Efficacy and Safety of Dapagliflozin in Acute Heart Failure

Patients with acute decompensated HF (ADHF) are generally admitted due to symptoms of congestion and 90% are treated with a loop diuretic. However at least one-third of these patients are inadequately decongested due primarily to "diuretic resistance" and/ or "cardiorenal syndrome". The inability to achieve decongestion is associated with a worse prognosis and a higher rate of re-hospitalization for ADHF. More than 40% of all patients admitted with ADHF have diabetes and that percentage is growing both in Heart Failure with Reduced Ejection Fraction (HFrEF) and Preserved Ejection Fraction (HFpEF).

The admission blood glucose is elevated in approximately one-half of ADHF hospitalizations. We recently demonstrated the admission blood glucose was within 50mg/dl of the chronic average blood glucose in 66% of patients with diabetes admitted with ADHF. The median (IQR) admission blood glucose change from the chronic blood glucose was only -7 (-29, 26) mg/dl. Thus, the acute glucose in patients with T2DM presenting with acute heart failure is most often related to poor chronic glucose control suggesting that these patients would benefit from attempts to initiate therapies to improve chronic glucose control while in the hospital.

No new therapies have been introduced in the United States for ADHF in several decades. Natriuretic peptides such as nesiritide and ularitide have failed to improve outcomes in either the chronic or acute heart failure patients. Diuretic resistance and hyperglycemia are common problems in ADHF admissions and represent a therapeutic opportunity for new therapies.

The sodium-glucose cotransporter-2(SGLT2) inhibitors, now approved for the anti-hyperglycemic therapies also have an osmotic diuretic and natriuretic effect. In the chronic setting SGLT2 inhibitors reduce weight with modest decrements in systolic and diastolic blood pressure with a marked drop in albuminuria and a small drop in estimated GFR (-5 mL min-1.1.73 m-2) which returns to baseline over time. In patients with diabetes the SGLT2 transporter likely accounts for as much as 14% of total sodium chloride absorption. In the acute setting following a single dose, SGLT2 inhibitors did not increase urine volume. However, the acute diuretic effects have not been studied in a population with heart failure with or without concomitant hyperglycemia who are undergoing diuresis. To our knowledge, no current trials are investigating the effects of SGLT2 inhibition in ADHF. The current studies planned in HF are investigating the acute effects of SGLT2 on stable HF (NCT03027960), the chronic effects of SGLT2 inhibition in compensated, chronic HF (NCT03619213, NCT02653482, NCT03030235, NCT03057977), changes in pulmonary pressure hemodynamics in patients monitored by CardioMEMs devices (NCT03030222), and effects on cardiopulmonary exercise fitness in chronic HF (NCT02862067).

Congestion remains the major cause of hospital readmission for heart failure and an inpatient plan of care that allowed more effective decongestion would be rapidly and widely adopted by the medical community. Therefore, we propose to test the decongesting effects of the SGLT2 inhibitor dapagliflozin in patients with or without Type II diabetes admitted with an acute decompensation of chronic heart failure.