糖尿病肾病(diabetic kidney disease,DKD)是糖尿病的主要并发症,晚期 1/3 的患者可进展至尿毒症,严重危害人们健康。近年来随着我国人民生活水平的提高,糖尿病发病率不断增加,目前已成为我国终末期肾脏病的主要原因。近 20 年来,人们对 DKD 的诊断与治疗认识也不断提高,例如提出了无蛋白尿 DKD 新概念以及研发了多种新型抗糖尿病药物等,但目前仍然以健康生活方式、控制血糖、控制血压、调节血脂为 DKD 治疗的基本策略。
引用本文: 韩雅纯, 孙林. 糖尿病肾病诊疗进展. 华西医学, 2019, 34(7): 813-822. doi: 10.7507/1002-0179.201906121 复制
全球成年人糖尿病和糖耐量受损的患病率逐年上升,2017 年全球估计有 4.25 亿人患有糖尿病,患病率约为 8.4%,到 2045 年,全球糖尿病患病人数预计将增至 6.29 亿人,约为 9.9%[1]。我国 2013 年糖尿病和糖尿病前期的总体患病率分别为 10.9% 和 35.7%[2]。在发达国家,2 型糖尿病(type 2 diabetes mellitus,T2DM)是导致终末期肾脏病(end stage renal disease,ESRD)的主要原因。在发展中国家,T2DM 正在迅速取代传染病,成为肾衰竭的主要原因[3]。近期我国一项横断面研究表明,糖尿病相关的慢性肾脏病(chronic kidney disease,CKD)患者居我国 CKD 住院人数的第 1 位(1.1%)[4],同时,糖尿病肾病(diabetic kidney disease,DKD)也成为引起我国 ESRD 的主要原因之一(占 16.4%),且呈逐年增长的趋势[5]。因此,及时诊断和治疗对管理 DKD 至关重要,本文将根据最近国内外有关 DKD 诊疗最新进展进行评述。
1 诊断
1.1 DKD 诊断
目前 DKD 诊断仍然按照传统的定义:糖尿病患者尿白蛋白排泄率(urinary albumin excretion rate,UAER)增加(>300 mg/d),伴或不伴肾小球滤过率(glomerular filtration rate,GFR)降低,动脉血压升高[6-7]。其中,UAER 升高是 DKD 最常见的特征。根据美国糖尿病协会(American Diabetes Association,ADA)最新发布的指南,病程≥5 年的 1 型糖尿病(type 1diabetes mellitus,T1DM)患者和所有 T2DM 患者及所有伴有高血压的患者,至少每年定量评估尿白蛋白排泄量,如随机尿的尿白蛋白/肌酐比值(urinary albumin/creatinine ratio,UACR)和估算肾小球滤过率(estimated glomerular filtration rate,eGFR)[8]。同时强调 UACR 与 24 h 尿标本中的 UAER 一样准确,但更方便。由于 UAE 生物变异性,因此要求 3~6 个月内检测 3 次 UACR,其中有 2 次异常才能考虑患者是否有蛋白尿。另外,需要注意的是在检测 UACR 时,下列因素可以影响 UACR 的含量:如运动、感染、发烧、充血性心力衰竭、明显的高血糖、月经和明显的高血压,因为这些因素可独立于肾脏损害而使 UACR 升高[8]。其次,评估患者 eGFR 时,建议采用公认的慢性肾脏病流行病学协作组公布的计算公式(CKD-EPI 公式)计算[8]。
1.2 正常蛋白尿糖尿病肾病诊断
DKD 诊断通常基于蛋白尿和/或 eGFR 减少,且缺乏其他原发性原因的肾脏损害迹象或症状。DKD 典型表现演变过程包括:长期的糖尿病史、视网膜病变、蛋白尿而无血尿、eGFR 逐渐进行性丧失[9-10]。然而,越来越多的证据表明,在糖尿病患者中,特别是 T2DM 患者中,正常蛋白尿糖尿病肾病(normoalbuminuric diabetic kidney disease,NA-DKD)的患病率很高。美国的一项包括 6 521 例成年糖尿病患者的国民健康和营养检查调查(NHANES)研究显示,CKD 的总体患病率并没有随着时间的推移而明显改变,从 1988 年— 1994 年的 28.4% 到 2009 年— 2014 年的 26.2%。然而,蛋白尿从 20.8% 降到 15.9%,eGFR 的下降率从由 9.2% 升至 14.1%,且 eGFR 降至<30 mL/(min·1.73 m2)从 1.0% 增加到 2.7%[9]。另外,美国亚利桑那州皮马印第安人糖尿病患者的 CKD 研究也显示了类似的趋势。在研究的第一阶段(1982 年— 1988 年),837 例 T2DM 患者中有 6.5% 的 eGFR<60 mL/(min·1.73 m2)。其中大量蛋白尿患者占 83.3%,微量蛋白尿患者仅占 7.4%,UACR 正常的患者占 9.3%。在研究第二阶段(2001 年— 2006 年)的 1 310 例受试者中,eGFR 降低的患病率与前相似(6.6%)。然而在 eGFR 降低的人群中,正常 UACR 患者所占比例约增长了 1 倍,达到 17.2%,微量白蛋白尿患病率达到 19.5%。同时,大量蛋白尿患者下降到 63.2%[11]。同样的,在 1980 年美国的慢性肾功能不全队列研究(CRIC)、英国前瞻性糖尿病研究(UKPDS)、ADVANCE 等大规模的糖尿病前瞻性研究中都出现了 NA-DKD 的高患病率[12-14]。这些研究结果提示尽管蛋白尿模式仍然是糖尿病患者中最常见的 CKD 表型,但在肾损害的 T2DM 患者中,NA-DKD 患者也占有相当大的比例,因此,值得引起注意。
NA-DKD 发生可能与血糖、血压和血脂的有效控制及广泛使用肾素-血管紧张素系统(renin - angiotensin system,RAS)阻滞剂和戒烟有关[15]。意大利的一项多中心的肾功能不全和心血管事件(RIACE)研究指出 NA-DKD 在女性中更为普遍,并且与高血压和冠状动脉疾病有关[16]。另外,NA-DKD 会增加糖尿病患者心肌梗死、卒中和心血管疾病(cardiovascular disease,CVD)死亡的风险[15]。目前有学者认为,NA-DKD 与以蛋白尿为特征的 DKD 可能均是不同形式的糖尿病肾脏损伤。正常蛋白尿的 DKD 表型可能与大血管病变有关,而不是微血管病变,或者是反复发作和/或未解决的急性肾损伤(acute kidney injury,AKI)的结果[17]。形态学研究发现 T1DM 患者正常白蛋白尿,但 GFR<90 mL/(min·1.73 m2)的患者与 GFR>90 mL/(min·1.73 m2)的患者比较,前者肾小球受累更明显,表现为肾小球基底膜的宽度和系膜基质的体积增加[18]。而 T2DM 的 NA-DKD 患者的肾活检显示,肾小管间质改变和动脉硬化比较明显,而肾小球病变较少[19-20]。
此外,近年来人们也积极开展在无蛋白尿的情况下,如何采用新的生物标志物诊断 NA-DKD,目前认为一些肾小管损伤和间质纤维化标志物、炎症介质的评估,以及蛋白质组学方法是 NA-DKD 具有前景的诊断和预后监测指标,例如血清和尿液中中性粒细胞明胶酶相关脂质运载蛋白、胱抑素 C、转化生长因子-β(transforming growth factor-β,TGF-β)、白细胞介素(interleukin,IL)-1β、IL-1 受体拮抗剂、IL-6、肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)、巨噬细胞集落刺激因子、C 反应蛋白等[21-24],但是上述部分标志物对肾脏病理判定的特异性较低,其诊断价值受到限制。而 eGFR 本身可能是 NA-DKD 患者重要的预后指标。一项包括 2 533 例 T2DM 患者的回顾性观察研究结果表明,eGFR 在 1 年下降>7.5% 是一个很好的预测肾功能衰竭的预后指标[25]。此外,一些炎症标志物是被认为是 DKD 预测的候选项,如血清中高水平的 TNF-α 可溶性受体(sTNFR1 和 sTNFR2)与 DKD 相关,可预测 T2DM 患者心血管事件以及死亡率[26]。高灵敏度 C 反应蛋白、视黄醇结合蛋白 4、成纤维细胞生长因子-21、α-klotho 等也可作为 eGFR>60 mL/(min·1.73 m2)和正常蛋白尿的 T2DM 患者肾病进展的预测因子[27-29]。但这些指标仍然需要大量的临床循证医学证据。
2 治疗
CKD 患者是发生心血管事件的高危人群[30],而 CVD 又是 DKD 患者的首要死亡原因[31]。DKD 病理生理学改变的主要特征为肾小球内高滤过和高血压、肾小球硬化和间质纤维化,临床表现为蛋白尿和高血压。因此控制心血管风险因素,抗蛋白尿和降压治疗是治疗 DKD 的基石[32-33]。近 20 年来,人们在治疗 DKD 方面积极研发了一系列新的药物,包括 PKC- 抑制剂(鲁伯斯塔)[34]、TGF-β 生成抑制剂(吡非尼酮)[35]、肾素抑制剂(阿利吉仑)[36]、Kept1-Nrf2 通路激活剂(甲基巴多索隆)[37]、内皮素拮抗剂(Avosentan)[38]、双重血管紧张素转化酶抑制剂/血紧张素Ⅱ受体阻滞剂(angiotensin-converting enzyme inhibitor/ angiotensin receptor antagonist,ACEI/ARB)(赖诺普利/氯沙坦)[39]等,但这些药物在 DKD 临床治疗方面并未完全取得满意的疗效。目前仍然主要围绕改变生活方式,控制血糖、控制血压、调节血脂等方面对 DKD 进行干预防治,下面就最新的,较为公认的研究成果进行介绍。
2.1 调节生活方式
日常生活中应采取体育活动,主要是有氧活动,提倡健康饮食生活方式,减少钠盐、饱和脂肪、蛋白质和酒精的摄入等。这些因素可增加体重、导致高脂血症和高血压,因此健康的生活方式可降低 CVD 的风险。此外,吸烟是 CVD 的危险因素,故 DKD 患者应该戒烟[40]。
2.2 血糖控制
血糖水平是评估 DKD 治疗效果的重要依据,2015 年欧洲肾脏最佳临床实践提出,与空腹血糖比较,糖化血红蛋白(hemoglobin A1c,HbA1c)能更好地反映体内血糖控制状态,提倡检测 HbA1c 作为监控指标[41]。HbA1c 治疗靶标应根据患者个体情况确定。糖尿病控制和并发症试验(DCCT)研究比较了强化血糖控制(HbA1c 7%)和常规治疗(HbA1c 9%)对 T1DM 患者长期并发症的影响,结果显示强化血糖控制与微血管并发症(视网膜病变、神经病变以及 DKD)发生和进展降低 50%~76% 有关[42]。后续的 EDIC 研究证实了这些微血管受益长期存在[43]。另外,英国前瞻性糖尿病研究(UKPDS)证实了强化血糖控制同样可显著降低 T2DM 患者微血管并发症发生率[44-45]。严格控制 HbA1c<6.5%,对 T1DM 患者和新发 T2DM 且无 CVD 患者有益[31]。因此,一般来说,对于非妊娠的成人糖尿病患者 HbA1c 治疗靶标为 7%(53 mmol/mol);在不出现明显低血糖或其他不良反应的前提下,对于糖尿病病程短、仅用生活方式或二甲双胍治疗的 T2DM 患者、预期寿命长或无明显 CVD 的患者,HbA1c 目标值可更为严格(如 6.5%)[46]。然而,ACCORD 研究发现严格控制 T2DM 患者血糖后虽然非致死心机梗死发生率明显降低,但是死亡率也有所增加[47],在年轻患者组(<65 岁)CVD 及总死亡风险增加尤为明显,而且严重低血糖风险在老年患者组及年轻患者组都相对增高[48],提示强化血糖控制并不适合有高危险因素的 T2DM 患者。因此,对于有严重低血糖病史,寿命有限,伴有微血管或大血管并发症,或罹患其他严重疾病以及尽管已实施了糖尿病自我管理教育,适当的血糖监测和有效剂量的包括胰岛素在内的多种降糖药物但仍难以达标的患者,可能 HbA1c<8% 作为靶标更为合适[46]。目前,较为有效的新型降糖药包括:
2.2.1 钠-葡萄糖协同转运体 2 抑制剂(sodium - glucose cotransporter 2 inhibitor,SGLT-2i)
已知约 90% 的葡萄糖再吸收通常发生在 S1 段[49],SGLT-2i 是一种新型的抗糖尿病药物,对近端肾小管 S1 段的 SGLT-2 具有高度选择性。抑制 SGLT-2 可增加尿中葡萄糖的排泄,降低血浆中的葡萄糖水平。除了降糖作用外,SGLT-2i 似乎还能降低血压、体重和血浆尿酸水平[49]。因此,SGLT-2i 在 T2DM 患者中已被广泛应用于二甲双胍后的二线治疗[50]。其中恩格列净(empagliflozin)、卡格列净(canagliflozin)和达格列净(dapagliflozin)在欧洲和美国获得批准。最近一项 meta 分析结果显示,与其他 SGLT-2i 和安慰剂相比,恩格列净在复合肾脏事件(肌酐或血尿素氮水平升高、eGFR 下降、肾功能衰竭或肾功能损害)方面的风险较低,同时导致 AKI 风险更低,而达格列净则具有更高的复合肾脏事件风险[51]。2015 年《新英格兰杂志》报道了达格列净对伴有 CVD,且 eGFR≥30 mL/(min·1.73 m2)的 T2DM 患者心肾结局的影响,发现该药物治疗组非致命性卒中、非致命性心肌梗死和 CVD 死亡的主要复合终点发生率较低[52]。并发现对 eGFR≥30 mL/(min·1.73 m2)糖尿病患者有肾脏保护作用,进展至大量蛋白尿、血清肌酐水平加倍(eGFR≤45 mL/(min·1.73 m2)及肾替代治疗开始风险均降低[53]。另外,CANVAS 研究显示卡格列净治疗后能降低非致命性心肌梗死、非致命性卒中和心血管事件死亡以及蛋白尿进展风险以及肾脏复合终点(eGFR、肾脏替代治疗开始和肾脏死亡)事件[54]。2019 年《新英格兰杂志》再次报道了 T2DM 合并 CKD 患者中的肾脏事件临床评估(CREDENCE)的研究结果,发现卡格列净联合 ACEI/ARB 能显著降低肾脏复合硬终点(ESRD、血清肌酐倍增、肾脏或心血管死亡)的风险达 30%,能够显著降低到白蛋白尿水平(31%),延缓 eGFR 下降,并再次印证了心血管获益,且不增加截肢风险[55]。其次,达格列净抑制肾脏葡萄糖重吸收的能力随着 GFR 的下降而降低,与肾功能正常或轻度受损的患者比较,CKD 3 期的 T2DM 患者在使用达格列净治疗后,尿糖的排泄率大约减少了 50%[56]。以往 Kohan 等[57]对 eGFR 30~60 mL/(min·1.73 m2)的中度肾功能损伤的糖尿病患者的长期研究中也发现,与安慰剂比较,达格列净组并不能改善中度肾功能损伤的糖尿病患者血糖控制,但可减轻体重、控制血压,而患者 GFR 在使用药物第 1 周时出现下降,但是治疗 104 周后趋于稳定,并且能够减少患者蛋白尿。一项 2 期临床试验显示,与安慰剂相比,达格列净联合 ACEI/ARB 治疗可降低伴高血压的 T2DM 患者蛋白尿风险,但 eGFR 呈下降趋势[58]。使用达格列净时,早期 eGFR 的下降可能与小剂量的降压利尿作用及球管反馈有关[57]。以上结果提示,达格列净对于晚期的 CKD 患者血糖影响并不明显,而其是否能够改善肾功能的丧失和蛋白尿的恶化仍需大规模的临床试验予以评估。
