Mechanisms of Benefits of SGLT2 Inhibitors in HFpEF: Key Points

Pandey AK, Bhatt DL, Pandey A, et al.
Mechanisms of Benefits of Sodium-Glucose Cotransporter 2 Inhibitors in Heart Failure With Preserved Ejection Fraction. Eur Heart J 2023;Sep 7:[Epub ahead of print].

The following are key points to remember from a state-of-the-art review on the mechanisms of benefits of sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with heart failure with preserved ejection fraction (HFpEF):

  1. HFpEF has proved an elusive entity to treat for decades. SGLT2 inhibitors have recently been shown to reduce the composite of HF hospitalization or cardiovascular death in patients with HFpEF in the landmark DELIVER and EMPEROR-Preserved trials.
  2. While improvements in blood sugar, blood pressure, and attenuation of kidney disease progression all may play some role, preclinical and translational research have identified additional mechanisms of these agents.
  3. Furthermore, the rapid time course of improvement as well as experimental evidence suggests a combination of mechanisms for benefit of SGLT2 inhibitors in HFpEF.
  4. The SGLT2 inhibitors have intriguingly been shown to induce a nutrient-deprivation and hypoxic-like transcriptional paradigm, with increased ketosis, erythropoietin, and autophagic flux in addition to altering iron homeostasis, which may contribute to improved cardiac energetics and function.
  5. These agents also reduce epicardial adipose tissue and alter adipokine signaling, which may play a role in the reductions in inflammation and oxidative stress observed with SGLT2 inhibition.
  6. Emerging evidence also indicates that these drugs impact cardiomyocyte ionic homeostasis, although whether this is through indirect mechanisms or via direct, off-target effects on other ion channels has yet to be clearly characterized.
  7. Finally, SGLT2 inhibitors have been shown to reduce myofilament stiffness as well as extracellular matrix remodeling/fibrosis in the heart, improving diastolic function.
  8. Overall, the SGLT2 inhibitors have established themselves as robust, disease-modifying therapies and as recent trial results are incorporated into clinical guidelines, will likely become foundational and drug of first choice in the therapy of HFpEF.
  9. In addition, two other classes of medications have also shown benefit in patients with diabetes and/or kidney disease, i.e., glucagon-like peptide-1 receptor agonists and nonsteroidal mineralocorticoid receptor antagonists, and evaluation of potential synergy of these classes of agents with SGLT2 inhibitors should be an area of future interest.

Clinical Topics: Heart Failure and Cardiomyopathies, Prevention, Acute Heart Failure

Keywords: Diabetes Mellitus, Heart Failure, Renal Insufficiency, Chronic, Secondary Prevention, Sodium-Glucose Transporter 2 Inhibitors

< Back to Listings