Department of Internal Medicine II, Kepler University Hospital, Linz, Austria.
Department of Internal Medicine III, Division of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria.
Diabetes Obes Metab. 2022 May;24(5):816-826. doi: 10.1111/dom.14639. Epub 2022 Jan 24.
Sodium glucose co-transporter-2 inhibitors (SGLT-2i) improve cardiorenal outcomes in patients with chronic kidney disease (CKD), with and without type 2 diabetes. The molecular mechanisms underlying these pleiotropic effects remain unclear, yet it is speculated that SGLT-2i elicit a neurohormonal modulation resulting in renin-angiotensin system (RAS) activation. We hypothesized that combined SGLT-2 and angiotensin-converting enzyme inhibition (ACEi) favours RAS regulation towards the beneficial angiotensin-(1-7)-driven axis.
This randomized controlled prospective study investigated the effect of 12 weeks treatment with the SGLT-2i empagliflozin on top of ACEi on the molecular RAS dynamics in 24 diabetic and 24 non-diabetic patients with CKD. Systemic RAS peptides were quantified by mass spectrometry.
In patients with type 2 diabetes, combined SGLT-2i and ACEi significantly upregulated plasma renin activity [pre-treatment median and interquartile range 298.0 (43.0-672.0) pmol/L versus post-treatment 577.0 (95.0-1543.0) pmol/L; p = .037] and angiotensin I levels [pre-treatment 289.0 (42.0-668.0) pmol/L versus post-treatment 573.0 (93.0-1522.0) pmol/L; p = .037], together with a significant increase of angiotensin-(1-7) levels [pre-treatment 14.0 (2.1-19.0) pmol/L versus post-treatment 32.0 (5.7-99.0) pmol/L; p = .012]. Empagliflozin treatment resulted in a 1.5 to 2-fold increase in main RAS peptides in patients with diabetes compared with placebo. No significant effect of empagliflozin on top of ACEi on RAS peptides was found in patients with CKD without diabetes.
A distinct RAS modulation by SGLT-2i occurs in diabetic kidney disease reflected by enhancement of the beneficial angiotensin-(1-7) providing a molecular background for this renoprotective therapeutic approach.
钠-葡萄糖协同转运蛋白 2 抑制剂（SGLT-2i）可改善伴有或不伴有 2 型糖尿病的慢性肾脏病（CKD）患者的心肾结局。这些多效作用的分子机制尚不清楚，但据推测，SGLT-2i 可引起神经激素调节，导致肾素-血管紧张素系统（RAS）激活。我们假设联合 SGLT-2 和血管紧张素转换酶抑制（ACEi）有利于 RAS 调节，偏向于有益的血管紧张素-(1-7)-驱动轴。
这项随机对照前瞻性研究调查了在 24 例糖尿病和 24 例非糖尿病 CKD 患者中，12 周 SGLT-2i 恩格列净联合 ACEi 治疗对分子 RAS 动态的影响。通过质谱法定量测定系统 RAS 肽。
在 2 型糖尿病患者中，联合 SGLT-2i 和 ACEi 可显著上调血浆肾素活性[治疗前中位数和四分位间距 298.0（43.0-672.0）pmol/L 与治疗后 577.0（95.0-1543.0）pmol/L；p=0.037]和血管紧张素 I 水平[治疗前 289.0（42.0-668.0）pmol/L 与治疗后 573.0（93.0-1522.0）pmol/L；p=0.037]，同时血管紧张素-(1-7)水平显著升高[治疗前 14.0（2.1-19.0）pmol/L 与治疗后 32.0（5.7-99.0）pmol/L；p=0.012]。与安慰剂相比，恩格列净治疗可使糖尿病患者的主要 RAS 肽增加 1.5 至 2 倍。在无糖尿病的 CKD 患者中，恩格列净联合 ACEi 对 RAS 肽无显著影响。
SGLT-2i 在糖尿病肾脏病中存在明显的 RAS 调节作用，表现为有益的血管紧张素-(1-7)增强，为这种肾脏保护治疗方法提供了分子基础。
