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.
authors.affiliation: Diabetes Center, Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Erik J M
authors.initials: EJM
authors.lastname: van Bommel
authors.forename: Marcel H A
authors.initials: MHA
authors.lastname: Muskiet
authors.forename: Lennart
authors.initials: L
authors.lastname: Tonneijck
authors.forename: Mark H H
authors.initials: MHH
authors.lastname: Kramer
authors.forename: Max
authors.initials: M
authors.lastname: Nieuwdorp
authors.forename: Daniel H
authors.initials: DH
authors.lastname: van Raalte
mesh_terms: D000419:Albuminuria / Q000188:drug therapy; D001559:Benzhydryl Compounds / Q000494:pharmacology; D001786:Blood Glucose / Q000187:drug effects*; D001794:Blood Pressure / Q000187:drug effects; D000068896:Canagliflozin / Q000494:pharmacology; D002318:Cardiovascular Diseases / Q000209:etiology* / Q000517:prevention & control; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy*; D003928:Diabetic Nephropathies / Q000150:complications / Q000188:drug therapy*; D005947:Glucose / Q000378:metabolism; D005960:Glucosides / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000494:pharmacology*; D050356:Lipid Metabolism / Q000187:drug effects; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D015431:Weight Loss / Q000187:drug effects
chemical_list: D001559:Benzhydryl Compounds; D001786:Blood Glucose; D005960:Glucosides; D007004:Hypoglycemic Agents; C089180:SLC5A2 protein, human; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D000068896:Canagliflozin; C529054:dapagliflozin; C570240:empagliflozin; D005947:Glucose
keywords: Benzhydryl Compounds; Body Weight; Cardiovascular Diseases; Chronic; Diabetes Mellitus; Diabetic Nephropathies; Dyslipidemias; Glucose; Glucose Transporter Type 2; Glucosides; Glycosuria; Humans; Hyperglycemia; Kidney Failure; Liraglutide; Sodium; Sodium-Glucose Transporter 2; Type 2; Up-Regulation; Uric Acid; blood pressure; cardiovascular disease; diabetes mellitus; diabetic nephropathy; hypertension; obesity; risk factors