Dapagliflozin, a selective SGLT2 Inhibitor, attenuated cardiac fibrosis by regulating the macrophage polarization via STAT3 signaling in infarcted rat hearts

Lee, Tsung Ming; Chang, Nen Chung; Lin, Shinn Zong

doi:10.1016/j.freeradbiomed.2017.01.035

Cited by 385 publications

(305 citation statements)

References 37 publications

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“…Indeed, empagliflozin reduced M1‐polarized macrophage (pro‐inflammatory) accumulation and induced the anti‐inflammatory M2 phenotype within adipose tissue and liver in a mouse model of diet‐induced obesity, which showed lower plasma cytokine levels and attenuated obesity‐related chronic inflammation . Similar findings were provided for dapagliflozin in a mouse model of myocardial infarction . It is noteworthy that postprandial, glycaemia‐induced inflammation is a tangible phenomenon, even in humans, and that empagliflozin increases postprandial glucose excretion in T2DM patients .…”

Section: Evidence Of the Anti‐inflammatory Effect Of Sglt2 Inhibitorssupporting

confidence: 60%

“…66 Similar findings were provided for dapagliflozin in a mouse model of myocardial infarction. 67 It is noteworthy that postprandial, glycaemia-induced inflammation is a tangible phenomenon, even in humans, and that empagliflozin increases postprandial glucose excretion in T2DM patients. 66,68 Compared with other glucoselowering agents, the peculiar mechanism of action of SGLT2 inhibitors could rationally support a more marked anti-inflammatory effect.…”

Section: Evidence Of the Anti-inflammatory Effect Of Sglt2 Inhibitomentioning

confidence: 99%

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Increases in circulating levels of ketone bodies and cardiovascular protection with SGLT2 inhibitors: Is low‐grade inflammation the neglected component?

Prattichizzo

Nigris

Micheloni

et al. 2018

Diabetes Obesity Metabolism

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Recent clinical trials have demonstrated a strong cardiovascular (CV) protective effect of sodium/glucose cotransporter (SGLT) 2 inhibitors, a recently introduced class of hypoglycaemic agents. The improvement in glycated haemoglobin and other conventional risk factors explains only a portion of the observed reduction in CV risk. A relevant feature of SGLT2-inhibitor-treated diabetic patients is the increase in circulating levels of ketone bodies, which has been proposed to mediate part of the beneficial effects of this class of drugs, mainly through their bioenergetic properties. However, ketone bodies are emerging as potent anti-inflammatory molecules, and inflammation is a recognized risk factor for the development of CV events. In this framework, we hypothesize that, through their unique mechanism of action and by increasing circulating ketone bodies, SGLT2 inhibitors indirectly target the IL-1β pathway and thus produce a consistent amelioration of low-grade inflammation, a clinically relevant phenomenon in diabetic patients with high CV risk. This attenuation could slow the progression of CV disease and especially the atherosclerotic process, which is sensitive to environmental changes, even over a short time period. To test this conceptual structure, it would be necessary to measure circulating pro-inflammatory molecules in patients treated with SGLT inhibitors. The addition of inflammatory markers to the list of clinical data measured in FDA-requested, large CV outcome trials could provide supplementary information regarding potential secondary effects of new anti-hyperglycaemic drugs, considering that the inflammatory process is an often neglected cornerstone of CV diseases.

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Section: Evidence Of the Anti‐inflammatory Effect Of Sglt2 Inhibitorssupporting

confidence: 60%

Section: Evidence Of the Anti-inflammatory Effect Of Sglt2 Inhibitomentioning

confidence: 99%

Increases in circulating levels of ketone bodies and cardiovascular protection with SGLT2 inhibitors: Is low‐grade inflammation the neglected component?

Prattichizzo

Nigris

Micheloni

et al. 2018

Diabetes Obesity Metabolism

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“…Studies in animal models have indicated that SGLT‐2is may directly reduce cardiac inflammation . Empagliflozin has been associated with attenuation of cardiac macrophage infiltration in diabetic rat and mouse models, while dapagliflozin has been shown to modulate inflammatory cytokines in rats with acute MI, including decreases in interleukin (IL)‐1β and IL‐6 and increases in IL‐10, as well as an increase in the ratio of M2/M1 (anti‐inflammatory/proinflammatory phenotype) macrophages …”

Section: Mechanisms Of CV and Renal Protection With Sglt‐2 Inhibitorsmentioning

confidence: 99%

Effects of sodium‐glucose cotransporter‐2 inhibitors on the cardiovascular and renal complications of type 2 diabetes

