SGLT-2-inhibition with dapagliflozin reduces tissue sodium content: a randomised controlled trial

Karg, Michael; Bosch, Aida; Kannenkeril, Dennis; Striepe, Kristina; Ott, Christian; Schneider, Markus P.; Boemke-Zelch, F.; Linz, Peter; Nagel, Armin M.; Titze, Jens; Uder, Michael; Schmieder, Roland E.

doi:10.1186/s12933-017-0654-z

Cited by 167 publications

(117 citation statements)

References 41 publications

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“…It is therefore noteworthy that SGLT2 inhibitors reduce intracellular sodium in cardiomyocytes, an action that is independent of glucose . This effect has been confirmed in the clinical setting and has been proposed to underlie the cardioprotective effect of these drugs seen in randomized controlled trials …”

Section: Novel Mechanisms By Which Sglt2 Inhibitors May Promote Cardimentioning

confidence: 78%

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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Section: Novel Mechanisms By Which Sglt2 Inhibitors May Promote Cardimentioning

confidence: 78%

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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“…As SGK1 activity may modulate NHE activity through Aktmediated signaling, these results suggest that empagliflozin could restore myocardial [Na + ] c in a sustained manner (55). Examinations using 23 Na + magnetic resonance imaging revealed that the tissue Na + content in diabetic patients was markedly reduced by treatment with dapagliflozin (56). An in silico docking study demonstrated that three SGLT2 inhibitors, empagliflozin, dapagliflozin, and canagliflozin, showed high binding affinity with the extracellular Na + -binding site of NHE (57).…”

Section: Sglt2 Inhibitors Promote Sodium Metabolism-mediated Cardioprmentioning

confidence: 85%

SGLT2 Inhibitors Play a Salutary Role in Heart Failure via Modulation of the Mitochondrial Function

Maejima

2020

Front. Cardiovasc. Med.

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Three cardiovascular outcome trials of sodium glucose cotransporter 2 (SGLT2) inhibitors, including the EMPA-REG OUTCOME trial, CANVAS Program, and DECLARE TIMI 58 trial, revealed that SGLT2 inhibitors were superior to a matching placebo in reducing cardiovascular events, including mortality and hospitalization for heart failure, in patients with type 2 diabetes. However, the detailed mechanism underlying the beneficial effects that SGLT2 inhibitors exert on cardiovascular diseases remains to be elucidated. We herein review the latest findings of the salutary mechanisms of SGLT2 inhibitors in cardiomyocytes, especially focusing on their mitochondrial function-mediated beneficial effects. The administration of SGLT2 inhibitors leads to the elevation of plasma levels of ketone bodies, which are an efficient energy source in the failing heart, by promoting oxidation of the mitochondrial coenzyme Q couple and enhancing the free energy of cytosolic ATP hydrolysis. SGLT2 inhibitors also promote sodium metabolism-mediated cardioprotective effects. These compounds could reduce the intracellular sodium overload to improve mitochondrial energetics and oxidative defense in the heart through binding with NHE and/or SMIT1. Furthermore, SGLT2 inhibitors could modulate mitochondrial dynamics by regulating the fusion and fission of mitochondria. Together with ongoing large-scale clinical trials to evaluate the efficacy of SGLT2 inhibitors in patients with heart failure, intensive investigations regarding the mechanism through which SGLT2 inhibitors promote the restoration in cases of heart failure would lead to the establishment of these drugs as potent anti-heart failure drugs.

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“…Diuretic treatment of patients with acute heart failure reduces tissue Na ϩ by 20 -26% (15). A recent clinical trial showed a modest decrease in skin Na (5.8%) and no change in muscle Na ϩ in diabetic patients treated with dapagliflozin for 6 wk (18). It is possible that reduced tissue osmolality due to lowering of glucose levels over 6 wk contributed to this response.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of renal and cardiovascular protection mechanisms of SGLT2 inhibitors: model-based analysis of clinical data

Hallow

Greasley

Helmlinger

et al. 2018

American Journal of Physiology-Renal Physiology

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The mechanisms of cardiovascular and renal protection observed in clinical trials of SGLT2 inhibitors (SGLT2i) are incompletely understood and likely multifactorial, including natriuretic, diuretic, and antihypertensive effects, glomerular pressure reduction, and lowering of plasma and interstitial fluid volume. To quantitatively evaluate the contribution of proposed SGLT2i mechanisms of action on changes in renal hemodynamics and volume status, we coupled a mathematical model of renal function and volume homeostasis with clinical data in healthy subjects administered 10 mg dapagliflozin once-daily. The minimum set of mechanisms necessary to reproduce observed clinical responses (urinary sodium and water excretion, serum creatinine and sodium) was determined, and important unobserved physiologic variables (glomerular pressure, blood and interstitial fluid volume) were then simulated. We further simulated the response to SGLT2i in diabetic virtual patients with and without renal impairment. Multiple mechanisms were required to explain the observed response: 1) direct inhibition of sodium and glucose reabsorption through SGLT2, 2) SGLT2-driven inhibition of NHE3 sodium reabsorption, and 3) osmotic diuresis coupled with peripheral sodium storage. The model also showed that the consequences of these mechanisms include lowering of glomerular pressure, reduction of blood and interstitial fluid volume, and mild blood pressure reduction, in agreement with clinical observations. The simulations suggest that these effects are more significant in diabetic patients than healthy subjects, and that while glucose excretion may diminish with renal impairment, improvements in glomerular pressure and blood volume are not diminished at lower GFR, suggesting cardiorenal benefits of SGLT2i may be sustained in renally impaired patients.

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SGLT-2-inhibition with dapagliflozin reduces tissue sodium content: a randomised controlled trial

Cited by 167 publications

References 41 publications

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

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

SGLT2 Inhibitors Play a Salutary Role in Heart Failure via Modulation of the Mitochondrial Function

Evaluation of renal and cardiovascular protection mechanisms of SGLT2 inhibitors: model-based analysis of clinical data

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