Association of triglyceride-glucose index and its related parameters with atherosclerotic cardiovascular disease: evidence from a 15-year follow-up of Kailuan cohort.

BACKGROUND: Triglyceride glucose (TyG) index and its related parameters have been introduced as cost-effective surrogate indicators of insulin resistance, while prospective evidence of their effects on atherosclerotic cardiovascular disease (ASCVD) remained scattered and inconsistent. We aimed to evaluate the association of TyG and its related parameters with new-onset ASCVD, and the predictive capacity were further compared. METHOD: A total of 95,342 ASCVD-free participants were enrolled from the Kailuan study. TyG and its related parameters were defined by fasting blood glucose, triglyceride, body mass index (BMI), waist circumstance (WC) and waist-to-height ratio (WHtR). The primary outcome was incident ASCVD, comprising myocardial infarction (MI) and ischemic stroke (IS). Cox proportional hazard models and restricted cubic spline (RCS) analyses were adopted to investigate the association between each index and ASCVD. The C-index, integrated discrimination improvement (IDI), and net reclassification improvement (NRI) were used for comparison of their predictive value for ASCVD. RESULTS: During a median follow-up of 15.0 years, 8,031 new cases of ASCVD were identified. The incidence rate of ASCVD increased along with elevated levels of each index, and the relationships were found to be nonlinear in the RCS analyses. The hazard ratio (HR) and 95% confidence interval (95% CI) for ASCVD was 1.39 (1.35, 1.43), 1.46 (1.41, 1.50), 1.50 (1.46, 1.55), and 1.52 (1.48, 1.57) per 1 IQR increase of baseline TyG, TyG-BMI, TyG-WC, and TyG-WHtR, respectively, and the association were more pronounced for females and younger individuals aged < 60 years (Pfor interaction<0.05). Using the updated mean or time-varying measurements instead of baseline indicators did not significantly alter the primary findings. Additionally, TyG-WC and TyG-WHtR showed better performance in predicting risk of ASCVD than TyG, with the IDI (95% CI) of 0.004 (0.001, 0.004) and 0.004 (0.001, 0.004) and the category-free NRI (95% CI) of 0.120 (0.025, 0.138) and 0.143 (0.032, 0.166), respectively. Similar findings were observed for MI and IS. CONCLUSIONS: Both the TyG index and its related parameters were significantly and positively associated with ASCVD. TyG-WC and TyG-WHtR had better performance in predicting incident ASCVD than TyG, which might be more suitable indices for risk stratification and enhance the primary prevention of ASCVD.

Review of Evolocumab for the Reduction of LDL Cholesterol and Secondary Prevention of Atherosclerotic Cardiovascular Disease.

Elevated low-density lipoprotein cholesterol (LDL-C) is a major causal factor for atherosclerotic cardiovascular disease (ASCVD), the leading cause of mortality worldwide. Statins are the recommended first-line lipid-lowering therapy (LLT) for patients with primary hypercholesterolemia and established ASCVD, with LLT intensification recommended in the substantial proportion of patients who do not achieve levels below guideline-recommended LDL-C thresholds with statin treatment alone. The proprotein convertase subtilisin/kexin type 9 inhibitor monoclonal antibody evolocumab has demonstrated significant LDL-C reductions of > 60% in the clinical trial and open-label extension settings, with LDL-C reductions observed early post-evolocumab initiation and maintained long term, during up to 8.4 years of follow-up. Evolocumab therapy, when added to a statin, also conferred a significant reduction in major cardiovascular (CV) events, including a 20% reduction in the composite of CV death, myocardial infarction (MI), or stroke. The absolute benefits were enhanced among various patient types at high and very high risk for secondary ASCVD (e.g., with recent MI, multiple events or peripheral artery disease). Importantly, evolocumab treatment resulted in incremental CV risk reductions during the extended follow-up, including a 23% reduction in CV mortality and no apparent LDL-C level below which there is no further CV risk reduction. Hence, the evolocumab clinical data support the need for early and significant LDL-C lowering, especially in vulnerable ASCVD patients, in order to derive the greatest benefit in the long term. Importantly, evolocumab had no impact on any treatment emergent adverse events apart from a small increase in local injection site reactions. A growing body of real-world evidence (RWE) for evolocumab in heterogeneous populations is consistent with the trial data, including robust LDL-C reductions below guideline-recommended thresholds, a favourable safety profile even at the lowest levels of LDL-C achieved, and a high treatment persistence rate of > 90%. Altogether, this review highlights findings from 50 clinical trials and RWE studies in > 51,000 patients treated with evolocumab, to demonstrate the potential of evolocumab to address the healthcare gap in LDL-C reduction and secondary prevention of ASCVD in a variety of high- and very high-risk patients.

