Mechanisms and Perspectives of Sodium-Glucose Co-transporter 2 Inhibitors in Heart Failure

Abstract

Heart failure (HF) is a common complication or late-stage manifestation of various heart diseases. Numerous risk factors and underlying causes may contribute to the occurrence and progression of HF. The pathophysiological mechanisms of HF are very complicated. Despite accumulating advances in treatment for HF during recent decades, it remains an intractable clinical syndrome with poor outcomes, significantly reducing the quality of life and expectancy of patients, and imposing a heavy economic burden on society and families. Although initially classified as antidiabetic agents, sodium-glucose co-transporter 2 (SGLT2) inhibitors have demonstrated reduced the prevalence of hospitalization for HF, cardiovascular death, and all-cause death in several large-scale randomized controlled clinical trials. These beneficial effects of SGLT-2 inhibitors can be attributed to multiple hemodynamic, inflammatory and metabolic mechanisms, not only reducing the serum glucose level. SGLT2 inhibitors have been used increasingly in treatment for patients with HF with reduced ejection fraction due to their surprising performance in improving the prognosis. In addition, their roles and mechanisms in patients with HF with preserved ejection fraction or acute HF have also attracted attention. In this review article, we discuss the possible mechanisms and applications of SGLT2 inhibitors in HF.

Overview of Sodium-Glucose Co-transporter 2 (SGLT2) Inhibitors for the Treatment of Non-diabetic Heart Failure Patients

“…The novel antidiabetic agents, SGLT2 inhibitors, have been gradually reconsidered as an important class of medications for heart failure, being recommended for their beneficial impact in patients with type 2 diabetes patients and multiple cardiovascular risk factors or heart failure with reduced ejection fraction [ 11 ]. The current clinical guidelines for the management of heart failure are concentrated on a triple neurohormonal blockade, including beta-blockers, angiotensin-converting enzyme inhibitors (ACEIs), or angiotensin receptor blockers (ARBs), and mineralocorticoid receptor antagonists with specific recommendations based on the patient’s comorbidities [ 12 ].…”

“…In 1998, Oyama et al concluded that the impaired nitric oxide and oxidative stress pathways are responsible for cytokine-induced left ventricle (LV) dysfunction, and impact various cells, including endotheliocytes, vascular smooth muscle cells, infiltrating inflammatory cells, and cardiomyocytes [ 15 ]. Based on these pathophysiological mechanisms, anti-inflammatory and anti-cytokine therapies could be considered beneficial, although the clinical trials have not significantly improved the survival of patients with HF [ 11 ].…”

“…For example, empagliflozin can reduce the cardiac macrophage infiltration in genetic/diabetes mouse model; or dapagliflozin improves the cardiac inflammation in Wistar rats by elevating the anti-inflammatory messenger RNA (mRNA) levels (IL10), attenuating the inflammatory cytokines mRNA levels (IL-1𝛃 and IL-6), and inducing the macrophage polarization to an anti-inflammatory phenotype [ 9 ]. Further to these preclinical researches, a recent meta-analysis published in 2020 has revealed that SGLT2 inhibitors decrease the serum level of C-reactive protein (CRP), IL-6, and TNF-ɑ, and, subsequently, inhibit the pro-inflammatory signaling pathways [ 11 ].…”

“…Oxidative stress is defined by the overproduction of reactive oxygen species (ROS) caused by mitochondrial dysfunction, increased activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and nitric oxide synthase combined with insufficient endogenous antioxidants [ 11 ]. Considerable experimental and clinical studies have demonstrated that ROS enhances the injury by non-specific interaction with proteins, lipid membranes, mitochondria, and DNA resulting in severe contractile dysfunction and heart failure [ 16 ].…”

“…Because oxidative stress and inflammation have a crucial impact on the pathogenesis of cardiac hypertrophy and remodeling, this report also validates that empagliflozin attenuates these effects and ameliorates the hypertrophic and fibrotic processes [ 17 ]. A recent systematic review has concluded that SGT2 inhibitors are involved in reducing the levels of some essential biomarkers of oxidative stress, prostaglandin-F2ɑ and 8-hydroxy-2′-deoxyguanosine [ 11 ]. Despite the mentioned benefits of SGLT2 inhibitors, further studies are needed to understand the precise mechanism of their cardioprotective effects.…”