Sympatholytic Mechanisms for the Beneficial Cardiovascular Effects of SGLT2 Inhibitors: A Research Hypothesis for Dapagliflozin’s Effects in the Adrenal Gland

Abstract

Heart failure (HF) remains the leading cause of morbidity and death in the western world, and new therapeutic modalities are urgently needed to improve the lifespan and quality of life of HF patients. The sodium-glucose co-transporter-2 (SGLT2) inhibitors, originally developed and mainly indicated for diabetes mellitus treatment, have been increasingly shown to ameliorate heart disease, and specifically HF, in humans, regardless of diabetes co-existence. Indeed, dapagliflozin has been reported to reduce cardiovascular mortality and hospitalizations in patients with HF and reduced ejection fraction (HFrEF). This SGLT2 inhibitor demonstrates these benefits also in non-diabetic subjects, indicating that dapagliflozin’s efficacy in HF is independent of blood glucose control. Evidence for the effectiveness of various SGLT2 inhibitors in providing cardiovascular benefits irrespective of their effects on blood glucose regulation have spurred the use of these agents in HFrEF treatment and resulted in FDA approvals for cardiovascular indications. The obvious question arising from all these studies is, of course, which molecular/pharmacological mechanisms underlie these cardiovascular benefits of the drugs in diabetics and non-diabetics alike. The fact that SGLT2 is not significantly expressed in cardiac myocytes (SGLT1 appears to be the dominant isoform) adds even greater perplexity to this answer. A variety of mechanisms have been proposed over the past few years and tested in cell and animal models and prominent among those is the potential for sympatholysis, i.e., reduction in sympathetic nervous system activity. The latter is known to be high in HF patients, contributing significantly to the morbidity and mortality of the disease. The present minireview first summarizes the current evidence in the literature supporting the notion that SGLT2 inhibitors, such as dapagliflozin and empagliflozin, exert sympatholysis, and also outlines the main putative underlying mechanisms for these sympatholytic effects. Then, we propose a novel hypothesis, centered on the adrenal medulla, for the sympatholytic effects specifically of dapagliflozin. Adrenal medulla is responsible for the production and secretion of almost the entire amount of circulating epinephrine and of a significant percentage of circulating norepinephrine in the human body. If proven true experimentally, this hypothesis, along with other emerging experimental evidence for sympatholytic effects in neurons, will shed new light on the pharmacological effects that mediate the cardiovascular benefits of SGLT2 inhibitor drugs, independently of their blood glucose-lowering effects.

Short-Chain Fatty Acid Receptors and Cardiovascular Function

“…Notably, in that same study, the ketone body β-hydroxybutyrate (or 3-hydroxybutyrate) was shown to block FFAR3 and antagonize its pro-sympathetic hyperactivity in neurons [ 21 ] ( Figure 2 ). On the other hand, sodium/glucose co-transporter (SGLT)-2 inhibitors, such as dapagliflozin and empagliflozin (anti-diabetic/diuretic drugs with a plethora of beneficial cardiovascular effects that have been coming to light at an accelerating pace), increase ketone body (including β-hydroxybutyrate) production in the heart and blood vessels [ 90 , 91 ]. Given that dapagliflozin and empagliflozin have been shown to possess sympatholytic properties that mediate, at least in part, their beneficial effects in chronic human heart failure [ 92 ], it is tempting to speculate that the sympatholytic effects of SGLT2 inhibitor drugs are mediated, at least partially, by the b-hydroxybutyrate-mediated blockade of FFAR3 signaling in sympathetic neurons, which normally raises cardiac norepinephrine levels and cardiovascular sympathetic nervous system activity [ 91 ].…”

A Systematic Review of Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors and Sympathetic Nervous System Inhibition: An Underrated Mechanism of Cardiorenal Protection

“…The fact that SGLT2 inhibitors lower blood pressure without raising heart rate implies that they may be linked to a reduction in sympathetic overactivity. Both animal models of diabetes and obesity [ 28 , 29 ] appear to have these sympathoinhibitory effects with SGLT2 inhibitors (without diabetes). When the kidneys are harmed, the brain senses this via the afferent renal nerve, increasing sympathetic outflow from the central nervous system.…”

“…A raised sympathetic tone for a long duration of time may cause advanced atherosclerosis and reduced blood flow to the kidneys, resulting in a decrease in renal function. Heart failure is also exacerbated [ 29 ]. In heart failure, overactivity of the sympathetic nervous system is linked to increased hospitalization and death.…”

Regulator of G-Protein Signaling-4 Attenuates Cardiac Adverse Remodeling and Neuronal Norepinephrine Release-Promoting Free Fatty Acid Receptor FFAR3 Signaling

“…FFAR3 is expressed in various tissues including in the heart [ 1 , 2 , 3 ] and is known to promote tissue inflammation and, as mentioned above, sympathetic nervous system (SNS) activity, neuronal firing, and NE release [ 1 , 2 , 3 ]. The latter is cardiotoxic, especially for the failing heart, as it increases myocardial oxygen/metabolic demand [ 24 , 25 ]. However, very little (virtually nothing) is currently known regarding cardiac FFAR3 signaling, per se.…”