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High-density lipoprotein (HDL) cholesterol is traditionally viewed as protective against cardiovascular disease (CVD). However, emerging evidence reveals that dysfunctional HDL, characterized by impaired reverse cholesterol transport (RCT), reduced anti-inflammatory and antioxidant activities and increased endothelial dysfunction, which can contribute to coronary artery disease (CAD). Dysfunctional HDL, resulting from oxidative modifications of Apolipoprotein A-1 (Apo A-1) and enzyme inactivation, fails to effectively remove cholesterol from peripheral tissues and may promote inflammation and atherosclerosis. Genetic mutations affecting HDL metabolism further complicate its role in cardiovascular health. Studies have shown that conventional therapies aimed at raising HDL-C levels do not necessarily reduce cardiovascular events, highlighting the need for new approaches that improve HDL functionality. Therapeutic strategies such as Apo A-1 mimetic peptides, reconstituted HDL infusions, and drugs targeting specific HDL metabolic pathways are being explored. Additionally, weight loss, statin therapy, and niacin have shown potential in enhancing HDL function. The pathophysiology of dysfunctional HDL involves complex mechanisms, including oxidative stress, inflammation, and genetic mutations, which alter its structure and function, diminishing its cardioprotective effects. New functional assays, such as the cholesterol efflux capacity (CEC) and HDL inflammatory index, provide more accurate predictions of cardiovascular risk by assessing HDL quality rather than quantity. As research progresses, the focus is shifting towards therapeutic strategies that enhance HDL function and address the root causes of its dysfunction, offering a more effective approach to reducing cardiovascular risk and preventing CAD. [ABSTRACT FROM AUTHOR]

Background: Low-density lipoprotein cholesterol (LDL-C) is considered the most important risk factor for coronary artery disease (CAD). Although lipid-lowering therapy using high-intensity statins for patients with stable CAD is one of the cornerstones of medication therapy, there is still a risk of residual cardiovascular events, even after controlling for LDL-C. Recently, attention has focused on the association between small dense LDL-C as a residual risk factor for CAD, and it has been reported that a formula can be used to calculate the small LDL-C. Methods: We investigated the association between estimated small dense LDL-C (Esd LDL-C) and the occurrence of new lesions with myocardial ischemia ≤2 years after percutaneous coronary intervention (PCI) in 537 patients with stable angina who underwent PCI. In this study, all patients had been prescribed statins. This study was based on previously reported data regarding the relationship between non-high-density lipoprotein cholesterol levels and stable angina pectoris after PCI. Results: Revascularization, including new lesions and in-stent restenosis, and new lesions appeared in 130 and 90 patients, respectively, ≤2 years after PCI. Age, diabetes mellitus (DM), LDL-C, and Esd LDL-C were associated with the occurrence of revascularization and new lesions ≤2 years after PCI. Multivariate logistic regression analysis models revealed that Esd LDL-C [odds ratio (OR) 1.03, 95% confidence interval (CI) 1.004-1.048, p = 0.020; and OR 1.03, 95% CI 1.009-1.057, p = 0.007, respectively] were associated with the revascularization and occurrence of new lesions ≤2 years after PCI. Conclusions: As well as total cholesterol and LDL-C, Esd LDL-C was an independent risk factor for the revascularization and occurrence of new lesions ≤2 years after PCI for stable angina in Japanese patients receiving statin therapy. In patients with stable angina who are on lipid-lowering therapy with statins, calculating the Esd LDL-C may provide useful information for predicting revascularization and the occurrence of new lesions. [ABSTRACT FROM AUTHOR]

Background: The objective of this research is to evaluate the efficacy and safety of drugs in the residual risk in any of its three components: lipid, inflammatory and thrombotic risk. Methods: A systematic review was conducted of randomized clinical trials that included as a primary outcome, at least one of the conditions related to atherosclerotic cardiovascular disease. The databases used were PUBMED/MEDLINE, Scopus and ClinicalTrials.gov. The risk of bias of the studies was assessed using the Risk of Bias 2 tool. Results: and discussion: 18 studies were included in the analysis. Half of the studies had low risk of bias or some concerns. Several drugs were effective in reducing the primary outcome: ethyl eicosapentaenoeic acid (17.2 % E-EPA versus 22 % placebo HR: 0.75; 95 % CI 0.68–0.83; p

Cardiovascular diseases represent the leading cause of death in the world and are subject to limitations in prevention strategies despite the use of very effective drugs. The concept of residual risk (RR) is intrinsically related to that of global risk of which it represents a very significant percentage. In the cardiovascular field, the term RR refers to the probability of incurring a major cardiovascular event, despite adequate control of the risk factors present in the individual patient. A significant portion of the RR in the cardiovascular field results from the underestimation of additional risk factors not subjected to adequate intervention such as, for example, triglyceride levels in patients treated for the presence of hypertension and/or hypercholesterolemia. The control of the RR therefore appears as an essential condition for the effective reduction of the global risk profile and is based on an integrated intervention that combines all the different prevention strategies derived from the available evidence and capable of interacting on the basis of a strengthening reciprocal between lifestyle and pharmacological and nutraceutical intervention methods. [ABSTRACT FROM AUTHOR]

• Residual cardiovascular (CV) risk constitutes a complex issue with many factors involved. • Residual CV risk factors include: triglyceride-rich lipoproteins (TRLs), remnant cholesterol (RC), lipoprotein (a): Lp (a) and inflammation. • Healthy habits as Mediterranean diet and physical activity modulate residual CV risk. • Apolipoprotein C-III (apoC-III) and angiopoietin-related protein 3 (ANGPTL3) inhibitors to reduce TRLs and RC could modulate residual CV risk. • Antisense oligonucleotides (ASO), small-interfering ribonucleic acid (siRNA) and oral agents (Muvalaplin) reduce Lp(a) modulating residual CV risk. Cardiovascular disease (CVD) still being the most common cause of death in worldwide. In spite of development of new lipid-lowering therapies which optimize low-density lipoprotein cholesterol (LDL-c) levels, recurrence of CVD events implies addressing factors related with residual cardiovascular (CV) risk. The key determinants of residual CV risk include triglyceride-rich lipoproteins (TRLs) and remnant cholesterol (RC), lipoprotein(a) [Lp(a)] and inflammation including its biochemical markers such as high sensitivity C reactive protein (hs-CRP). On the other hand, unhealthy lifestyle habits, environmental pollution, residual thrombotic risk and the residual metabolic risk determined by obesity and type 2 diabetes (T2D) have a specific weight in the residual CV risk. New pharmacologic therapies and pathways are being explored such as inhibition of apolipoprotein C-III (apoC-III) and angiopoietin-related protein 3 (ANGPTL3) in order to explore if a reduction in TRLs and RC reduce CVD events. Therapeutic target of inflammation plays an attractive way to reduce the atherosclerotic process and to date, approved therapies as colchicine plays a beneficial effect in chronic inflammation and residual CV risk. Lp(a) constitutes one of the most residual CV risk factor due to linkage with CVD and aortic valve stenosis. New and hopeful treatments including antisense oligonucleotides (ASO) and small-interfering ribonucleic acid (siRNA) which interfere in LP(a) codification have been developed to achieve an adequate control in Lp(a) levels. This review points out the paradigms of residual CV risk, discus how we should manage their features and summarize the different therapies targeting each residual CV risk factor. [ABSTRACT FROM AUTHOR]

We believe that there is sufficient evidence from basic science, longitudinal cohort studies and randomised controlled trials which validates the low-density lipoprotein cholesterol (LDL-C) or lipid hypothesis. It is important that we can communicate details of the cardiovascular disease (CVD) risk reduction that the average patient could expect depending on the scale of LDL-C decrease following lipid lowering therapy. It is also essential that residual risk (ResR) of CVD be highlighted. To achieve this aim by using existing trial evidence, we developed mathematical models initially for relative risk reduction (RRR) and absolute risk (AR) reduction and then showed that despite optimising LDL-C levels, a considerable degree of ResR remains that is dependent on AR. Age is significantly associated with AR (odds ratio: 1.02, 95% confidence intervals: 1.01–1.04) as was previously demonstrated by analysing the Whickham study cohort using a logistic regression model (age remaining significant even when all the other significant risk factors such as sex, smoking, systolic blood pressure, diabetes and family history were included in the regression model). A discussion of a paper by Ference et al. provided detailed evidence of the relationship between age and AR, based on lifetime LDL-C exposure. Finally, we discussed non-traditional CVD risk factors that may contribute to ResR based on randomised controlled trials investigating drugs improving inflammation, thrombosis, metabolic and endothelial status. [ABSTRACT FROM AUTHOR]

