Sodium Glucose Cotransporter-2 Inhibitors for the Amelioration of Acute Cardio-Renal Syndrome

Yale University, New Haven CT

Investigators

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Abstract

PROJECT SUMMARY | Candidate: The candidate is an Instructor of Medicine (Nephrology) with 3 years of ongoing training in clinical research in acute kidney injury (AKI) and clinical trial design and conduct under the mentorship of the director of Yale’s Clinical and Translational Research Accelerator, a leading expert in clinical trials and pharmaco-epidemiology in AKI. This award will also allow her to receive mentorship from renowned experts in heart failure translational research, renal physiology and biostatistics to eventually become an independent clinical researcher in cardiorenal syndromes. Proposed Study: More than 1/3rd of patients hospitalized with acute heart failure (AHF) develop AKI, which is an independent risk factor for cardiovascular and kidney disease progression and mortality. AKI in this setting, often known as acute cardiorenal syndrome (CRS), is a cycle of venous congestion and overactive sodium reabsorption mechanisms characterized by diuretic resistance leading to prolonged patient distress and interruptions of essential HF therapy. The long-term goal of this study is to assess the efficacy of sodium-glucose cotransporter-2 inhibitors (SGLT2i) for acute CRS. SGLT2i are oral anti-hyperglycemic drugs which target a key sodium and glucose reabsorption mechanism in the kidney that have consistently slowed long-term kidney and cardiovascular disease progression in randomized clinical trials, independent of patients’ diabetes status or heart failure type. There is also pre-clinical evidence supporting their kidney tubular and endothelial protective and reparative effects in AKI. However, the efficacy and safety of SGLT2i in humans with acute CRS is unknown and AKI in this setting is a frequent reason for discontinuation. In a multicenter cohort study, we have shown that SGLT2 inhibition during AHF-associated AKI is not associated with prolonged AKI. By inhibiting an energy- demanding sodium reabsorption mechanism in the kidney’s proximal tubule, SGLT2i particularly when added to standard loop diuretic therapy, could promote energy efficient diuresis by reducing O2 demand in the kidney’s already O2-deprived environment, reduce oxidative stress and promote tubular integrity which may enhance tubular secretion of loop diuretics and their efficient delivery to their downstream target. Based on these assumptions, we hypothesize that SGLT2i improve diuretic response and promote quicker kidney recovery in patients with acute CRS which we will test as follows. In Aim 1, we will assess the impact of SGLT2i on the clinical improvement of individuals with acute CRS in a randomized placebo-controlled clinical trial of hospitalized adults with AHF-associated AKI by comparing established symptomatic and biochemical metrics of diuretic response. We will also examine safety and tolerability. In Aim 2, we will further assess the impact of SGLT2i on early biomarkers of kidney tubular injury and health. This study has the potential to improve the lives of patients with heart failure by establishing SGLT2i as a therapy for this challenging to treat syndrome and the potential to mitigate unnecessary interruptions of SGLT2i.