When Does Primary Prevention Encroach on Secondary Prevention?

PURPOSE OF REVIEW: The risk of incident atherosclerotic cardiovascular disease (ASCVD) in primary prevention is typically lower than in secondary prevention. However, there is a spectrum of risk among individuals undergoing primary prevention with the risk in some individuals approaching those of secondary prevention. We review the clinical conditions wherein the risk in primary prevention is similar to that observed in secondary prevention. RECENT FINDINGS: Among individuals without established ASCVD, coronary artery calcium (CAC) scores ≥ 300 AU are associated with ASCVD event rates similar to secondary prevention populations. CAC score ≥ 1,000 AU are associated with an ASCVD risk seen in very high-risk secondary prevention populations. Interpretation of these observations must however consider differences in the risk reduction strategies. Current guidelines dichotomize ASCVD prevention into primary and secondary prevention, but certain primary prevention patients have an ASCVD risk equivalent to that of secondary prevention populations. Identifying higher risk primary prevention populations will allow for better risk mitigation strategies.

Obicetrapib: Reversing the Tide of CETP Inhibitor Disappointments.

PURPOSE OF REVIEW: To discuss the history of cardiovascular outcomes trials of cholesteryl ester transfer protein (CETP) inhibitors and to describe obicetrapib, a next-generation, oral, once-daily, low-dose CETP inhibitor in late-stage development for dyslipidemia and atherosclerotic cardiovascular disease (ASCVD). RECENT FINDINGS: Phase 1 and 2 trials have evaluated the safety and lipid/lipoprotein effects of obicetrapib as monotherapy, in conjunction with statins, on top of high-intensity statins (HIS), and with ezetimibe on top of HIS. In ROSE2, 10 mg obicetrapib monotherapy and combined with 10 mg ezetimibe, each on top of HIS, significantly reduced low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B, total LDL particles, small LDL particles, small, dense LDL-C, and lipoprotein (a), and increased HDL-C. Phase 3 pivotal registration trials including a cardiovascular outcomes trial are underway. Obicetrapib has an excellent safety and tolerability profile and robustly lowers atherogenic lipoproteins and raises HDL-C. As such, obicetrapib may be a promising agent for the treatment of ASCVD.

Mechanisms of ferroptosis and glucagon-like peptide-1 receptor agonist in post-percutaneous coronary intervention restenosis.

Cardiovascular disease (CVD) claims millions of lives every year, with atherosclerotic cardiovascular disease (ASCVD) being the main cause. ASCVD treatment includes drug therapy, lifestyle intervention, and Percutaneous Coronary Intervention (PCI) all of which significantly enhance cardiovascular function and reduce mortality. However, hyperplasia can lead to vascular obstruction, worsen angina symptoms, or even cause heart disease, affecting patients' long-term prognosis. Therefore, finding effective ways to combat hyperplasia is crucial for cardiovascular therapy. In recent years, ferroptosis has gained attention as a new form of cell death closely associated with several diseases, including cardiovascular diseases. It involves complex metabolic processes critical for cellular homeostasis and normal function. Abnormal proliferation and phenotypic transformation of vascular smooth muscle cells (VSMC) are crucial mechanisms underlying cardiovascular disease development. Inhibiting ferroptosis in VSMC has the potential to significantly reduce neointima proliferation. Glucagon-like peptide-1 receptor agonist (GLP-1RA) constitutes a widely employed class of hypoglycemic agents with direct implications for the cardiovascular system, mitigating adverse cardiovascular events. Research indicates that the stimulation of GLP-1 holds promise as a therapeutic strategy in mitigating cardiovascular events such as restenosis. Hence, investigating the potential of GLP-1RA as a treatment option for cardiovascular ailments carries immense clinical significance.