Abstract Background The presence of residual cardiovascular risk is an important cause of cardiovascular events. Despite the significant advances in our understanding of residual cardiovascular risk, a comprehensive analysis through bibliometrics has not been performed to date. Our objective is to conduct bibliometric studies to analyze and visualize the current research hotspots and trends related to residual cardiovascular risk. This will aid in understanding the future directions of both basic and clinical research in this area. Methods The literature was obtained from the Web of Science Core Collection database. The literature search date was September 28, 2022. Bibliometric indicators were analyzed using CiteSpace, VOSviewer, Bibliometrix (an R package), and Microsoft Excel. Result A total of 1167 papers were included, and the number of publications is increasing rapidly in recent years. The United States and Harvard Medical School are the leading country and institution, respectively, in the study of residual cardiovascular risk. Ridker PM and Boden WE are outstanding investigators in this field. According to our research results, the New England Journal of Medicine is the most influential journal in the field of residual cardiovascular risk, whereas Atherosclerosis boasts the highest number of publications on this topic. Analysis of keywords and landmark literature identified current research hotspots including complications of residual cardiovascular risk, risk factors, and pharmacological prevention strategies. Conclusion In recent times, global attention toward residual cardiovascular risk has significantly increased. Current research is focused on comprehensive lipid-lowering, residual inflammation risk, and dual-pathway inhibition strategies. Future efforts should emphasize strengthening international communication and cooperation to promote the comprehensive evaluation and management of residual cardiovascular risk.

Abstract Background Elevated triglyceride levels are a clinically useful marker of remnant cholesterol. It is unknown whether triglycerides are associated with residual cardiovascular risk in CVD-naïve patients with newly diagnosed type 2 diabetes mellitus (T2DM), who are already on statin therapy. We aimed to assess the association between triglyceride levels and risk of major cardiovascular events (MACE) in statin-treated patients with newly diagnosed T2DM managed in routine clinical care. Methods This cohort study included newly diagnosed T2DM patients without a previous diagnosis of cardiovascular disease in Northern Denmark during 2005–2017. Individual triglyceride levels while on statin treatment were assessed within 1 year after T2DM diagnosis. The primary outcome was a composite of myocardial infarction, ischemic stroke, or cardiac death (MACE). Patients were followed from one year after T2DM diagnosis until 30 April 2021, MACE, emigration, or death. We used Cox regression to compute hazard ratios (HRs) controlling for confounding factors. Results Among 27,080 statin-treated patients with T2DM (median age 63 years; 53% males), triglyceride levels were

Background: The presence of residual cardiovascular risk is an important cause of cardiovascular events. Despite the significant advances in our understanding of residual cardiovascular risk, a comprehensive analysis through bibliometrics has not been performed to date. Our objective is to conduct bibliometric studies to analyze and visualize the current research hotspots and trends related to residual cardiovascular risk. This will aid in understanding the future directions of both basic and clinical research in this area. Methods: The literature was obtained from the Web of Science Core Collection database. The literature search date was September 28, 2022. Bibliometric indicators were analyzed using CiteSpace, VOSviewer, Bibliometrix (an R package), and Microsoft Excel. Result: A total of 1167 papers were included, and the number of publications is increasing rapidly in recent years. The United States and Harvard Medical School are the leading country and institution, respectively, in the study of residual cardiovascular risk. Ridker PM and Boden WE are outstanding investigators in this field. According to our research results, the New England Journal of Medicine is the most influential journal in the field of residual cardiovascular risk, whereas Atherosclerosis boasts the highest number of publications on this topic. Analysis of keywords and landmark literature identified current research hotspots including complications of residual cardiovascular risk, risk factors, and pharmacological prevention strategies. Conclusion: In recent times, global attention toward residual cardiovascular risk has significantly increased. Current research is focused on comprehensive lipid-lowering, residual inflammation risk, and dual-pathway inhibition strategies. Future efforts should emphasize strengthening international communication and cooperation to promote the comprehensive evaluation and management of residual cardiovascular risk. [ABSTRACT FROM AUTHOR]

Copyright of Revista Argentina de Cardiología is the property of Sociedad Argentina de Cardiologia and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Chronic coronary syndrome (CCS), which encompasses a broad spectrum of clinical presentations of coronary artery disease (CAD), is the leading cause of morbidity and mortality worldwide. Recent guidelines for the management of CCS emphasize the dynamic nature of the CAD process, replacing the term "stable" with "chronic", as this disease is never truly "stable". Despite significant advances in the treatment of CAD, patients with CCS remain at an elevated risk of major cardiovascular events (MACE) due to the so-called residual cardiovascular risk. Several pathogenetic pathways (thrombotic, inflammatory, metabolic, and procedural) may distinctly contribute to the residual risk in individual patients and represent a potential target for newer preventive treatments. Identifying the level and type of residual cardiovascular risk is essential for selecting the most appropriate diagnostic tests and follow-up procedures. In addition, new management strategies and healthcare models could further support available treatments and lead to important prognostic benefits. This review aims to provide an overview of the diagnostic and therapeutic challenges in the management of patients with CCS and to promote more effective multidisciplinary care. [ABSTRACT FROM AUTHOR]

Residual cardiovascular risk is defined as the risk of cardiovascular events that persists in patients despite reaching low-density lipoprotein cholesterol, blood pressure and blood sugar treatment goals, according to the current treatment standards. In light of today’s evidence, residual risk changes the perspective beyond the current definition toward several aspects like residual thrombotic risk; residual metabolic risk and the role of lipoprotein a, triglycerides, remnant cholesterol and HDL; the residual risk of diabetics aside from A1C control; and residual inflammatory risk. All of these are treatment goals which affect the outcomes, producing a greater reduction of residual cardiovascular risk. [ABSTRACT FROM AUTHOR]

Mitigating residual risk is one of the primary objectives of cardiovascular medicine, achieved through a holistic and transdisciplinary approach to managing cardiovascular risk factors. It involves the use of increasingly potent therapies that can positively impact clinical outcomes while ensuring patient safety. Consequently, the use of PCSK9-inhibiting medications has become a straightforward and highly recommended strategy in clinical practice guidelines for lipid management and lipid-related risk factor intervention. These medications have effectively been proven to reduce recurrent cardiovascular events and have a legacy effect on lipid levels, and are considered safe in achieving extremely low LDL-c levels. [ABSTRACT FROM AUTHOR]

As time has come to translate trial results into individualized medical diagnosis and therapy, we analyzed how to minimize residual risk of cardiovascular disease (CVD) by reviewing papers on “residual cardiovascular disease risk”. During this review process we found 989 papers that started off with residual CVD risk after initiating statin therapy, continued with papers on residual CVD risk after initiating therapy to increase high-density lipoprotein-cholesterol (HDL-C), followed by papers on residual CVD risk after initiating therapy to decrease triglyceride (TG) levels. Later on, papers dealing with elevated levels of lipoprotein remnants and lipoprotein(a) [Lp(a)] reported new risk factors of residual CVD risk. And as new risk factors are being discovered and new therapies are being tested, residual CVD risk will be reduced further. As we move from CVD risk reduction to improvement of patient management, a paradigm shift from a reductionistic approach towards a holistic approach is required. To that purpose, a personalized treatment dependent on the individual’s CVD risk factors including lipid profile abnormalities should be configured, along the line of P5 medicine for each individual patient, i.e., with Predictive, Preventive, Personalized, Participatory, and Psycho-cognitive approaches.

