The effect of sodium glucose cotransporter 2 inhibition with empagliflozin on microalbuminuria and macroalbuminuria in patients with type 2 diabetes.
Sodium glucose cotransporter 2 (SGLT2) inhibition lowers HbA1c, systolic BP (SBP) and weight in patients with type 2 diabetes and reduces renal hyperfiltration associated with type 1 diabetes, suggesting decreased intraglomerular hypertension. As lowering HbA1c, SBP, weight and intraglomerular pressure is associated with anti-albuminuric effects in diabetes, we hypothesised that SGLT2 inhibition would reduce the urine albumin-to-creatinine ratio (UACR) to a clinically meaningful extent.



We examined the effect of the SGLT2 inhibitor empagliflozin on UACR by pooling data from patients with type 2 diabetes and prevalent microalbuminuria (UACR = 30-300 mg/g; n = 636) or macroalbuminuria (UACR > 300 mg/g; n = 215) who participated in one of five phase III randomised clinical trials. Primary assessment was defined as percentage change in geometric mean UACR from baseline to week 24.



After controlling for clinical confounders including baseline log-transformed UACR, HbA1c, SBP and estimated GFR (according to the Modification of Diet in Renal Disease [MDRD] formula), treatment with empagliflozin significantly reduced UACR in patients with microalbuminuria (-32% vs placebo; p < 0.001) or macroalbuminuria (-41% vs placebo; p < 0.001). Intriguingly, in regression models, most of the UACR-lowering effect with empagliflozin was not explained by SGLT2 inhibition-related improvements in HbA1c, SBP or weight.



In patients with type 2 diabetes and either micro- or macroalbuminuria, empagliflozin reduced UACR by a clinically meaningful amount. This effect was largely independent of the known metabolic or systemic haemodynamic effects of this drug class. Our results further support a direct renal effect of SGLT2 inhibitors. Prospective studies are needed to explore the potential of this intervention to alter the course of kidney disease in high-risk patients with diabetes.



Clinicaltrials.gov NCT01177813 (study 1); NCT01159600 (study 2); NCT01159600 (study 3); NCT01210001 (study 4); and NCT01164501 (study 5).
Toronto General Hospital, 585 University Ave, 8N-845, Toronto, ON, Canada, M5G 2N2. david.cherney@uhn.ca.|Department of Medicine, Division of Nephrology, and Department of Physiology, University of Toronto, Toronto, ON, Canada. david.cherney@uhn.ca.
David
D
Cherney
Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany.
Søren S
SS
Lund
Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.
Bruce A
BA
Perkins
Abdominal Centre Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.|Folkhälsan Research Centre, Biomedicum Helsinki, Helsinki, Finland.|Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia.
Per-Henrik
PH
Groop
Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia.
Mark E
ME
Cooper
Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany.
Stefan
S
Kaspers
Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany.
Egon
E
Pfarr
Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany.
Hans J
HJ
Woerle
Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany.
Maximilian
M
von Eynatten
D000368:Aged; D000419:Albuminuria / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D001559:Benzhydryl Compounds / Q000627:therapeutic use*; D001786:Blood Glucose / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D005960:Glucosides / Q000627:therapeutic use*; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism*; D000077203:Sodium-Glucose Transporter 2 Inhibitors
D001559:Benzhydryl Compounds; D001786:Blood Glucose; D005960:Glucosides; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C089180:SLC5A2 protein, human; C570240:empagliflozin
Empagliflozin; Macroalbuminuria; Microalbuminuria; Sodium glucose cotransporter 2; Type 2 diabetes; Urine albumin-to-creatinine ratio