Sodium-dependent glucose transporters (SGLT) in human ischemic heart: A new potential pharmacological target

Franco, A. Di; Cantini, Giulia; Tani, Akio; Coppini, Raffaele; Zecchi‐Orlandini, Sandra; Raimondi, Laura; Luconi, Michaela; Mannucci, Edoardo

doi:10.1016/j.ijcard.2017.05.032

Cited by 140 publications

(115 citation statements)

References 13 publications

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“…However, all these proposed mechanisms are primarily speculation and need further clinical and experimental evidence for validation. A recent study examined the relative expression of SGLT2 and SGLT1, the two most relevant members of the SGLT family, in normal, ischemic and hypertrophic human hearts [14]. Consistent with previous reports, Di Franco et al [14] reported that SGLT2 does not express in either healthy or failing (ischemic/hypertrophic) human heart.…”

supporting

confidence: 61%

“…However, a high-level of SGLT1 expression is seen. Furthermore, SGLT1 expression was significantly increased in injured heart, suggesting that increased expression of SGLT1 in cardiomyocytes may represent a potential target for empagliflozin and provides another possible explanation for the observed cardiovascular effects of empagliflozin treatment [14]. This hypothesis can be easily tested by employing cardiac-specific SGLT1 KO animals.…”

mentioning

confidence: 99%

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Mechanistic Insights of Empagliflozin-Mediated Cardiac Benefits: Nearing the Starting Line

Gupte

Umbarkar

Lal

2017

Cardiovasc Drugs Ther

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supporting

confidence: 61%

mentioning

confidence: 99%

Mechanistic Insights of Empagliflozin-Mediated Cardiac Benefits: Nearing the Starting Line

Gupte

Umbarkar

Lal

2017

Cardiovasc Drugs Ther

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“…Based on available trials, the possibility that empagliflozin has specific effects on mortality, different from those of other molecules of the class, cannot be excluded, although molecular mechanisms underlying such difference remain elusive [7]. On the other hand, other hypotheses should be considered.…”

Section: Discussionmentioning

confidence: 99%

Exploring the heterogeneity of the effects of SGLT-2 inhibitors in cardiovascular outcome trials

Mannucci

Dicembrini

Nreu

et al. 2020

Nutrition, Metabolism and Cardiovascular Diseases

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Background and aim: The interpretation of discrepancies across cardiovascular safety trials (CVOT) with SGLT-2 inhibitors in the incidence of major cardiovascular events (MACE) and mortality is complex, because of heterogeneity in trial protocols and baseline characteristics of patients enrolled. Aim of this analysis is the exploration of possible determinants of heterogeneity of relative risk reduction for major cardiovascular events (MACE) and all-cause mortality. Methods and results: Incidence of events (MACE and mortality) in intervention and control groups and baseline characteristics of patients were extracted for each trial (EMPAREG, CANVAS, and DECLARE). For studies including both primary and secondary prevention cohorts, those two subgroups were considered separately. Metaregression analysis was used to assess the association of relative risk reduction with baseline characteristics of patients, including observed incidence of events with placebo. The estimated reduction in the incidence of MACE associated with SGLT-2 inhibitors showed a significant association with the incidence of MACE in the control group, suggesting that a greater effect was observed in trials enrolling patients at higher risk (Slope À0.008 [À0.023; 0.007], p Z 0.31). A higher proportion of patients treated with statins, bblockers and insulin at baseline was associated with a greater reduction of MACE, but not of mortality. Conclusions: In CVOT trials, the magnitude of the effect of SGLT-2 inhibitors on MACE is driven by absolute risk of enrolled patients; as a consequence, the estimated risk reduction is lower in primary prevention cohorts, which have a lower risk. This result supports the hypothesis of a class effect of SGLT-2 inhibitors on MACE. jo urnal homep age: www.el sevie r.co m/locate/nm cd

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“…This pattern of response is similar to that seen in the DECLARE‐TIMI 58 trial, which showed the most marked reduction in heart failure events in patients with the lowest ejection fraction before randomization. Taken collectively, these observations suggest that SGLT2 inhibitors exert a direct cardioprotective effect that is proportional to the severity of myocardial stress, even though there is no detectable SGLT2 expression in the heart . Two possible mechanisms have been proposed to account for such a cardioprotective action ( Figure ).…”

Section: Novel Mechanisms By Which Sglt2 Inhibitors May Promote Cardimentioning

confidence: 91%

Autophagy stimulation and intracellular sodium reduction as mediators of the cardioprotective effect of sodium–glucose cotransporter 2 inhibitors

Packer

2020

European J of Heart Fail

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In five large-scale trials involving >40 000 patients, sodium-glucose cotransporter 2 (SGLT2) inhibitors decreased the risk of serious heart failure events by 25-40%. This effect cannot be explained by control of hyperglycaemia, since it is not observed with antidiabetic drugs with greater glucose-lowering effects. It cannot be attributed to ketogenesis, since it is not causally linked to ketone body production, and the benefit is not enhanced in patients with diabetes. The effect cannot be ascribed to a natriuretic action, since SGLT2 inhibitors decrease natriuretic peptides only modestly, and they reduce cardiovascular death, a benefit that diuretics do not possess. Although SGLT2 inhibitors increase red blood cell mass, enhanced erythropoiesis does not favourably influence the course of heart failure. By contrast, experimental studies suggest that SGLT2 inhibitors may reduce intracellular sodium, thereby preventing oxidative stress and cardiomyocyte death. Additionally, SGLT2 inhibitors induce a transcriptional paradigm that mimics nutrient and oxygen deprivation, which includes activation of adenosine monophosphate-activated protein kinase, sirtuin-1, and/or hypoxia-inducible factors-1 /2 . The interplay of these mediators stimulates autophagy, a lysosomally-mediated degradative pathway that maintains cellular homeostasis. Autophagy-mediated clearance of damaged organelles reduces inflammasome activation, thus mitigating cardiomyocyte dysfunction and coronary microvascular injury. Interestingly, the action of hypoxia-inducible factors-1 /2 to both stimulate erythropoietin and induce autophagy may explain why erythrocytosis is strongly correlated with the reduction in heart failure events. Therefore, the benefits of SGLT2 inhibitors on heart failure may be mediated by a direct cardioprotective action related to modulation of pathways responsible for cardiomyocyte homeostasis.In four large-scale clinical trials in patients with type 2 diabetes followed for 2-5 years who largely did not have a diagnosis of heart failure at the time of study entry, patients assigned to treatment

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Sodium-dependent glucose transporters (SGLT) in human ischemic heart: A new potential pharmacological target

Cited by 140 publications

References 13 publications

Mechanistic Insights of Empagliflozin-Mediated Cardiac Benefits: Nearing the Starting Line

Mechanistic Insights of Empagliflozin-Mediated Cardiac Benefits: Nearing the Starting Line

Exploring the heterogeneity of the effects of SGLT-2 inhibitors in cardiovascular outcome trials

Autophagy stimulation and intracellular sodium reduction as mediators of the cardioprotective effect of sodium–glucose cotransporter 2 inhibitors

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