Sodium-glucose cotransporter 2 inhibitors’ mechanisms of action in heart failure

Abstract

Three major cardiovascular outcome trials (CVOTs) with a new class of antidiabetic drugs - sodium-glucose cotransporter 2 (SGLT2) inhibitors (EMPA-REG OUTCOME trial with empagliflozin, CANVAS Program with canagliflozin, DECLARE-TIMI 58 with dapagliflozin) unexpectedly showed that cardiovascular outcomes could be improved possibly due to a reduction in heart failure risk, which seems to be the most sensitive outcome of SGLT2 inhibition. No other CVOT to date has shown any significant benefit on heart failure events. Even more impressive findings came recently from the DAPA-HF trial in patients with confirmed and well-treated heart failure: Dapagliflozin was shown to reduce heart failure risk for patients with heart failure with reduced ejection fraction regardless of diabetes status. Nevertheless, despite their possible wide clinical implications, there is much doubt about the mechanisms of action and a lot of questions to unravel, especially now when their benefits translated to non-diabetic patients, rising doubts about the validity of some current mechanistic assumptions.The time frame of their cardiovascular benefits excludes glucose-lowering and antiatherosclerotic-mediated effects and multiple other mechanisms, direct cardiac as well as systemic, are suggested to explain their early cardiorenal benefits. These are: Anti-inflammatory, antifibrotic, antioxidative, antiapoptotic properties, then renoprotective and hemodynamic effects, attenuation of glucotoxicity, reduction of uric acid levels and epicardial adipose tissue, modification of neurohumoral system and cardiac fuel energetics, sodium-hydrogen exchange inhibition. The most logic explanation seems that SGLT2 inhibitors timely target various mechanisms underpinning heart failure pathogenesis. All the proposed mechanisms of their action could interfere with evolution of heart failure and are discussed separately within the main text.

Effects of sodium‐glucose cotransporter 2 inhibitors on serum uric acid in patients with type 2 diabetes mellitus: A systematic review and network meta‐analysis

“…For the use of dapagliflozin, Yuan et al found that SUA levels decreased from 347.75 ± 7.75 μmol/L before dapagliflozin treatment to 273.25 ± 43.18 μmol/L after dapagliflozin treatment, with a statistically significant difference ( p = .001), and the SUA‐lowering effect of dapagliflozin could be driven by increasing UA excretion within 1 week of treatment, which may be the mechanism of SGLT‐2 inhibitors in lowering SUA 52 . In addition, dapagliflozin has early cardiorenal benefits, which included anti‐inflammatory, antifibrotic, antioxidative, antiapoptotic properties, renoprotective and haemodynamic effects, as well as attenuation of glucotoxicity, reduction of SUA levels and epicardial adipose tissue, modification of the neurohumoral system and cardiac fuel energetics, and inhibition of the sodium–hydrogen exchange 53 …”

The Mystery of Diabetic Cardiomyopathy: From Early Concepts and Underlying Mechanisms to Novel Therapeutic Possibilities

“…The first class of glucose-lowering drugs that have demonstrated a consistent and robust reduction in the risk of heart failure hospitalization in patients with diabetes make them game-changers in cardiometabolic pharmacotherapy. Additionally, the efficacy in primary and secondary prevention of heart failure has already translated to efficacy in the treatment of heart failure in HFrEF patients with or without diabetes, but they may also be of value in the treatment of HFpEF [ 171 , 172 ]. The potential mechanisms of their action have already been mentioned before.…”

“…In this way, SGLT2 inhibitors could synergistically work with angiotensin receptor neprilysin inhibitors (ARNIs). In theory, this would be of value especially in the failing heart when the natriuretic peptides are markedly raised [ 172 , 173 , 174 ].…”

PUFA Supplementation and Heart Failure: Effects on Fibrosis and Cardiac Remodeling

“…To date, therapies include treatment with vasodilators, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs) as well as beta-blockers and mineralocorticoid receptor antagonists (MRAs) [ 34 , 35 , 36 ]. In addition, the US Food and Drug Administration (FDA) has recently approved the sodium–glucose co-transporter 2 (SGLT2) inhibitors as a novel therapeutic approach to treating HFrEF patients, irrespective of the presence or absence of type 2 diabetes (T2D) [ 37 , 38 , 39 , 40 ]. However, the risk to patients remains high, and further studies are required to define new pharmacological approaches [ 34 , 35 , 36 ].…”