Koshino Akihiko, Heerspink Hiddo J L, Jongs Niels, Badve Sunil V, Arnott Clare, Neal Bruce, Jardine Meg, Mahaffey Kenneth W, Pollock Carol, Perkovic Vlado, Hansen Michael K, Bakker Stephan J L, Wada Takashi, Neuen Brendon L
Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Department of Nephrology and Rheumatology, Kanazawa University, Ishikawa, Japan.
Nephrol Dial Transplant. 2025 Apr 1;40(4):696-706. doi: 10.1093/ndt/gfae198.
Studies in patients with heart failure have indicated that sodium-glucose cotransporter 2 (SGLT2) inhibitors increase iron use and enhance erythropoiesis. In this post hoc analysis of the Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial, we evaluated the effects of canagliflozin on iron metabolism in patients with chronic kidney disease (CKD) and whether the effects of canagliflozin on hemoglobin and cardiorenal outcomes were modified by iron deficiency.
We measured serum iron, total iron binding capacity (TIBC), transferrin saturation (TSAT) and ferritin at baseline and 12 months. The effects of canagliflozin, relative to placebo, on iron markers were assessed with analysis of covariance. Interactions between baseline iron deficiency, defined as TSAT <20%, and the effects of canagliflozin on hemoglobin and cardiorenal outcomes were evaluated with mixed effect models and Cox regression models, respectively.
Of 4401 participants randomized in CREDENCE, 2416 (54.9%) had iron markers measured at baseline, of whom 924 (38.2%) were iron deficient. Canagliflozin, compared with placebo, increased TIBC by 2.1% [95% confidence interval (CI) 0.4, 3.8; P = .014] and decreased ferritin by 11.5% (95% CI 7.1, 15.7; P < .001) with no clear effect on serum iron or TSAT. Canagliflozin increased hemoglobin over the trial duration by 7.3 g/L (95% CI 6.2, 8.5; P < .001) and 6.7 g/L (95% CI 5.2, 8.2; P < .001) in patients with and without iron deficiency, respectively (P for interaction = .38). The relative effect of canagliflozin on the primary outcome of doubling of serum creatinine, kidney failure or death due to cardiovascular disease or kidney failure (hazard ratio 0.70, 95% CI 0.56, 0.87) was consistent regardless of iron deficiency (P for interaction = .83), as were effects on other cardiovascular and mortality outcomes (all P for interactions ≥0.10).
Iron deficiency is highly prevalent in patients with type 2 diabetes and CKD. Canagliflozin increased TIBC and decreased ferritin in patients with type 2 diabetes and CKD, suggesting increased iron utilization, and improved hemoglobin levels and clinical outcomes regardless of iron deficiency.
对心力衰竭患者的研究表明，钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂可增加铁的利用并促进红细胞生成。在这项对卡格列净与糖尿病合并已确诊肾病临床评估（CREDENCE）试验的事后分析中，我们评估了卡格列净对慢性肾脏病（CKD）患者铁代谢的影响，以及铁缺乏是否会改变卡格列净对血红蛋白和心肾结局的影响。
我们在基线和12个月时测量了血清铁、总铁结合力（TIBC）、转铁蛋白饱和度（TSAT）和铁蛋白。通过协方差分析评估卡格列净相对于安慰剂对铁指标的影响。分别使用混合效应模型和Cox回归模型评估基线铁缺乏（定义为TSAT<20%）与卡格列净对血红蛋白和心肾结局影响之间的相互作用。
在CREDENCE试验中随机分组的4401名参与者中，2416名（54.9%）在基线时测量了铁指标，其中924名（38.2%）存在铁缺乏。与安慰剂相比，卡格列净使TIBC增加了2.1%[95%置信区间（CI）0.4，3.8；P = 0.014]，使铁蛋白降低了11.5%（95%CI 7.1，15.7；P < 0.001），而对血清铁或TSAT没有明显影响。在试验期间，无论有无铁缺乏，卡格列净分别使血红蛋白水平升高了7.3 g/L（95%CI 6.2，8.5；P < 0.001）和6.7 g/L（95%CI 5.2，8.2；P < 0.001）（交互作用P = 0.38）。无论铁缺乏情况如何，卡格列净对血清肌酐翻倍、肾衰竭或因心血管疾病或肾衰竭导致的死亡这一主要结局的相对影响（风险比0.70，95%CI 0.56，0.87）是一致的（交互作用P = 0.83），对其他心血管和死亡率结局的影响也是如此（所有交互作用P≥0.10）。
铁缺乏在2型糖尿病和CKD患者中非常普遍。卡格列净可增加2型糖尿病和CKD患者的TIBC并降低铁蛋白，提示铁利用增加，且无论铁缺乏情况如何，均可改善血红蛋白水平和临床结局。