2.2.2 胰高血糖素样肽-1 受体激动剂(glucagon - like peptide -1 receptor agonist,GLP-1RA)
胰高血糖素样肽-1(glucagon - like peptide -1,GLP-1)是胃肠道黏膜 L 细胞分泌的一种肠促胰素。GLP-1 与靶器官(胰岛 α 和 β 细胞、胃肠、肺、脑、肾脏、下丘脑、心血管)等特异受体相结合后发挥效应,如刺激胰岛素合成和分泌,抑制 β 细胞凋亡、促进 β 细胞增殖,抑制胰高糖素的分泌等。GLP-1RA 可以促进 β 胰岛细胞分泌胰岛素[59]。GLP-1RA 是最新开发研制的另一类新型抗糖尿病药物,包括利拉鲁肽(liraglutide)、索玛鲁肽(sermaglutide)、阿必鲁肽(albiglutide)、杜拉鲁肽(dulaglutide)、艾塞那肽(exenatide)、他司鲁泰(taspoglutide)、利西拉肽(lixisenatide)等[59]。2016 年 LEADER 研究显示,利拉鲁肽能够降低伴有高 CVD 风险[eGFR 为 80 mL/(min·1.73 m2)]T2DM 患者心血管死亡、非致死性心肌梗死和非致死性卒中的综合风险[60]。最近对 LEADER 研究中肾脏结局的分析显示,利拉鲁肽治疗组患者肾死亡、血清肌酐水平翻倍、新发大量蛋白尿和 ESRD 的肾脏复合终点事件减少[61]。另外,SUSTAIN-6 研究提示,与安慰剂比较,索玛鲁肽治疗后,伴有 CVD、CKD3 期或以上,或两者兼有的 T2DM 患者,不仅其主要心脏不良反应的风险较低,同时新发肾病或现有肾病进展[包括大量蛋白尿、血清肌酐水平加倍、eGFR<45 mL/(min·1.73 m2)或需要肾脏替代治疗]的风险也较低[62]。最近另一项研究发现,口服索玛鲁肽在降低 T2DM 患者 HbA1c 方面并不劣于皮下注射,且有降低体重的优势,其安全性和耐受性与皮下注射利拉鲁肽相似[63]。但最近有研究对索玛鲁肽口服安全性进行了一项随机、双盲、安慰剂对照试验,结果 3 183 例 T2DM 患者(年龄≥50 岁伴有 CVD 或 CKD,年龄≥60 岁伴有心血管风险),口服索玛鲁肽组心血管不良事件(因心血管原因死亡、非致命性心肌梗死或非致命性卒中)的发生率为 3.8%,并没有特别优于安慰剂组(4.8%)[64]。提示口服索玛鲁肽对 DKD 肾脏保护作用仍需要进一步证实。另一方面,AWARD 最近的研究结果显示在伴有中度至重度 CKD 的 T2DM 患者中,每周 1 次皮下注射杜拉鲁肽,可产生与甘精胰岛素类似的血糖控制作用,并能延缓 eGFR 下降[65]。提示杜拉鲁肽在 T2DM 伴有中至重度 CKD 患者的血糖控制方面的有效与安全性。2019 年一项包括 24 个国家 371 个中心的杜拉鲁肽临床观察,观察对象为既往发生过心血管事件或心血管危险因素的 T2DM 患者,发现杜拉鲁肽对伴有 CVD 或心血管危险因素的 T2DM 的中老年患者血糖控制有较好疗效[66]。最新报道的 REWIND 研究结果,发现杜拉鲁肽组患者新发大量蛋白尿、eGFR 下降以及肾脏替代治疗的肾脏复合微血管事件较安慰剂组减少,提示杜拉鲁肽在控制 T2DM 患者血糖的同时能带来肾脏获益[67]。
2.2.3 二肽基肽酶-4(dipeptidyl peptidase -4,DPP-4)抑制剂
DPP-4 抑制剂也是一类新型的用于 T2DM 的口服降糖药物。DPP-4 抑制剂抑制 DPP-4,减少 GLP-1 失活,增加 GLP-1 在体内的水平,从而发挥其调节血糖作用,发生低血糖或体重增加的风险较低,第一代药物西格列汀(sitagliptin)于 2006 年在美国食品药品管理局获得批准使用[68]。目前研究表明 DPP-4 抑制剂有肾脏保护作用,并与降糖作用无关[69-70]。在全球上市的 DPP-4 抑制剂中,利格列汀(linagliptin)是唯一通过非肾途径排泄药物[71],因此,在 CKD 状态下不需要进行剂量调整[72-73]。而西格列汀、沙格列汀(saxagliptin)、阿格列汀(alogliptin)和 维格列汀(vildagliptin)主要通过肾脏排泄[72],因此对于肾损伤患者需考虑剂量调整。最近 SAVOR-TIMI 53 研究发现,沙格列汀能明显减少 T2DM 患者蛋白尿,但对 eGFR 或透析或肾移植等肾脏预后无明显改善。而且沙格列汀的降蛋白作用与其对血糖控制的作用无关[74]。但类似的 TECOS 研究提示,西格列汀对 T2DM 患者蛋白尿没有显著性改变[75]。另外报道西格列汀不影响 T2DM 患者的肾血流动力学[76]。沙格列汀和西格列汀这两种 DPP-4 抑制剂与 GLP-1RA,如利拉鲁肽在对肾脏保护作用上呈现出不同效应,可能是因为利拉鲁肽能够诱导 GLP-1 信号达到药理水平,而前两者只将 GLP-1 提高到较高的生理水平[77]。另外一项有趣的研究发现,使用 DPP-4 抑制剂治疗糖尿病可降低 AKI 的风险[78]。其次,与其他 DPP-4 抑制剂一样,利格列汀在 DKD 患者中也表现出降糖效果和耐受性[79-80],对合并高血压和微量白蛋白尿的 T2DM 患者也同样有效[81]。一项 meta 分析发现,利格列汀能够显著降低已接受了 DKD 标准治疗(ARB 或 ACEI)的伴有大量蛋白尿的 DKD 患者的 UACR(32%)[82]。此外,利格列汀治疗后患者肾脏不良事件的平均发生率显著降低[83]。然而,由于这些基础研究的目的不是评估肾脏预后,以上发现只是假设产生的。事实上,旨在研究利格列汀对降低 T2DM 早期患者蛋白尿效果的 MARLINA-T2DTM 临床试验结果显示利格列汀只能使 UACR 显著降低 6%[84],其肾脏保护作用可能主要是通过其抗纤维化作用介导的。也有报道,利格列汀治疗 4 周后可预防肾内皮功能受损[85],改善微血管内皮功能[86]。最近的 CARMELINA 研究发现,在伴有高心血管和肾脏风险的 T2DM 患者常规治疗中加用利格列汀,在减轻复合心血管结局并没有优于安慰剂组,但利格列汀组患者蛋白尿进展(即从正常蛋白尿到微量或至大蛋白尿)较少,但是在肾脏复合终点结局方面与安慰剂组比较无明显差别[87]。
2.3 血压控制
糖尿病患者的血压目标需要个体化,CVD(尤其是卒中)和蛋白尿风险较高的患者需要更严格的血压控制[88-89]。最近一项研究将 ACCROD-BP 中符合 SPRINT 条件的参与者合并入 SPRINT 研究中,以讨论强化血压控制是否与 T2DM 相互作用,发现与标准治疗[收缩压<140 mm Hg(1 mm Hg=0.133 kPa)]比较,对有 CVD 风险和 T2DM 患者强化血压控制(收缩压<120 mm Hg)后,CVD 死亡、非致死性心肌梗死、非致死性卒中、任何血管重建以及心力衰竭的综合发生率降低,但与治疗相关的不良事件也相对更高,而且强化血压控制对 T2DM 患者和非 T2DM 患者 CVD 结局影响无差异[90]。一项包含有 45 个随机对照试验的 meta 分析显示,将血压≥140 mm Hg 的 T2DM 患者的收缩压降至 130~140 mm Hg,全因死亡及 CVD 风险明显减少,降至<130 mm Hg 后,卒中风险减少更为显著。另外,收缩压每降低 10 mm Hg 与视网膜病变和蛋白尿低风险相关[91]。2019 年 ADA 指南指出对于心血管风险较高(存在动脉粥样硬化性 CVD 或 10 年动脉粥样性硬化 CVD 风险>15%)的糖尿病和高血压患者血压若能安全达到控制目标<130/80 mm Hg,是较为合适的[89],与 2017 年中国医师协会肾脏内分会合制定的 DKD 患者血压控制靶标一致[92]。对于低 CVD 风险(10 年动脉粥样硬化 CVD 风险<15%)的糖尿病和高血压患者,血压控制目标为<140/90 mm Hg[89]。DKD 抗高血压治疗应根据患者血压水平合理选择单药或联合药物治疗。如血压仍未达标,当患者 GFR≥30 mL/(min·1.73 m2)时,应加用噻嗪类利尿剂,当 GFR<30 mL/(min·1.73 m2)时,应加用袢利尿剂,并注意监测肾功能和血钾水平[89]。
ACEI 和 ARB 可阻止 CKD 患者的蛋白尿进展的作用在 Collaborative(卡托普利)、RENAAL(氯沙坦)、IRMA(厄贝沙坦)和 IDNT(厄贝沙坦)这 4 个经典研究中均得到证实[93-96]。ACEI 和 ARB 在减少早期和进展期 DKD 患者蛋白尿和肾脏保护作用上无明显差异[97-99]。另外,适当控制无蛋白尿的糖尿病患者可以预防蛋白尿和 CKD 的发生。ROADMAP 研究结果表明,奥美沙坦可延缓 T2DM 患者微量白蛋白尿的发生[100]。在 ADVANCE 研究中,使用培哚普利和吲达帕胺治疗的糖尿病患者,DKD 的新发或进展,以及微量白蛋白尿的新发都有所降低[101]。然而,最近发表的一项 meta 分析显示,与其他抗高血压药物相比,用 ACEI/ARB 治疗糖尿病高血压患者(主要无蛋白尿患者)在 ESRD 进展方面没有明显的肾脏益处[102]。2018 年 ADA 建议,无蛋白尿的高血压糖尿病患者的治疗可采用 ACEI/ARB、二氢吡啶钙通道阻滞剂以及噻嗪类利尿剂[103]。对于无蛋白尿、无高血压的糖尿病患者,不推荐使用 RAS 抑制剂以预防 DKD 发生[101]。ACEI 和 ARB 的联用在 ONTARGET 及 VA NEPHROND 研究中都显示有发生肾功能不全、AKI 和高血钾的风险,因此不建议联合使用[39, 104],另一项联合使用阿利吉仑(一种肾素抑制剂)和 ARB 或 ACEI 的 ALTTUDE 研究结果也表明会导致主要的 CVD 和肾脏不良事件,因此也不推荐使用[105]。
2.4 调节血脂
DKD 患者存在明显的血脂异常,包括高胆固醇与高甘油三脂(triglycerides,TG)。虽然近年来对降脂药治疗 DKD 患者有不同认识,如有观点认为降脂药可降低 CVD 风险,对肾脏预后有待证实[106],但由于血脂异常与 DKD 进展密切相关,因此,调节血脂仍然是目前治疗 DKD 的重要举措[107]。2019 年 ADA 指南指出,他汀类药物控制低密度脂蛋白胆固醇(low density lipoprotein cholesterol,LDL-C)达标是治疗糖尿病并发高脂血症的首要选择。另外,该指南进一步明确了 DKD 高血脂治疗靶标:① 糖尿病患者无论是否伴 CVD,当年龄>40 岁,并有 1 个以上 CVD 危险因素者,以及 LDL-C≥100 mg/dL 或具有多个 CVD 危险因素者,建议在生活方式干预的基础上使用他汀类药物。② 不伴有 CVD 的糖尿病患者,治疗靶标值是 LDL-C<100 mg/dL(2.6 mmol/L),伴有 CVD 的糖尿病患者,应使用最大剂量的他汀类药物,使 LDL-C<70 mg/dL(1.8 mmol/L)。如未达标,可考虑降低 LDL-C 水平至基线下 30%~40% 为目标。③ 降低 TG 的靶标是<150 mg/dL(1.7 mmol/L),男性 HDL-C>40 mg/dL(1.0 mmol/L),女性 HDL-C>50 mg/dL(1.3 mmol/L)[89]。
目前研究表明,对于 DKD 患者他汀类药物治疗越早越好[108],可以改善蛋白尿和 GFR 的丧失[109],他汀类药物(主要是阿托伐他汀)对肾脏[GFR>30 mL/(min·1.73 m2)]和心脏(有无 CVD)都有益处[110-112],尤其是对糖尿病患者[113]。另外,如果最大耐受剂量的他汀类药物(阿托伐他汀或瑞舒伐他汀)治疗未达标,可考虑联用他汀和其他降脂药物[89]。最近研究表明依折麦布和前蛋白转化酶枯草杆菌蛋白酶9抑制剂(proprotein convertase subtilisin/kexin type 9 inhibitor,PCSK9-i)能够降低 LDL-C 水平,2015 年的 IMPROVE-IT 研究显示,与单用辛伐他汀比较,他汀和依折麦布的联用可以降低糖尿病患者 LDL-C 水平,CVD 获益[114]。2017 年,包括有 27 564 例高 CVD 风险的患者的 FOURIER 研究发现,evolocumab(一种 PCSK9-i)与他汀类药物联用时,能明显降低糖尿病伴动脉粥样硬化性 CVD 患者的 LDL-C 水平[115]。最近 Alirocumab 和 evolocumab 研究表明,PCSK9-i 可作为最大限度耐受他汀类药物治疗的联合用药,也可用于包括糖尿病患者在内的他汀类药物耐受不良的患者[115-116],甚至 DKD-ESRD 透析患者[117]。
