Cardio-renal benefits of sodium–glucose co-transporter 2 inhibitors in heart failure with reduced ejection fraction: mechanisms and clinical evidence

Abstract

The heart and the kidneys are closely interconnected, and disease in one organ system can lead to disease in the other. This interdependence is illustrated in heart failure with reduced ejection fraction (HFrEF), where worsening heart failure can lead to renal dysfunction and vice versa. Further complicating this situation is the fact that drugs that serve as guideline directed medical therapy (GDMT) for HFrEF can affect renal function. Sodium glucose co-transporter 2 (SGLT2) inhibitors are a new class of medication with an evolving role in heart failure (HF) and chronic kidney disease (CKD). Initially found to have benefits in diabetics, new research established potential cardiovascular and renal benefits in patients with HF independent of their diabetic status and in populations with CKD. This has been established by landmark trials such as EMPEROR-Reduced, EMPA-TROPISM, CREDENCE, DAPA-CKD, DAPA-HF, and DEFINE-HF. Multiple mechanisms responsible for these benefits have been suggested by clinical and non-clinical studies, and involve cardiac and renal energetic efficiency, cardiac remodeling, preservation of renal function, immunomodulation, changes in hematocrit, and control of risk factors. As such, SGLT2 inhibitors have tremendous potential to improve outcomes in populations with HF and CKD. The purpose of this review is to discuss the current evidence and underlying mechanisms for the cardio-renal benefits of SGLT2 inhibitors in patients with HFrEF.

Clinical Evidence and Proposed Mechanisms of Sodium–Glucose Cotransporter 2 Inhibitors in Heart Failure with Preserved Ejection Fraction: A Class Effect?

“…[ 26 – 28 ] The osmotic diuresis with resultant free water loss has been projected to explain the beneficial relatively higher interstitial versus intravascular fluid losses with a reduced reflexive neurohormonal activation thought to make SGLT2is unique when compared with conventional diuretics. [ 20 , 29 , 30 ] SGLT2i-induced osmotic diuresis may improve myocardial oedema by increasing plasma oncotic pressure and stimulating plasma refill, thereby pulling fluid from the cardiac interstitium through Starling's forces. [ 25 ] A reduction in myocardial oedema is associated with a rightward shift in end-diastolic pressure volume relationship with decreases in left ventricular (LV) mass on cardiac magnetic resonance, and may be contributory in the early improvement of functional status demonstrated by PRESERVED-HF and CHIEF-HF, and may also partly explain EMPEROR-Preserved reaching significance in just 18 days with a reduction in worsening HF events.…”

Edema formation in congestive heart failure and the underlying mechanisms

“…Several clinical trials have demonstrated that SGLT2 inhibitors cause a significant reduction in HF hospitalization ( 268 – 270 ). These beneficial effects on HFrEF patients persist even in non-diabetic patients as was reported by DAPA-HF and EMPEROR-Reduced trials ( 271 – 273 ).…”

Pharmacological mechanisms of sodium-glucose co-transporter 2 inhibitors in heart failure with preserved ejection fraction

“…In recent years, more and more evidence shows that hypoglycemic drugs also have cardiovascular benefits [ 10 , 11 ]. Sodium-glucose cotransporter-2 inhibitors (SGLT2is), including empagliflozin, dapagliflozin, canagliflozin, and ertugliflozin, show a good prospect in the treatment of HF [ 12 – 16 ].…”