Introduction: Adverse cardiovascular events that arise in patients with established cardiovascular disease have prompted researchers to seek variables that can help estimate residual cardiovascular risk and aid in its reduction. In Latin-America, there is limited data assessing this type of risk. Objective: Estimate residual cardiovascular risk in ambulatory patients diagnosed with Chronic Coronary Syndrome (CCS) using the SMART-Score scale seen at five clinics in Nicaragua; determine the prevalence of patients that achieve a serum LDL level of

Background: Elevated triglyceride levels are a clinically useful marker of remnant cholesterol. It is unknown whether triglycerides are associated with residual cardiovascular risk in CVD-naïve patients with newly diagnosed type 2 diabetes mellitus (T2DM), who are already on statin therapy. We aimed to assess the association between triglyceride levels and risk of major cardiovascular events (MACE) in statin-treated patients with newly diagnosed T2DM managed in routine clinical care. Methods: This cohort study included newly diagnosed T2DM patients without a previous diagnosis of cardiovascular disease in Northern Denmark during 2005–2017. Individual triglyceride levels while on statin treatment were assessed within 1 year after T2DM diagnosis. The primary outcome was a composite of myocardial infarction, ischemic stroke, or cardiac death (MACE). Patients were followed from one year after T2DM diagnosis until 30 April 2021, MACE, emigration, or death. We used Cox regression to compute hazard ratios (HRs) controlling for confounding factors. Results: Among 27,080 statin-treated patients with T2DM (median age 63 years; 53% males), triglyceride levels were < 1.0 mmol/L in 17%, 1.0–1.9 mmol/L in 52%, 2.0–2.9 mmol/L in 20%, and ≥ 3.0 mmol/L in 11%. During follow-up, 1,957 incident MACE events occurred (11.0 per 1000 person-years). Compared with triglyceride levels < 1.0 mmol/L, confounder-adjusted HRs for incident MACE were 1.14 (95% CI 1.00–1.29) for levels between 1.0 and 1.9 mmol/L, 1.30 (95% CI 1.12–1.51) for levels between 2.0 and 2.9 mmol/L, and 1.44 (95% CI 1.20–1.73) for levels ≥ 3.0 mmol/L. This association was primarily driven by higher rates of myocardial infarction and cardiac death and attenuated only slightly after additional adjustment for LDL cholesterol. Spline analyses confirmed a linearly increasing risk of MACE with higher triglyceride levels. Stratified analyses showed that the associations between triglyceride levels and MACE were stronger among women. Conclusions: In statin-treated patients with newly diagnosed T2DM, triglyceride levels are associated with MACE already from 1.0 mmol/L. This suggests that high triglyceride levels are a predictor of residual cardiovascular risk in early T2DM and could be used to guide allocation of additional lipid-lowering therapies for CVD prevention. [ABSTRACT FROM AUTHOR]

Low-density lipoprotein (LDL)-cholesterol (LDL-C) promotes atherosclerotic cardiovascular disease (ASCVD), with changes in LDL electronegativity modulating its pro-atherogenic/pro-thrombotic effects. Whether such alterations associate with adverse outcomes in patients with acute coronary syndromes (ACS), a patient population at particularly high cardiovascular risk, remains unknown. This is a case-cohort study using data from a subset of 2619 ACS patients prospectively recruited at four university hospitals in Switzerland. Isolated LDL was chromatographically separated into LDL particles with increasing electronegativity (L1-L5), with the L1-L5 ratio serving as a proxy of overall LDL electronegativity. Untargeted lipidomics revealed lipid species enriched in L1 (least) vs. L5 (most electronegative subfraction). Patients were followed at 30 days and 1 year. The mortality endpoint was reviewed by an independent clinical endpoint adjudication committee. Multivariable-adjusted hazard ratios (aHR) were calculated using weighted Cox regression models. Changes in LDL electronegativity were associated with all-cause mortality at 30 days (aHR, 2.13, 95% CI, 1.07–4.23 per 1 SD increment in L1/L5; p=.03) and 1 year (1.84, 1.03–3.29; p=.04), with a notable association with cardiovascular mortality (2.29; 1.21–4.35; p=.01; and 1.88; 1.08–3.28; p=.03). LDL electronegativity superseded several risk factors for the prediction of 1-year death, including LDL-C, and conferred improved discrimination when added to the updated GRACE score (area under the receiver operating characteristic curve 0.74 vs. 0.79, p=.03). Top 10 lipid species enriched in L1 vs. L5 were: cholesterol ester (CE) (18:2), CE (20:4), free fatty acid (FA) (20:4), phosphatidyl-choline (PC) (36:3), PC (34:2), PC (38:5), PC (36:4), PC (34:1), triacylglycerol (TG) (54:3), and PC (38:6) (all p <.001), with CE (18:2), CE (20:4), PC (36:3), PC (34:2), PC (38:5), PC (36:4), TG (54:3), and PC (38:6) independently associating with fatal events during 1-year of follow-up (all p <.05). Reductions in LDL electronegativity are linked to alterations of the LDL lipidome, associate with all-cause and cardiovascular mortality beyond established risk factors, and represent a novel risk factor for adverse outcomes in patients with ACS. These associations warrant further validation in independent cohorts. [Display omitted] • Reduced low-density lipoprotein (LDL) electronegativity associates independently with mortality risk at 30 days and 1 year after the acute event. • LDL electronegativity supersedes several risk factors for the prediction of 1-year death, including LDL-cholesterol. • When added to the GRACE risk score, it enhances the discriminatory performance of the score. • LDL particles of different electronegativity have a distinct lipidome, with potential implications for their athero-/thrombogenicity. • LDL electronegativity is a novel and independent determinant of mortality risk in patients with established atherosclerotic cardiovascular disease. [ABSTRACT FROM AUTHOR]

Omega-3 polyunsaturated fatty acids (ω-3 PUFAs), including alpha-linolenic acid (ALA) and its derivatives eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are "essential" fatty acids mainly obtained from diet sources comprising plant oils, marine blue fish, and commercially available fish oil supplements. Many epidemiological and retrospective studies suggested that ω-3 PUFA consumption decreases the risk of cardiovascular disease, but results of early intervention trials have not consistently confirmed this effect. In recent years, some large-scale randomized controlled trials have shed new light on the potential role of ω-3 PUFAs, particularly high-dose EPA-only formulations, in cardiovascular prevention, making them an attractive tool for the treatment of "residual" cardiovascular risk. ω-3 PUFAs' beneficial effects on cardiovascular outcomes go far beyond the reduction in triglyceride levels and are thought to be mediated by their broadly documented "pleiotropic" actions, most of which are directed to vascular protection. A considerable number of clinical studies and meta-analyses suggest the beneficial effects of ω-3 PUFAs in the regulation of blood pressure in hypertensive and normotensive subjects. These effects occur mostly through regulation of the vascular tone that could be mediated by both endothelium-dependent and independent mechanisms. In this narrative review, we summarize the results of both experimental and clinical studies that evaluated the effect of ω-3 PUFAs on blood pressure, highlighting the mechanisms of their action on the vascular system and their possible impact on hypertension, hypertension-related vascular damage, and, ultimately, cardiovascular outcomes. [ABSTRACT FROM AUTHOR]

Copyright of Hypertonia és Nephrologia is the property of LifeTime Media Kft. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Randomized clinical trials with statins and other lipid-lowering drugs have shown the presence of a "residual cardiovascular risk" in those treated to "target" for LDL-cholesterol. This risk is mainly associated to lipid components other than LDL and in particular to remnant cholesterol (RC) and to lipoproteins rich in triglycerides in fasting and non-fasting conditions. During fasting, RCs correspond to the cholesterol content of the VLDL and their partially depleted triglyceride remnant containing apoB-100. Conversely, in non-fasting conditions, RCs include also cholesterol present in chylomicrons containing apoB-48. Therefore, RCs refer to total plasma cholesterol minus HDL-cholesterol and LDL-cholesterol, that is, all the cholesterol present in the VLDL, chylomicrons and in their remnants. A large body of experimental and clinical data suggests a major role of RCs in the development of atherosclerosis. In fact, RCs easily pass the arterial wall and bind to the connective matrix stimulating the progression of smooth muscle cells and the proliferation of resident macrophages. RCs are a causal risk factor for cardiovascular events. Fasting and non-fasting RCs are equivalent for predicting vascular events. Further studies on drugs effect on RC levels and clinical trials to evaluate the efficacy of RC reduction on cardiovascular events are needed. [ABSTRACT FROM AUTHOR]

