Emerging concepts in heart failure treatment and management: focus on SGLT2 inhibitors in heart failure with preserved ejection fraction

Abstract

The role of sodium–glucose cotransporter 2 inhibitors (SLTG2i), developed initially as glucose-lowering agents, has represented a novelty in patients with heart failure (HF) and reduced ejection fraction (HFrEF) since dapagliflozin (DAPA-HF study) and empagliflozin (EMPEROR-Reduced study) were able to reduce morbidity and mortality in this setting regardless of the presence or absence of diabetes. In previous large clinical trials (EMPA-REG OUTCOME study, CANVAS, DECLARE-TIMI 58), SGLT2i have been shown to attenuate HF progression expressed by reducing the risk of HF hospitalizations in patients with type 2 diabetes mellitus mostly without HF at baseline. This benefit was then corroborated with positive results in HF outcomes (cardiovascular mortality and HF hospitalizations) in patients with HF with preserved ejection fraction (HFpEF) in the EMPEROR-Preserved (empagliflozin) and DELIVER (dapagliflozin) trials. Several biological mechanisms apart from the glycosuria are attributed to these agents in this last context, including anti-inflammatory effects, reduction of fibrosis and apoptosis, improvement of myocardial metabolism, mitochondrial function optimization, and oxidative stress protection. Moreover, SGLT2i can also improve ventricular loading conditions by forcing diuresis and natriuresis, and by enhancing vascular and renal function. In addition, SGLT2i can reduce myocardial passive stiffness (diastolic function) by enforcing the phosphorylation of myofilament modulatory proteins. This article provided an overview of the main pathophysiological characteristics of HFpEF and of the diverse mechanisms of action of SGLT2i in this setting. The supporting clinical evidence of SGLT2i in HFpEF (EMPEROR-Preserved and DELIVER trials) is also reviewed. This article is part of the Emerging concepts in heart failure management and treatment Special Issue: https://www.drugsincontext.com/special_issues/emerging-concepts-in-heart-failure-management-and-treatment

Effects of empagliflozin on cardiac structure, function and biomarkers in patients with heart failure with preserved ejection fraction: study protocol for a randomised, placebo-controlled prospective trial

“…Meanwhile, the possible mechanisms remain unclear. The processes of fibrosis development may be secondary to an underlying factor of inflammation or increased oxidative stress,22 which would be a possible antifibrotic mechanism of SGLT2 inhibitors. In a female rodent model of diabetes, empagliflozin improved cardiac diastolic function measured by echocardiography, which was accompanied by a reduction in the expression of pro-fibrotic proteins and attenuation of interstitial fibrosis 23.…”

Current Role of SLGT2 Inhibitors in the Management of the Whole Spectrum of Heart Failure: Focus on Dapagliflozin

“…The pathogenesis of HF is complex, as different neurohormonal systems are involved, including the overactivation of deleterious pathways, such as the renin-angiotensin and the sympathetic nervous systems, but also the inhibition of protective pathways, such as the natriuretic peptides system and the nitric oxide-soluble guanylate cyclase-cGMP system [16][17][18][19]. SGLT2i promotes glucosuria, osmotic diuresis and natriuresis, improves volume status and cardiac metabolism, sodium-hydrogen exchange in the myocardium, reduces cardiac fibrosis, prevents and reverses adverse cardiac remodeling through the reduction of apoptosis, necrosis and autophagy and the improvement of myocardial oxygen supply/demand, reduce sympathetic stimulation, modulate the levels of leptin and adiponectin, improve control of risk factors, preserve renal function and decrease inflammation and oxidative stress [20][21][22][23][24][25][26][27][28].…”