Legacy in Cardiovascular Risk Factors Control: From Theory to Future Therapeutic Strategies?

Pothen, Lucie; Balligand, Jean‐Luc

doi:10.3390/antiox10111849

Cited by 5 publications

(4 citation statements)

References 84 publications

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“…Relevant mechanistic studies indicate the legacy effect may be mediated through pathways including epigenetic modifications, non-enzymatic glycosylation of proteins and chronic inflammation, and endothelial dysfunction induced by hyperglycemia-related oxidative stress ( 5 , 31 , 32 ). Recent researches shows that SGLT-2i and GLP-1RA, which can provide cardiovascular benefits, may have the potential to mitigate these harmful legacy effects through their mechanisms of action.…”

Section: Discussionmentioning

confidence: 99%

Influence of early use of sodium-glucose transport protein 2 inhibitors, glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors on the legacy effect of hyperglycemia

Deng,

Zhao,

Chai

et al. 2024

Front. Endocrinol.

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BackgroundA phenomenon known as legacy effect was observed that poor glycemic control at early stage of patients with newly-diagnosed type 2 diabetes (T2D) increases the risk of subsequent cardiovascular diseases (CVD). Early use of some novel anti-hyperglycemic agents, such as sodium-glucose transport protein 2 inhibitors (SGLT-2i), may attenuate this effect, but the evidence is limited.MethodsTwo retrospective cohorts of newly diagnosed T2D patients from 2010–2023 were assembled using the Yinzhou Regional Health Care Database (YRHCD) with different definitions of the early exposure period - the 1-year exposure cohort and 2-year exposure cohort, which were comprised of subjects who had HbA1c measurement data within 1 year and 2 years after their T2D diagnosis, respectively. Using Cox proportional hazards models, we examined the association between high HbA1c level (HbA1c>7%) during the early exposure period and the risk of subsequent CVD. This analysis was performed in the overall cohort and three subpopulations with different treatments during the early exposure period, including patients initiating SGLT-2i or glucagon-like peptide-1 receptor agonists (GLP-1RA), patients using dipeptidyl peptidase-4 inhibitors (DPP-4i), and patients without using SGLT-2i, GLP-1RA, and DPP-4i. Besides, subgroup analyses were performed by stratifying patients into age <55 and ≥55 years.ResultsA total of 21,477 and 22,493 patients with newly diagnosed T2D were included in the two final cohorts. Compared with patients with mean HbA1c ≤ 7% during the early exposure period, those with HbA1c>7% had higher risks of incident CVD, with a HR of 1.165 (95%CI, 1.056–1.285) and 1.143 (95%CI, 1.044–1.252) in 1-year and 2-year exposure period cohort. Compared to non-users, in patients initiating SGLT-2i/GLP-1RA within 1 or 2 years after T2D diagnosis, higher HbA1c level at baseline was not associated with CVD in both two cohorts. In subgroup analyses, results were generally consistent with the main analysis.ConclusionsPoor glycemic control in the early stage of T2D increased later CVD risk in Chinese adults with newly diagnosed T2D. Compared to non-users, this association was smaller and non-significant in patients receiving SGLT-2i/GLP-1RA during the early stage of T2D, indicating early use of these drugs may have the potential to mitigate legacy effects of hyperglycemia.

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Section: Discussionmentioning

confidence: 99%

Influence of early use of sodium-glucose transport protein 2 inhibitors, glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors on the legacy effect of hyperglycemia

Deng,

Zhao,

Chai

et al. 2024

Front. Endocrinol.