Obesity is a heterogeneous disease that affects almost one-third of the global population. A clear association has been established between obesity and cardiovascular disease (CVD). However, CVD risk is known to be related more to the local distribution of fat than to total body fat. Visceral adipose tissue (VAT) in particular has a high impact on CVD risk. This manuscript reviews the role of VAT in residual CV risk and the available therapeutic strategies for decreasing residual CV risk related to VAT accumulation. Among the many pathways involved in residual CV risk, obesity and particularly VAT accumulation play a major role by generating low-grade systemic inflammation, which in turn has a high prognostic impact on all-cause mortality and myocardial infarction. In recent years, many therapeutic approaches have been developed to reduce body weight. Orlistat was shown to reduce both weight and VAT but has low tolerability and many drug-drug interactions. Naltrexone-bupropion combination lowers body weight but has frequent side effects and is contraindicated in patients with uncontrolled hypertension. Liraglutide and semaglutide, glucagon-like peptide 1 (GLP-1) agonists, are the latest drugs approved for the treatment of obesity, and both have been shown to induce significant body weight loss. Liraglutide, semaglutide and other GLP-1 agonists also showed a positive effect on CV outcomes in diabetic patients. In addition, liraglutide showed to specifically reduce VAT and inflammatory biomarkers in obese patients without diabetes. GLP-1 agonists are promising compounds to limit inflammation in human visceral adipocytes.

We believe that there is sufficient evidence from basic science, longitudinal cohort studies and randomised controlled trials which validates the low-density lipoprotein cholesterol (LDL-C) or lipid hypothesis. It is important that we can communicate details of the cardiovascular disease (CVD) risk reduction that the average patient could expect depending on the scale of LDL-C decrease following lipid lowering therapy. It is also essential that residual risk (ResR) of CVD be highlighted. To achieve this aim by using existing trial evidence, we developed mathematical models initially for relative risk reduction (RRR) and absolute risk (AR) reduction and then showed that despite optimising LDL-C levels, a considerable degree of ResR remains that is dependent on AR. Age is significantly associated with AR (odds ratio: 1.02, 95% confidence intervals: 1.01–1.04) as was previously demonstrated by analysing the Whickham study cohort using a logistic regression model (age remaining significant even when all the other significant risk factors such as sex, smoking, systolic blood pressure, diabetes and family history were included in the regression model). A discussion of a paper by Ference et al. provided detailed evidence of the relationship between age and AR, based on lifetime LDL-C exposure. Finally, we discussed non-traditional CVD risk factors that may contribute to ResR based on randomised controlled trials investigating drugs improving inflammation, thrombosis, metabolic and endothelial status.

BACKGROUND AND AIMS:In patients with cardiovascular disease, considerable residual risk remains despite evidence-based secondary prevention measures. Alkaline phosphatase (ALP) has been suggested as a modifiable cardiovascular risk factor. We sought to determine whether cardiovascular risk reduction by the bromodomain and extra-terminal (BET) protein inhibitor apabetalone is associated with the concomitant lowering of serum ALP. METHODS:In a post-hoc analysis of 795 patients with established coronary heart disease and statin treatment, who participated in phase 2 placebo-controlled trials of apabetalone, we determined the effect of assigned treatment for up to 24 weeks on the incidence of major adverse cardiovascular events (MACE) and serum ALP. RESULTS:Baseline ALP (median 72 U/L) predicted MACE (death, non-fatal myocardial infarction, coronary revascularization, or hospitalization for cardiovascular causes), independent of high-sensitivity C-reactive protein (hsCRP), sex, age, race, study, cardiovascular risk factors, chronic kidney disease (CKD), liver function markers and treatment allocation (hazard ratio [HR] per standard deviation [SD] 1.6, 95% CI 1.19-2.16, p = 0.002). Mean placebo-corrected decreases in ALP from baseline were 9.2% (p

Cardiovascular disease (CVD) caused by atherosclerosis is the leading cause of death worldwide. The level of low-density lipoprotein cholesterol (LDL-C), considered as the initiator of atherosclerosis, is the most widely used predictor for CVD risk and LDL-C has been the primary target for lipid-lowering therapies. However, residual CVD risk remains high even with very low levels of LDL-C. This residual CVD risk may be due to remnant cholesterol, high triglyceride levels, and low high-density lipoprotein cholesterol (HDL-C). Non-high density lipoprotein cholesterol (non-HDL-C), which is calculated as total cholesterol minus HDL-C (and represents the cholesterol content of all atherogenic apolipoprotein B-containing lipoproteins), has emerged as a better risk predictor for CVD than LDL-C and an alternative target for CVD risk reduction. Major international guidelines recommend evaluating non-HDL-C as part of atherosclerotic CVD risk assessment, especially in people with high triglycerides, diabetes, obesity, or very low LDL-C. A non-HDL-C target of <130 mg/dL (3.4 mmol/L) has been recommended for patients at very high risk, which is 30 mg/dL (0.8 mmol/L) higher than the corresponding LDL-C target goal. Non-HDL-C lowering approaches include reducing LDL-C and triglyceride levels, increasing HDL-C, or targeting multiple risk factors simultaneously. However, despite the growing evidence for the role of non-HDL-C in residual CVD risk, and recommendations for its assessment in major guidelines, non-HDL-C testing is not routinely done in clinical practice. Thus, there is a need for increased awareness of the need for non-HDL-C testing for ascertaining CVD risk and concomitant prevention of CVD. [ABSTRACT FROM AUTHOR]

Purpose of Review: Elevated low-density lipoprotein cholesterol (LDL-C) and triglyceride-rich lipoproteins (TRLs) or remnants are important risk factors for the development of atherosclerotic cardiovascular disease (ASCVD). The ongoing challenge of not being able to achieve recommended LDL-C targets despite maximally tolerated lipid-lowering therapy (LLT) has led to the development of novel therapeutic agents including angiopoietin-like 3 (ANGPTL3) inhibitors. Recent Findings: ANGPTL3 is a glycoprotein produced by the liver that inhibits lipoprotein lipase and endothelial lipase. Data from genetic and clinical studies have shown that a lower ANGPTL3 level is associated with lower plasma LDL-C, triglyceride (TG), and other lipoproteins. Pharmacological inactivation of ANGPTL3 with the monoclonal antibody, evinacumab, results in a 50% reduction in LDL-C, even in patients with homozygous familial hypercholesterolemia (HoFH). The safe and effective targeted delivery of nucleic acid–based therapies will shape the future of the lipid arena. Summary: ANGPTL3 is a novel target in lipoprotein metabolism, targeting not only LDL-C via an LDL-receptor (LDLR) independent mechanism but also TRLs and carries a significant promise for further ASCVD risk reduction. [ABSTRACT FROM AUTHOR]

