Effects of SGLT2 Inhibitors on Atherosclerosis: Lessons from Cardiovascular Clinical Outcomes in Type 2 Diabetic Patients and Basic Researches

Xu, Jing; Hirai, Taro; Koya, Daisuke; Kitada, Munehiro

doi:10.3390/jcm11010137

Cited by 27 publications

(15 citation statements)

References 122 publications

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“…Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a successful form of treatment for the control of blood glucose levels that also contribute to the regulation of insulin and lipid profiles, however, they have also demonstrated positive cardiovascular benefits in some recent studies ( Xu et al, 2021 ). The SGLTi works by preventing the reabsorption of glucose in the proximal convoluted tubule in the kidneys and consequentially promoting the excretion of excess glucose ( Kalra, 2014 ).…”

Section: Current Treatmentsmentioning

confidence: 99%

Posing the rationale for synthetic lipoxin mimetics as an adjuvant treatment to gold standard atherosclerosis therapies

Millar

Gaetano²

2023

Front. Pharmacol.

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Atherosclerosis is a progressive, multifactorial inflammatory, and dyslipidaemic disease, responsible for the majority of cardiovascular diseases globally. The chronic inflammation is the main driver of the initiation and progression of such disease, as a result of an imbalanced lipid metabolism and an ineffective immune response to attenuate the inflammatory component. The importance of inflammation resolution is being increasingly recognised in atherosclerosis and cardiovascular disease. It has a complex mechanism consisting of multiple stages, including restoring an effective removal of apoptotic bodies (efferocytosis) and their degradation (effero-metabolism), a macrophage phenotype switching towards resolving phenotypes, and the promotion of tissue healing and regeneration. The low-grade inflammation associated with atherosclerosis development is a driving force in disease exacerbation, and hence inflammation resolution is a key area of research. In this review, we explore the complex disease pathogenesis and its many contributing factors to gain a greater understanding of the disease and identify the current and potential therapeutic targets. First-line treatments and their efficacy will also be discussed in detail, to highlight the emerging field of resolution pharmacology. Despite the great efforts made by current gold-standard treatments, such as lipid-lowering and glucose-lowering drugs, they remain ineffective at tackling residual inflammatory risk and residual cholesterol risk. Resolution pharmacology represents a new era of atherosclerosis therapy, as endogenous ligands associated with inflammation resolution are exploited for their pharmacological benefits in a more potent and longer-acting manner. Novel FPR2-agonists, such as synthetic lipoxin analogues, provide an exciting new approach to enhance the pro-resolving response of the immune system and subsequently end the pro-inflammatory response to allow for an anti-inflammatory and pro-resolving environment for tissue healing, regeneration, and return to homeostasis.

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Section: Current Treatmentsmentioning

confidence: 99%

Posing the rationale for synthetic lipoxin mimetics as an adjuvant treatment to gold standard atherosclerosis therapies

Millar

Gaetano²

2023

Front. Pharmacol.

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“…Canagliflozin, characterized by a thiophene derivative of C-glucoside, showed over 400-fold difference in inhibitory activities between human SGLT-2 and SGLT-1 [ 72 ]. Thereafter, empagliflozin, which has the highest selectivity for SGLT-2 over SGLT-1 (approximately 2700-fold), was the third agent approved by both the European Medicines Agency (EMA) and the FDA, while other SGLT-2i, namely luseogliflozin and topogliflozin, are approved so far for use only in Japan, and ipragliflozin only in Japan and Russia [ 73 , 74 , 75 , 76 , 77 ].…”

Section: Sglt-2i Overviewmentioning

confidence: 99%

SGLT-2 Inhibitors in NAFLD: Expanding Their Role beyond Diabetes and Cardioprotection

