Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Urinary Excretion of Intact and Total Angiotensinogen in Patients with Type 2 Diabetes

Abstract

We conducted a descriptive case study to examine the effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on urinary angiotensinogen excretion, which represents the function of the intrarenal renin–angiotensin system, in patients with type 2 diabetes. An SGLT2 inhibitor (canagliflozin 100 mg/day, ipragliflozin 25 mg/day, dapagliflozin 5 mg/day, luseogliflozin 2.5 mg/day or tofogliflozin 20 mg/day) was administered for 1 month (n=9). ELISA kits were used to measure both urinary intact and total angiotensinogen levels. Treatment with SGLT2 inhibitors significantly decreased hemoglobin A1c, body weight, systolic blood pressure and diastolic blood pressure (8.5±1.3 to 7.5%±1.0%, 82.5±20.2 to 80.6±20.9 kg, 143±8 to 128±14 mm Hg, 78±10 to 67±9 mm Hg, p<0.05, respectively), while urinary albumin/creatinine ratio was not significantly changed (58.6±58.9 to 29.2±60.7 mg/g, p=0.16). Both total urinary angiotensinogen/creatinine ratio and intact urinary angiotensinogen/creatinine ratio tended to decrease after administration of SGLT2 inhibitors. However, these changes were not significant (p=0.19 and p=0.08, respectively). These data suggest that treatment with SGLT2 inhibitors does not activate the intrarenal renin–angiotensin system in patients with type 2 diabetes.

Canagliflozin Prevents Intrarenal Angiotensinogen Augmentation and Mitigates Kidney Injury and Hypertension in Mouse Model of Type 2 Diabetes Mellitus

“…Other studies also showed no changes in albuminuria by SGLT2 inhibitors [27,30]. The issue is complicated in that the duration of treatment appears to influence the effects of treatment on albuminuria.…”

“…Furthermore, augmentation of AGT expression by high glucose and palmitic acid in cultured human PTC was blunted by Dapagliflozin [26]. In a small study, patients with T2DM, SGLT2 inhibitors exhibited a decreasing trend, but not significant, in urinary AGT excretion rates [27]. In contrast, the db/db mouse model of T2DM exhibited decreased renal AGT mRNA expression that was enhanced by treatment with an SGLT2 inhibitor [28] and increased urinary AGT levels in response to Empagliflozin treatment of the OLETF DM rat [29] has been reported.…”

Effects of glucose-lowering agents on surrogate endpoints and hard clinical renal outcomes in patients with type 2 diabetes

“…Recent results for biomarkers have suggested that the albuminuria-lowering effect of SGLT2is may be the result of decreased intraglomerular pressure or less tubular cell injury possibly related to decreased inflammation [117] and perhaps also linked to reduced activity of the intrarenal renin-angiotensin system [118]. SGLT2is also lower serum uric acid levels [119,120], an independent risk factor for diminished eGFRs in patients with T2DM [121,122].…”

Reply to ‘Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Urinary Excretion of Intact and Total Angiotensinogen in Patients with Type 2 Diabetes’ by Yoshimoto Et Al.

“…First, the Yoshimoto et al 1 study has been performed using different iSGLT2, even though they work in a similar way, they do not have the same potency blocking the SGLT2 receptors. In addition, the doses used are not comparable.…”