SGLT2 inhibition in the diabetic kidney—from mechanisms to clinical outcome

Research output: Contribution to journalReview articleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)700-710
Number of pages11
JournalClinical Journal of the American Society of Nephrology
Volume12
Issue number4
DOIs
Publication statusPublished - 2017

Cite this

@article{d067f252e92345cfa08c318e52a3447c,
title = "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.",
keywords = "Benzhydryl compounds, Blood pressure, Body weight, Cardiovascular disease, Cardiovascular diseases, Chronic, Diabetes mellitus, Diabetic nephropathies, Diabetic nephropathy, Dyslipidemias, Glucose, Glucose transporter type 2, Glucosides, Glycosuria, Humans, Hyperglycemia, Hypertension, Kidney failure, Liraglutide, Obesity, Risk factors, Sodium, Sodium-glucose transporter 2, Type 2, Up-regulation, Uric acid",
author = "{van Bommel}, {Erik J.M.} and Muskiet, {Marcel H.A.} and Lennart Tonneijck and Kramer, {Mark H.H.} and Max Nieuwdorp and {van Raalte}, {Daniel H.}",
year = "2017",
doi = "10.2215/CJN.06080616",
language = "English",
volume = "12",
pages = "700--710",
journal = "Clinical Journal of the American Society of Nephrology",
issn = "1555-9041",
publisher = "American Society of Nephrology",
number = "4",

}

TY - JOUR

T1 - SGLT2 inhibition in the diabetic kidney—from mechanisms to clinical outcome

AU - van Bommel, Erik J.M.

AU - Muskiet, Marcel H.A.

AU - Tonneijck, Lennart

AU - Kramer, Mark H.H.

AU - Nieuwdorp, Max

AU - van Raalte, Daniel H.

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

KW - Benzhydryl compounds

KW - Blood pressure

KW - Body weight

KW - Cardiovascular disease

KW - Cardiovascular diseases

KW - Chronic

KW - Diabetes mellitus

KW - Diabetic nephropathies

KW - Diabetic nephropathy

KW - Dyslipidemias

KW - Glucose

KW - Glucose transporter type 2

KW - Glucosides

KW - Glycosuria

KW - Humans

KW - Hyperglycemia

KW - Hypertension

KW - Kidney failure

KW - Liraglutide

KW - Obesity

KW - Risk factors

KW - Sodium

KW - Sodium-glucose transporter 2

KW - Type 2

KW - Up-regulation

KW - Uric acid

UR - http://www.scopus.com/inward/record.url?scp=85021642011&partnerID=8YFLogxK

U2 - 10.2215/CJN.06080616

DO - 10.2215/CJN.06080616

M3 - Review article

VL - 12

SP - 700

EP - 710

JO - Clinical Journal of the American Society of Nephrology

JF - Clinical Journal of the American Society of Nephrology

SN - 1555-9041

IS - 4

ER -