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Review
. 2019 Dec;11(12):938-948.
doi: 10.1111/1753-0407.12969. Epub 2019 Aug 14.

Review of glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes mellitus in patients with chronic kidney disease and their renal effects

Lance A Sloan  1   2
Affiliations
Review

Review of glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes mellitus in patients with chronic kidney disease and their renal effects

Lance A Sloan. J Diabetes. 2019 Dec.

Abstract
in English, Chinese

Type 2 diabetes mellitus (T2DM) is the most common cause of chronic kidney disease (CKD), and when it causes CKD it is collectively referred to as diabetic kidney disease. One of the newer therapies for managing hyperglycemia is the glucagon-like peptide-1 receptor agonist (GLP-1RA) drug class. This review summarizes the effects of GLP-1RAs in patients with T2DM with CKD and evidence for renoprotection with GLP-1RAs using data from observational studies, prospective clinical trials, post hoc analyses, and meta-analyses. Evidence from some preclinical studies was also reviewed. Taken together, subgroup analyses of patients with varying degrees of renal function demonstrated that glycemic control with GLP-1RAs was not markedly less effective in patients with mild or moderate renal impairment vs that in patients with normal function. GLP-1RAs were associated with improvements in some cardiorenal risk factors, including systolic blood pressure and body weight. Furthermore, several large cardiovascular outcome studies showed reduced risks of composite renal outcomes, mostly driven by a reduction in macroalbuminuria, suggesting potential renoprotective effects of GLP-1RAs. In conclusion, GLP-1RAs effectively reduced hyperglycemia in patients with mild or moderately impaired kidney function in the limited number of studies to date. GLP-1RAs may be considered in combination with other glucose-lowering medications because of their ability to lower glucose in a glucose-dependent manner, lowering their risk for hypoglycemia, while improving some cardiorenal risk factors. Potential renoprotective effects of GLP-1RAs, and their renal mechanisms of action, warrant further investigation.

2型糖尿病(type 2 diabetes mellitus, T2DM)是慢性肾脏病(chronic kidney disease, CKD)最常见的病因, 当引起CKD时统称为糖尿病肾病。胰高血糖素样肽-1受体激动剂(glucagon-like peptide-1 receptor agonist, GLP-1RA)是一类较新的降糖药物。本综述利用来自观察性研究、前瞻性临床试验、事后分析以及meta分析的数据, 总结了GLP-1RAs在T2DM合并CKD患者中的疗效及GLP-1RAs肾脏保护的证据。同时还回顾了一些来自临床前研究的证据。分析显示, 不同程度肾功能患者的亚组分析表明, 与肾功能正常的患者相比较, 轻度或中度肾功能受损患者使用GLP-1Ras治疗的降糖疗效并未明显降低。GLP-1RAs可改善一些心肾危险因素, 包括收缩压与体重。此外, 几项大型心血管结局研究结果显示, 复合肾脏结局的风险降低, 这主要是由于大量白蛋白尿减少所致, 表明GLP-1RAs具有潜在的肾脏保护作用。总之, 迄今为止有限的几项研究显示GLP-1RAs可有效降低轻度或中度肾功能受损患者的血糖水平。目前认为GLP-1RAs可与其他降糖药物联合使用, 因其降糖作用呈葡萄糖依赖性, 可降低发生低血糖的风险, 同时还可改善一些心肾危险因素。GLP-1RAs的潜在肾脏保护作用及其作用机制值得进一步研究。.

Keywords: 2型糖尿病; chronic kidney disease; diabetic kidney disease; glucagon-like peptide-1 receptor agonist; type 2 diabetes mellitus; visceral insulin resistance adiposity syndrome; 内脏胰岛素抵抗肥胖综合征。; 慢性肾脏病变; 糖尿病肾病; 胰高血糖素样肽-1受体激动剂.

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Figures

Figure 1
Figure 1
Composite renal outcomes with GLP‐1RA treatment in patients with T2DM in cardiovascular outcome trials.44, 45, 46, 48, 49 †Adjusted for age, sex, ethnicity, race, region, duration of diabetes, history of CV event, insulin use, baseline HbA1c, eGFR, and body mass index. CI, confidence interval; CrCl, creatinine clearance; CV, cardiovascular; EXSCEL, Exenatide Study of Cardiovascular Event Lowering; eGFR, estimated glomerular filtration rate; GLP‐1RA, glucagon‐like peptide‐1 receptor agonist; HbA1c, glycated hemoglobin; HR, hazard ratio; LEADER, Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results; qd, once daily; qw, once weekly; REWIND, Researching Cardiovascular Events with a Weekly Incretin in Diabetes; sCr, serum creatinine; SUSTAIN, Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes; T2DM, type 2 diabetes mellitus
Figure 2
Figure 2
The GLP‐1 gut‐renal axis. The role of GLP‐1 is to facilitate macronutrient storage through multiple pathways. Two of the pathways shown—the CNS and direct pathways—may affect the kidneys by decreasing intraglomerular pressure. This potentially may result in decreased nutrient loss or energy expenditure needed to reabsorb nutrients such as glucose or amino acids. GLP‐1 works through the pancreatic pathway to increase macronutrient storage in the liver, skeletal muscle, and fat by increasing insulin and decreasing glucagon levels in a glucose‐dependent manner. The dotted lines represent proposed mechanisms whereby the brain, potentially through the autonomic nervous system, may reduce sympathetic activity, insulin resistance, and intraglomerular pressure. Green text indicates an increase; red text indicates a reduction. ATP, adenosine triphosphate; CNS, central nervous system; GI, gastrointestinal; GLP‐1, glucagon‐like peptide‐1; NHE, sodium‐hydrogen exchanger
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