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

doi:10.3877/cma.j.issn.1674-0785.2025.04.010

Abstract

Abstract:

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

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]. Chinese Journal of Clinicians(Electronic Edition), 2025, 19(04): 307-314.

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References 65

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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

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

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
中国糖尿病防治指南，2024	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
中国糖尿病合并慢性肾脏病临床管理共识，2024	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
ADA/EASD共识报告，2022	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

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
中国糖尿病防治指南，2024	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
中国糖尿病合并慢性肾脏病临床管理共识，2024	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
ADA/EASD共识报告，2022	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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