另外,有研究发现瑞舒伐他汀(而非阿托伐他汀)可降低 DKD 血透患者致命性和非致命性心脏事件的风险[118]。但现有的数据表明,降低 LDL-C 有助于预防 CKD 患者和肾移植受者的主要动脉粥样硬化事件,但不利于需要透析的患者[119],而新型降脂药物也仍待进一步研究。总之,对于 DKD 患者,降脂治疗,特别是有效降低 LDL-C 水平对延缓 DKD 进展具有积极作用。
3 结语
DKD 是糖尿病主要并发症,在糖尿病患者中发生率占 20%~40%,晚期 1/3 患者可进入尿毒症,严重危害人们健康。近年来国内外对 DKD 发病机制与治疗开展了深入研究与探讨,并取得了一定成绩。本文综述了 DKD 临床研究的最新进展,介绍了 DKD 及无蛋白尿 DKD 最新定义与机制,并重点从控制血糖、控制血压、调节血脂 3 个公认治疗 DKD 有效措施的角度,对相关的新型药物临床研究进展进行了详细介绍。这些新药物对延缓 DKD 进展提供了有益帮助,但它们对 DKD 远期疗效、副作用,特别是新型降糖药物对 DKD 大量蛋白尿及肾脏远期保护作用仍需要进一步循证医学证实。
1. | Cho NH, Shaw JE, Karuranga S, et al. IDF diabetes atlas: global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract, 2018, 138: 271-281. |
2. | Wang L, Gao P, Zhang M, et al. Prevalence and ethnic pattern of diabetes and prediabetes in China in 2013. JAMA, 2017, 317(24): 2515-2523. |
3. | Koye DN, Magliano DJ, Nelson RG, et al. The global epidemiology of diabetes and kidney disease. Adv Chronic Kidney Dis, 2018, 25(2): 121-132. |
4. | Huang YM, Xu D, Long J, et al. Spectrum of chronic kidney disease in China: a national study based on hospitalized patients from 2010 to 2015. Nephrology (Carlton), 2019, 24(7): 725-736. |
5. | Liu ZH. Nephrology in China. Nat Rev Nephrol, 2013, 9(9): 523-528. |
6. | Gheith O, Farouk N, Nampoory N, et al. Diabetic kidney disease: world wide difference of prevalence and risk factors. J Nephropharmacol, 2016, 5(1): 49-56. |
7. | A/L B Vasanth Rao VR, Tan SH, Candasamy M, et al. Diabetic nephropathy: an update on pathogenesis and drug development. Diabetes Metab Syndr, 2019, 13(1): 754-762. |
8. | American Diabetes Association. 11. Microvascular complications and foot care: Standards of Medical Care in Diabetes-2019. Diabetes Care, 2019, 42(Suppl 1): S124-S138. |
9. | Afkarian M, Zelnick LR, Hall YN, et al. Clinical manifestations of kidney disease among US adults with diabetes, 1988-2014. JAMA, 2016, 316(6): 602-610. |
10. | de Boer IH, Rue TC, Hall YN, et al. Temporal trends in the prevalence of diabetic kidney disease in the United States. JAMA, 2011, 305(24): 2532-2539. |
11. | Pavkov ME, Mason CC, Bennett PH, et al. Change in the distribution of albuminuria according to estimated glomerular filtration rate in Pima Indians with type 2 diabetes. Diabetes Care, 2009, 32(10): 1845-1850. |
12. | Koye DN, Magliano DJ, Reid CM, et al. Risk of progression of nonalbuminuric CKD to end-stage kidney disease in people with diabetes: the CRIC (Chronic Renal Insufficiency Cohort) Study. Am J Kidney Dis, 2018, 72(5): 653-661. |
13. | Retnakaran R, Cull CA, Thorne KI, et al. Risk factors for renal dysfunction in type 2 diabetes: U. K. prospective diabetes study 74. Diabetes, 2006, 55(6): 1832-1839. |
14. | Ninomiya T, Perkovic V, de Galan BE, et al. Albuminuria and kidney function independently predict cardiovascular and renal outcomes in diabetes. J Am Soc Nephrol, 2009, 20(8): 1813-1821. |
15. | Klimontov VV, Korbut AI. Normoalbuminuric chronic kidney disease in diabetes. Ter Arkh, 2018, 90(10): 94-98. |
16. | Penno G, Solini A, Bonora E, et al. Clinical significance of nonalbuminuric renal impairment in type 2 diabetes. J Hypertens, 2011, 29(9): 1802-1809. |
17. | Pugliese G. Updating the natural history of diabetic nephropathy. Acta Diabetol, 2014, 51(6): 905-915. |
18. | Caramori ML, Fioretto P, Mauer M. Low glomerular filtration rate in normoalbuminuric type 1 diabetic patients: an indicator of more advanced glomerular lesions. Diabetes, 2003, 52(4): 1036-1040. |
19. | Ekinci EI, Jerums G, Skene A, et al. Renal structure in normoalbuminuric and albuminuric patients with type 2 diabetes and impaired renal function. Diabetes Care, 2013, 36(11): 3620-3626. |
20. | Moriya T, Omura K, Matsubara M, et al. Arteriolar hyalinosis predicts increase in albuminuria and GFR decline in normo- and microalbuminuric Japanese patients with type 2 diabetes. Diabetes Care, 2017, 40(10): 1373-1378. |
21. | Papadopoulou-Marketou N, Chrousos GP, Kanaka-Gantenbein C. Diabetic nephropathy in type 1 diabetes: a review of early natural history, pathogenesis, and diagnosis. Diabetes Metab Res Rev, 2017, 33(2). |
22. | Bacci MR, Chehter EZ, Azzalis LA, et al. Serum ngal and cystatin c comparison with urinary albumin-to-creatinine ratio and inflammatory biomarkers as early predictors of renal dysfunction in patients with type 2 diabetes. Kidney Int Rep, 2017, 2(2): 152-158. |
23. | Winter L, Wong LA, Jerums G, et al. Use of readily accessible inflammatory markers to predict diabetic kidney disease. Front Endocrinol (Lausanne), 2018, 9: 225. |
24. | Konenkov VI, Klimontov VV, Myakina NE, et al. Increased serum concentrations of inflammatory cytokines in type 2 diabetic patients with chronic kidney disease. Ter Arkh, 2015, 87(6): 45-49. |
25. | Nojima J, Meguro S, Ohkawa N, et al. One-year eGFR decline rate is a good predictor of prognosis of renal failure in patients with type 2 diabetes. Proc Jpn Acad Ser B Phys Biol Sci, 2017, 93(9): 746-754. |
26. | Carlsson AC, Ostgren CJ, Nystrom FH, et al. Association of soluble tumor necrosis factor receptors 1 and 2 with nephropathy, cardiovascular events, and total mortality in type 2 diabetes. Cardiovasc Diabetol, 2016, 15: 40. |
27. | Klisic A, Kavaric N, Ninic A. Retinol-binding protein 4 versus albuminuria as predictors of estimated glomerular filtration rate decline in patients with type 2 diabetes. J Res Med Sci, 2018, 23: 44. |
28. | Lee CH, Hui EY, Woo YC, et al. Circulating fibroblast growth factor 21 levels predict progressive kidney disease in subjects with type 2 diabetes and normoalbuminuria. J Clin Endocrinol Metab, 2015, 100(4): 1368-1375. |
29. | Kim SS, Song SH, Kim IJ, et al. Decreased plasma α-Klotho predict progression of nephropathy with type 2 diabetic patients. J Diabetes Complications, 2016, 30(5): 887-892. |
30. | Kidney Disease: Improving Global Outcomes(KDIGO). KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl, 2013, 3(1): 1-150. |
