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SGLT2 Inhibition in the Diabetic Kidney-From Mechanisms to Clinical Outcome.

ABSTRACT: Diabetic kidney disease not only has become the leading cause for ESRD worldwide but also, highly contributes to increased cardiovascular morbidity and mortality in type 2 diabetes. Despite increased efforts to optimize renal and cardiovascular risk factors, like hyperglycemia, hypertension, obesity, and dyslipidemia, they are often insufficiently controlled in clinical practice. Although current drug interventions mostly target a single risk factor, more substantial improvements of renal and cardiovascular outcomes can be expected when multiple factors are improved simultaneously. Sodium-glucose cotransporter type 2 in the renal proximal tubule reabsorbs approximately 90% of filtered glucose. In type 2 diabetes, the maladaptive upregulation of sodium-glucose cotransporter type 2 contributes to the maintenance of hyperglycemia. Inhibiting these transporters has been shown to effectively improve glycemic control through inducing glycosuria and is generally well tolerated, although patients experience more genital infections. In addition, sodium-glucose cotransporter type 2 inhibitors favorably affect body weight, BP, serum uric acid, and glomerular hyperfiltration. Interestingly, in the recently reported first cardiovascular safety trial with a sodium-glucose cotransporter type 2 inhibitor, empagliflozin improved both renal and cardiovascular outcomes in patients with type 2 diabetes and established cardiovascular disease. Because the benefits were seen rapidly after initiation of therapy and other glucose-lowering agents, with the exception of liraglutide and semaglutide, have not been able to improve cardiovascular outcome, these observations are most likely explained by effects beyond glucose lowering. In this mini review, we present the drug class of sodium-glucose cotransporter type 2 inhibitors, elaborate on currently available renal and cardiovascular outcome data, and discuss how the effects of these agents on renal physiology may explain the data.

SUBMITTER: van Bommel EJ

PROVIDER: S-EPMC5383382 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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SGLT2 Inhibition in the Diabetic Kidney-From Mechanisms to Clinical Outcome.

van Bommel Erik J M EJM Muskiet Marcel H A MHA Tonneijck Lennart L Kramer Mark H H MHH Nieuwdorp Max M van Raalte Daniel H DH

Clinical journal of the American Society of Nephrology : CJASN 20170302 4

Diabetic kidney disease not only has become the leading cause for ESRD worldwide but also, highly contributes to increased cardiovascular morbidity and mortality in type 2 diabetes. Despite increased efforts to optimize renal and cardiovascular risk factors, like hyperglycemia, hypertension, obesity, and dyslipidemia, they are often insufficiently controlled in clinical practice. Although current drug interventions mostly target a single risk factor, more substantial improvements of renal and ca ...[more]

PMID: 28254770

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Project description:IntroductionSodium-glucose cotransporter 2 inhibitors (SGLT2i) have emerged as novel therapeutics to treat diabetic kidney disease (DKD). Although the beneficial effects of SGLT2i have been demonstrated, their target mechanisms on kidney function are unknown. The current study aimed to elucidate these mechanisms by studying SGLT2i-induced changes in the urinary proteome of persons with type 2 diabetes (T2D) and DKD.MethodsA total of 40 participants with T2D were enrolled in a double-blinded randomized cross-over trial at the Steno Diabetes Center Copenhagen, Denmark. They were treated with 10 mg of dapagliflozin for 12 weeks. Thirty-two participants with complete urinary proteomics measures before and after the trial were included. All participants received renin-angiotensin system blockade and had albuminuria, (urine albumin-to-creatinine ratio [UACR] ≥30 mg/g). A type 1 diabetes (T1D) cohort consisting of healthy controls and persons with DKD was included for validation. Urinary proteome changes were analyzed using Wilcoxon signed-rank test. Functional enrichment analysis was conducted to discover affected biological processes.ResultsDapagliflozin treatment significantly (Padjusted < 0.05) affected 36 urinary peptide fragments derived from 19 proteins. Eighteen proteins were correspondingly reflected in the validation cohort. A multifold change in peptide abundance was observed in many proteins (A1BG, urinary albumin [ALB], Caldesmon 1, COLCRNN, heat shock protein 90-β [HSP90AB1], IGLL5, peptidase inhibitor 16 [PI16], prostaglandin-H2-D-isomerase [PTGDS], SERPINA1). These also included urinary biomarkers of kidney fibrosis and function (type I and III collagens and albumin). Biological processes relating to inflammation, wound healing, and kidney fibrosis were enriched.ConclusionThe current study discovers the urinary proteome impacted by the SGLT2i, thereby providing new potential target sites and pathways, especially relating to wound healing and inflammation.

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SGLT2 Inhibition in the Diabetic Kidney-From Mechanisms to Clinical Outcome.

Publications

SGLT2 Inhibition in the Diabetic Kidney-From Mechanisms to Clinical Outcome.

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