Untargeted Lipidomic Profiling Reveals Lysophosphatidylcholine and Ceramide as Atherosclerotic Risk Factors in apolipoprotein E Knockout Mice.

Despite the availability and use of numerous cholesterol-lowering drugs, atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of mortality globally. Many researchers have focused their effort on identifying modified lipoproteins. However, lipid moieties such as lysophosphatidylcholine (LPC) and ceramide (CER) contribute to atherogenic events. LPC and CER both cause endothelial mitochondrial dysfunction, leading to fatty acid and triglyceride (TG) accumulation. In addition, they cause immune cells to differentiate into proinflammatory phenotypes. To uncover alternative therapeutic approaches other than cholesterol- and TG-lowering medications, we conducted untargeted lipidomic investigations to assess the alteration of lipid profiles in apolipoprotein E knockout (apoE-/-) mouse model, with or without feeding a high-fat diet (HFD). Results indicated that, in addition to hypercholesterolemia and hyperlipidemia, LPC levels were two to four times higher in apoE-/- mice compared to wild-type mice in C57BL/6 background, regardless of whether they were 8 or 16 weeks old. Sphingomyelin (SM) and CER were elevated three- to five-fold in apoE-/- mice both at the basal level and after 16 weeks when compared to wild-type mice. After HFD treatment, the difference in CER levels elevated more than ten-fold. Considering the atherogenic properties of LPC and CER, they may also contribute to the early onset of atherosclerosis in apoE-/- mice. In summary, the HFD-fed apoE-/- mouse shows elevated LPC and CER contents and is a suitable model for developing LPC- and CER-lowering therapies.

Elevated red cell distribution width and cardiovascular mortality in ASCVD risk cohorts: National Health and Nutrition Examination Survey (NHANES III).

BACKGROUND: Although red cell distribution width (RDW) is associated with increased cardiovascular mortality, the relationship between an elevated RDW and cardiovascular mortality among various ASCVD risk groups is unknown. METHODS: We utilized the National Health and Nutrition Examination Survey (NHANES) III, which uses a complex, multistage, clustered design to represent the civilian, community-based US population. Out of 30,818 subjects whose data were entered during the 1988-1994 period, 8884 subjects over 40 years of age, representing a weighted sample of 85,323,902 patients, were selected after excluding missing variables. The ACC/AHA pooled cohort equation (PCE) was used to calculate atherosclerotic cardiovascular disease (ASCVD) risk, and low (<7.5%), intermediate (7.5-20%), and high (>20%) risk groups were created. The primary endpoint was cardiovascular mortality. A multivariate proportional hazard regression was performed using the Fine and Gray (sub-distribution) method. Red cell distribution (RDW), C-reactive protein (CRP), age, sex, race, diabetes, smoking status, high-density lipoprotein (HDL), and chronic kidney disease (CKD) were used as covariates in each of the ACC/AHA pooled cohort risk groups. RESULTS: The adjusted hazard ratios for RDW >14 (Normal range 12.5-14.5 %) as compared to <13 were 2.79 (95% confidence intervals (95% CI) 2.77-2.81, p < 0.01), 2.02 (95% CI 2.01-2.02, p < 0.01), 1.18 (95% CI 1.18-1.18, p < 0.01) in the low, intermediate and high-risk groups respectively. The 20-year cumulative cardiovascular mortality (RDW >14 vs. <13) was 4% vs. 1.3% low, 17.7% vs. 7.7% in intermediate and 28.1% vs. 24.6% in high ASCVD risk groups respectively. CONCLUSION: Our findings support that measurement of RDW in the intermediate ASCVD group may be clinically valuable for further risk stratification and prognostication in the general population of people aged more than 40 years of age with regards to identifying those at an increased risk for cardiovascular mortality.

Inflammatory Links Between Hypertriglyceridemia and Atherogenesis.

