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中华临床医师杂志(电子版) ›› 2025, Vol. 19 ›› Issue (04) : 307 -314. doi: 10.3877/cma.j.issn.1674-0785.2025.04.010

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综述

胰高血糖素样肽-1受体激动剂应用于糖尿病肾脏疾病的进展更新
唐梦楚1, 段俗言1,†(), 王宁宁1, 毛慧娟1, 刘云2   
  1. 1210029　南京，南京医科大学第一附属医院江苏省人民医院肾科
    2210029　南京，南京医科大学第一附属医院江苏省人民医院老年内分泌科
  • 收稿日期:2025-04-08 出版日期:2025-04-15
  • 通信作者: 段俗言
  • 基金资助:
    国家自然科学基金青年科学基金项目(82100767); 江苏省自然科学基金青年基金项目(BK20191075); 江苏省基础研究计划自然科学基金-基础研究计划重点项目(BK20243054)

Pleiotropic effects of glucagon-like peptide-1 receptor agonists in treatment of diabetic kidney disease

Mengchu Tang1, Suyan Duan1,†(), Ningning Wang1, Huijuan Mao1, Yun Liu2   

  1. 1Department of Nephrology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Provincial People’s Hospital, Nanjing 210029, China
    2Department of Geriatric Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Provincial People’s Hospital, Nanjing 210029, China
  • Received:2025-04-08 Published:2025-04-15
  • Corresponding author: Suyan Duan
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唐梦楚, 段俗言, 王宁宁, 毛慧娟, 刘云. 胰高血糖素样肽-1受体激动剂应用于糖尿病肾脏疾病的进展更新[J/OL]. 中华临床医师杂志(电子版), 2025, 19(04): 307-314.

Mengchu Tang, Suyan Duan, Ningning Wang, Huijuan Mao, Yun Liu. Pleiotropic effects of glucagon-like peptide-1 receptor agonists in treatment of diabetic kidney disease[J/OL]. Chinese Journal of Clinicians(Electronic Edition), 2025, 19(04): 307-314.

糖尿病肾脏疾病（DKD）是一种进行性疾病，是糖尿病最严重的并发症之一，可能导致肾功能衰竭甚至死亡。胰高血糖素样肽-1受体激动剂（GLP-1RA）是一种治疗2型糖尿病（T2DM）的新型降糖药物，具有优良的心血管效益。大量研究表明，GLP-1RA可以通过降糖、降压、减重、调脂，改善肾脏血流动力学，调节炎性反应，抗氧化和抑制肾脏纤维化等机制发挥肾脏保护作用，在防治DKD的发生和进展方面具有很大的前景。本文就GLP-1RA已有的肾脏保护机制、临床试验的肾脏结局及目前指南建议进行综述。但GLP-1RA肾脏获益背后复杂的机制仍有待进一步发掘，需要更多的研究来阐明。

关键词: 糖尿病肾脏疾病, 胰高血糖素样肽-1受体激动剂, 肾脏获益

Diabetic kidney disease (DKD) is a progressive disease and one of the most serious complications of diabetes, which may lead to renal failure and even death. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are a novel class of hypoglycemic drugs for the treatment of type 2 diabetes mellitus (T2DM), offering notable cardiovascular advantages. Numerous studies have shown that GLP-1RAs play a renal protective role by exerting hypoglycemic and hypertensive effects, weight loss, lipid regulation, improving renal hemodynamics, regulating inflammatory response, reducing oxidative stress. and inhibiting renal fibrosis. GLP-1RAs hold significant promise in the management of DKD. This article reviews the renal protective mechanisms, clinical evidence of renal outcomes, and current guideline recommendations of GLP-1RAs. However, the complex mechanism behind the renal benefits of GLP-1RAs still needs further exploration and more research to clarify.