Chilton

2019

Diabetes Obesity Metabolism

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Sodium‐glucose cotransporter‐2 inhibitors (SGLT‐2is) have been shown to mitigate the risks of cardiovascular (CV) and renal complications in patients with type 2 diabetes (T2D) and CV risk factors or CV disease (CVD). In CV outcomes trials (CVOTs) of patients with T2D and established CVD or multiple CV risk factors, empagliflozin and canagliflozin were associated with significant reductions in the risks of major adverse CV events (MACE), hospitalization for heart failure (HF) and kidney disease progression. In the DECLARE–TIMI 58 study, in which the majority of patients did not have established CVD, dapagliflozin was associated with significant reductions in the composite end point of CV death or hospitalization for HF and was noninferior to placebo with regard to MACE; although patients had relatively good renal function, dapagliflozin also showed renal benefits similar to those seen with empagliflozin and canagliflozin. This article reviews the increased risk of CVD and renal disease in patients with T2D and discusses the potential mechanisms of the cardioprotective and renoprotective effects of SGLT‐2i therapy. The observed improvements in CV and renal outcomes with SGLT‐2is in CVOTs suggest a class effect in this patient population and have influenced treatment guidelines for the way add‐on therapy to metformin is initiated in patients with T2D and high CV risk. The overall cardioprotective and renoprotective effects of SGLT‐2is in patients with T2D and high CV risk are most likely attributable to multiple mechanisms, including cardiac, haemodynamic, metabolic, anti‐inflammatory and renal effects.

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“…In animals, SGLT2 inhibition reduces cardiac fibrosis, inflammation, and oxidative stress 85 . In several rodent models of T2D, SGLT2 inhibition improves diastolic function and left ventricular hypertrophy while simultaneously reducing myocardial fibrosis and expression of profibrotic/prohypertrophic proteins 86–88 . Verma et al have also demonstrated cardioprotective effects in a zebrafish model of HF, suggesting conservation of cardiovascular protective effects across species 89 .…”

Section: Impact Of Sglt2 Inhibition On Cardiac Structure and Functionmentioning

confidence: 99%

Sodium Glucose Cotransporter-2 Inhibition in Heart Failure

et al. 2017

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Despite current established therapy, heart failure (HF) remains a leading cause of hospitalization and mortality worldwide. Novel therapeutic targets are therefore needed to improve the prognosis of patients with HF. The EMPA-REG OUTCOME trial demonstrated significant reductions in mortality and HF hospitalization risk in patients with type 2 diabetes (T2D) and cardiovascular disease with the antihyperglycemic agent, empagliflozin – a sodium glucose co-transporter 2 (SGLT2) inhibitor. The CANVAS trial subsequently reported a reduction in 3-point MACE (major adverse cardiovascular events) and HF hospitalization risk. While SGLT2 inhibition may have potential application beyond T2D, including HF, the mechanisms responsible for the cardioprotective effects of SGLT2 inhibitors remain incompletely understood. SGLT2 inhibition promotes natriuresis and osmotic diuresis, leading to plasma volume contraction and reduced preload, as well as decreases in blood pressure, arterial stiffness and afterload, thereby improving subendocardial blood flow in patients with HF. SGLT2 inhibition is also associated with preservation of renal function. Based on data from mechanistic studies and clinical trials, large clinical trials with SGLT2 inhibitors are now investigating the potential use of SGLT2 inhibition in patients with HF with and without T2D. Accordingly, in this review, we summarize key pharmacodynamic effects of SGLT2 inhibitors and the clinical evidence which support the rationale for the use of SGLT2 inhibitors in HF patients with T2D. Since presumably these favorable effects occur independent of blood-glucose lowering, we also explore the potential use of SGLT2 inhibition in patients without T2D with HF or at risk of HF, such as in patients with coronary artery disease or hypertension. Finally, we provide a detailed overview and summary of ongoing cardiovascular outcome trials with SGLT2 inhibitors.

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Dapagliflozin, a selective SGLT2 Inhibitor, attenuated cardiac fibrosis by regulating the macrophage polarization via STAT3 signaling in infarcted rat hearts

Cited by 385 publications

References 37 publications

Increases in circulating levels of ketone bodies and cardiovascular protection with SGLT2 inhibitors: Is low‐grade inflammation the neglected component?

Increases in circulating levels of ketone bodies and cardiovascular protection with SGLT2 inhibitors: Is low‐grade inflammation the neglected component?

Effects of sodium‐glucose cotransporter‐2 inhibitors on the cardiovascular and renal complications of type 2 diabetes

Sodium Glucose Cotransporter-2 Inhibition in Heart Failure

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