SGLT-2 Inhibition with Dapagliflozin Reduces the Activation of the Nlrp3/ASC Inflammasome and Attenuates the Development of Diabetic Cardiomyopathy in Mice with Type 2 Diabetes. Further Augmentation of the Effects with Saxagliptin, a DPP4 Inhibitor

Ye, Yumei; Bajaj, Mandeep S; Yang, Hsiu Chiung; Perez‐Polo, J. Regino; Birnbaum, Yochai

doi:10.1007/s10557-017-6725-2

Cited by 312 publications

(236 citation statements)

References 48 publications

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“…Clearly, many of these findings are preliminary, proposing multiple exciting hypotheses and needs further investigation. In agreement with the present study, numerous in vivo studies using different rodent models of diabetes have demonstrated the beneficial effect of SGLT-2 inhibition on adverse cardiac remodeling and ventricular function [8–13]. However, most of the previous studies were descriptive in nature and do not provide mechanistic insight of empagliflozin mediated cardiac benefits (table 1).…”

supporting

confidence: 89%

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

Gupte

Umbarkar

Lal

2017

Cardiovasc Drugs Ther

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supporting

confidence: 89%

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

Gupte

Umbarkar

Lal

2017

Cardiovasc Drugs Ther

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“…These mechanisms are likely to be complementary, rather than mutually exclusive, all converging on one primary target, that is, IL‐1β, a major cytokine with a recognized role in the development of atherosclerosis and CV disease (Figure ). Finally, a glycaemia‐independent, molecule‐intrinsic, anti‐inflammatory mechanism has been proposed for canagliflozin and dapagliflozin, as has been shown in vitro in vascular endothelial cells and cardiofibroblast …”

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

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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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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“…The heart failure phenotype in these trials was not investigated, but since patients with diabetes are prone to development of HFpEF, these drugs may have primarily acted to reduce the risk of HFpEF. It is therefore noteworthy that SGLT2 inhibitors reduce the accumulation and inflammation of epicardial fat, which may explain why this class of drugs appears to decrease myocardial fibrosis and improve ventricular diastolic filling dynamics, both experimentally and clinically . This anti‐inflammatory effect may be far more relevant to patients with HFpEF than those with HFrEF .…”

Section: Implications For Anti‐inflammatory and Antidiabetic Drugsmentioning

confidence: 99%

Are the effects of drugs to prevent and to treat heart failure always concordant? The statin paradox and its implications for understanding the actions of antidiabetic medications

Packer

2018

European J of Heart Fail

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Most treatments for chronic heart failure are effective both in preventing its onset and reducing its progression. However, statins prevent the development of heart failure, but they do not decrease morbidity and mortality in those with established heart failure. This apparent discordance cannot be explained by an effect to prevent interval myocardial infarctions. Instead, it seems that the disease that statins were preventing in trials of patients with a metabolic disorder was different from the disease that they were treating in trials of chronic heart failure. The most common phenotype of heart failure in patients with obesity and diabetes is heart failure with a preserved ejection fraction (HFpEF). In this disorder, the anti-inflammatory effects of statins might ameliorate myocardial fibrosis and cardiac filling abnormalities, but these actions may have little relevance to patients with heart failure and a reduced ejection fraction (HFrEF), whose primary derangement is cardiomyocyte loss and stretch. These distinctions may explain why statins were ineffective in trials that focused on HFrEF, but have been reported to produce favourable effects in observational studies of HFpEF. Similarly, selective cytokine antagonists were ineffective in HFrEF, but have been associated with benefits in HFpEF. These observations may have important implications for our understanding of the effects of antihyperglycaemic medications. Glucagon-like peptide-1 receptor agonists have had neutral effects on heart failure events in people at risk for HFpEF, but have exerted deleterious actions in HFrEF. Similarly, sodium-glucose co-transporter 2 inhibitors, which exert anti-inflammatory effects and reduce heart failure events in patients who are prone to HFpEF, may not be effective in HFrEF. The distinctions between HFrEF and HFpEF may explain why the effects of drugs on heart failure events in diabetes trials may not be relevant to their use in patients with systolic dysfunction.

show abstract

SGLT-2 Inhibition with Dapagliflozin Reduces the Activation of the Nlrp3/ASC Inflammasome and Attenuates the Development of Diabetic Cardiomyopathy in Mice with Type 2 Diabetes. Further Augmentation of the Effects with Saxagliptin, a DPP4 Inhibitor

Cited by 312 publications

References 48 publications

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

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

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

Are the effects of drugs to prevent and to treat heart failure always concordant? The statin paradox and its implications for understanding the actions of antidiabetic medications

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