背景:钠-葡萄糖协同转运蛋白2抑制剂(SGLT2i)的大规模临床试验证明了在糖尿病肾病中降低蛋白尿的作用,即使在用肾素-血管紧张素抑制剂治疗后。这种有利作用的确切机制仍不清楚。这项前瞻性开放标签单臂研究调查了SGLT2i给药后与蛋白尿减少相关的因素。
方法:招募尽管饮食和/或口服降糖单一疗法但糖化血红蛋白(HbA1c)水平≥6.5%的2型糖尿病(T2DM)患者,并给予推荐的每日剂量SGLT2i,持续4个月。双主要结果为从基线开始第4个月时尿白蛋白-肌酐比值(uACR)和尿肝型脂肪酸结合蛋白(L-FABP)-肌酐比值(uL-FABPCR)的变化。肾损伤的变化,炎症,和氧化应激生物标志物作为次要终点进行研究,以检查该治疗对肾脏的影响.肾脏结局与临床指标的相关性,包括循环肿瘤坏死因子受体(TNFR)1和2,采用单变量和多变量分析进行评估.
结果:参与者(n=123)的平均年龄为64.1岁(SD13.4),50.4%是男性。BMI中位数为25.8kg/m2(四分位数间距(IQR)23.1-28.9),HbA1c中位数水平为7.3%(IQR6.9-8.3)。在SGLT2i管理之后,uACR从19.2mg/gCr(IQR7.1-48.7)下降到13.3mg/gCr(IQR7.5-31.6),而uL-FABPCR不受影响。在单变量分析中,SGLT2i给药引起的对数转化uACR的变化与血清TNFR1水平的变化呈正相关(R=0.244,p<0.01)。多元回归分析,包括混杂因素,显示血清TNFR1水平的变化与对数转化的uACR的变化独立相关(独立t=2.102,p<0.05)。
结论:SGLT2i给药4个月后,2型糖尿病患者蛋白尿水平降低与血清TNFR水平降低相关.
背景:UMIN000031947.
先前的研究已经证明了钠-葡萄糖协同转运蛋白2抑制剂(SGLT2i)与肾素-血管紧张素系统阻滞剂联合治疗的协同性蛋白尿减少作用;然而,这种效应的潜在机制知之甚少。这项研究基于我们的假设,即减少蛋白尿的作用与SGLT2i的抗炎作用有关,而不是对血糖控制的作用。总的来说,123例2型糖尿病(T2DM)患者接受推荐日剂量SGLT2i治疗4个月。双主要结果是尿白蛋白-肌酐比值(uACR)和尿肝型脂肪酸结合蛋白(L-FABP)-肌酐比值(uL-FABPCR)作为肾小球和近端肾小管损伤标志物的变化。次要结果包括肾损伤生物标志物的变化,炎症,和氧化应激来检查治疗对肾脏的影响。肾脏结局与临床指标的相关性,包括循环肿瘤坏死因子受体(TNFR)1和2,采用单变量和多变量分析进行评估.我们发现SGLT2i的给药降低了尿白蛋白与肌酐的比率,但不影响尿肝型脂肪酸结合蛋白与肌酐的比率。Further,SGLT2i可能在T2DM患者中发挥依赖于抗炎作用的蛋白尿减少作用。SGLT2i的炎症减轻和肾脏保护机制仍有待完全阐明。但是这项研究提供了有关机制的新证据。研究结果可以帮助开发用于代谢性疾病的抗炎药。
BACKGROUND: Large-scale clinical trials of sodium-glucose cotransporter 2 inhibitors (SGLT2i) demonstrate proteinuria-reducing effects in diabetic kidney disease, even after treatment with renin-angiotensin inhibitors. The precise mechanism for this favorable effect remains unclear. This prospective open-label single-arm study investigated factors associated with a reduction in proteinuria after SGLT2i administration.
METHODS: Patients with type 2 diabetes (T2DM) who had glycated hemoglobin (HbA1c) levels ≥ 6.5% despite dietary and/or oral hypoglycemic monotherapy were recruited and administered the recommended daily dose of SGLT2i for 4 months. Dual primary outcomes were changes in the urine albumin-to-creatinine ratio (uACR) and urine liver-type fatty acid-binding protein (L-FABP)-to-creatinine ratio (uL-FABPCR) at month 4 from baseline. Changes in kidney injury, inflammation, and oxidative stress biomarkers were investigated as secondary endpoints to examine the effects of this treatment on the kidney. The correlation between renal outcomes and clinical indicators, including circulating tumor necrosis factor receptors (TNFR) 1 and 2, was evaluated using univariate and multivariate analyses.
RESULTS: Participants (n = 123) had a mean age of 64.1 years (SD 13.4), with 50.4% being male. The median BMI was 25.8 kg/m2 (interquartile range (IQR) 23.1-28.9), and the median HbA1c level was 7.3% (IQR 6.9-8.3). After SGLT2i administration, the uACR declined from 19.2 mg/gCr (IQR 7.1-48.7) to 13.3 mg/gCr (IQR 7.5-31.6), whereas the uL-FABPCR was not influenced. In univariate analysis, the change in log-transformed uACR due to SGLT2i administration showed a positive correlation with the change in serum TNFR1 level (R = 0.244, p < 0.01). Multivariate regression analysis, including confounding factors, showed that the changes in serum TNFR1 level were independently associated with the changes in the log-transformed uACR (independent t = 2.102, p < 0.05).
CONCLUSIONS: After the 4-month SGLT2i administration, decreased albuminuria level was associated with decreased serum TNFR level in patients with T2DM.
BACKGROUND: UMIN000031947.
Previous studies have demonstrated the synergistic proteinuria-reducing effect of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in combination therapy with renin–angiotensin system blockers; however, the underlying mechanisms of this effect are poorly understood. This study was based on our hypothesis that the proteinuria-reducing effect is associated with the anti-inflammatory effects of SGLT2i beyond the effect on glycemic control. In total, 123 patients with type 2 diabetes mellitus (T2DM) were administered the recommended daily dose of SGLT2i for 4 months. Dual primary outcomes were changes in the urine albumin-to-creatinine ratio (uACR) and urine liver-type fatty acid-binding protein (L-FABP)-to-creatinine ratio (uL-FABPCR) as markers of glomerular and proximal tubular damage at 4 months from the baseline. Secondary outcomes included changes in kidney injury biomarkers, inflammation, and oxidative stress to examine the effects of treatment on the kidneys. The correlation between renal outcomes and clinical indicators, including circulating tumor necrosis factor receptors (TNFR) 1 and 2, was evaluated using univariate and multivariate analyses. We found that administration of SGLT2i decreased the urine albumin-to-creatinine ratio but did not affect the urine liver-type fatty acid-binding protein-to-creatinine ratio. Further, SGLT2i may exert a proteinuria-reducing effect dependent on the anti-inflammatory effect in patients with T2DM. The inflammation-reducing and renoprotective mechanisms of SGLT2i remain to be fully clarified, but this study provides novel evidence regarding the mechanism. The study findings can help in developing anti-inflammatory agents for metabolic diseases.