SGLT2 Inhibitors and the Diabetic Kidney

Abstract

Diabetic nephropathy (DN) is the most common cause of end-stage renal disease worldwide. Blood glucose and blood pressure control reduce the risk of developing this complication; however, once DN is established, it is only possible to slow progression. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, the most recent glucose-lowering oral agents, may have the potential to exert nephroprotection not only through improving glycemic control but also through glucose-independent effects, such as blood pressure-lowering and direct renal effects. It is important to consider, however, that in patients with impaired renal function, given their mode of action, SGLT2 inhibitors are less effective in lowering blood glucose. In patients with high cardiovascular risk, the SGLT2 inhibitor empagliflozin lowered the rate of cardiovascular events, especially cardiovascular death, and substantially reduced important renal outcomes. Such benefits on DN could derive from effects beyond glycemia. Glomerular hyperfiltration is a potential risk factor for DN. In addition to the activation of the renin-angiotensin-aldosterone system, renal tubular factors, including SGLT2, contribute to glomerular hyperfiltration in diabetes. SGLT2 inhibitors reduce sodium reabsorption in the proximal tubule, causing, through tubuloglomerular feedback, afferent arteriole vasoconstriction and reduction in hyperfiltration. Experimental studies showed that SGLT2 inhibitors reduced hyperfiltration and decreased inflammatory and fibrotic responses of proximal tubular cells. SGLT2 inhibitors reduced glomerular hyperfiltration in patients with type 1 diabetes, and in patients with type 2 diabetes, they caused transient acute reductions in glomerular filtration rate, followed by a progressive recovery and stabilization of renal function. Interestingly, recent studies consistently demonstrated a reduction in albuminuria. Although these data are promising, only dedicated renal outcome trials will clarify whether SGLT2 inhibitors, in addition to their glycemic and blood pressure benefits, may provide nephroprotective effects.Diabetes is a worldwide growing public health problem with high risks of severe microvascular and macrovascular complications. Diabetic nephropathy (DN) is a major burden among the chronic complications of diabetes, given that it affects ;30% of patients with diabetes. Indeed, DN is the most common cause of end-stage renal disease in the U.S. (1) and worldwide. Known risk factors for DN include hyperglycemia, hypertension, dyslipidemia, smoking, and obesity as well as ethnic, familial, and genetic predispositions (2). Key clinical trials have demonstrated that early interventions, especially those aimed at primary prevention, are by far more effective and that it is only possible to slow progression once DN is established (2). Thus, large intervention trials on the impact of long-term intensified glucose control on chronic diabetes complications, both in type 1 and type 2 diabetes (2-6), have documented the critical role of glycemic control i...

SGLT-2 Inhibition: A Potential New Treatment for Diabetic Kidney Disease?

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A randomized clinical trial of the efficacy and safety of sitagliptin compared with dapagliflozin in patients with type 2 diabetes mellitus and mild renal insufficiency: The CompoSIT‐R study

“…These clinical observations are consistent with the distinct mechanisms of action of the two classes of agents. DPP‐4 inhibitors stabilize the incretins GLP‐1 and GIP, two peptides which stimulate the release of insulin in a glucose‐dependent manner,12 while the mechanism of action of SGLT‐2 inhibitors depends on renal function 13. However, until now, these two classes of AHAs have not been prospectively evaluated in a study limited to a population of patients with mild renal insufficiency.…”

Rodent models of diabetic nephropathy: their utility and limitations

“…A recent clinical trial of empagliflozin, a sodium-glucose cotransporter (SGLT) 2 inhibitor, in type 2 diabetic patients clearly demonstrated that the SGLT2 inhibitor slowed a decline in renal function compared with the placebo group. 84 Although the renoprotective effects of SGLT2 inhibition may be due to an improvement in diabetesinduced hyperfiltration 85 or a reduction in the overloading of renal tubular cells through an increase in ketone body production, 86 the detailed mechanisms are still unclear. Therefore, rodent models of diabetes that exhibit both glomerular lesions and tubulointerstitial damage/fibrosis should be useful for elucidating the mechanisms of the renal protective effects of SGLT2 inhibitors.…”