PURPOSE OF REVIEW: Recent studies indicate an association between hypertriglyceridemia (HTG) and atherosclerotic cardiovascular disease (ASCVD). The purpose of this review is to discuss the potential mechanism connecting HTG and ASCVD risk and the potential efficacy of HTG-targeting therapies in ASCVD prevention. RECENT FINDINGS: HTG, with elevations in triglyceride-rich lipoproteins (TGRL) and their remnants, are causal ASCVD risk factors. The mechanisms whereby HTG increases ASCVD risk are not well understood but may include multiple factors. Inflammation plays a crucial role in atherosclerosis. TGRL compared to low-density lipoproteins (LDL) correlate better with inflammation. TGRL remnants can penetrate endothelium and interact with macrophages leading to foam cell formation and inflammation in arterial walls, thereby contributing to atherogenesis. In addition, circulating monocytes can take up TGRL and become lipid-laden foamy monocytes, which infiltrate the arterial wall and may also contribute to atherogenesis. Novel therapies targeting HTG or inflammation are in development and have potential of reducing residual ASCVD risk associated with HTG. Clinical and preclinical studies show a causal role of HTG in promoting ASCVD, in which inflammation plays a vital role. Novel therapies targeting HTG or inflammation have potential of reducing residual ASCVD risk.

PCSK9 Inhibitors in Real-world Practice: Analysis of Data from 314 Patients and 2 Years of Experience in a Center of Preventive Cardiology.

PURPOSE OF REVIEW: PCSK9 inhibitors have been shown to be the most effective class of drugs modifying the levels of LDL-cholesterol as the main risk factor for atherosclerotic cardiovascular disease. The aim of this paper is to assess the effect of monoclonal antibodies on lipid and lipoprotein metabolism in real-world practice. RECENT FINDINGS: The outcome trials showed effective reduction of LDL-C by 56-62%. Landmark studies enrolling over a total of 46,000 patients with CHD in their medical history demonstrated the beneficial effect of both agents on cardiovascular morbidity and mortality. The data from real everyday clinical practice are very limited or missing. Even in real-world practice, PCSK9 inhibitors have been shown to be an effective, safe, and well-tolerated class of drugs with effects comparable with those reported from large randomized controlled trials.

Search for familial hypercholesterolemia patients in an Italian community: A real-life retrospective study.

BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is a common inherited disorder of low-density lipoprotein (LDL) catabolism that causes elevated LDL-cholesterol (LDL-C) and premature atherosclerotic cardiovascular disease (ASCVD). Despite the availability of effective treatments, FH remains underdiagnosed and undertreated. The aims of the study were to identify putative FH subjects using data from laboratory and cardiology databases, genetically characterize suspected FH patients referred to the Lipid Clinic and monitor attainment of treatment goals in identified patients. METHODS AND RESULTS: We retrieved the electronic health records of 221,644 individuals referred to laboratory for routine assessment and of 583 ASCVD patients (age ≤65) who underwent percutaneous transluminal coronary angioplasty (PTCA). We monitored the lipid profiles of subjects with LDL-C ≥ 250 mg/dl identified by laboratory survey (LS-P), PTCA patients and patients from the Lipid Clinic (LC-P). The laboratory survey identified 1.46% of subjects with LDL-C ≥ 190 mg/dl and 0.08% with LDL-C ≥ 250 mg/dl. Probable/definite FH was suspected in 3% of PTCA patients. Molecularly-confirmed FH was found in 44% of LC-P subjects. Five new LDLR mutations were identified. The 50% LDL-C reduction target was achieved by 70.6% of LC-P patients. Only 18.5% of PTCA patients reached the LDL-C < 55 mg/dl target. CONCLUSION: By using a combined approach based on laboratory lipid profiles, documented ASCVD and Lipid Clinic data, we were able to identify subjects with a high probability of being FH. Attainment of LDL-C goals was largely suboptimal. Efforts are needed to improve FH detection and achievement of lipid targets.

HDL and ASCVD.

In this chapter, we summarize the relationship between circulating high-density lipoprotein (HDL) and atherosclerotic cardiovascular disease (ASCVD). HDL acts in many types of cells, such as endothelial cell, macrophage, T lymphocyte, etc. Recently, novel HDL-related therapies have been developed to treat ASCVD.

SGLT2 Inhibition for CKD and Cardiovascular Disease in Type 2 Diabetes: Report of a Scientific Workshop Sponsored by the National Kidney Foundation.

