Department of Nephrology, Friedrich Alexander University of Erlangen, Erlangen, Germany.
KfH Kidney Centre, Munich, Germany.
Diabetes Obes Metab. 2021 Sep;23(9):2058-2066. doi: 10.1111/dom.14443. Epub 2021 Jun 1.
To investigate whether effects on chronic kidney disease risk factors could explain the apparent reduction in kidney outcomes (composite of macroalbuminuria, doubling of serum creatinine, renal replacement therapy, or renal death), primarily driven by changes in albuminuria, after treatment with the glucagon-like peptide-1 receptor agonists (GLP-1RAs) liraglutide and semaglutide in patients with type 2 diabetes in the LEADER and SUSTAIN 6 trials.
We evaluated the mediation effect of glycated haemoglobin (HbA1c), systolic blood pressure (BP), and body weight on the kidney effects of GLP-1RAs. Diastolic BP, haemoglobin, heart rate, low-density lipoprotein and total cholesterol, and white blood cell count were also investigated. The mediation effect was estimated by the novel Vansteelandt statistical method. Subgroups with estimated glomerular filtration rate (eGFR) <60 and ≥60 mL/min/1.73 m were examined in LEADER.
We observed that HbA1c mediated 25% (95% confidence interval [CI] -7.1; 67.3) and 26% (95% CI noncalculable), and systolic BP 9% (95% CI 2.8; 22.7) and 22% (95% CI noncalculable) of kidney effects of GLP-1RAs in LEADER and SUSTAIN 6, respectively. Small or no mediation was observed for the other parameters; for example, body weight mediated 9% (95% CI -7.9; 35.5) in the former and did not mediate effects in the latter study. Mediation by HbA1c was greater in patients with eGFR ≥60 mL/min/1.73 m (57%) versus those with eGFR <60 mL/min/1.73 m (no mediation).
Our results suggest that HbA1c and systolic BP may moderately mediate kidney benefits of liraglutide and semaglutide, with all other variables having a small to no effect. Potential kidney benefits may be driven by other mediators or potentially by direct mechanisms.
研究利拉鲁肽和司美格鲁肽治疗 2 型糖尿病患者时，慢性肾脏病危险因素的变化是否可以解释白蛋白尿以外的肾脏结局（主要包括大量白蛋白尿、血清肌酐翻倍、肾脏替代治疗或肾脏死亡的复合终点）的明显改善。
我们评估了糖化血红蛋白（HbA1c）、收缩压（BP）和体重对 GLP-1RA 肾脏作用的中介效应。还研究了舒张压、血红蛋白、心率、低密度脂蛋白胆固醇和总胆固醇以及白细胞计数。中介效应通过新的 Vansteelandt 统计方法进行评估。在 LEADER 中，还对估计肾小球滤过率（eGFR）<60 和≥60mL/min/1.73m2 的亚组进行了检查。
我们观察到，HbA1c 介导了 LEADER 和 SUSTAIN 6 中 GLP-1RA 肾脏作用的 25%（95%置信区间[CI] -7.1；67.3）和 26%（95%CI 不可计算），收缩压介导了 9%（95%CI 2.8；22.7）和 22%（95%CI 不可计算）。其他参数观察到的中介作用较小或没有；例如，体重在前者中介导了 9%（95%CI -7.9；35.5），而在后者中没有介导作用。eGFR≥60mL/min/1.73m2 的患者中 HbA1c 介导作用更大（57%），而 eGFR<60mL/min/1.73m2 的患者则没有介导作用。
我们的结果表明，HbA1c 和收缩压可能适度介导利拉鲁肽和司美格鲁肽的肾脏获益，其他所有变量的影响较小或没有。潜在的肾脏获益可能由其他介质或潜在的直接机制驱动。