31. | Skyler JS, Bergenstal R, Bonow RO, et al. Intensive glycemic control and the prevention of cardiovascular events: implications of the ACCORD, ADVANCE, and VA diabetes trials: a position statement of the American Diabetes Association and a Scientific Statement of the American College of Cardiology Foundation and the American Heart Association. J Am Coll Cardiol, 2009, 53(3): 298-304. |
32. | Umanath K, Lewis JB. Update on diabetic nephropathy: core curriculum 2018. Am J Kidney Dis, 2018, 71(6): 884-895. |
33. | Yakush Williams JK. Management strategies for patients with diabetic kidney disease and chronic kidney disease in diabetes. Nurs Clin North Am, 2017, 52(4): 575-587. |
34. | Al-Onazi AS, Al-Rasheed NM, Attia HA, et al. Ruboxistaurin attenuates diabetic nephropathy via modulation of TGF-β1/Smad and GRAP pathways. J Pharm Pharmacol, 2016, 68(2): 219-232. |
35. | RamachandraRao SP, Zhu Y, Ravasi T, et al. Pirfenidone is renoprotective in diabetic kidney disease. J Am Soc Nephrol, 2009, 20(8): 1765-1775. |
36. | Bhattacharjee N, Barma S, Konwar N, et al. Mechanistic insight of diabetic nephropathy and its pharmacotherapeutic targets: an update. Eur J Pharmacol, 2016, 791: 8-24. |
37. | de Zeeuw D, Akizawa T, Audhya P, et al. Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. N Engl J Med, 2013, 369(26): 2492-2503. |
38. | Mann JF, Green D, Jamerson K, et al. Avosentan for overt diabetic nephropathy. J Am Soc Nephrol, 2010, 21(3): 527-535. |
39. | Fried LF, Emanuele N, Zhang JH, et al. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med, 2013, 369(20): 1892-1903. |
40. | American Diabetes Association. 5. Lifestyle management: standards of medical care in diabetes -2019. Diabetes Care, 2019, 42(Suppl 1): S46-S60. |
41. | Guideline development group. Clinical practice guideline on management of patients with diabetes and chronic kidney disease stage 3b or higher (eGFR<45 mL/min). Nephrol Dial Transplant, 2015, 30(Suppl 2): ii1-142. |
42. | The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med, 1993, 329(14): 977-986. |
43. | The Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) Research Group. Effect of intensive diabetes therapy on the progression of diabetic retinopathy in patients with type 1 diabetes: 18 years of follow-up in the DCCT/EDIC. Diabetes, 2015, 64(2): 631-642. |
44. | Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet, 1998, 352(9131): 854-865. |
45. | Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet, 1998, 352(9131): 837-853. |
46. | American Diabetes Association. 6. Glycemic targets: standards of medical care in diabetes-2019. Diabetes Care, 2019, 42(Suppl 1): S61-S70. |
47. | The ACCORD Study Group. Long-term effects of intensive glucose lowering on cardiovascular outcomes. N Engl J Med, 2011, 364(9): 818-828. |
48. | Miller ME, Williamson JD, Gerstein HC, et al. Effects of randomization to intensive glucose control on adverse events, cardiovascular disease, and mortality in older versus younger adults in the ACCORD Trial. Diabetes Care, 2014, 37(3): 634-643. |
49. | Stavropoulos K, Imprialos KP, Stavropoulos N, et al. Sodium-glucose cotransporter 2 inhibitors: nephroprotective impact on diabetic kidney disease. Cardiovasc Hematol Disord Drug Targets, 2018, 18(2): 120-126. |
50. | Vasilakou D, Karagiannis T, Athanasiadou E, et al. Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med, 2013, 159(4): 262-274. |
51. | Tang H, Li D, Zhang J, et al. Sodium-glucose co-transporter-2 inhibitors and risk of adverse renal outcomes among patients with type 2 diabetes: a network and cumulative meta-analysis of randomized controlled trials. Diabetes Obes Metab, 2017, 19(8): 1106-1115. |
52. | Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med, 2015, 373(22): 2117-2128. |
53. | Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med, 2016, 375(4): 323-334. |
54. | Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med, 2017, 377(7): 644-657. |
55. | Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med, 2019, 380(24): 2295-2306. |
56. | List JF, Woo V, Morales E, et al. Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes. Diabetes Care, 2009, 32(4): 650-657. |
57. | Kohan DE, Fioretto P, Tang W, et al. Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control. Kidney Int, 2014, 85(4): 962-971. |
58. | Heerspink HJ, Johnsson E, Gause-Nilsson I, et al. Dapagliflozin reduces albuminuria in patients with diabetes and hypertension receiving renin-angiotensin blockers. Diabetes Obes Metab, 2016, 18(6): 590-597. |
59. | de Vos LC, Hettige TS, Cooper ME. New glucose-lowering agents for diabetic kidney disease. Adv Chronic Kidney Dis, 2018, 25(2): 149-157. |
60. | Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med, 2016, 375(4): 311-322. |
61. | Mann JFE, Ørsted DD, Brown-Frandsen K, et al. Liraglutide and renal outcomes in type 2 diabetes. N Engl J Med, 2017, 377(9): 839-848. |
62. | Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med, 2016, 375(19): 1834-1844. |
63. | Pratley R, Amod A, Hoff ST, et al. Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial. Lancet, 2019, 394(10192): 39-50. |
64. | Husain M, Birkenfeld AL, Donsmark M, et al. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med, 2019. |
65. | Tuttle KR, Lakshmanan MC, Rayner B, et al. Dulaglutide versus insulin glargine in patients with type 2 diabetes and moderate-to-severe chronic kidney disease (AWARD-7): a multicentre, open-label, randomised trial. Lancet Diabetes Endocrinol, 2018, 6(8): 605-617. |
66. | Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet, 2019, pii: S0140-6736(19): 31149-3. |
67. | Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial. Lancet, 2019, pii: S0140-6736(19): 31150-X. |
68. | Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycaemia in type 2 diabetes, 2015: a patient-centred approach. Update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia, 2015, 58(3): 429-442. |
69. | Shi S, Koya D, Kanasaki K. Dipeptidyl peptidase-4 and kidney fibrosis in diabetes. Fibrogenesis Tissue Repair, 2016, 9: 1. |
70. | Takagaki Y, Koya D, Kanasaki K. Dipeptidyl peptidase-4 inhibition and renoprotection: the role of antifibrotic effects. Curr Opin Nephrol Hypertens, 2017, 26(1): 56-66. |