Utilising real-world data, we quantified the burden of cardiovascular risk factors and long-term residual risk of atherothrombotic events among routine care cohorts with coronary (CAD) or peripheral (PAD) artery disease or ischemic stroke (IS) on guideline-recommended antiplatelet monotherapy (APMT). Retrospective cohort study using data (2010–2020) from the United Kingdom Clinical Practice Research Datalink (CPRD) and Hospital Episode Statistics, including adults with CAD, PAD or IS who were first prescribed APMT (CAD/IS: aspirin; PAD: clopidogrel). Primary outcomes (recurrent events): major adverse cardiovascular events (MACE) for CAD/PAD/IS cohorts, major adverse limb events (MALE) for PAD. 266,478 CAD, 13,162 PAD, and 14,788 IS patients were included (mean age: 71 years; women 37.7%–47.5 %). Risk factor burden was high and attainment of recommended goals was low. There were 73,691, 3,121 and 7,137 MACE among CAD, PAD and IS patients, respectively (median follow-up: 89.9, 42.4 and 75.9 months, respectively), and 4,767 MALE among PAD patients. MACE incidence rate per 1000 person-years was higher in IS (268.7; 95%CI 265.3–272.0) than CAD (92.9; 95%CI 92.5–93.4) or PAD cohorts (97.2; 95%CI 94.6–99.8). MALE incidence rate was 195.9 (95%CI 192.2–199.6) per 1000 person-years. IS patients presented a lower rate of hospitalisations and longer time-to-first hospitalisation, but once hospitalised, they had a longer length-of-stay. PAD patients had the highest hospitalisation rate. Among a contemporary cohort with cardiovascular disease on APMT, long-term residual atherothrombotic risk remains high despite being on APMT. Greater attention to risk factor control and use of appropriate evidence-based therapy is required to reduce residual risk among this very high-risk population. [Display omitted] • Cohort study using real-world, comtemporary data to quantify residual risk while on recommended antiplatelet monotherapy. • Long-term residual atherothrombotic risk remains high in routine care cohorts with stable Coronary Artery Disease (CAD), Ischemic Stroke (IS) or Peripheral Artery Disease (PAD). • Major Adverse Cardiovascular Events (MACE) incidence was >2.5 times higher in IS than CAD/PAD cohorts; Major Adverse Limb Events (MALE) incidence was ∼2 times higher than MACE in PAD patients. • Women with CAD had a lower risk of MACE, with no sex differences in PAD and IS patients; women with PAD had a lower risk of MALE. • IS patients had a lower hospitalisation rate and longer time-to-first hospitalisation; PAD patients had the highest rate. [ABSTRACT FROM AUTHOR]

The residual risk in patients with atherosclerosis, despite the its controversial aspects, remains an urgent problem of modern cardiology. The article presents a review of publications on the prevalence and significance for determining the prognosis of residual risk, which is currently interpreted as the risk of macroand microvascular complications in patients with atherosclerotic cardiovascular disease (ACVD) taking standard therapy, with the achievement of optimal levels of low-density lipoprotein cholesterol, blood pressure and glucose. Based on available publications, we highlighted current views on the factors associated with residual inflammatory and lipid risks in ACVD patients, including those associated with heart failure and diabetes, and the prognostic significance of residual risk in such patients. An attempt was made to rationale the significance of determining the residual risk for secondary prevention of cardiovascular events.

The importance of high-quality randomized controlled trials cannot be overemphasized. Each such study attempts to answer a specific clinical question. To do this, it is necessary to determine in advance the indicator of achievement of a specific result for a certain period of time. This indicator is the endpoint (EP) of the study, i.e. one or another outcome of the disease or a change in the laboratory and functional characteristics. Its choice directly affects the intended design and sample size of the study. The article provides a classification and hierarchy of EPs (depending on the purpose), describes the features and limitations of the use of important clinical outcomes and surrogate indicators. The reasons why composite EPs are widely used in cardiology studies are described. Special attention should be paid to EP interpretation within secondary analysis, a positive result of which can only be assessed if a treatment effect is demonstrated in terms of the primary indicator of efficacy or safety. The current review is supplemented by clinical examples of cardiology studies.

Remnant cholesterol (RC) and insulin resistance (IR) have been independently associated with cardiovascular risk. Here, we evaluated the role of IR and RC on cardiovascular disease (CVD) mortality. We conducted an analysis of 16,113 individuals ≥20 years without diabetes from the National Health and Nutrition Examination Survey (NHANES-III/IV). RC levels were calculated using total cholesterol, non-HDL-c, and LDL-c; IR was defined as HOMA2-IR≥2.5 and CVD mortality as a composite of cardiovascular and cerebrovascular mortality. Multiple linear regression was used to assess the relationship between HOMA2-IR and RC and Cox regression models to assess their joint role in CVD mortality. Causally ordered mediation models were used to explore the mediating role of IR in RC-associated CVD mortality. We identified an association between higher HOMA2-IR and higher RC levels. The effect of IR on CVD mortality was predominant (HR 1.32, 95%CI 1.18–1.48) and decreased at older ages (HR 0.934, 95%CI 0.918–0.959) compared to RC (HR 0.983, 95%CI 0.952–1.014). Higher risk of CVD mortality was observed in individuals with IR but normal RC (HR 1.37, 95%CI 1.25–1.50) and subjects with IR and high RC (HR 1.24, 95%CI 1.13–1.37), but not in subjects without IR but high RC. In mediation models, HOMA2-IR accounted for 78.2% (95%CI 28.11–98.89) of the effect of RC levels on CVD mortality. Our findings suggest that RC potentiates the risk of CVD mortality through its effect on whole-body insulin sensitivity, particularly among younger individuals. [Display omitted] • We evaluated the role of insulin resistance (IR) and remnant cholesterol (RC) on cardiovascular disease (CVD) mortality in 16,113 individuals ≥20 years without diabetes. • The effect of IR on the risk of CVD mortality predominated over the effect of RC. • Higher risk of CVD mortality was observed in individuals with IR but normal RC and subjects with IR and high RC, but not in subjects without IR but high RC. • HOMA2-IR accounted for approximately 78.2% of the effect of RC levels on CVD mortality. • IR is a partial mediator of the effect of RC on CVD mortality in adults without diabetes. [ABSTRACT FROM AUTHOR]

Background There is a paucity of evidence regarding the association between visit‐to‐visit blood pressure variability and residual cardiovascular risk. We aimed to provide relevant evidence by determining whether high systolic blood pressure (SBP) variability in the optimal SBP levels still influences the risk of cardiovascular disease. Methods and Results We studied 7065 participants (aged 59.3±5.6 years; 44.3% men; and 82.9% White) in the ARIC (Atherosclerosis Risk in Communities) study with optimal SBP levels from visit 1 to visit 3. Visit‐to‐visit SBP variability was measured by variability independent of the mean in the primary analysis. The primary outcome was the major adverse cardiovascular event (MACE), defined as the first occurrence of all‐cause mortality, coronary heart disease, stroke, and heart failure. During a median follow‐up of 19.6 years, 2691 participants developed MACEs. After multivariable adjustment, the MACE risk was higher by 21% in participants with the highest SBP variability (variability independent of the mean quartile 4) compared with the lowest SBP variability participants (variability independent of the mean quartile 1) (hazard ratio, 1.21; 95% CI, 1.09–1.35). The restricted cubic spline showed that the hazard ratio for MACE was relatively linear, with a higher variability independent of the mean being associated with higher risk. These association were also found in the stratified analyses of participants with or without hypertension. Conclusions In adults with optimal SBP levels, higher visit‐to‐visit SBP variability was significantly associated with a higher risk of MACE regardless of whether they had hypertension. Therefore, it may be necessary to further focus on the visit‐to‐visit SBP variability even at the guideline‐recommended optimal blood pressure levels.

Purpose: Interest in improving residual cardiovascular (CV) risk by targeting multiple causative pathways has been growing. Several medications including icosapent ethyl, rivaroxaban, and ezetimibe have been shown to individually improve outcomes in the secondary prevention of atherosclerotic cardiovascular disease (ASCVD) beyond conventional therapy consisting of aspirin and statins. While each drug has been shown to individually improve outcomes, the expected treatment benefit of the combined use of these drugs for enhanced secondary prevention of ASCVD is not known. Methods: In this cross-trial analysis, we estimated the aggregate treatment effect of comprehensive medical therapy consisting of icosapent ethyl, rivaroxaban, and ezetimibe added to background aspirin and statin therapy through established methods of indirect comparisons of the results of three key clinical trials (REDUCE-IT [n = 8,179], COMPASS [n = 27,395], and IMPROVE-IT [n = 18,144]). The primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction (MI), or non-fatal stroke. Secondary endpoints included each individual component of the primary endpoint. Results: The hazard ratio (HR) of the imputed aggregate treatment effects for enhanced secondary prevention of ASCVD with comprehensive disease modifying therapy compared to aspirin and statin alone for the primary endpoint was 0.51 (95% confidence interval [CI] 0.42-0.61). The HR for CV death was 0.62 (95% CI 0.46-0.85), non-fatal MI was 0.52 (95% CI 0.40-0.69), and non-fatal stroke was 0.35 (95% CI 0.23-0.54). The results were similar in sensitivity analyses. Conclusion: The estimated aggregate treatment effect of enhanced secondary prevention of ASCVD through comprehensive medical therapy is substantial. This exploratory analysis supports further study of comprehensive therapy to reduce residual CV risk for the secondary prevention of ASCVD. [ABSTRACT FROM AUTHOR]

