SGLT-2 inhibitors in Diabetic Kidney Disease: What Lies Behind their Renoprotective Properties?

(E-pub Ahead of Print)

Author(s): Panagiotis I. Georgianos , Maria Divani , Theodoros Eleftheriadis , Peter R. Mertens , Vassilios Liakopoulos* .

Journal Name: Current Medicinal Chemistry


Background: Despite optimal management of diabetic kidney disease (DKD) with intensive glycemic control and administration of agents blocking the renin-angiotensinaldosterone- system, the residual risk for nephropathy progression to end-stage-renal-disease (ESRD) remains high. Sodium-glucose co-transporter type 2 (SGLT-2)-inhibitors represent a newly-introduced anti-diabetic drug class with pleiotropic actions extending above their glucose-lowering efficacy. Herein, we provide an overview of preclinical and clinical-trial evidence supporting a protective effect of SGLT-2 inhibitors on DKD. Methods: A systematic literature search of bibliographic databases was conducted to identify preclinical studies and randomized trials evaluating the effects SGLT-2 inhibitors on DKD. Results: Preclinical studies performed in animal models of DKD support the renoprotective action of SGLT-2 inhibitors showing that these agents exert albuminuria-lowering effects and reverse glomerulosclerosis. The renoprotective action of SGLT-2 inhibitors is strongly supported by human studies showing that these agents prevent the progression of albuminuria and retard nephropathy progression to ESRD. This beneficial effect of SGLT-2 inhibitors is not fully explained by their glucose-lowering properties. Attenuation of glomerular hyperfiltration and improvement in a number of surrogate risk factors, including associated reduction in systemic blood pressure, body weight, and serum uric acid levels may represent plausible mechanistic explanations for the cardio-renal protection offered by SGLT-2 inhibitors. Furthermore, the tubular cell metabolism seems to be altered towards a ketone-prone pathway with protective activities. Conclusion: SGLT-2 inhibition emerges as a novel therapeutic approach to type 2 diabetes with anticipated benefits towards cardio-renal risk reduction. Additional research efforts are clearly warranted to elucidate this favorable effect in patients with overt DKD.

Keywords: albuminuria, diabetic nephropathy, ESRD, SGLT-2.

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(E-pub Ahead of Print)
DOI: 10.2174/0929867325666180524114033
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