Comparison of the urinary glucose excretion contributions of SGLT2 and SGLT1: A quantitative systems pharmacology analysis in healthy individuals and patients with type 2 diabetes treated with SGLT2 inhibitors

Abstract

Aim To develop a quantitative drug‐disease systems model to investigate the paradox that sodium‐glucose co‐transporter (SGLT)2 is responsible for >80% of proximal tubule glucose reabsorption, yet SGLT2 inhibitor treatment results in only 30% to 50% less reabsorption in patients with type 2 diabetes mellitus (T2DM). Materials and methods A physiologically based four‐compartment model of renal glucose filtration, reabsorption and excretion via SGLT1 and SGLT2 was developed as a system of ordinary differential equations using R/IQRtools. SGLT2 inhibitor pharmacokinetics and pharmacodynamics were estimated from published concentration‐time profiles in plasma and urine and from urinary glucose excretion (UGE) in healthy people and people with T2DM. Results The final model showed that higher renal glucose reabsorption in people with T2DM versus healthy people was associated with 54% and 28% greater transporter capacity for SGLT1 and SGLT2, respectively. Additionally, the analysis showed that UGE is highly dependent on mean plasma glucose and estimated glomerular filtration rate (eGFR) and that their consideration is critical for interpreting clinical UGE findings. Conclusions Quantitative drug‐disease system modelling revealed mechanistic differences in renal glucose reabsorption and UGE between healthy people and those with T2DM, and clearly showed that SGLT2 inhibition significantly increased glucose available to SGLT1 downstream in the tubule. Importantly, we found that the findings of lower than expected UGE with SGLT2 inhibition are explained by the shift to SGLT1, which recovered additional glucose (~30% of total).

Differentiating the Sodium‐Glucose Cotransporter 1 Inhibition Capacity of Canagliflozin vs. Dapagliflozin and Empagliflozin Using Quantitative Systems Pharmacology Modeling

“…A QSP model of renal glucose filtration, SGLT‐mediated reabsorption, and urinary excretion was developed and reported . The structural model explicitly represented flux and concentrations in the S1/S2 and S3 segments of the proximal tubules.…”

“…SGLT2‐specific K i values were estimated based on cumulative 24‐hour urinary glucose excretion (UGE) in healthy and T2DM subjects treated with gliflozins. SGLT1‐specific K i values were calculated using in vitro SGLT1/SGLT2 ratio values determined through an AstraZeneca SGLT‐mediated glucose uptake assay …”

“…Relative contributions of SGLT1 and SGLT2 to renal glucose reabsorption were estimated from 24‐hour (UGE) data in clinical studies of healthy and T2DM subjects treated with SGLT inhibitors. Detailed information on model development, verification, and validation procedures is available in the original publication …”

“…Also, adaptive changes in kidney filtration rates—caused by SGLT2 treatment—were not considered in this modeling analysis because the model was built with a focus on short‐term UGE data. We refer the reader to a discussion of overall model limitations and qualifications, as presented in a companion publication …”

“…Among the most commonly used SGLT inhibitors, canagliflozin is the least selective for SGLT2 and may inhibit, at approved therapeutic doses, SGLT1 in the small intestine from the luminal side, warranting further investigation into the differential pharmacology of the class. In a related model‐based analysis, we demonstrated that SGLT1‐mediated glucose reabsorption capacity was greater in T2DM patients than in healthy individuals . Furthermore, the inhibition of SGLT2 in the S1/S2 (segment 1 of the proximal tubule, a location of SGLT2/segment 2 of the proximal tubule, a location of SGLT2) proximal tubule segments raised the glucose availability for SGLT1 located downstream in the S3 segment and resulted in a shift to much greater SGLT1‐mediated urinary glucose reabsorption.…”