Renal Hemodynamic Effect of Sodium-Glucose Cotransporter 2 Inhibition in Patients With Type 1 Diabetes Mellitus

• Published in: Circulation (New York, N.Y.) Vol. 129; no. 5; pp. 587 - 597
• Main Authors: Cherney, David Z.I., Perkins, Bruce A., Soleymanlou, Nima, Maione, Maria, Lai, Vesta, Lee, Alana, Fagan, Nora M., Woerle, Hans J., Johansen, Odd Erik, Broedl, Uli C., von Eynatten, Maximilian
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD by the American College of Cardiology Foundation and the American Heart Association, Inc 04.02.2014; Lippincott Williams & Wilkins
• Subjects: Adult; Associated diseases and complications; Benzhydryl Compounds - pharmacology; Benzhydryl Compounds - therapeutic use; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Diabetes Mellitus, Type 1 - blood; Diabetes Mellitus, Type 1 - drug therapy; Diabetes Mellitus, Type 1 - physiopathology; Diabetes. Impaired glucose tolerance; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; Glomerular Filtration Rate - drug effects; Glomerular Filtration Rate - physiology; Glucose Clamp Technique - methods; Glucosides - pharmacology; Glucosides - therapeutic use; Hemodynamics - drug effects; Hemodynamics - physiology; Humans; Kidney - drug effects; Kidney - physiology; Kidneys; Male; Medical sciences; Nephrology. Urinary tract diseases; Sodium-Glucose Transporter 2 - antagonists & inhibitors; Sodium-Glucose Transporter 2 - physiology; Treatment Outcome; Urinary system involvement in other diseases. Miscellaneous; Young Adult; Endocrinopathy; Autoimmune disease; Cardiovascular disease; diabetes mellitus; Glucose; Kidney; Diabetic nephropathy; Inhibition; Cardiology; diabetic nephropathies; hypertension, renal; Kidney disease; Human; Hypertension; Immunopathology; Urinary system disease; Patient; Protein; SGLT2 protein; Concomitant disease; Renin angiotensin system; Urinary system; Sodium; Type 1 diabetes; Nitric oxide; Circulatory system; Hemodynamics; renin-angiotensin system; nitric oxide
• ISSN: 0009-7322; 1524-4539; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.113.005081

BACKGROUND—The primary objective of this mechanistic open-label, stratified clinical trial was to determine the effect of 8 weeks’ sodium glucose cotransporter 2 inhibition with empagliflozin 25 mg QD on renal hyperfiltration in subjects with type 1 diabetes mellitus (T1D). METHODS AND RESULTS—Inulin (glomerular filtration rate; GFR) and paraaminohippurate (effective renal plasma flow) clearances were measured in individuals stratified based on having hyperfiltration (T1D-H, GFR ≥ 135 mL/min/1.73m, n=27) or normal GFR (T1D-N, GFR 90–134 mL/min/1.73m, n=13) at baseline. Renal function and circulating levels of renin-angiotensin-aldosterone system mediators and NO were measured under clamped euglycemic (4–6 mmol/L) and hyperglycemic (9–11 mmol/L) conditions at baseline and end of treatment. During clamped euglycemia, hyperfiltration was attenuated by −33 mL/min/1.73m with empagliflozin in T1D-H, (GFR 172±23–139±25 mL/min/1.73 m, P<0.01). This effect was accompanied by declines in plasma NO and effective renal plasma flow and an increase in renal vascular resistance (all P<0.01). Similar significant effects on GFR and renal function parameters were observed during clamped hyperglycemia. In T1D-N, GFR, other renal function parameters, and plasma NO were not altered by empagliflozin. Empagliflozin reduced hemoglobin A1c significantly in both groups, despite lower insulin doses in each group (P≤0.04). CONCLUSIONS—In conclusion, short-term treatment with the sodium glucose cotransporter 2 inhibitor empagliflozin attenuated renal hyperfiltration in subjects with T1D, likely by affecting tubular-glomerular feedback mechanisms. CLINICAL TRIAL REGISTRATION—URLhttp://www.clinicaltrials.gov. Unique identifierNCT01392560.