71. | Blech S, Ludwig-Schwellinger E, Grafe-Mody EU, et al. The metabolism and disposition of the oral dipeptidyl peptidase-4 inhibitor, linagliptin, in humans. Drug Metab Dispos, 2010, 38(4): 667-678. |
72. | Golightly LK, Drayna CC, McDermott MT. Comparative clinical pharmacokinetics of dipeptidyl peptidase-4 inhibitors. Clin Pharmacokinet, 2012, 51(8): 501-514. |
73. | Graefe-Mody U, Friedrich C, Port A, et al. Effect of renal impairment on the pharmacokinetics of the dipeptidyl peptidase-4 inhibitor linagliptin(*). Diabetes Obes Metab, 2011, 13(10): 939-946. |
74. | Mosenzon O, Leibowitz G, Bhatt DL, et al. Effect of saxagliptin on renal outcomes in the SAVOR-TIMI 53 trial. Diabetes Care, 2017, 40(1): 69-76. |
75. | Cornel JH, Bakris GL, Stevens SR, et al. Effect of sitagliptin on kidney function and respective cardiovascular outcomes in type 2 diabetes: outcomes from TECOS. Diabetes Care, 2016, 39(12): 2304-2310. |
76. | Tonneijck L, Smits MM, Muskiet MH, et al. Renal effects of dpp-4 inhibitor sitagliptin or glp-1 receptor agonist liraglutide in overweight patients with type 2 diabetes: a 12-week, randomized, double-blind, placebo-controlled trial. Diabetes Care, 2016, 39(11): 2042-2050. |
77. | Kanasaki K. The role of renal dipeptidyl peptidase-4 in kidney disease: renal effects of dipeptidyl peptidase-4 inhibitors with a focus on linagliptin. Clin Sci (Lond), 2018, 132(4): 489-507. |
78. | Chao CT, Wang J, Wu HY, et al. Dipeptidyl peptidase 4 inhibitor use is associated with a lower risk of incident acute kidney injury in patients with diabetes. Oncotarget, 2017, 8(32): 53028-53040. |
79. | Laakso M, Rosenstock J, Groop PH, et al. Treatment with the dipeptidyl peptidase-4 inhibitor linagliptin or placebo followed by glimepiride in patients with type 2 diabetes with moderate to severe renal impairment: a 52-week, randomized, double-blind clinical trial. Diabetes Care, 2015, 38(2): e15-e17. |
80. | McGill JB, Sloan L, Newman J, et al. Long-term efficacy and safety of linagliptin in patients with type 2 diabetes and severe renal impairment: a 1-year, randomized, double-blind, placebo-controlled study. Diabetes Care, 2013, 36(2): 237-244. |
81. | von Eynatten M, Gong Y, Emser A, et al. Efficacy and safety of linagliptin in type 2 diabetes subjects at high risk for renal and cardiovascular disease: a pooled analysis of six phaseⅢclinical trials. Cardiovasc Diabetol, 2013, 12: 60. |
82. | Groop PH, Cooper ME, Perkovic V, et al. Linagliptin lowers albuminuria on top of recommended standard treatment in patients with type 2 diabetes and renal dysfunction. Diabetes Care, 2013, 36(11): 3460-3468. |
83. | Cooper ME, Perkovic V, McGill JB, et al. Kidney disease end points in a pooled analysis of individual patient-level data from a large clinical trials program of the dipeptidyl peptidase 4 inhibitor linagliptin in type 2 diabetes. Am J Kidney Dis, 2015, 66(3): 441-449. |
84. | Groop PH, Cooper ME, Perkovic V, et al. Linagliptin and its effects on hyperglycaemia and albuminuria in patients with type 2 diabetes and renal dysfunction: the randomized MARLINA-T2D trial. Diabetes Obes Metab, 2017, 19(11): 1610-1619. |
85. | Ott C, Kistner I, Keller M, et al. Effects of linagliptin on renal endothelial function in patients with type 2 diabetes: a randomised clinical trial. Diabetologia, 2016, 59(12): 2579-2587. |
86. | Jax T, Stirban A, Terjung A, et al. A randomised, active- and placebo-controlled, three-period crossover trial to investigate short-term effects of the dipeptidyl peptidase-4 inhibitor linagliptin on macro- and microvascular endothelial function in type 2 diabetes. Cardiovasc Diabetol, 2017, 16(1): 13. |
87. | Rosenstock J, Perkovic V, Johansen OE, et al. Effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk: the CARMELINA randomized clinical trial. JAMA, 2019, 321(1): 69-79. |
88. | Van Biesen W, Van de Velde T, Slabbaert M, et al. Blood pressure management in patients with chronic kidney disease: an appraisal and summary of existing guidelines. Acta Clin Belg, 2013, 68(6): 394-398. |
89. | American Diabetes Association. 10. Cardiovascular disease and risk management: standards of medical care in diabetes-2019. Diabetes Care, 2019, 42(Suppl 1): S103-S123. |
90. | Buckley LF, Dixon DL, Wohlford GFt, et al. Intensive versus standard blood pressure control in SPRINT-eligible participants of ACCORD-BP. Diabetes Care, 2017, 40(12): 1733-1738. |
91. | Emdin CA, Rahimi K, Neal B, et al. Blood pressure lowering in type 2 diabetes: a systematic review and meta-analysis. JAMA, 2015, 313(6): 603-615. |
92. | 中国医师协会肾脏内科医师分会, 中国中西医结合学会肾脏疾病专业委员会. 中国肾性高血压管理指南2016(简版). 中华医学杂志, 2017, 97(20): 1547-1555. |
93. | Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med, 2001, 345(12): 861-869. |
94. | Parving HH, Lehnert H, Brochner-Mortensen J, et al. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med, 2001, 345(12): 870-878. |
95. | Lewis EJ, Hunsicker LG, Bain RP, et al. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The collaborative study group. N Engl J Med, 1993, 329(20): 1456-1462. |
96. | Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med, 2001, 345(12): 851-860. |
97. | Lacourcière Y, Bélanger A, Godin C, et al. Long-term comparison of losartan and enalapril on kidney function in hypertensive type 2 diabetics with early nephropathy. Kidney Int, 2000, 58(2): 762-769. |
98. | Barnett AH, Bain SC, Bouter P, et al. Angiotensin-receptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathy. N Engl J Med, 2004, 351(19): 1952-1961. |
99. | Ozturk S, Sar F, Bengi-Bozkurt O, et al. Study of ACEI versus ARB in managing hypertensive overt diabetic nephropathy: long-term analysis. Kidney Blood Press Res, 2009, 32(4): 268-275. |
100. | Haller H, Ito S, Izzo JL Jr, et al. Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes. N Engl J Med, 2011, 364(10): 907-917. |
101. | ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet, 2007, 370(9590): 829-840. |
