Effects of a New SGLT2 Inhibitor, Luseogliflozin, on Diabetic Nephropathy in T2DN Rats

Abstract

This study examined the effect of long-term control of hyperglycemia with a new sodium glucose cotransporter 2 inhibitor, luseogliflozin, given alone or in combination with lisinopril on the progression of renal injury in the T2DN rat model of type 2 diabetic nephropathy. Chronic treatment with luseogliflozin (10 mg/kg/day) produced a sustained increase in glucose excretion and normalized blood glucose and glycosylated hemoglobin levels to the same level as seen in the rats treated with insulin. It had no effect on blood pressure. In contrast, lisinopril (10 mg/kg/day) reduced mean blood pressure from 140 to 113 mmHg. Combination therapy significantly reduced blood pressure more than that seen in the rats treated with lisinopril. T2DN rats treated with vehicle exhibited progressive proteinuria, a decline in glomerular filtration rate (GFR), focal glomerulosclerosis, renal fibrosis, and tubular necrosis. Control of hyperglycemia with luseogliflozin prevented the fall in GFR and reduced the degree of glomerular injury, renal fibrosis, and tubular necrosis. In contrast, control of hyperglycemia with insulin had no effect on the progression of renal disease in T2DN rats. Reducing blood pressure with lisinopril prevented the fall in GFR and reduced proteinuria and the degree of glomerular injury and tubular necrosis. Combination therapy reduced the degree of glomerular injury, renal fibrosis, and tubular necrosis to a greater extent than administration of either drug alone. These results suggest that control of hyperglycemia with luseogliflozin slows the progression of diabetic nephropathy more than that seen with insulin, and combination therapy is more renoprotective than administration of either compound alone.

Renal Hemodynamic Effect of Sodium-Glucose Cotransporter 2 Inhibition in Patients With Type 1 Diabetes Mellitus

“…38,39 Importantly, RAAS blockade with SGlT2 inhibition in animals has recently been shown to lead to additive renoprotective effects compared to either drug alone. 21 Hence, it is tempting to speculate that combined use of SGlT2 and RAAS inhibitors may lead to similar synergistic effects through combined blockade of neurohormonal and tubular factors in humans. Future studies should examine whether a combined strategy of dual RAAS and SGlT2 inhibition has the potential to exert longterm renal and systemic vascular protection, in part through normalizing hyperfiltration.…”

“…19 Based on previous findings with phlorizin and other SGlT2 inhibitors in animals, the concept of altering renal hyperfiltration by blocking renal glucose absorption with SGlT2 inhibitors is intriguing, because reducing this surrogate marker of intraglomerular pressure is renal protective in experimental models of diabetes mellitus. 13,20,21 However, potential renal hemodynamic effects of these drugs in subjects with diabetes mellitus, including effects on renal hyperfiltration, remain unknown. Accordingly, the primary objective of this 8-week, openlabel, stratified clinical trial (NCT01392560) was to determine the impact of treatment with the oral and highly selective SGlT2 inhibitor empagliflozin (Boehringer Ingelheim), 25 mg qd, on renal hyperfiltration in subjects with T1D.…”

The effect of sodium glucose cotransporter 2 inhibition with empagliflozin on microalbuminuria and macroalbuminuria in patients with type 2 diabetes

“…It is important to highlight that while SGLT2 inhibition exerts renal protective effects in animals, including preservation of renal function, decreased glomerulosclerosis and tubulointerstitial fibrosis, and decreased albuminuria, these effects could be enhanced when combined with traditional ACE inhibition [37]. Whether this additive effect is achieved via haemodynamic or non-haemodynamic (i.e.…”

The Non-glycemic Effects of SGLT2 Inhibitor

“…반면에 familial renal glycosuria 환자에서는 RAAS축의 활 성이 증가되어 있다는 보고들이 있으며 당뇨병 환자에 서 SGLT2 억제제 투여 시 혈압감소와 과여과의 감소 등 이로운 혈역학적 변화와 동반해서 레닌-안지오텐신 알도스테론 축의 활성이 증가한다고 보고되었다 [10,28]. 또한 RAAS 차단제와 SGLT2 억제제가 각 약 제의 단독요법 보다 신장보호효과가 더 우수하다는 동 물실험 결과가 있으므로 향후 임상연구를 통해서 확인 할 필요가 있다 [10,23]. 혈청 요산 농도는 신장의 배설에 의해서도 영향을 받 는데 사구체로 여과된 요산의 ~90%는 근위관세포에 의해서 재흡수된다 [30].…”