Evaluation of renal and cardiovascular protection mechanisms of SGLT2 inhibitors: model-based analysis of clinical data

Abstract

The mechanisms of cardiovascular and renal protection observed in clinical trials of 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 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 physiologic 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 NHE3 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 GFR, suggesting cardiorenal benefits of SGLT2i may be sustained in renally impaired patients.

Evaluation of the effects of sodium–glucose co‐transporter 2 inhibition with empagliflozin on morbidity and mortality in patients with chronic heart failure and a preserved ejection fraction: rationale for and design of the EMPEROR‐Preserved Trial

“…14 In clinical trials, the use of SGLT2 inhibitors has been shown to reduce the quantity of epicardial adipose tissue (independently of effect on body weight), [35][36][37] and these drugs ameliorate the inflammation of adipose tissue surrounding the heart and great vessels 38,39 and the associated abnormalities of cardiac filling and aortic distensibility in both experimental and clinical HFpEF. 18,[40][41][42] Furthermore, SGLT2 inhibitors act to inhibit sodium reabsorption in the proximal renal tubules, in which the majority of renal sodium retention occurs [43][44][45] ; this action explains the marked reduction in plasma and/or interstitial volume and haemoconcentration seen in randomized controlled trials in type 2 diabetes. 25,46 Moreover, SGLT2 inhibitors can attenuate renal inflammation and fibrosis.…”

Quantitative Systems Pharmacology: An Exemplar Model‐Building Workflow With Applications in Cardiovascular, Metabolic, and Oncology Drug Development

“…We expected that this analysis would improve our understanding of the renal benefits of SGLT2 inhibition but did not anticipate, initially, insight into the protective effects in heart failure. However, this analysis provided, ultimately, mechanistic insights into both, as we have described previously . We continue to use the model to further explore the cardiac effects of SGLT2 inhibition.…”

“…In addition, prospective simulations with the model indicated that SGLT2 inhibition reduces interstitial fluid volume to a greater extent than blood volume—an experimentally testable hypothesis that may explain the positive effects of these drugs on heart failure hospitalization. These results were communicated through both presentations and peer‐reviewed publications . Importantly, this differential volume mechanism lent decision support to development teams weighing the hypothesis that SGLT2 inhibitors would demonstrate clinical benefit in heart failure and slowing renal disease progression, both indications now pursued in several outcomes trials.…”

“…Fortuitously, a previously conducted drug–drug interaction (DDI) study of dapagliflozin and bumetanide had collected daily urinary excretion data of sodium, glucose, water, and other substrates as well as serum measures of creatinine and sodium concentrations. We sought to couple these data with the existing cardio‐renal QSP model to test various hypothesized renal mechanisms of SGLT2 inhibition and to determine which mechanism or combinations of mechanisms were most consistent with the observed data . We expected that this analysis would improve our understanding of the renal benefits of SGLT2 inhibition but did not anticipate, initially, insight into the protective effects in heart failure.…”

“…In addition, we found that the inclusion of this mechanism altered the relative removal of fluid from the blood and interstitium in ways that are likely to be beneficial in volume‐overloaded patients at risk for heart failure. For more details, see the primary publications of these results …”