102. | Bangalore S, Fakheri R, Toklu B, et al. Diabetes mellitus as a compelling indication for use of renin angiotensin system blockers: systematic review and meta-analysis of randomized trials. BMJ, 2016, 352: i438. |
103. | American Diabetes Association. 10. Microvascular complications and foot care: standards of medical care in diabetes-2018. Diabetes Care, 2018, 41(Suppl 1): S105-S118. |
104. | ONTARGET Investigators, Yusuf S, Teo KK, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med, 2008, 358(15): 1547-1559. |
105. | Parving HH, Brenner BM, McMurray JJ, et al. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med, 2012, 367(23): 2204-2213. |
106. | Elam MB, Ginsberg HN, Lovato LC, et al. Association of fenofibrate therapy with long-term cardiovascular risk in statin-treated patients with type 2 diabetes. JAMA Cardiol, 2017, 2(4): 370-380. |
107. | Chen SC, Tseng CH. Dyslipidemia, kidney disease, and cardiovascular disease in diabetic patients. Rev Diabet Stud, 2013, 10(2-3): 88-100. |
108. | Athyros VG, Tziomalos K, Karagiannis A, et al. Statins and cardiovascular events in patients with end-stage renal disease on hemodialysis. The AURORA results suggest the need for earlier intervention. Curr Vasc Pharmacol, 2009, 7(3): 264-266. |
109. | Athyros VG, Karagiannis A, Katsiki N, et al. Statins in patients with renal dysfunction. Am J Cardiol, 2012, 109(10): 1537. |
110. | Athyros VG, Karagiannis A, Liberopoulos EN, et al. Statin treatment may be beneficial to both the kidneys and the heart. Perit Dial Int, 2007, 27(2): 215-216. |
111. | Athyros VG, Mikhailidis DP, Papageorgiou AA, et al. The effect of statins versus untreated dyslipidaemia on renal function in patients with coronary heart disease. A subgroup analysis of the Greek atorvastatin and coronary heart disease evaluation (GREACE) study. J Clin Pathol, 2004, 57(7): 728-734. |
112. | Afzali B, Goldsmith DJ. Beneficial effects of statins on the kidney. J Clin Pathol, 2004, 57(7): 673-674. |
113. | Athyros VG, Papageorgiou AA, Elisaf M, et al. Statins and renal function in patients with diabetes mellitus. Curr Med Res Opin, 2003, 19(7): 615-617. |
114. | Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med, 2015, 372(25): 2387-2397. |
115. | Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med, 2017, 376(18): 1713-1722. |
116. | Standl E, Schnell O, McGuire DK, et al. Integration of recent evidence into management of patients with atherosclerotic cardiovascular disease and type 2 diabetes. Lancet Diabetes Endocrinol, 2017, 5(5): 391-402. |
117. | González Sanchidrián S, Labrador Gómez PJ, Aguilar Aguilar JC, et al. Evolocumab for the treatment of heterozygous familial hypercholesterolemia in end-stage chronic kidney disease and dialysis. Nefrologia, 2019, 39(2): 218-220. |
118. | Holdaas H, Holme I, Schmieder RE, et al. Rosuvastatin in diabetic hemodialysis patients. J Am Soc Nephrol, 2011, 22(7): 1335-1341. |
119. | Ferro CJ, Mark PB, Kanbay M, et al. Lipid management in patients with chronic kidney disease. Nat Rev Nephrol, 2018, 14(12): 727-749. |
- 1. Cho NH, Shaw JE, Karuranga S, et al. IDF diabetes atlas: global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract, 2018, 138: 271-281.
- 2. Wang L, Gao P, Zhang M, et al. Prevalence and ethnic pattern of diabetes and prediabetes in China in 2013. JAMA, 2017, 317(24): 2515-2523.
- 3. Koye DN, Magliano DJ, Nelson RG, et al. The global epidemiology of diabetes and kidney disease. Adv Chronic Kidney Dis, 2018, 25(2): 121-132.
- 4. Huang YM, Xu D, Long J, et al. Spectrum of chronic kidney disease in China: a national study based on hospitalized patients from 2010 to 2015. Nephrology (Carlton), 2019, 24(7): 725-736.
- 5. Liu ZH. Nephrology in China. Nat Rev Nephrol, 2013, 9(9): 523-528.
- 6. Gheith O, Farouk N, Nampoory N, et al. Diabetic kidney disease: world wide difference of prevalence and risk factors. J Nephropharmacol, 2016, 5(1): 49-56.
- 7. A/L B Vasanth Rao VR, Tan SH, Candasamy M, et al. Diabetic nephropathy: an update on pathogenesis and drug development. Diabetes Metab Syndr, 2019, 13(1): 754-762.
- 8. American Diabetes Association. 11. Microvascular complications and foot care: Standards of Medical Care in Diabetes-2019. Diabetes Care, 2019, 42(Suppl 1): S124-S138.
- 9. Afkarian M, Zelnick LR, Hall YN, et al. Clinical manifestations of kidney disease among US adults with diabetes, 1988-2014. JAMA, 2016, 316(6): 602-610.
- 10. de Boer IH, Rue TC, Hall YN, et al. Temporal trends in the prevalence of diabetic kidney disease in the United States. JAMA, 2011, 305(24): 2532-2539.
- 11. Pavkov ME, Mason CC, Bennett PH, et al. Change in the distribution of albuminuria according to estimated glomerular filtration rate in Pima Indians with type 2 diabetes. Diabetes Care, 2009, 32(10): 1845-1850.
- 12. Koye DN, Magliano DJ, Reid CM, et al. Risk of progression of nonalbuminuric CKD to end-stage kidney disease in people with diabetes: the CRIC (Chronic Renal Insufficiency Cohort) Study. Am J Kidney Dis, 2018, 72(5): 653-661.
- 13. Retnakaran R, Cull CA, Thorne KI, et al. Risk factors for renal dysfunction in type 2 diabetes: U. K. prospective diabetes study 74. Diabetes, 2006, 55(6): 1832-1839.
- 14. Ninomiya T, Perkovic V, de Galan BE, et al. Albuminuria and kidney function independently predict cardiovascular and renal outcomes in diabetes. J Am Soc Nephrol, 2009, 20(8): 1813-1821.
- 15. Klimontov VV, Korbut AI. Normoalbuminuric chronic kidney disease in diabetes. Ter Arkh, 2018, 90(10): 94-98.
- 16. Penno G, Solini A, Bonora E, et al. Clinical significance of nonalbuminuric renal impairment in type 2 diabetes. J Hypertens, 2011, 29(9): 1802-1809.
- 17. Pugliese G. Updating the natural history of diabetic nephropathy. Acta Diabetol, 2014, 51(6): 905-915.
- 18. Caramori ML, Fioretto P, Mauer M. Low glomerular filtration rate in normoalbuminuric type 1 diabetic patients: an indicator of more advanced glomerular lesions. Diabetes, 2003, 52(4): 1036-1040.
