The Acute Effect of Empagliflozin on Fractional Excretion of Sodium and eGFR in Youth with Type 2 Diabetes

Abstract

Sodium-glucose cotransporter-2 (SGLT2) inhibition reduces hyperfiltration in adults with T1D, likely by inducing natriuresis, which stimulates tubuloglomerular feedback. This exploratory analysis aimed to examine whether these renal effects occur acutely within 24 hours of SGLT2 inhibition following a single exposure to empagliflozin (EMPA) in youth with T2D. In this single-administration, open-label, randomized, parallel-group study (NCT02121483), 27 patients with T2D (mean age 14.1 years, 67% girls, mean BMI 35.5 kg/m2) received EMPA 5, 10 or 25 mg. The effects of EMPA on fractional sodium excretion (FENa+) and estimated GFR (eGFR as assessed by Zappitelli-combined creatinine and cystatin C equation) were investigated by pooling the three doses of EMPA for analyses. At baseline, mean (SD) baseline FENa+ was 0.55% (0.46), and eGFR was 123.4 ml/min/1.73m2 (15.6). After a single dose of EMPA, the adjusted mean change from baseline in FENa+ was +0.81% (95% CI 0.27, 1.36; p=0.006). The adjusted mean change from baseline in eGFR was -5.5 ml/min/1.73m2 (95% CI -8.3, -2.7; p=0.0006). In eGFR subgroups of interest, eGFR decreased by -6.7 (9.7) ml/min/1.73m2 in patients with hyperfiltration (n=8, eGFR >119.1 ml/min/1.73m2, [95th percentile of eGFR for obese youth in NHANES]) and by -5.0 (6.0) ml/min/1.73m2 in patients with normofiltration (n=19). SGLT2 inhibition following a single dose of EMPA was associated with acute natriuresis and attenuation of elevated GFR in youth with T2D, suggesting a reduction in intraglomerular pressure. Further mechanistic studies are required to define changes in renal function, and longer-term trials examining renal protective effects in youth with diabetes are needed. Disclosure P. Bjornstad: Consultant; Self; Boehringer Ingelheim GmbH. L.M. Laffel: Consultant; Self; Eli Lilly and Company, Novo Nordisk Inc., Sanofi US, MannKind Corporation, Roche Diagnostics Corporation, Dexcom, Inc., Insulet Corporation, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Johnson & Johnson Diabetes Institute, LLC. W.V. Tamborlane: Consultant; Self; AstraZeneca, Boehringer Ingelheim GmbH, Eli Lilly and Company, Medtronic MiniMed, Inc., Novo Nordisk Inc., Sanofi, Takeda Pharmaceuticals U.S.A., Inc. G. Simons: Employee; Self; Boehringer Ingelheim GmbH. S. Hantel: Employee; Self; Boehringer Ingelheim GmbH. M. von Eynatten: Employee; Self; Boehringer Ingelheim GmbH. J.T. George: Employee; Self; Boehringer Ingelheim GmbH. J. Marquard: Employee; Self; Boehringer Ingelheim GmbH. D. Cherney: Consultant; Self; AbbVie Inc.. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim GmbH, Eli Lilly and Company. Consultant; Self; Sanofi. Other Relationship; Self; Merck & Co., Inc.. Consultant; Self; Mitsubishi Tanabe Pharma Corporation. Other Relationship; Self; Janssen Pharmaceuticals, Inc..