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“…On the other hand, it should be underlined that the concept of ‘metabolic memory’ was developed for diabetes, and experimental studies in this disease reasonably support the validity of this concept. However, similar constructs for hyperlipidaemia and hypertension have a weaker experimental basis [ 44 ]. Another difficult problem is that the optimal duration of early and intensive intervention to achieve a legacy effect remains unclear.…”

Section: Legacy Effects In Chronic Kidney Diseasementioning

confidence: 99%

The long-term benefits of early intensive therapy in chronic diseases—the legacy effect

Zoccali

Mallamaci

Tripepi

et al. 2023

Clinical Kidney Journal

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The ‘legacy effect’ refers to the long-term benefits of intensive therapy that are observed long after the end of clinical trials and trial interventions in chronic diseases such as diabetes, hyperlipidaemia and hypertension. It emphasizes the importance of intensive treatment to prevent long-term complications and mortality. In chronic kidney disease (CKD), the legacy effect is evident in various studies. Long-term nephroprotection in diabetes is well documented in major studies in the early stages of diabetes, such as Diabetes Control and Complications Trial-Epidemiology of Diabetes Interventions and Complications (DCCT-EDIC), UK Prospective Diabetes Study (UKPDS) and Intensified Multifactorial Intervention in Patients with Type 2 Diabetes and Microalbuminuria (STENO-2). These studies highlight the importance of intensive glycaemic control in reducing microvascular complications, including nephropathy, in patients with recently diagnosed type 1 and type 2 diabetes. However, the legacy effect is less evident in patients with long-term, established diabetes. In chronic glomerulonephritis, studies on immunoglobulin A nephropathy showed that early immunosuppressive treatment could have long-term beneficial effects on kidney function in children and adults with CKD. The Frequent Hemodialysis (FH) and the EXerCise Introduction To Enhance Performance in Dialysis (EXCITE) trials indicated that frequent haemodialysis and a personalized walking exercise program could improve clinical outcomes and reduce the long-term risk of death and hospitalization. The legacy effect concept underscores the importance of intensive intervention in chronic diseases, including CKD. This concept has significant implications for public health and warrants in-depth basic and clinical research to be better understood and exploited in clinical practice. However, its limitations should be considered when interpreting long-term observational data collected after a clinical trial. Appropriate study designs are necessary to investigate an unbiased legacy effect.

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“…Other sources are also important as ROS producers. Angiotensin II (Ang II), the main product and effector of the renin-angiotensin system stimulation, is a regulator of blood pressure and produces ROS by stimulating NOX ( Nguyen Dinh Cat et al, 2013 ; Forrester et al, 2018 ; Pothen and Balligand, 2021 ). Ang II-induced ROS production leads to mitogen-activated protein kinase (MAPK) activation, where ROS play a role as a second messenger ( Nishida et al, 2005 ; Forrester et al, 2018 ).…”

Section: Intracellular Sources Of Ros and Initiating Eventsmentioning

confidence: 99%

Reactive Oxygen Species in the Adverse Outcome Pathway Framework: Toward Creation of Harmonized Consensus Key Events

et al. 2022

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Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are formed as a result of natural cellular processes, intracellular signaling, or as adverse responses associated with diseases or exposure to oxidizing chemical and non-chemical stressors. The action of ROS and RNS, collectively referred to as reactive oxygen and nitrogen species (RONS), has recently become highly relevant in a number of adverse outcome pathways (AOPs) that capture, organize, evaluate and portray causal relationships pertinent to adversity or disease progression. RONS can potentially act as a key event (KE) in the cascade of responses leading to an adverse outcome (AO) within such AOPs, but are also known to modulate responses of events along the AOP continuum without being an AOP event itself. A substantial discussion has therefore been undertaken in a series of workshops named “Mystery or ROS” to elucidate the role of RONS in disease and adverse effects associated with exposure to stressors such as nanoparticles, chemical, and ionizing and non-ionizing radiation. This review introduces the background for RONS production, reflects on the direct and indirect effects of RONS, addresses the diversity of terminology used in different fields of research, and provides guidance for developing a harmonized approach for defining a common event terminology within the AOP developer community.

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Legacy in Cardiovascular Risk Factors Control: From Theory to Future Therapeutic Strategies?

Cited by 5 publications

References 84 publications

Influence of early use of sodium-glucose transport protein 2 inhibitors, glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors on the legacy effect of hyperglycemia

Influence of early use of sodium-glucose transport protein 2 inhibitors, glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors on the legacy effect of hyperglycemia

The long-term benefits of early intensive therapy in chronic diseases—the legacy effect

Reactive Oxygen Species in the Adverse Outcome Pathway Framework: Toward Creation of Harmonized Consensus Key Events

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