7-LB: Sodium–Glucose Cotransporter-2 Inhibitors (SGLT2i) Decrease Kidney Oxygen Consumption in Adults with Type 2 Diabetes (T2D)—A Randomized Clinical Trial Using 11C-Acetate Positron Emission Tomography (PET) Imaging

Abstract

Kidney hypoxia has been proposed as key pathophysiological mechanism in the development of chronic kidney disease, potentially stemming from a mismatch between oxygen delivery and oxygen consumption. SGLT2i are kidney protective drugs that initially lower glomerular filtration rate (GFR). Accordingly, we hypothesized that SGLT2i lower kidney oxygen consumption by reducing GFR and associated tubular workload. Twenty adults with T2D (sex 80% male, age 68±6 years, BMI 30±4 kg/m2, HbA1c 7.5±0.9%, eGFR 76 ± 11 mL/min/1.73m2) received a 4-week treatment with SGLT2i ertugliflozin (ERTU) and matched placebo (PLB) in a randomized, double-blind cross-over study. Participants were treated with metformin and received maximal tolerable dose of an angiotensin receptor blocker. Whole-kidney oxygen consumption (Kmono) was measured by PET using 11C-acetate. GFR was measured by gold-standard iohexol clearance. Tubular sodium transport (TNa) was calculated by kidney sodium load (([arterial Na]*mGFR) - urinary sodium excretion). Kidney efficiency calculated as TNa/ Kmono. GFR was lower during ERTU (94 ± 14 mL/min) vs. PLB (99 ± 15 mL/min) treatment (p=0.02). Kmono was 0.086 ± 0.006 min-1 during ERTU and 0.091 ± 0.009 min-1 during PLB (p<0.01). Kidney sodium load (12.9 ± 1.90 vs 13.7 ± 2.22 mmol/min) and TNa (12.7 ± 1.87 vs 13.6 ± 2.18 mmol/min) were lower during ERTU (p=0.02 for both), while urinary sodium excretion (p=0.1) and TNa/ Kmono remained unchanged (p=0.7). TNa strongly associated with Kmono (r=0.50; p<0.0001). In conclusion, SGLT2i lowers mGFR, TNa, and kidney oxygen consumption, potentially decreasing hypoxia risk. SGLT2i treatment did not lower overall kidney efficiency, despite the ATP efficiency of cortical sodium transport. Additional data on cortex and medulla-specific oxygen consumption and multiparametric kidney MRI data will be presented at ADA. Disclosure A. Hesp: None. L. I. P. Snel: None. P. Schober: None. L. A. Schwarte: None. R. Boellaard: None. P. Bjornstad: Advisory Panel; AstraZeneca. Consultant; Bayer Inc., Bristol-Myers Squibb Company. Advisory Panel; Novo Nordisk, Lilly, Horizon Therapeutics plc, Boehringer Ingelheim (Canada) Ltd., LG Chem. D. van Raalte: Consultant; Boehringer Ingelheim and Eli Lilly Alliance, AstraZeneca, Merck & Co., Inc. Research Support; Boehringer Ingelheim and Eli Lilly Alliance, AstraZeneca, Merck & Co., Inc. Funding MSD