Providence Medical Research Center, Providence Health Care, Spokane, WA, USA.
Department of Medicine, University of Washington School of Medicine, Spokane and Seattle, WA, USA.
Nat Rev Nephrol. 2021 Apr;17(4):227-244. doi: 10.1038/s41581-020-00367-2. Epub 2020 Nov 20.
As the prevalence of diabetes continues to climb, the number of individuals living with diabetic complications will reach an unprecedented magnitude. The emergence of new glucose-lowering agents - sodium-glucose cotransporter 2 inhibitors and incretin therapies - has markedly changed the treatment landscape of type 2 diabetes mellitus. In addition to effectively lowering glucose, incretin drugs, which include glucagon-like peptide 1 receptor (GLP1R) agonists and dipeptidyl peptidase 4 (DPP4) inhibitors, can also reduce blood pressure, body weight, the risk of developing or worsening chronic kidney disease and/or atherosclerotic cardiovascular events, and the risk of death. Although kidney disease events have thus far been secondary outcomes in clinical trials, an ongoing phase III trial in patients with diabetic kidney disease will test the effect of a GLP1R agonist on a primary kidney disease outcome. Experimental data have identified the modulation of innate immunity and inflammation as plausible biological mechanisms underpinning the kidney-protective effects of incretin-based agents. These drugs block the mechanisms involved in the pathogenesis of kidney damage, including the activation of resident mononuclear phagocytes, tissue infiltration by non-resident inflammatory cells, and the production of pro-inflammatory cytokines and adhesion molecules. GLP1R agonists and DPP4 inhibitors might also attenuate oxidative stress, fibrosis and cellular apoptosis in the kidney.
随着糖尿病患病率的持续攀升，患有糖尿病并发症的人数将达到前所未有的规模。新型降糖药物——钠-葡萄糖共转运蛋白 2 抑制剂和肠促胰岛素治疗药物的出现，显著改变了 2 型糖尿病的治疗格局。除了有效降低血糖外，肠促胰岛素类药物（包括胰高血糖素样肽 1 受体 [GLP1R] 激动剂和二肽基肽酶 4 [DPP4] 抑制剂）还可以降低血压、体重，减少发生或加重慢性肾脏病和/或动脉粥样硬化性心血管事件的风险，以及死亡风险。尽管到目前为止，肾病事件一直是临床试验中的次要终点，但一项正在进行的糖尿病肾病患者的 III 期试验将测试 GLP1R 激动剂对主要肾病结局的影响。实验数据已经确定，固有免疫和炎症的调节可能是基于肠促胰岛素类药物的肾脏保护作用的合理生物学机制。这些药物阻断了导致肾脏损伤的发病机制相关的机制，包括常驻单核吞噬细胞的激活、非常驻炎性细胞的组织浸润以及促炎细胞因子和黏附分子的产生。GLP1R 激动剂和 DPP4 抑制剂还可能减轻肾脏中的氧化应激、纤维化和细胞凋亡。