Key words: Diabetic kidney disease, Glucagon-like peptide-1 receptor agonists, Kidney benefits
表1 GLP-1 RA类药物相关肾脏结局的临床试验总结
研究名称 患者数（例） 研究设计 基线特征 药物 中位随访时间（年）/肾脏终点 基线按SGLT2i随机化分层（是/否）） 结果/结论
LEADER（NCT01179048） 9340 双盲-RCT T2DM+心血管事件高风险 利拉鲁肽 3.8/新发大量白蛋白尿，血清肌酐倍增（eGFR≤45 ml/min1.73 m2），肾脏替代治疗，肾源性死亡 否 HR：0.78
95%CI（0.67~0.92）/有肾脏获益
SUSTAIN6（NCT01720446） 3297 双盲-RCT T2DM+≥50岁+CVD/CKD Ⅲ~Ⅴ期，T2DM+≥60岁+心血管风险因素 司美格鲁肽 2.1/新发大量白蛋白尿，血清肌酐倍增（eGFR≤45 ml/min·1.73 m2），肾脏替代治疗，肾源性死亡 否 HR：0.64
95%CI（0.46~0.88）/有肾脏获益
PIONEER-6（NCT02692716） 3183 双盲-RCT T2DM+≥50岁+CVD/CKD Ⅲ~Ⅴ期，T2DM+≥60岁+心血管风险因素 口服司美格鲁肽 1.3/eGFR变化值 否 差异无统计学意义
FLOW（NCT03819153） 3533 四盲-RCT T2DM+CKD Ⅲ~Ⅳ期 司美格鲁肽 3.4/复合肾脏终点（起始持续性肾脏替代治疗、持续性eGFR<15 ml/min/1.73 m2、eGFR较基线持续降低≥50%、肾性死亡或心血管疾病死亡） 是 HR：0.76
95%CI（0.66~0.88）/有肾脏获益
AWARD-7（NCT01621178） 577 开放标签-RCT T2DM+CKD Ⅲ~Ⅳ期 度拉糖肽 0.997/eGFR和UACR 否 差异无统计学意义
REWIND（NCT01394952） 9901 双盲-RCT T2DM+≥50岁+既往有心血管事件或心血管危险因素 度拉糖肽 5.4/新发大量白蛋白尿，eGFR恶化≥30%，肾脏替代治疗 否 HR：0.85
95%CI（0.77~0.93）/有肾脏获益
EXSCEL（NCT01144338） 14752 双盲-RCT T2DM（70%既往发生过心血管事件） 艾塞那肽周制剂 3.2/新发大量白蛋白尿，eGFR下降40%，肾脏替代治疗，肾脏疾病导致的死亡 否 HR：0.88
95%CI（0.76~1.01）/有肾脏获益
HARMONY（NCT02465515） 9463 双盲-RCT T2DM+≥40岁+CVD 阿必鲁肽 1.6/eGFR变化值 否 HR：0.78
95%CI（0.68~0.90）/有肾脏获益
ELIXA（NCT01147250） 6068 双盲-RCT T2DM+近期急性冠脉事件 利司那肽 2.1/新发大量白蛋白尿 否 HR：0.84
95%CI（0.68~1.02）/有肾脏获益
AMPLITUDE-O（NCT03730662） 4076 双盲-RCT ≥18岁+既往有CVD
≥50岁+ eGFR 25~59.9 ml/min/1.73 m2+心血管风险因素		 艾培格那肽 1.8/肾移植，肾脏替代治疗（≥90 d），持续eGFR<15 ml/min/1.73 m2（≥30 d），持续eGFR较基线降低≥40%（≥30 d），新发大量白蛋白尿伴UACR较基线升高≥30% 是 HR：0.68
95%CI（0.57~0.79）/有肾脏获益
SURPASS-4（NCT03730662） 2002 开放标签-RCT T2DM+BMI≥25 kg/m2+已确诊的心血管疾病或心血管事件的高风险 替尔泊肽 1.63/eGFR较基线下降≥ 40%、终末期肾病、肾源性死亡或新发大量白蛋白尿 是 HR：0.58
95%CI（0.43~0.80）有肾脏获益
SURMOUNT-2（NCT04657003） 938 双盲-RCT T2DM+BMI≥27 kg/m2 替尔泊肽 1.38/eGFR（Cr-Cys-C-eGFR）和UACR较基线变化值 否 eGFR较基线变化的估计治疗差异（ETD）0.0 ml/min/1.73 m2（95%CI：-1.7~1.7）
UACR（ETD）31.1%，95%CI：-40.9~-19.7/有肾脏获益
表2 GLP-1 RA类药物治疗DKD的指南建议
指南共识 适用人群 建议
ADA糖尿病诊疗标准，2025 T2DM伴CKD的患者 建议使用已证明对该人群有益的GLP-1RA
KDIGO慢性肾脏病评估与管理指南，2024 对于已使用二甲双胍和SGLT2i治疗但仍未达到个体化血糖目标，或无法使用这些药物的T2DM伴CKD患者 建议使用长效GLP-1RA
中国糖尿病防治指南，2024 T2DM伴CKD的患者 推荐使用SGLT2i或GLP-1RA，以降低肾病进展及心血管病风险
对于eGFR≥15 ml·min-1·（1.73 m2）-1的DKD患者 可使用具有心肾获益循证依据的GLP-1RA
中国糖尿病合并慢性肾脏病临床管理共识，2024 T2DM伴CKD患者 优先考虑具有心肾获益的降糖药物如SGLT2i或GLP-1RA
不宜使用二甲双胍和SGLT2i，或治疗后血糖未能达标的DKD患者 建议使用GLP-1RA
ADA/EASD共识报告，2022 T2DM合并CKD患者 建议使用SGLT2i，如果SGLT2i不耐受或禁忌，则推荐使用GLP-1RA
T2DM并具有ASCVD、HF或CKD的确定风险或高风险的患者 对于使用其中一类药物后HbA1c高于目标值的患者，建议SGLT2i和GLP-1RA联合治疗
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