Abstract
The mechanisms of cardiovascular and renal protection observed in clinical trials of sodium-glucose cotransporter 2 (SGLT2) inhibitors (SGLT2i) are incompletely understood and likely multifactorial, including natriuretic, diuretic, and antihypertensive effects, glomerular pressure reduction, and lowering of plasma and interstitial fluid volume. To quantitatively evaluate the contribution of proposed SGLT2i mechanisms of action on changes in renal hemodynamics and volume status, we coupled a mathematical model of renal function and volume homeostasis with clinical data in healthy subjects administered 10 mg of dapagliflozin once daily. The minimum set of mechanisms necessary to reproduce observed clinical responses (urinary sodium and water excretion, serum creatinine and sodium) was determined, and important unobserved physiological variables (glomerular pressure, blood and interstitial fluid volume) were then simulated. We further simulated the response to SGLT2i in diabetic virtual patients with and without renal impairment. Multiple mechanisms were required to explain the observed response: 1) direct inhibition of sodium and glucose reabsorption through SGLT2, 2) SGLT2-driven inhibition of Na(+)/H(+) exchanger 3 sodium reabsorption, and 3) osmotic diuresis coupled with peripheral sodium storage. The model also showed that the consequences of these mechanisms include lowering of glomerular pressure, reduction of blood and interstitial fluid volume, and mild blood pressure reduction, in agreement with clinical observations. The simulations suggest that these effects are more significant in diabetic patients than healthy subjects and that while glucose excretion may diminish with renal impairment, improvements in glomerular pressure and blood volume are not diminished at lower glomerular filtration rate, suggesting that cardiorenal benefits of SGLT2i may be sustained in renally impaired patients.