Abstract
Heart failure (HF) affects up to over 20% of patients with type 2 diabetes (T2DM), even more in the elderly. Although, in T2DM, both hyperglycemia and the proinflammatory status induced by insulin resistance are crucial in cardiac function impairment, SGLT2i cardioprotective mechanisms against HF are several. In particular, these beneficial effects seem attributable to the significant reduction of intracellular sodium levels, well-known to exert a cardioprotective role in the prevention of oxidative stress and consequent cardiomyocyte death. From a molecular perspective, patients’ exposure to gliflozins’ treatment mimics nutrient and oxygen deprivation, with consequent autophagy stimulation. This allows to maintain the cellular homeostasis through different degradative pathways. Thus, since their introduction in the clinical practice, the hypotheses on SGLT2i mechanisms of action have changed: from simple glycosuric drugs, with consequent glucose lowering, erythropoiesis enhancing and ketogenesis stimulating, to intracellular sodium-lowering molecules. This provides their consequent cardioprotective effect, which justifies its significant reduction in CV events, especially in populations at higher risk. Finally, the updated clinical evidence of SGLT2i benefits on HF was summarized. Thus, this review aimed to analyze the cardioprotective mechanisms of sodium glucose transporter 2 inhibitors (SGLT2i) in patients with HF, as well as their clinical impact on cardiovascular events.
Highlights
sodium glucose transporter 2 inhibitors (SGLT2i) causes a reduction in the autonomic nervous system (ANS) activity by decreasing the insulin, leptin and glucose blood levels, improving insulin resistance (IR), hyperinsulinemia and anemia. All those contribute to a reduction of the carotid body (CB) activation, as well as of the volume of sodium and the level of protein-bound uremic toxins, which inhibit the activation of the organum vasculosum of the lamina terminalis (OVLT) in the region of the third anteroventral ventricle (AV3V) of the hypothalamus [150]
These findings suggest a potential effect of SGLT2i on inverse cardiac remodeling in Heart failure (HF) patients with both preserved (HFpEF) and reduced (HFrEF) and, in nondiabetic patients
The DAPA-HF (Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure) study was instead the first international, multicenter, parallel-group, randomized, doubleblind clinical trial on a SGLT2i designed to assess the effect of Dapagliflozin 10 mg vs. a placebo in 4744 patients with HFrEF and NYHA classes II–IV, both with and without Type 2 diabetes mellitus (T2DM) [162]
Summary
HF estimated prevalence among T2DM patients ranges between 9–22%, even higher in those aged ≥60 years old [2,3,4,5]. Several large cohort studies have reported an incidence of diabetes in patients affected by HF ranging between 30% and 50%, suggesting a mutual relationship between these two diseases [12,13]. Up until gliflozins commercialization and evidence from randomized control trials, no antidiabetic therapy showed significant improvements in HF hospitalization [19]. While, initially, this benefit was attributed to the diuretic and antihypertensive effect of this class of drug, mechanisms other than SGLT2 inhibition have been recently proposed. Aim of this review is to assess the cardioprotective role of sodium glucose transporter 2 inhibitors (SGLT2i) in patients affected by both these conditions
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