- 19. Ekinci EI, Jerums G, Skene A, et al. Renal structure in normoalbuminuric and albuminuric patients with type 2 diabetes and impaired renal function. Diabetes Care, 2013, 36(11): 3620-3626.
- 20. Moriya T, Omura K, Matsubara M, et al. Arteriolar hyalinosis predicts increase in albuminuria and GFR decline in normo- and microalbuminuric Japanese patients with type 2 diabetes. Diabetes Care, 2017, 40(10): 1373-1378.
- 21. Papadopoulou-Marketou N, Chrousos GP, Kanaka-Gantenbein C. Diabetic nephropathy in type 1 diabetes: a review of early natural history, pathogenesis, and diagnosis. Diabetes Metab Res Rev, 2017, 33(2).
- 22. Bacci MR, Chehter EZ, Azzalis LA, et al. Serum ngal and cystatin c comparison with urinary albumin-to-creatinine ratio and inflammatory biomarkers as early predictors of renal dysfunction in patients with type 2 diabetes. Kidney Int Rep, 2017, 2(2): 152-158.
- 23. Winter L, Wong LA, Jerums G, et al. Use of readily accessible inflammatory markers to predict diabetic kidney disease. Front Endocrinol (Lausanne), 2018, 9: 225.
- 24. Konenkov VI, Klimontov VV, Myakina NE, et al. Increased serum concentrations of inflammatory cytokines in type 2 diabetic patients with chronic kidney disease. Ter Arkh, 2015, 87(6): 45-49.
- 25. Nojima J, Meguro S, Ohkawa N, et al. One-year eGFR decline rate is a good predictor of prognosis of renal failure in patients with type 2 diabetes. Proc Jpn Acad Ser B Phys Biol Sci, 2017, 93(9): 746-754.
- 26. Carlsson AC, Ostgren CJ, Nystrom FH, et al. Association of soluble tumor necrosis factor receptors 1 and 2 with nephropathy, cardiovascular events, and total mortality in type 2 diabetes. Cardiovasc Diabetol, 2016, 15: 40.
- 27. Klisic A, Kavaric N, Ninic A. Retinol-binding protein 4 versus albuminuria as predictors of estimated glomerular filtration rate decline in patients with type 2 diabetes. J Res Med Sci, 2018, 23: 44.
- 28. Lee CH, Hui EY, Woo YC, et al. Circulating fibroblast growth factor 21 levels predict progressive kidney disease in subjects with type 2 diabetes and normoalbuminuria. J Clin Endocrinol Metab, 2015, 100(4): 1368-1375.
- 29. Kim SS, Song SH, Kim IJ, et al. Decreased plasma α-Klotho predict progression of nephropathy with type 2 diabetic patients. J Diabetes Complications, 2016, 30(5): 887-892.
- 30. Kidney Disease: Improving Global Outcomes(KDIGO). KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl, 2013, 3(1): 1-150.
- 31. Skyler JS, Bergenstal R, Bonow RO, et al. Intensive glycemic control and the prevention of cardiovascular events: implications of the ACCORD, ADVANCE, and VA diabetes trials: a position statement of the American Diabetes Association and a Scientific Statement of the American College of Cardiology Foundation and the American Heart Association. J Am Coll Cardiol, 2009, 53(3): 298-304.
- 32. Umanath K, Lewis JB. Update on diabetic nephropathy: core curriculum 2018. Am J Kidney Dis, 2018, 71(6): 884-895.
- 33. Yakush Williams JK. Management strategies for patients with diabetic kidney disease and chronic kidney disease in diabetes. Nurs Clin North Am, 2017, 52(4): 575-587.
- 34. Al-Onazi AS, Al-Rasheed NM, Attia HA, et al. Ruboxistaurin attenuates diabetic nephropathy via modulation of TGF-β1/Smad and GRAP pathways. J Pharm Pharmacol, 2016, 68(2): 219-232.
- 35. RamachandraRao SP, Zhu Y, Ravasi T, et al. Pirfenidone is renoprotective in diabetic kidney disease. J Am Soc Nephrol, 2009, 20(8): 1765-1775.
- 36. Bhattacharjee N, Barma S, Konwar N, et al. Mechanistic insight of diabetic nephropathy and its pharmacotherapeutic targets: an update. Eur J Pharmacol, 2016, 791: 8-24.
- 37. de Zeeuw D, Akizawa T, Audhya P, et al. Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. N Engl J Med, 2013, 369(26): 2492-2503.
- 38. Mann JF, Green D, Jamerson K, et al. Avosentan for overt diabetic nephropathy. J Am Soc Nephrol, 2010, 21(3): 527-535.
- 39. Fried LF, Emanuele N, Zhang JH, et al. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med, 2013, 369(20): 1892-1903.
- 40. American Diabetes Association. 5. Lifestyle management: standards of medical care in diabetes -2019. Diabetes Care, 2019, 42(Suppl 1): S46-S60.
- 41. Guideline development group. Clinical practice guideline on management of patients with diabetes and chronic kidney disease stage 3b or higher (eGFR<45 mL/min). Nephrol Dial Transplant, 2015, 30(Suppl 2): ii1-142.
- 42. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med, 1993, 329(14): 977-986.
- 43. The Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) Research Group. Effect of intensive diabetes therapy on the progression of diabetic retinopathy in patients with type 1 diabetes: 18 years of follow-up in the DCCT/EDIC. Diabetes, 2015, 64(2): 631-642.
- 44. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet, 1998, 352(9131): 854-865.
- 45. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet, 1998, 352(9131): 837-853.
- 46. American Diabetes Association. 6. Glycemic targets: standards of medical care in diabetes-2019. Diabetes Care, 2019, 42(Suppl 1): S61-S70.
- 47. The ACCORD Study Group. Long-term effects of intensive glucose lowering on cardiovascular outcomes. N Engl J Med, 2011, 364(9): 818-828.
- 48. Miller ME, Williamson JD, Gerstein HC, et al. Effects of randomization to intensive glucose control on adverse events, cardiovascular disease, and mortality in older versus younger adults in the ACCORD Trial. Diabetes Care, 2014, 37(3): 634-643.
- 49. Stavropoulos K, Imprialos KP, Stavropoulos N, et al. Sodium-glucose cotransporter 2 inhibitors: nephroprotective impact on diabetic kidney disease. Cardiovasc Hematol Disord Drug Targets, 2018, 18(2): 120-126.
- 50. Vasilakou D, Karagiannis T, Athanasiadou E, et al. Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med, 2013, 159(4): 262-274.
- 51. Tang H, Li D, Zhang J, et al. Sodium-glucose co-transporter-2 inhibitors and risk of adverse renal outcomes among patients with type 2 diabetes: a network and cumulative meta-analysis of randomized controlled trials. Diabetes Obes Metab, 2017, 19(8): 1106-1115.
- 52. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med, 2015, 373(22): 2117-2128.
- 53. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med, 2016, 375(4): 323-334.
- 54. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med, 2017, 377(7): 644-657.
- 55. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med, 2019, 380(24): 2295-2306.
- 56. List JF, Woo V, Morales E, et al. Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes. Diabetes Care, 2009, 32(4): 650-657.
- 57. Kohan DE, Fioretto P, Tang W, et al. Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control. Kidney Int, 2014, 85(4): 962-971.
- 58. Heerspink HJ, Johnsson E, Gause-Nilsson I, et al. Dapagliflozin reduces albuminuria in patients with diabetes and hypertension receiving renin-angiotensin blockers. Diabetes Obes Metab, 2016, 18(6): 590-597.
- 59. de Vos LC, Hettige TS, Cooper ME. New glucose-lowering agents for diabetic kidney disease. Adv Chronic Kidney Dis, 2018, 25(2): 149-157.
- 60. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med, 2016, 375(4): 311-322.
- 61. Mann JFE, Ørsted DD, Brown-Frandsen K, et al. Liraglutide and renal outcomes in type 2 diabetes. N Engl J Med, 2017, 377(9): 839-848.
- 62. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med, 2016, 375(19): 1834-1844.
- 63. Pratley R, Amod A, Hoff ST, et al. Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial. Lancet, 2019, 394(10192): 39-50.
- 64. Husain M, Birkenfeld AL, Donsmark M, et al. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med, 2019.
- 65. Tuttle KR, Lakshmanan MC, Rayner B, et al. Dulaglutide versus insulin glargine in patients with type 2 diabetes and moderate-to-severe chronic kidney disease (AWARD-7): a multicentre, open-label, randomised trial. Lancet Diabetes Endocrinol, 2018, 6(8): 605-617.
- 66. Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet, 2019, pii: S0140-6736(19): 31149-3.
- 67. Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial. Lancet, 2019, pii: S0140-6736(19): 31150-X.
- 68. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycaemia in type 2 diabetes, 2015: a patient-centred approach. Update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia, 2015, 58(3): 429-442.
- 69. Shi S, Koya D, Kanasaki K. Dipeptidyl peptidase-4 and kidney fibrosis in diabetes. Fibrogenesis Tissue Repair, 2016, 9: 1.
- 70. Takagaki Y, Koya D, Kanasaki K. Dipeptidyl peptidase-4 inhibition and renoprotection: the role of antifibrotic effects. Curr Opin Nephrol Hypertens, 2017, 26(1): 56-66.
- 71. Blech S, Ludwig-Schwellinger E, Grafe-Mody EU, et al. The metabolism and disposition of the oral dipeptidyl peptidase-4 inhibitor, linagliptin, in humans. Drug Metab Dispos, 2010, 38(4): 667-678.
- 72. Golightly LK, Drayna CC, McDermott MT. Comparative clinical pharmacokinetics of dipeptidyl peptidase-4 inhibitors. Clin Pharmacokinet, 2012, 51(8): 501-514.