Abstract Background Despite the chronicled success of low-density lipoprotein cholesterol (LDLc)-lowering statin therapy, substantial residual cardiovascular (CV) disease risk remains a problem worldwide, highlighting the need to for combination therapies targeting non-LDLc factors, such as with fenofibrate. Methods/design The STAFENO trial is a prospective, randomized, open-label, multi-center trial to compare the effect of statin plus fenofibrate with statin alone on the reduction and stabilization of plaque in non-diabetic, combined dyslipidemia patients with non-intervened, intermediate coronary artery disease (CAD) using virtual histology-intravascular ultrasound at 12 months. A total of 106 eligible patients are planned to be randomized to receive either a combination therapy (rosuvastatin 10 mg plus fenofibrate 160 mg/day) or monotherapy (rosuvastatin 10 mg/day) for 12 months. The primary endpoint of this study is the percentage change in the necrotic core volume. Secondary endpoints include changes in tissue characteristics and 1-year major CV events, including all-cause mortality, CV mortality, nonfatal myocardial infarction, stroke, and revascularization of the intervened and non-intervened lesions. Discussion The STAFENO trial will address whether combination treatment of statin and fenofibrate has an additive beneficial effect compared to statin alone on the reduction and stabilization of plaque and CV events in non-diabetic, combined dyslipidemia patients with non-intervened intermediate CAD. Trial registration ClinicalTrials.gov, NCT02232360 . Registered 9 February 2014. https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S0004ULE&selectaction=Edit&uid=U00023SZ&ts=2&cx=juppd2

Aims: Assessment of residual cardiovascular risk in statin-treated patients with atherosclerotic cardiovascular disease (ASCVD) is pivotal for optimizing secondary preventive therapies. This study investigates if non-high-density lipoprotein cholesterol (non-HDL-C) is associated with residual ASCVD risk in statin-treated ischaemic heart disease (IHD) patients with and without diabetes., Methods and Results: Using the Western Denmark Heart Registry, we identified statin-treated patients with IHD examined by coronary angiography (CAG) from 2011 to 2020. Non-HDL-C was assessed within 1 year after CAG. Outcomes were ASCVD (myocardial infarction, ischaemic stroke, and cardiovascular death) and all-cause death. Cox regression analyses obtained hazard ratios (HRs) adjusted for age, sex, smoking, and hypertension. A total of 42 057 patients were included: 8196 patients with diabetes and 33 861 without diabetes. During the median 4.6 years of follow-up, event rates per 1000 person-years of ASCVD were 28.8 (27.1-30.5) and 17.2 (16.5-17.8) among patients with and without diabetes. In patients with diabetes, the adjusted HRs of ASCVD as compared with non-HDL-C < 25th percentile were 1.0 (0.9-1.2), 1.3 (1.1-1.6), and 1.6 (1.2-2.1) for patients in the 25th-74th, 75th-94th, and ≥95th percentiles. In patients without diabetes, the corresponding adjusted HRs were 1.1 (0.9-1.1), 1.2 (1.1-1.4), and 1.7 (1.4-2.0). Results were consistent across sex, age, clinical presentation, and low-density lipoprotein cholesterol strata., Conclusion: In statin-treated IHD patients with and without diabetes, non-HDL-C, especially above the 75th percentile, is associated with residual cardiovascular risk. These results have implications for secondary prevention, targeting patients who may benefit most from intensified preventive therapy., Competing Interests: Conflict of interest: M.K.H. has received a research grant from the Novo Nordisk Foundation (grant number NNF22OC0074083). M.B.M. has achieved lecture fees from Novo Nordisk, AstraZeneca, Amarin, Sanofi, and Amgen. K.K.W.O. is supported by a grant from the Danish Cardiovascular Academy funded by the Danish Heart Association and Novo Nordisk. P.G.T.: none. RWT: the Department of Clinical Epidemiology, Aarhus University, receives funding for other studies in the form of institutional research grants to (and administered by) Aarhus University. None of these studies has any relation to the present study. M.M. is supported by a grant from the Novo Nordisk Foundation (grant number NNF22OC0074083), has received lecture and/or advisory board fees from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, and Novo Nordisk, has received research grants from Philips, Bayer, and Novo Nordisk, has received a travel grant from Novo Nordisk, has ongoing institutional research contracts with Janssen, Novo Nordisk, and Philips, and is a minor shareholder in Novo Nordisk, Eli Lilly and Company, and Verve Therapeutics., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: The remnant-like particle cholesterol (RLP-C) has been demonstrated to be associated with residual cardiovascular risk. The meta-analysis aimed to evaluate the impact of baseline RLP-C on the incidence of major cardiovascular adverse events (MACEs) in patients with coronary artery disease (CAD). Methods: A systematic literature search was performed in PubMed and Embase electronic databases from the inception of the databases through 1 October 2022. Studies evaluating the association between baseline RLP-C and the risk of MACEs in patients with CAD were included. Hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled by a random-effect method (RLP-C analyzed as a categorical variable) and a fixed-effects model (RLP-C analyzed as a continuous variable). Results: Ten studies including 18,053 subjects were finally included in this meta-analysis. In our pooled analysis, compared to CAD patients with the lowest RLP-C category, the CAD patients with the highest RLP-C category had a significantly higher risk of future MACEs during follow-up (HR 1.79, 95% CI, 1.42–2.26, I2 = 60.31%, p < 0.01), which was consistent with outcomes of meta-analysis with the RLP-C analyzed as a continuous variable (HR 1.40, 95% CI, 1.28–1.53, I2 = 38.20%, p < 0.01). The sensitivity analysis confirmed the robustness of the results, and no significant publication bias was identified. Conclusion: The present meta-analysis suggests that the RLP-C was associated with an increased risk of long-term MACEs in patients with CAD at baseline. It is necessary to conduct randomized controlled trials to explore whether reducing the RLP-C level is conducive to reducing residual cardiovascular risk, even coronary plaque regression.

Background: Low-density lipoprotein cholesterol (LDL-C) is considered the most important risk factor for coronary artery disease (CAD). Although lipid-lowering therapy using high-intensity statins for patients with stable CAD is one of the cornerstones of medication therapy, there is still a risk of residual cardiovascular events, even after controlling for LDL-C. Recently, attention has focused on the association between small dense LDL-C as a residual risk factor for CAD, and it has been reported that a formula can be used to calculate the small LDL-C., Methods: We investigated the association between estimated small dense LDL-C (Esd LDL-C) and the occurrence of new lesions with myocardial ischemia ≤ 2 years after percutaneous coronary intervention (PCI) in 537 patients with stable angina who underwent PCI. In this study, all patients had been prescribed statins. This study was based on previously reported data regarding the relationship between non-high-density lipoprotein cholesterol levels and stable angina pectoris after PCI., Results: Revascularization, including new lesions and in-stent restenosis, and new lesions appeared in 130 and 90 patients, respectively, ≤ 2 years after PCI. Age, diabetes mellitus (DM), LDL-C, and Esd LDL-C were associated with the occurrence of revascularization and new lesions ≤ 2 years after PCI. Multivariate logistic regression analysis models revealed that Esd LDL-C [odds ratio (OR) 1.03, 95% confidence interval (CI) 1.004-1.048, p = 0.020; and OR 1.03, 95% CI 1.009-1.057, p = 0.007, respectively] were associated with the revascularization and occurrence of new lesions ≤ 2 years after PCI., Conclusions: As well as total cholesterol and LDL-C, Esd LDL-C was an independent risk factor for the revascularization and occurrence of new lesions ≤ 2 years after PCI for stable angina in Japanese patients receiving statin therapy. In patients with stable angina who are on lipid-lowering therapy with statins, calculating the Esd LDL-C may provide useful information for predicting revascularization and the occurrence of new lesions., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2024 The Author(s). Published by IMR Press.)

