1829-P: A Modeling Approach to Quantify Empagliflozin's Effect on Urinary Glucose Excretion in Nondiabetic Individuals with Post-Bariatric Hypoglycemia

Introduction and Objective: Empagliflozin, a highly selective inhibitor of the SGLT2 transporter, lowers blood glucose by inducing glucosuria. However, methods to dynamically quantify this effect in response to individual glycemic profiles are lacking. To address this gap, a mathematical model was developed. Methods: Data from a double-blind, randomized, two-period crossover trial (NCT05057819) were used. Twenty-two non-diabetic adults with postbariatric hypoglycaemia following RYGB surgery (age=48 [34, 51] y, median [IQR]; BMI= 25.4 [23.0, 27.0] kg/m2; GMI= 5.89 [5.74, 5.99] %; eGFR≥90 mL/min/1.73m²) completed two 20 day-trial periods, receiving once daily empagliflozin 25mg (E) first and placebo (P) second, or vice versa. Glycaemic responses were evaluated via continuous glucose monitoring (CGM) throughout the study, a 2h solid mixed meal test (MMT), and a 24h urinary glucose excretion (UGE) measurement via a 24h urine collection prior to the MMT. The oral glucose minimal model was adapted to incorporate a term describing the rate of UGE, assumed to be proportional to glucose concentration exceeding a threshold (Th) for glucose spillage into the urine. Model parameters, including Th and insulin sensitivity (IS), were estimated from plasma glucose and UGE data, with plasma insulin and CGM used as inputs. Results: Fasting glucose levels were lower in E vs P (88.3 [84.7, 91.9] vs. 92.8 [86.5, 96.4] mg/dl, p=0.002), while incremental area under the glucose curve was similar (5.3 [3.1, 7.5] vs. 5.0 [3.0, 8.3] g/dl·min). The model predicted a reduction of Th in E vs P (72.1 [55.8, 85.3] vs. 173.1 [156.4, 179.8] mg/dl, p<0.001), and similar IS. In E, daily glucosuria in the fasting state was 14.6 [8.32, 22.1] g/day. Conclusion: The proposed model provides a quantitative, individualized estimate of empagliflozin's effect on UGE, which mechanistically explains the observed reduction in fasting glucose and can be used to dynamically assess treatment response over time. Disclosure A. Brunasso: None. C. Dalla Man: Other - Webinar provider; Ended; Sanofi. Other - Joint research project; Current; Sanofi-Aventis Deutschland GmbH. D. Herzig: None. L. Bally: Research Support; Current; Dexcom, Inc., Ypsomed AG, Novo Nordisk, Eli Lilly and Company. Advisory Panel; Ended; Ypsomed AG, Novo Nordisk, Eli Lilly and Company. M. Schiavon: Research Support; Current; Sanofi. Funding Swiss National Science Foundation (PCEGP3_186978); MIUR (Italian Minister for Education, 39-411-19-DOT1319501-6721) (Brunasso)