Impact of SGLT2 Inhibitors on Heart Failure: From Pathophysiology to Clinical Effects

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.

Comparative effect of statin intensity between prediabetes and type 2 diabetes mellitus after implanting newer-generation drug-eluting stents in Korean acute myocardial infarction patients: a retrospective observational study

“…However, because this study was based on discharge medications, we could not precisely determine the adherence or non-adherence of the enrolled patients to their prescribed discharge medications during the follow-up period; this might constitute an additional bias. Moreover, recent antidiabetic medications have been shown to improve cardiovascular outcomes [ 47 – 49 ]. Especially, sodium-glucose co-transporter 2 (SGLT-2) inhibitors, initially introduced for the treatment of DM, demonstrates cardiovascular and renal benefit in patients with heart failure (HF) [ 47 ].…”

“…Lu et al [ 48 ] demonstrated that beneficial effects SGLT-2 inhibitors were robust in HF patients regardless of T2DM status, and a strong trend to be effective in HF with preserved EF. Recent review [ 49 ] also introduced that the hypotheses on SGLT-2 inhibitors mechanisms of action have changed: from simple glycosuric drugs, with consequent glucose lowering, erythropoiesis enhancing and ketogenesis stimulating, to intracellular sodium-lowering molecules. However, unfortunately, this registry data did not include information concerning SGLT-2 inhibitors.…”

Kidney Cancer and Chronic Kidney Disease: Too Close for Comfort

“…Anti-hypertension drugs may exert a long-term protective effect in the kidneys by minimizing the effects of high blood pressure and facilitating vasodilation [ 35 ]. Moreover, evidence also shows that SLGT2 inhibitors have a cardioprotective role, given their anti-inflammatory and anti-fibrotic effects in cardiomyocytes derived from lower intracellular sodium levels [ 36 ]. Allegedly, one of the reasons behind the very limited therapeutic options for CKD is our limited understanding of its pathophysiology.…”

Inflammation and Oxidative Stress in Diabetic Kidney Disease: The Targets for SGLT2 Inhibitors and GLP-1 Receptor Agonists

“…SGLT2i were also shown to reduce the cardiovascular risk by means of decreased all-cause mortality, cardiovascular death, first hospitalization due to heart failure and decreased risk of combined endpoints composed of the above-mentioned events in patients with heart failure with reduced and preserved ejection fraction. These benefits were observed in patients with and without diabetes and were independent from age category (with a trend to achieve even better results in older patients), gender, BMI, and were evident across the entire spectrum of kidney function (to the values of GFR as low as 25 mL/min/1.7 m 2 ) [ 3 , 4 , 5 , 6 , 7 , 8 , 9 ]. A recently published meta-analysis of four landmark cardio-vascular outcome trials on SGLT2i performed in patients with diabetes raised the possibility that this group of drugs may also protect from stroke and that this effect may be most pronounced for canagliflozin when used in patients with advanced DKD.…”