- 73. Graefe-Mody U, Friedrich C, Port A, et al. Effect of renal impairment on the pharmacokinetics of the dipeptidyl peptidase-4 inhibitor linagliptin(*). Diabetes Obes Metab, 2011, 13(10): 939-946.
- 74. Mosenzon O, Leibowitz G, Bhatt DL, et al. Effect of saxagliptin on renal outcomes in the SAVOR-TIMI 53 trial. Diabetes Care, 2017, 40(1): 69-76.
- 75. Cornel JH, Bakris GL, Stevens SR, et al. Effect of sitagliptin on kidney function and respective cardiovascular outcomes in type 2 diabetes: outcomes from TECOS. Diabetes Care, 2016, 39(12): 2304-2310.
- 76. Tonneijck L, Smits MM, Muskiet MH, et al. Renal effects of dpp-4 inhibitor sitagliptin or glp-1 receptor agonist liraglutide in overweight patients with type 2 diabetes: a 12-week, randomized, double-blind, placebo-controlled trial. Diabetes Care, 2016, 39(11): 2042-2050.
- 77. Kanasaki K. The role of renal dipeptidyl peptidase-4 in kidney disease: renal effects of dipeptidyl peptidase-4 inhibitors with a focus on linagliptin. Clin Sci (Lond), 2018, 132(4): 489-507.
- 78. Chao CT, Wang J, Wu HY, et al. Dipeptidyl peptidase 4 inhibitor use is associated with a lower risk of incident acute kidney injury in patients with diabetes. Oncotarget, 2017, 8(32): 53028-53040.
- 79. Laakso M, Rosenstock J, Groop PH, et al. Treatment with the dipeptidyl peptidase-4 inhibitor linagliptin or placebo followed by glimepiride in patients with type 2 diabetes with moderate to severe renal impairment: a 52-week, randomized, double-blind clinical trial. Diabetes Care, 2015, 38(2): e15-e17.
- 80. McGill JB, Sloan L, Newman J, et al. Long-term efficacy and safety of linagliptin in patients with type 2 diabetes and severe renal impairment: a 1-year, randomized, double-blind, placebo-controlled study. Diabetes Care, 2013, 36(2): 237-244.
- 81. von Eynatten M, Gong Y, Emser A, et al. Efficacy and safety of linagliptin in type 2 diabetes subjects at high risk for renal and cardiovascular disease: a pooled analysis of six phaseⅢclinical trials. Cardiovasc Diabetol, 2013, 12: 60.
- 82. Groop PH, Cooper ME, Perkovic V, et al. Linagliptin lowers albuminuria on top of recommended standard treatment in patients with type 2 diabetes and renal dysfunction. Diabetes Care, 2013, 36(11): 3460-3468.
- 83. Cooper ME, Perkovic V, McGill JB, et al. Kidney disease end points in a pooled analysis of individual patient-level data from a large clinical trials program of the dipeptidyl peptidase 4 inhibitor linagliptin in type 2 diabetes. Am J Kidney Dis, 2015, 66(3): 441-449.
- 84. Groop PH, Cooper ME, Perkovic V, et al. Linagliptin and its effects on hyperglycaemia and albuminuria in patients with type 2 diabetes and renal dysfunction: the randomized MARLINA-T2D trial. Diabetes Obes Metab, 2017, 19(11): 1610-1619.
- 85. Ott C, Kistner I, Keller M, et al. Effects of linagliptin on renal endothelial function in patients with type 2 diabetes: a randomised clinical trial. Diabetologia, 2016, 59(12): 2579-2587.
- 86. Jax T, Stirban A, Terjung A, et al. A randomised, active- and placebo-controlled, three-period crossover trial to investigate short-term effects of the dipeptidyl peptidase-4 inhibitor linagliptin on macro- and microvascular endothelial function in type 2 diabetes. Cardiovasc Diabetol, 2017, 16(1): 13.
- 87. Rosenstock J, Perkovic V, Johansen OE, et al. Effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk: the CARMELINA randomized clinical trial. JAMA, 2019, 321(1): 69-79.
- 88. Van Biesen W, Van de Velde T, Slabbaert M, et al. Blood pressure management in patients with chronic kidney disease: an appraisal and summary of existing guidelines. Acta Clin Belg, 2013, 68(6): 394-398.
- 89. American Diabetes Association. 10. Cardiovascular disease and risk management: standards of medical care in diabetes-2019. Diabetes Care, 2019, 42(Suppl 1): S103-S123.
- 90. Buckley LF, Dixon DL, Wohlford GFt, et al. Intensive versus standard blood pressure control in SPRINT-eligible participants of ACCORD-BP. Diabetes Care, 2017, 40(12): 1733-1738.
- 91. Emdin CA, Rahimi K, Neal B, et al. Blood pressure lowering in type 2 diabetes: a systematic review and meta-analysis. JAMA, 2015, 313(6): 603-615.
- 92. 中国医师协会肾脏内科医师分会, 中国中西医结合学会肾脏疾病专业委员会. 中国肾性高血压管理指南2016(简版). 中华医学杂志, 2017, 97(20): 1547-1555.
- 93. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med, 2001, 345(12): 861-869.
- 94. Parving HH, Lehnert H, Brochner-Mortensen J, et al. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med, 2001, 345(12): 870-878.
- 95. Lewis EJ, Hunsicker LG, Bain RP, et al. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The collaborative study group. N Engl J Med, 1993, 329(20): 1456-1462.
- 96. Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med, 2001, 345(12): 851-860.
- 97. Lacourcière Y, Bélanger A, Godin C, et al. Long-term comparison of losartan and enalapril on kidney function in hypertensive type 2 diabetics with early nephropathy. Kidney Int, 2000, 58(2): 762-769.
- 98. Barnett AH, Bain SC, Bouter P, et al. Angiotensin-receptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathy. N Engl J Med, 2004, 351(19): 1952-1961.
- 99. Ozturk S, Sar F, Bengi-Bozkurt O, et al. Study of ACEI versus ARB in managing hypertensive overt diabetic nephropathy: long-term analysis. Kidney Blood Press Res, 2009, 32(4): 268-275.
- 100. Haller H, Ito S, Izzo JL Jr, et al. Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes. N Engl J Med, 2011, 364(10): 907-917.
- 101. ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet, 2007, 370(9590): 829-840.
- 102. Bangalore S, Fakheri R, Toklu B, et al. Diabetes mellitus as a compelling indication for use of renin angiotensin system blockers: systematic review and meta-analysis of randomized trials. BMJ, 2016, 352: i438.
- 103. American Diabetes Association. 10. Microvascular complications and foot care: standards of medical care in diabetes-2018. Diabetes Care, 2018, 41(Suppl 1): S105-S118.
- 104. ONTARGET Investigators, Yusuf S, Teo KK, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med, 2008, 358(15): 1547-1559.
- 105. Parving HH, Brenner BM, McMurray JJ, et al. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med, 2012, 367(23): 2204-2213.
- 106. Elam MB, Ginsberg HN, Lovato LC, et al. Association of fenofibrate therapy with long-term cardiovascular risk in statin-treated patients with type 2 diabetes. JAMA Cardiol, 2017, 2(4): 370-380.
- 107. Chen SC, Tseng CH. Dyslipidemia, kidney disease, and cardiovascular disease in diabetic patients. Rev Diabet Stud, 2013, 10(2-3): 88-100.
- 108. Athyros VG, Tziomalos K, Karagiannis A, et al. Statins and cardiovascular events in patients with end-stage renal disease on hemodialysis. The AURORA results suggest the need for earlier intervention. Curr Vasc Pharmacol, 2009, 7(3): 264-266.
- 109. Athyros VG, Karagiannis A, Katsiki N, et al. Statins in patients with renal dysfunction. Am J Cardiol, 2012, 109(10): 1537.
- 110. Athyros VG, Karagiannis A, Liberopoulos EN, et al. Statin treatment may be beneficial to both the kidneys and the heart. Perit Dial Int, 2007, 27(2): 215-216.
- 111. Athyros VG, Mikhailidis DP, Papageorgiou AA, et al. The effect of statins versus untreated dyslipidaemia on renal function in patients with coronary heart disease. A subgroup analysis of the Greek atorvastatin and coronary heart disease evaluation (GREACE) study. J Clin Pathol, 2004, 57(7): 728-734.
- 112. Afzali B, Goldsmith DJ. Beneficial effects of statins on the kidney. J Clin Pathol, 2004, 57(7): 673-674.
- 113. Athyros VG, Papageorgiou AA, Elisaf M, et al. Statins and renal function in patients with diabetes mellitus. Curr Med Res Opin, 2003, 19(7): 615-617.
- 114. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med, 2015, 372(25): 2387-2397.
- 115. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med, 2017, 376(18): 1713-1722.
- 116. Standl E, Schnell O, McGuire DK, et al. Integration of recent evidence into management of patients with atherosclerotic cardiovascular disease and type 2 diabetes. Lancet Diabetes Endocrinol, 2017, 5(5): 391-402.
- 117. González Sanchidrián S, Labrador Gómez PJ, Aguilar Aguilar JC, et al. Evolocumab for the treatment of heterozygous familial hypercholesterolemia in end-stage chronic kidney disease and dialysis. Nefrologia, 2019, 39(2): 218-220.
- 118. Holdaas H, Holme I, Schmieder RE, et al. Rosuvastatin in diabetic hemodialysis patients. J Am Soc Nephrol, 2011, 22(7): 1335-1341.
- 119. Ferro CJ, Mark PB, Kanbay M, et al. Lipid management in patients with chronic kidney disease. Nat Rev Nephrol, 2018, 14(12): 727-749.