Background: The objective of this research is to evaluate the efficacy and safety of drugs in the residual risk in any of its three components: lipid, inflammatory and thrombotic risk., Methods: A systematic review was conducted of randomized clinical trials that included as a primary outcome, at least one of the conditions related to atherosclerotic cardiovascular disease. The databases used were PUBMED/MEDLINE, Scopus and ClinicalTrials.gov. The risk of bias of the studies was assessed using the Risk of Bias 2 tool., Results: and discussion: 18 studies were included in the analysis. Half of the studies had low risk of bias or some concerns. Several drugs were effective in reducing the primary outcome: ethyl eicosapentaenoeic acid (17.2 % E-EPA versus 22 % placebo HR: 0.75; 95 % CI 0.68-0.83; p < 0.001), colchicine in stable coronary artery disease (6.8 % vs placebo 9.6 %, HR 0.59, 95 % CI 0.57-0.83; p < 0.001), Canakinumab (150 mg vs placebo ARR 15 %, HR 0.85, 95 % CI 0.74-0.98; p = 0.021) and Rivaroxaban with Aspirin in stable atherosclerotic disease (4.1 % versus aspirin 5.4 %, HR 0.76, 95 % CI 0.66-0.86, P < 0.001). Serious adverse events did not differ between study groups, except for a higher rate of bleeding with the use of combination antithrombotic therapy., Conclusion: The residual risk can be reduced through the use of different drugs that act by modifying atherogenic lipid levels, modulating inflammatory pathways and the risk of thrombosis, with an acceptable safety profile in most studies., (© 2024 The Authors.)

Introduction: Obesity is a chronic disease associated with other comorbidities, including atherogenic dyslipidemia (AD). Bariatric surgery (BS) has shown to reduce cardiovascular risk (CVR) by achieving a significant weight reduction and improving the lipid profile. Different surgical techniques may have a different effect on the lipoprotein profile. Purpose: To evaluate the lipid profile at 3 years after BS according to the surgical technique used and to determine which variables predict variation in the lipid profile at 3 years after BS. Methods: Retrospective observational study of 206 patients who underwent BS between 2010 and 2019. We analyzed the variation of lipid parameters in the 3 years of follow-up according to the surgical technique, including a group analysis of patients according to whether they had dyslipidemia and whether they were treated or untreated and determined which variables predict variation in the lipid profile at 3 years after BS. Results: There was a significant increase in high-density lipoprotein cholesterol (HDL-c) with sleeve gastrectomy (SG) and a significant decrease in total cholesterol (TC), LDL-cholesterol (LDL-c), non-HDL, and LDL/non-HDL with biliopancreatic diversion (BPD). Variables predicting lipid profile variation were surgical technique and pre-surgery lipoprotein level. Conclusions: Malabsorptive techniques achieve a greater decrease in TC and LDL-c throughout follow-up and could also improve residual cardiovascular risk (non-HDL and LDL/non-HDL). The type of surgical technique and the presurgery lipid profile predict variation after 3 years of BS. [ABSTRACT FROM AUTHOR]

Abstract In the era of precision medicine, treatments that target specific modifiable characteristics of high-risk patients have the potential to lower further the residual risk of atherosclerotic cardiovascular events. Correction of atherogenic dyslipidemia, however, remains a major unmet clinical need. Elevated plasma triglycerides, with or without low levels of high-density lipoprotein cholesterol (HDL-C), offer a key modifiable component of this common dyslipidemia, especially in insulin resistant conditions such as type 2 diabetes mellitus. The development of selective peroxisome proliferator-activated receptor alpha modulators (SPPARMα) offers an approach to address this treatment gap. This Joint Consensus Panel appraised evidence for the first SPPARMα agonist and concluded that this agent represents a novel therapeutic class, distinct from fibrates, based on pharmacological activity, and, importantly, a safe hepatic and renal profile. The ongoing PROMINENT cardiovascular outcomes trial is testing in 10,000 patients with type 2 diabetes mellitus, elevated triglycerides, and low levels of HDL-C whether treatment with this SPPARMα agonist safely reduces residual cardiovascular risk.

Omega-3 fatty acids have emerged as a new option for controlling the residual risk for cardiovascular disease (CVD) in the statin era after a clinical trial (REDUCE-IT) reported positive results with icosapent ethyl (IPE) in patients receiving maximally tolerated statin therapy. However, another trial which used high dose eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) combination (STRENGTH) has failed. Together, these results raise clinically important questions. Are effects of omega-3 fatty acids neutral or beneficial in patients on statin therapy, or perhaps even harmful? The current contradictory results could be attributed to different types of omega-3 fatty acids (only EPA or combination of EPA + DHA), doses (higher vs. lower dose) of omega-3 fatty acids or different comparators (corn oil or mineral oil), as well as the underlying severity of the CVD risk or use of statins. Together with these issues, we will discuss different biological and clinical effects of various types of omega-3 fatty acids and then interpret different results of past and current clinical studies and propose practical suggestions, which could be applied in patient management. [Display omitted] • Effects of randomized clinical trials of omega-3 fatty acids are controversial. • We discuss different biological and clinical effects of various types of omega-3 fatty acids. • We discuss how to interpret different results of clinical studies that apply to patient management. [ABSTRACT FROM AUTHOR]

The review provides data on a modern cardiovascular risk management according to Russian and European guidelines Particular emphasis is placed on residual cardiovascular risk and related marker — atherogenic dyslipidemia. The contribution of residual risk factors, in particular hypertriglyceridemia, to the pathogenesis of cardiovascular events in type 2 diabetes and other metabolic disorders is considered in depth. Current guidelines on the modern therapy of hypertriglyceridemia are given. The important role of omega-3 polyunsaturated fatty acids in cardiovascular risk management is discussed in the context of recent large clinical trials.

Purpose of Review: Chronic kidney disease (CKD) poses a major global challenge, which is exacerbated by aging populations and the pandemic of type 2 diabetes mellitus. Much of the escalating burden of CKD is due to cardiovascular complications. Current treatment guidelines for dyslipidemia in CKD prioritize low-density lipoprotein cholesterol management, but still leave a high residual cardiovascular risk. Targeting elevated triglycerides and low plasma high-density lipoprotein cholesterol, a common feature of CKD, could offer additional benefit. There are, however, safety issues with current fibrates (peroxisome proliferator–activated receptor alpha [PPARα] agonists), notably the propensity for elevation in serum creatinine, indicating the need for new approaches. Recent Findings: Interactions between the ligand and PPARα receptor influence the specificity and potency of receptor binding, and downstream gene and physiological effects. The peroxisome proliferator–activated receptor alpha modulator (SPPARMα) concept aims to modulate the ligand structure so as to enhance binding at the PPARα receptor, thereby improving the ligand’s selectivity, potency, and safety profile. This concept has led to the development of pemafibrate, a novel SPPARMα agent. This review discusses evidence that differentiates pemafibrate from current fibrates, especially the lack of evidence for elevation in serum creatinine or worsening of renal function in high-risk patients, including those with CKD. Summary: Differentiation of pemafibrate from current fibrates aims to address unmet clinical needs in CKD. The ongoing PROMINENT study will provide critical information regarding the long-term efficacy and safety of pemafibrate in patients with type 2 diabetes mellitus, including those with CKD, and whether the favorable lipid-modifying profile translates to reduction in residual cardiovascular risk. [ABSTRACT FROM AUTHOR]

