Effect SGLT2 inhibitors on heart failure by sodium-hydrogen exchange?
Effects of Sodium-Glucose Cotransporter 2 Inhibitors for the Treatment of Patients With Heart Failure
Proposal of a Novel Mechanism of Action
The way of cardiovascular (CV) benefit recently observed by antidiabetic agents (GLP-1 agonists, SGLT2i) differs among therapeutic classes [1-3]. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are the only class of agents of which is reported to decrease the risk of cardiovascular events primarily through risk reduction of heart failure (HF) development or progression and not by reducing risk of myocardial infarction or stroke (EMPA-REG OUTCOME trial with empagliflozin) [1,4]. Unfortunately, it was not investigated whether this affected HF with reduced (HFrEF), preserved (HFpEF) or both. A class effect cannot be confirmed yet, as data with SGLT2 inhibitors canagliflozin and dapagliflozin are insufficient to establish this [5,6].
How do SGLT2 inhibitors affect HF?
When examining data from large randomized trials, the benefit of SGLT2 inhibitors on HF cannot be explained by improved glycemic control. However, one hypothesis may be that the benefit comes from its diuretic effect. It is known diuretics as well as SGLT2 inhibitors increase urine volume and long-term decrease systolic blood pressure. However, whereas diuretics do hardly change plasma volume and body weight and go along with potassium depletion and worsening renal function at the long-term, SGLT2 inhibitors reduce body weight and plasma volume sustainably, result in hemoconcentration and improve renal function. This means they not simply act as diuretics to prevent HF.
A hypothesis: effect on sodium-hydrogen exchange mechanisms
One explanation of the positive effect of SGLT2 inhibitors on the renal function is the affected interaction of SGLT2 with sodium-hydrogen exchanger (NHE) 3. This exchanger is primarily responsible for the majority of sodium tubular reuptake following filtration and its activity is increased in HF. It has been shown that SGLT2 inhibitors interfere with the actions of NHE3 as bicarbonate excretion is increased after SGLT2 inhibition as well as risk of acidosis [7-9]. Mechanisms of increased natriuresis by NHE3 inhibition may also be enhanced by treatments that block sodium reabsorption other parts of the nephron, such as by loop diuretics and mineralocorticoid receptor antagonists (MRAs) that are routinely prescribed in HF patients. The resulting decrease in intravascular volume might be expected to lead to important short-term and long-term decreases in cardiac wall stress, with a resultant favorable effect on the development and progression of HF.
Direct effects on the heart
In experimental models of HF, NHE activity is also increased in the heart, which would be sufficient to enhance the intracellular sodium concentration in cardiomyocytes and thereby increase intracellular calcium, leading to cardiomyocyte injury. Although SGLT2 is not expressed in the human heart, empagliflozin inhibits sodium-hydrogen exchange and reduces intracellular calcium  and inhibition of SGLT2 slows the development and progression of cardiac hypertrophy and cardiomyopathy in experimental models. Intracellular calcium was not reduced when the NHE activity was pre-blocked. The cardiac benefits of NHE inhibition has been proved in a range of experimental models.
In addition, the benefits of the diuretic spironolactone in patients with HFrEF or HFpEF may also be attributable to the actions of the drug to inhibit the sodium-hydrogen exchange mechanism in large vessels .
It seems that the reduction in risk of HF with SGLT2 inhibitors is independent of its effects on glycemia and is not similarly achieved as diuretics do. Instead, the favorable effects of SGLT2 inhibitors may be primarily mediated by an inhibitory effect on the sodium-hydrogen exchange mechanisms in both the kidney and the heart.