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

Abstract

2, n=13) at baseline. Renal function and circulating levels of renin-angiotensin-aldosterone system mediators and NO were measured under clamped euglycemic (4-6 mmol/l) and hyperglycemic (9-11 mmol/l) conditions at baseline and end of treatment. During clamped euglycemia, hyperfiltration was attenuated by −33 ml/min/1.73m 2 with empagliflozin in T1D-H, (GFR 172±23-139±25 ml/min/1.73 m 2 , P<0.01). This effect was accompanied by declines in plasma NO and effective renal plasma flow and an increase in renal vascular resistance (all P<0.01). Similar significant effects on GFR and renal function parameters were observed during clamped hyperglycemia. In T1D-N, GFR, other renal function parameters, and plasma NO were not altered by empagliflozin. Empagliflozin reduced hemoglobin A1c significantly in both groups, despite lower insulin doses in each group (P≤0.04). This distal tubular condition is sensed as a low effective circulating volume stimulus at the level of the juxtaglomerular apparatus, causing an afferent renal vasodilatory response ( Figure 1B). The consequence of this altered TGF results in supranormal glomerular filtration rate (GFR) values into the hyperfiltration range. Targeting TGF in renal hyperfiltration has shown promising results in experimental animal models by using phlorizin, a nonspecific inhibitor of the renal tubular glucose transporters SGlT1 and SGlT2. 13,14 The clinical relevance of these findings, however, could not be conclusively studied in humans, because of the poor tolerability of phlorizin resulting from its low selectivity for SGlT2, SGlT1 inhibition-related gastrointestinal side effects and very limited oral bioavailability. Conclusions-In14 Subsequent studies with selective SGlT2 inhibitors in animals have also shown similar significant effects on renal hyperfiltration. 15 More recently, several highly selective SGlT2 inhibitors have been developed for use in clinical trials in patients with type 2 diabetes mellitus (T2D). 16,17 These compounds generally do not affect SGlT1 at clinical doses and have pharmacological features that allow once daily oral dosing. In T2D, this class of drugs is well-tolerated and has consistently improved glycemic control, along with weight loss, and antihypertensive effects. 17,18 Available evidence for SGlT2 inhibitors in T1D is however limited, and is mainly derived from experimental animal models. Only 1 clinical pilot study has been conducted, which demonstrated that a single dose of remogliflozin improved postprandial glucose profiles. 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 p...

Empagliflozin as adjunct to insulin in patients with type 1 diabetes: a 4‐week, randomized, placebo‐controlled trial (EASE‐1)

“…High fasting β‐hydroxybutyrate levels were observed in two patients on empagliflozin during routine safety laboratory monitoring at week 4, but these were not considered AEs by the investigator. Small changes in eGFR were observed with empagliflozin, likely as a result of haemodynamic changes attributable to effects on tubular‐feedback mechanisms 25.…”

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

“…In patients with type 2 diabetes, empagliflozin is consistently associated with declines in HbA 1c , systolic BP (SBP) and weight [7][8][9][10]. Empagliflozin has been shown to decrease renal hyperfiltration in patients with type 1 diabetes [11]. This renal physiological characteristic has been linked to the development of nephropathy in type 1 and type 2 diabetes [12][13][14].…”

“…Furthermore, SGLT2 inhibition may improve this early glomerular haemodynamic abnormality through inhibition of sodium-glucose reabsorption at the proximal tubule [12][13][14]. Such a natriuretic effect increases sodium delivery to the distal tubule, thereby stimulating tubuloglomerular feedback, ultimately causing afferent renal arteriolar vasoconstriction and a reduction in intraglomerular pressure [11,12]. Based on available data in healthy humans and in patients with type 1 diabetes, the renal haemodynamic effects of SGLT2 inhibition appear to be RAAS independent, as plasma and urinary levels of RAAS mediators increase modestly, rather than decline, in response to the intervention [11,13,14].…”

“…Such a natriuretic effect increases sodium delivery to the distal tubule, thereby stimulating tubuloglomerular feedback, ultimately causing afferent renal arteriolar vasoconstriction and a reduction in intraglomerular pressure [11,12]. Based on available data in healthy humans and in patients with type 1 diabetes, the renal haemodynamic effects of SGLT2 inhibition appear to be RAAS independent, as plasma and urinary levels of RAAS mediators increase modestly, rather than decline, in response to the intervention [11,13,14]. The renal protective effect of empagliflozin, including effects on established clinical renal biomarkers such as albuminuria, remains to be systematically studied.…”

Diabetic nephropathy: newer therapeutic perspectives

“…The renal significance of these drugs comes from their ability to restore a dysregulated TGF. Restoration of this mechanism results in reduced glomerular filtration and glomerulomegaly [21]. Figure 1 explains how the enhanced absorption of sodium proximally leads to a decreased distal sodium delivery, which results in afferent arteriolar vasodilation and glomerulomegaly.…”