The aims of this clinical review are to: (i) highlight the importance of elevated baseline triglycerides (TG) in the setting of well-controlled low-density lipoprotein cholesterol (LDL-C) on statins as a major contributor to residual atherosclerotic cardiovascular disease (ASCVD) risk, particularly among patients with type 2 diabetes mellitus, metabolic syndrome, and obesity whose distinctive lipid phenotype cannot be optimally treated with LDL-C reduction therapy alone; (ii) describe the findings and clinical implications of the landmark REDUCE-IT trial in which ethyl eicosapentaenoic acid significantly improved ASCVD outcomes. While many genetic studies have shown that elevated TG are an independent causal factor for ASCVD, prior placebo-controlled trials using niacin, fibrates, omega-3 fatty acids, and dietary supplement fish oil preparations have failed to demonstrate significant CV event reduction when added to statin therapy. In contrast, the REDUCE-IT trial in 8179 participants showed convincingly that the administration of 4 g daily of icosapent ethyl (an ethyl ester of eicosapentaenoic acid) in patients at high risk for ASCVD with increased levels of baseline TG [median value, 2.44 mmol/L (216.0 mg/dL)] but well-controlled LDL-C [median value, 1.94 mmol/L (75.0 mg/dL)] reduced significantly incident events across both the trial primary endpoint and multiple prespecified secondary endpoints, including cardiovascular death, as well as both subsequent and total primary endpoint and key secondary endpoint events. Icosapent ethyl unequivocally contributed to ASCVD event reduction over and above statin therapy. The REDUCE-IT trial results should alter our approach to managing a growing population of hypertriglyceridaemic patients whose lipid phenotype requires more intensive treatment beyond LDL-C lowering alone. Open in new tab Download slide Open in new tab Download slide [ABSTRACT FROM AUTHOR]

Abstract Despite best evidence-based treatment including statins, residual cardiovascular risk poses a major challenge for clinicians in the twenty first century. Atherogenic dyslipidaemia, in particular elevated triglycerides, a marker for increased triglyceride-rich lipoproteins and their remnants, is an important contributor to lipid-related residual risk, especially in insulin resistant conditions such as type 2 diabetes mellitus. Current therapeutic options include peroxisome proliferator-activated receptor alpha (PPARα) agonists, (fibrates), but these have low potency and limited selectivity for PPARα. Modulating the unique receptor–cofactor binding profile to identify the most potent molecules that induce PPARα-mediated beneficial effects, while at the same time avoiding unwanted side effects, offers a new therapeutic approach and provides the rationale for development of pemafibrate (K-877, Parmodia™), a novel selective PPARα modulator (SPPARMα). In clinical trials, pemafibrate either as monotherapy or as add-on to statin therapy was effective in managing atherogenic dyslipidaemia, with marked reduction of triglycerides, remnant cholesterol and apolipoprotein CIII. Pemafibrate also increased serum fibroblast growth factor 21, implicated in metabolic homeostasis. There were no clinically meaningful adverse effects on hepatic or renal function, including no relevant serum creatinine elevation. A major outcomes study, PROMINENT, will provide definitive evaluation of the role of pemafibrate for management of residual cardiovascular risk in type 2 diabetes patients with atherogenic dyslipidaemia despite statin therapy.

Introduction: Extremely low high-density lipoprotein cholesterol (HDL-C) is defined as levels below 20 mg/dL. Association between extremely low HDL-C levels may occur from artifactual, primary monogenic disorders or from secondary causes. We present a 55-year-old known diabetic male with extremely low HDL, in the absence of severe hypertriglyceridemia, with apolipoprotein A1 deficiency and presenting with acute myocardial infarction. Results: Transradial angiography revealed triple vessel disease, for which the patient was medically managed and sent home in a stable condition and is presently on follow-up. Conclusion: Such cases are infrequent and pose a diagnostic challenge. [ABSTRACT FROM AUTHOR]

Introduction: The current way to assess the risk of cardiovascular disease (CVD) is to measure conventional lipid and lipoprotein cholesterol fractions. Despite the success of statin treatment, residual cardiovascular risk remains high. Therefore, the value of extensive serum apolipoprotein (apo) profiling to assess the risk of ST-segment elevation myocardial infarction (STEMI) and of major adverse cardiac events (MACE) in patients with STEMI was investigated in a case–control design. Methods and results: Serum apo levels were measured using liquid chromatography and mass spectrometry in 299 healthy individuals and 220 patients with STEMI. First, the association of apo profiles in baseline samples with risk of STEMI was examined, and second, the association of apo profiles at baseline with risk of recurrent MACE in patients with STEMI in a longitudinal study design was studied. High baseline (> 1.25 g/L) apoA1 levels were associated with a decreased risk of STEMI [odds ratio (OR) 0.17; 95% CI 0.11–0.26], whereas high apoB (> 1.00 g/L) levels (OR 2.17; 95% CI 1.40–3.36) and apoB/apoA1 ratio (OR per 1 SD (OR/SD): 2.16; 95% CI 1.76–2.65) were associated with an increased risk. Very-low-density-lipoprotein (VLDL)-associated apos gave conflicting results. Neither conventional lipid levels nor apo levels were associated with MACE in the STEMI group. Conclusion: In conclusion, apoA1, apoB, and apoB/apoA1 were strongly associated with risk of STEMI. No clear relation between VLDL-associated apos and the risk of STEMI was found. Neither baseline serum apos nor lipids predicted MACE in statin-treated patients during long-term follow-up after a first STEMI. [ABSTRACT FROM AUTHOR]

As time has come to translate trial results into individualized medical diagnosis and therapy, we analyzed how to minimize residual risk of cardiovascular disease (CVD) by reviewing papers on "residual cardiovascular disease risk". During this review process we found 989 papers that started off with residual CVD risk after initiating statin therapy, continued with papers on residual CVD risk after initiating therapy to increase high-density lipoprotein-cholesterol (HDL-C), followed by papers on residual CVD risk after initiating therapy to decrease triglyceride (TG) levels. Later on, papers dealing with elevated levels of lipoprotein remnants and lipoprotein(a) [Lp(a)] reported new risk factors of residual CVD risk. And as new risk factors are being discovered and new therapies are being tested, residual CVD risk will be reduced further. As we move from CVD risk reduction to improvement of patient management, a paradigm shift from a reductionistic approach towards a holistic approach is required. To that purpose, a personalized treatment dependent on the individual's CVD risk factors including lipid profile abnormalities should be configured, along the line of P5 medicine for each individual patient, i.e., with Predictive, Preventive, Personalized, Participatory, and Psycho-cognitive approaches., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Reijnders, van der Laarse, Jukema and Cobbaert.)

Background Despite lipid-lowering therapy (LLT), some patients with familial hypercholesterolemia (FH) still develop cardiovascular events. Data about the quantification and factors contributing to this residual risk are lacking. Objective This study assessed how many patients with FH developed a cardiovascular event despite LLT and which factors contribute to this risk. Methods We performed a time-dependent analysis in a cohort of consecutive heterozygous FH patients using stable LLT to evaluate first and subsequent cardiovascular events. Univariate and multivariate regression analyses were conducted to study the association between clinical characteristics and cardiovascular events. Results Of 821 FH patients (median age 47.4 [interquartile range (IQR) 35.3–58.3] years) treated with LLT for a median period of 9.5 (IQR 5.1–14.2) years, 102 patients (12%) developed cardiovascular disease (CVD) in 8538 statin-treated person-years. Patients who developed a cardiovascular event had a median age of 52.0 (IQR 43.8–59.3) years. These patients more often had previous cardiovascular events (32% vs 9%, P < .001), a family history of premature CVD (58% vs 40%, P = .001), hypertension (70% vs 22%, P < .001), higher on-treatment low-density lipoprotein cholesterol (162 ± 54 vs 135 ± 58 mg/dL, P < .001), lower on-treatment high-density lipoprotein cholesterol (50 ± 15 vs 54 ± 15 mg/dL, P < .001), and were smokers (32% vs 14%, P < .001), compared to patients without cardiovascular events. In 31 patients (30%), a subsequent cardiovascular event occurred with a median interval of 5.7 (IQR 2.4–9.3) years between events. They were more often smokers (32% vs 10%, P = .01) compared to patients with a single cardiovascular event. Conclusions Despite LLT, FH patients still develop cardiovascular events and especially subsequent events. Classical risk factors such as smoking and hypertension are driving factors for this risk, indicating the high priority of optimizing risk factor reduction in addition to maximum LLT. [ABSTRACT FROM AUTHOR]