Ανδρουτσάκος

Nasiri-Ansari

Bakasis

et al. 2022

IJMS

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Non-alcoholic fatty liver disease (NAFLD) is an ‘umbrella’ term, comprising a spectrum ranging from benign, liver steatosis to non-alcoholic steatohepatitis, liver fibrosis and eventually cirrhosis and hepatocellular carcinoma. NAFLD has evolved as a major health problem in recent years. Discovering ways to prevent or delay the progression of NAFLD has become a global focus. Lifestyle modifications remain the cornerstone of NAFLD treatment, even though various pharmaceutical interventions are currently under clinical trial. Among them, sodium-glucose co-transporter type-2 inhibitors (SGLT-2i) are emerging as promising agents. Processes regulated by SGLT-2i, such as endoplasmic reticulum (ER) and oxidative stress, low-grade inflammation, autophagy and apoptosis are all implicated in NAFLD pathogenesis. In this review, we summarize the current understanding of the NAFLD pathophysiology, and specifically focus on the potential impact of SGLT-2i in NAFLD development and progression, providing current evidence from in vitro, animal and human studies. Given this evidence, further mechanistic studies would advance our understanding of the exact mechanisms underlying the pathogenesis of NAFLD and the potential beneficial actions of SGLT-2i in the context of NAFLD treatment.

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“…The protective effects of SGLT2is against the cardiovascular (CV) and renal complications of T2DM appear to be independent of their glucose-lowering activity, with particular value being demonstrated in the reduction of risk regarding hospitalisation for heart failure (HHF) and progression of diabetic kidney disease (DKD) as well as lowering the incidence of major adverse cardiovascular events (MACE) [ 4 – 36 ]. Recently published reviews have described and explored the putative mechanisms underlying the cardiorenal benefits of SGLT2is, emphasising the direct and indirect effects that these medicines have on pathways that mediate inflammation, oxidative stress and endothelial cell dysfunction [ 37 , 38 ].…”

Section: The Clinical Effects Of Sglt2i Therapies: From Glucose-lower...mentioning

confidence: 99%

The Place and Value of Sodium-Glucose Cotransporter 2 Inhibitors in the Evolving Treatment Paradigm for Type 2 Diabetes Mellitus: A Narrative Review

et al. 2022

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Over recent years, the expanding evidence base for sodium-glucose cotransporter-2 inhibitor (SGLT2i) therapies has revealed benefits beyond their glucose-lowering efficacy in the treatment of Type 2 diabetes mellitus (T2DM), resulting in their recognition as cardiorenal medicines. While SGLT2is continue to be recommended among the second-line therapies for the treatment of hyperglycaemia, their true value now extends to the prevention of debilitating and costly cardiovascular and renal events for high-risk individuals, with particular benefit shown in reducing major adverse cardiac events and heart failure (HF) and slowing the progression of chronic kidney disease. However, SGLT2i usage is still suboptimal among groups considered to be at greatest risk of cardiorenal complications. The ongoing coronavirus disease 2019 (COVID-19) pandemic has intensified financial pressures on healthcare systems, which may hamper further investment in newer effective medicines. Emerging evidence indicates that glycaemic control should be prioritised for people with T2DM in the era of COVID-19 and practical advice on the use of T2DM medications during periods of acute illness remains important, particularly for healthcare professionals working in primary care who face multiple competing priorities. This article provides the latest update from the Improving Diabetes Steering Committee, including perspectives on the value of SGLT2is as cost-effective therapies within the T2DM treatment paradigm, with particular focus on the latest published evidence relating to the prevention or slowing of cardiorenal complications. The implications for ongoing and future approaches to diabetes care are considered in the light of the continuing coronavirus pandemic, and relevant aspects of international treatment guidelines are highlighted with practical advice on the appropriate use of SGLT2is in commonly occurring T2DM clinical scenarios. The ‘SGLT2i Prescribing Tool for T2DM Management’, previously published by the Steering Committee, has been updated to reflect the latest evidence and is provided in the Supplementary Materials to help support clinicians delivering T2DM care. Supplementary Information The online version contains supplementary material available at 10.1007/s13300-022-01228-w.

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Effects of SGLT2 Inhibitors on Atherosclerosis: Lessons from Cardiovascular Clinical Outcomes in Type 2 Diabetic Patients and Basic Researches

Cited by 27 publications

References 122 publications

Posing the rationale for synthetic lipoxin mimetics as an adjuvant treatment to gold standard atherosclerosis therapies

Posing the rationale for synthetic lipoxin mimetics as an adjuvant treatment to gold standard atherosclerosis therapies

SGLT-2 Inhibitors in NAFLD: Expanding Their Role beyond Diabetes and Cardioprotection

The Place and Value of Sodium-Glucose Cotransporter 2 Inhibitors in the Evolving Treatment Paradigm for Type 2 Diabetes Mellitus: A Narrative Review

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