janssen, and Merck, lecture fees from Sun Pharmaceutical Industries and EOCI Pharmacomm, grant support and advisory board fees from Amgen, and lecture fees and advisory board fees from Sanofi and Eli Lilly; Dr. Held, receiving grant support, advisory board fees, and lecture fees from Bayer, grant support and advisory board fees from Boehringer Ingelheim, grant support from Bristol-Myers Squibb, advisory board fees from Coala Life, and fees for serving on a data and safety monitoring board (paid to his institution) from Idorsia; Dr. DeMets, receiving consulting fees from Frontier Science, Actelion, Bristol-Myers Squibb, Medtronic, Boston Scientific, GlaxoSmithKline, and Merck, and consulting fees and being owner of DL DeMets Consulting; Dr. Docherty, receiving grant support from Novartis; Dr. Jhund, receiving consulting fees, advisory board fees, and lecture fees from Novartis, advisory board fees from Cytokinetics, and grant support from Boehringer Ingelheim; Drs. Bengtsson and Sj?strand, being employed by AstraZeneca; and Dr. Langkilde, being employed by and holding shares in AstraZeneca. No other potential conflict of interest relevant to this article was reported.
This article was published on September 19, 2019, at NEJM.org.
A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.
譯者：時(shí)境遷，職業(yè)翻譯
校對(duì)：侯海燕，NEJM醫(yī)學(xué)前沿
John J.V. McMurray, M.D., Scott D. Solomon, M.D., Silvio E. Inzucchi, M.D., Lars K?ber, M.D., D.M.Sc., Mikhail N. Kosiborod, M.D., Felipe A. Martinez, M.D., Piotr Ponikowski, M.D., Ph.D., Marc S. Sabatine, M.D., M.P.H., Inder S. Anand, M.D., Jan Bělohlávek, M.D., Ph.D., Michael B?hm, M.D., Ph.D., Chern-En Chiang, M.D., Ph.D., Vijay K. Chopra, M.D., Rudolf A. de Boer, M.D., Ph.D., Akshay S. Desai, M.D., M.P.H., Mirta Diez, M.D., Jaroslaw Drozdz, M.D., Ph.D., Andrej Dukát, M.D., Ph.D., Junbo Ge, M.D., Jonathan G. Howlett, M.D., Tzvetana Katova, M.D., Ph.D., Masafumi Kitakaze, M.D., Ph.D., Charlotta E.A. Ljungman, M.D., Ph.D., Béla Merkely, M.D., Ph.D., Jose C. Nicolau, M.D., Ph.D., Eileen O’Meara, M.D., Mark C. Petrie, M.B., Ch.B., Pham N. Vinh, M.D., Ph.D., Morten Schou, M.D., Ph.D., Sergey Tereshchenko, M.D., Ph.D., Subodh Verma, M.D., Ph.D., Claes Held, M.D., Ph.D., David L. DeMets, Ph.D., Kieran F. Docherty, M.B., Ch.B., Pardeep S. Jhund, M.B., Ch.B., Ph.D., Olof Bengtsson, Ph. Lic., Mikaela Sj?strand, M.D., Ph.D., and Anna-Maria Langkilde, M.D., Ph.D. for the DAPA-HF Trial Committees and Investigators*
From the BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom (J.J.V.M., M.C.P., K.F.D., P.S.J.); the Cardiovascular Division (S.D.S., A.S.D.) and the TIMI Study Group, Brigham and Women’s Hospital and Harvard Medical School (M.S.S.) — all in Boston; Section of Endocrinology, Yale University School of Medicine, New Haven, CT (S.E.I.); Rigshospitalet Copenhagen University Hospital (L.K.) and the Department of Cardiology, Gentofte University Hospital (M. Schou), Copenhagen; the Department of Medicine, Saarland University Hospital, Homburg–Saar, Germany (M.B.); Saint Luke’s Mid America Heart Institute, University of Missouri, Kansas City (M.N.K.); National University of Cordoba, Cordoba (F.A.M.), and the Division of Cardiology, Instituto Cardiovascular de Buenos Aires, Buenos Aires (M.D.) — both in Argentina; Wroclaw Medical University, Wroclaw (P.P.), and the Department of Cardiology, Medical University of Lodz, Lodz (J.D.) — both in Poland; the Department of Cardiology, University of Minnesota, Minneapolis (I.S.A.); 2nd Department of Internal Medicine, Cardiovascular Medicine, General Teaching Hospital and 1st Faculty of Medicine, Charles University, Prague, Czech Republic (J.B.); the Division of Cardiology, Taipei Veterans General Hospital and National Yang-Ming University, Taipei, Taiwan (C.-E.C.); the Department of Cardiology, Medanta, Gurgaon, India (V.K.C.); the Department of Cardiology, University Medical Center and University of Groningen, Groningen, the Netherlands (R.A.B.); the 5th Department of Internal Medicine, Comenius University in Bratislava, Bratislava, Slovakia (A.D.); the Department of Cardiology, Shanghai Institute of Cardiovascular Disease and Zhongshan Hospital Fudan University, Shanghai, China (J.G.); Cumming School of Medicine and Libin Cardiovascular Institute, University of Calgary, Calgary, AB (J.G.H.), the Department of Cardiology, Montreal Heart Institute, Montreal (E.O.), and the Division of Cardiac Surgery, St. Michael’s Hospital, University of Toronto, Toronto (S.V.) — all in Canada; Clinic of Cardiology, National Cardiology Hospital, Sofia, Bulgaria (T.K.); the Cardiovascular Division of Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan (M.K.); the Department of Molecular and Clinical Medicine and Cardiology, Sahlgrenska Academy (C.E.A.L.), and AstraZeneca (O.B., M. Sj?strand, A.M.L.), Gothenburg, and the Department of Medical Sciences, Cardiology, Uppsala Clinical Research Center, Uppsala University (C.H.), Uppsala — all in Sweden; the Heart and Vascular Center, Semmelweis University, Budapest, Hungary (B.M.); Instituto do Coracao, Hospital das Clinicas da Faculdade de Medicina, Universidade de S?o Paolo, S?o Paolo (J.C.N.); the Department of Internal Medicine, Tan Tao University, Tan Duc, Vietnam (P.N.V.); the Department of Myocardial Disease and Heart Failure, National Medical Research Center of Cardiology, Moscow (S.T.); and the Department of Biostatistics and Medical Informatics, University of Wisconsin, Madison (D.L.D.).Address reprint requests to Dr. McMurray at the British Heart Foundation Cardiovascular Research Centre, University of Glasgow, 126 University Pl., Glasgow G12 8TA, United Kingdom, or at john.mcmurray@glasgow.ac.uk.*A complete list of DAPA-HF committee members and investigators is provided in the Supplementary Appendix, available at NEJM.org.
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