Ferrannini Ele, Baldi Simona, Scozzaro Maria Tiziana, Ferrannini Giulia, Hansen Michael K
CNR (National Research Council) Institute of Clinical Physiology, Pisa, Italy.
Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
JCI Insight. 2024 Dec 20;9(24):e180637. doi: 10.1172/jci.insight.180637.
BACKGROUNDSodium-glucose cotransporter 2 inhibitors slow down progression of chronic kidney disease (CKD). We tested whether the circulating substrate mix is related to CKD progression and cardiovascular outcomes in patients with type 2 diabetes (T2D) and albuminuric CKD in the CREDENCE trial.METHODSWe measured fasting substrates in 2,543 plasma samples at baseline and 1 year after randomization to either 100 mg canagliflozin or placebo and used multivariate Cox models to explore their association with CKD progression, heart failure hospitalization/cardiovascular death (hHF/CVD), and mortality.RESULTSHigher baseline lactate and free fatty acids (FFAs) were independently associated with a lower risk of CKD progression (HR = 0.73 [95% CI: 0.54-0.98] and HR = 0.67 [95% CI: 0.48-0.95], respectively) and hHF/CVD HR = 0.70 [95% CI: 0.50-0.99] and HR = 0.63 [95% CI: 0.42-0.94]). Canagliflozin led to a rise in plasma FFAs, glycerol, β-hydroxybutyrate, and acetoacetate. Changes in substrate between baseline and year 1 predicted an approximately 30% reduction in relative risk of both CKD progression and hHF/CVD independently of treatment. More patients who did not respond to canagliflozin treatment in terms of CKD progression belonged to the bottom lactate and FFA distribution tertiles.CONCLUSIONIn T2D patients with albuminuric CKD, basic energy substrates selectively influenced major long-term endpoints; canagliflozin treatment amplified their effects by chronically raising their circulating levels.
钠-葡萄糖协同转运蛋白2抑制剂可减缓慢性肾脏病（CKD）的进展。在CREDENCE试验中，我们测试了2型糖尿病（T2D）合并白蛋白尿性CKD患者的循环底物组合是否与CKD进展及心血管结局相关。
我们在基线时以及随机分组接受100 mg卡格列净或安慰剂治疗1年后，对2543份血浆样本中的空腹底物进行了测量，并使用多变量Cox模型来探讨它们与CKD进展、心力衰竭住院/心血管死亡（hHF/CVD）和死亡率之间的关联。
较高的基线乳酸和游离脂肪酸（FFA）分别独立与较低的CKD进展风险（风险比[HR]=0.73[95%置信区间（CI）：0.54-0.98]和HR=0.67[95%CI：0.48-0.95]）以及hHF/CVD风险（HR=0.70[95%CI：0.50-0.99]和HR=0.63[95%CI：0.42-0.94]）相关。卡格列净导致血浆FFA、甘油、β-羟基丁酸和乙酰乙酸升高。基线至第1年底物的变化独立于治疗可预测CKD进展和hHF/CVD的相对风险降低约30%。在CKD进展方面对卡格列净治疗无反应的患者中，更多患者属于乳酸和FFA分布最低三分位数。
在合并白蛋白尿性CKD的T2D患者中，基础能量底物选择性地影响主要长期终点；卡格列净治疗通过长期提高其循环水平增强了它们的作用。
