• 1.

    van der Aart-van der Beek AB, et al. Kidney and heart failure outcomes associated with SGLT2 inhibitor use. Nat Rev Nephrol [published online ahead of print February 10, 2022]. doi: 10.1038/s41581-022-00535-6; https://www.nature.com/articles/s41581-022-00535-6

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  • 2.

    Wichaiyo S, Saengklub N. Alterations of sodium-hydrogen exchanger 1 function in response to SGLT2 inhibitors: What is the evidence? Heart Fail Rev [published online ahead of print February 18, 2022]. doi: 10.1007/s10741-022-10220-2; https://link.springer.com/article/10.1007/s10741-022-10220-2

    • Search Google Scholar
    • Export Citation
  • 3.

    Tomasoni D, et al. Sodium-glucose co-transporter 2 inhibitors as an early, first-line therapy in patients with heart failure and reduced ejection fraction. Eur J Heart Fail [published online ahead of print December 10, 2021]. doi: 10.1002/ejhf.2397; https://onlinelibrary.wiley.com/doi/10.1002/ejhf.2397

    • Search Google Scholar
    • Export Citation
  • 4.

    Packer M, et al. Empagliflozin and major renal outcomes in heart failure. N Engl J Med 2021; 385:15311533. doi: 10.1056/NEJMc2112411

  • 5.

    Murphy SP, et al. Heart failure with reduced ejection fraction: A review. JAMA 2020; 324:488504. doi: 10.1001/jama.2020.10262

Mechanism of Heart Protection by SGLT2 Inhibitors, Direct and Indirect Effects

Jianxiang XueJianxiang Xue, PhD, and Timo Rieg, MD, are with the Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, and Dr. Rieg is also with the James A. Haley Veterans' Hospital, Tampa, FL.

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Timo RiegJianxiang Xue, PhD, and Timo Rieg, MD, are with the Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, and Dr. Rieg is also with the James A. Haley Veterans' Hospital, Tampa, FL.

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A series of clinical trials demonstrated promising outcomes of sodium glucose co-transporter 2 (SGLT2) inhibitors, a novel class of anti-diabetic drugs, in patients with heart failure (HF), with either reduced ejection fraction or preserved ejection fraction. Of note, these positive outcomes are irrespective of the diabetic status and with rapid onset, suggesting the clinical benefits of SGLT2 inhibition are not fully attributable to glycemic control. Based on various experimental studies, a substantial number of hypotheses have been proposed to explain the beneficial effects of SGLT2 inhibition in HF. These effects can be divided into two groups: indirect systemic effects and direct myocardial effects (Figure 1).

Figure 1
Figure 1

Beneficial effects of SGLT2 inhibition in heart failure

Citation: Kidney News 14, 4

Potential indirect systemic effects include but are not limited to the following:

  1. Natriuresis and diuresis induce blood pressure-lowering effects with subsequent reductions in preload and afterload (potentially occurring via lowering of arterial pressure and stiffness), favorably altering ventricular loading conditions. Importantly, natriuresis and diuresis, induced by SGLT2 inhibition, are not associated with a compensatory activation of the renin-angiotensin-aldosterone system.

  2. Prevention of cardiac remodeling and associated cardiac fibrosis (a feature of HF), probably owing to systemic hemodynamic and metabolic effects

  3. Improvement in endothelial dysfunction and vascular stiffness

  4. Increased hematopoiesis with an increase in hematocrit due to enhanced erythropoietin (EPO) production, resulting from improved renal function by SGLT2 inhibition. The increased hematocrit and EPO might exert beneficial effects on mitochondrial function in cardiomyocytes, angiogenesis, and oxygen delivery to the myocardial tissue.

  5. Inhibition of sympathetic nervous system activity, which is postulated to be secondary to attenuated renal “stress”

  6. Increased circulating proangiogenic progenitor cells

  7. Suppression of advanced glycation end-products, which may contribute to improve vascular dysfunction, prevent progressive atherosclerosis, and reduce inflammation

  8. Glucosuria improves glucose control and results in body weight and epicardial fat loss, as well as an overall metabolic shift from glucose to ketone body metabolism (specifically increases in β-hydroxybutyrate production).

  9. Lowering of uric acid levels

All of these changes contribute to improve cardiac energetics and efficiency, oxidative stress, and inflammation.

Potential direct myocardial effects include but are not limited to the following:

  1. Direct inhibition of the cardiac sodium/hydrogen exchanger isoform 1 (NHE1), which alters intracellular Na+ and Ca2+ handling, leading to attenuation of cardiac injury, hypertrophy, and systolic dysfunction. However, whether NHE1 inhibition plays a role in cardiovascular protection by SGLT2 inhibitors is still controversial, and conflicting results have been reported in the literature.

  2. Improved cardiac autophagy and lysosomal degradation

  3. Inhibition of the nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing 3 (NLRP3) inflammasome

  4. A decrease in calmodulin kinase II activity, resulting in improved sarcoplasmic reticulum Ca2+ flux and increased contractility

It is clear that none of the aforementioned mechanisms can solely explain the clinical benefits of SGLT2 inhibitors in HF, and all possible mechanisms may play a role at one point or another during the treatment of the disease. Although most of these mechanisms are closely interrelated, it is conceivable that the effects on the kidneys are predominating, and cardiovascular benefits are secondary to this. Consistent with this theory, various clinical trials show that worsening of renal function is associated with a higher risk of both hospitalization for HF (hHF) and atherothrombotic events, and the reduction in hHF by SGLT2 inhibition is greater in patients with lower baseline renal function. These observations support that the reduction in hHF is more likely due to SGLT2 inhibitor-mediated kidney protection.

Although current clinical trials give positive outcomes supporting the efficacy of SGLT2 inhibitors in the prevention of HF, the outcomes do not necessarily translate to efficacy in treatment of HF. It is encouraging that the US Food and Drug Administration just approved empagliflozin (Jardiance®) as a treatment option for a wider range of patients with HF. However, it remains to be determined if these are class effects of SGLT2 inhibitors.

Suggested Reading and General References

  • 1.

    van der Aart-van der Beek AB, et al. Kidney and heart failure outcomes associated with SGLT2 inhibitor use. Nat Rev Nephrol [published online ahead of print February 10, 2022]. doi: 10.1038/s41581-022-00535-6; https://www.nature.com/articles/s41581-022-00535-6

    • Search Google Scholar
    • Export Citation
  • 2.

    Wichaiyo S, Saengklub N. Alterations of sodium-hydrogen exchanger 1 function in response to SGLT2 inhibitors: What is the evidence? Heart Fail Rev [published online ahead of print February 18, 2022]. doi: 10.1007/s10741-022-10220-2; https://link.springer.com/article/10.1007/s10741-022-10220-2

    • Search Google Scholar
    • Export Citation
  • 3.

    Tomasoni D, et al. Sodium-glucose co-transporter 2 inhibitors as an early, first-line therapy in patients with heart failure and reduced ejection fraction. Eur J Heart Fail [published online ahead of print December 10, 2021]. doi: 10.1002/ejhf.2397; https://onlinelibrary.wiley.com/doi/10.1002/ejhf.2397

    • Search Google Scholar
    • Export Citation
  • 4.

    Packer M, et al. Empagliflozin and major renal outcomes in heart failure. N Engl J Med 2021; 385:15311533. doi: 10.1056/NEJMc2112411

  • 5.

    Murphy SP, et al. Heart failure with reduced ejection fraction: A review. JAMA 2020; 324:488504. doi: 10.1001/jama.2020.10262

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