Diabetes is the most frequent cause of chronic kidney disease (CKD), leading to nearly half of all cases of kidney failure requiring replacement therapy. The principal cause of death among patients with diabetes and CKD is cardiovascular disease (CVD). Sodium/glucose cotransporter 2 (SGLT2) inhibitors were developed to lower blood glucose levels by inhibiting glucose reabsorption in the proximal tubule. In clinical trials designed to demonstrate the CVD safety of SGLT2 inhibitors in type 2 diabetes mellitus (T2DM), consistent reductions in risks for secondary kidney disease end points (albuminuria and a composite of serum creatinine doubling or 40% estimated glomerular filtration rate decline, kidney failure, or death), along with reductions in CVD events, were observed. In patients with CKD, the kidney and CVD benefits of canagliflozin were established by the CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) trial in patients with T2DM, urinary albumin-creatinine ratio>300mg/g, and estimated glomerular filtration rate of 30 to<90mL/min/1.73m2. To clarify and support the role of SGLT2 inhibitors for treatment of T2DM and CKD, the National Kidney Foundation convened a scientific workshop with an international panel of more than 80 experts. They discussed the current state of knowledge and unanswered questions to propose therapeutic approaches and delineate future research. SGLT2 inhibitors improve glomerular hemodynamic function and are thought to ameliorate other local and systemic mechanisms involved in the pathogenesis of CKD and CVD. SGLT2 inhibitors should be used when possible by people with T2DM to reduce risks for CKD and CVD in alignment with the clinical trial entry criteria. Important risks of SGLT2 inhibitors include euglycemic ketoacidosis, genital mycotic infections, and volume depletion. Careful consideration should be given to the balance of benefits and harms of SGLT2 inhibitors and risk mitigation strategies. Effective implementation strategies are needed to achieve widespread use of these life-saving medications.

PREVENTIVE CARDIOLOGY AS NEW SUBSPECIALTY OF CARDIOVASCULAR MEDICINE.

Although management of ischemic cardiovascular disease has improved by leaps and bounds and significantly reduced the risk of mortality from a heart attack relative to decades past, the life trajectory of the average person (with stress, poor diet, excess body weight, inactivity, smoking, exposure to pollutants, poor management of metabolic comorbidities, etc.) still leads straight to development of this disease. Therefore, we have an unprecedented opportunity to focus on prevention of atherosclerosis before cardiovascular events occur, an endeavor that needs expert intervention with cardiovascular risk assessment, risk factor management, lifestyle counseling, dietary interventions, use of natural supplements, and pharmacotherapy. It is time for the budding specialty of preventive cardiology to come to the fore, from the historic background of fragmented clinical services such as lipid, hypertension, diabetes, endocrine, and cardiology clinics. Many patients need this specialized service, which cannot be provided anywhere else but in a dedicated practice well integrated with all other hospital services. Here we discuss the origin of preventive cardiology, the organization and core competencies required for excellence in this medical art, and the structure for education and fellowship training for professional recognition and board certification.

Lipids, Apolipoproteins, and Risk of Atherosclerotic Cardiovascular Disease in Persons With CKD.

RATIONALE & OBJECTIVE: A large residual risk for atherosclerotic cardiovascular disease (ASCVD) remains in the setting of chronic kidney disease (CKD) despite treatment with statins. We sought to evaluate the associations of lipid and apolipoprotein levels with risk for ASCVD in individuals with CKD. STUDY DESIGN: Prospective cohort study. SETTINGS & PARTICIPANTS: Adults aged 21 to 74 years with non-dialysis-dependent CKD at baseline enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study in 7 clinical study centers in the United States. PREDICTOR: Baseline total cholesterol, non-high-density lipoprotein cholesterol (non-HDL-C), very low-density lipoprotein cholesterol (VLDL-C), triglycerides, low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo-B), HDL-C, and apolipoprotein AI (Apo-AI) values stratified into tertiles. OUTCOME: A composite ASCVD event of myocardial infarction or ischemic stroke. ANALYTIC APPROACH: Multivariable Cox proportional hazards regression to estimate the risk for ASCVD for each tertile of lipoprotein predictor. RESULTS: Among 3,811 CRIC participants (mean age, 57.7 years; 41.8% white), there were 451 ASCVD events during a median follow-up of 7.9 years. There was increased ASCVD risk among participants with VLDL-C levels in the highest tertile (HR, 1.28; 95% CI, 1.01-1.64), Apo-B levels in the middle tertile (HR, 1.30; 95% CI, 1.03-1.64), HDL-C levels in the middle and lowest tertiles (HRs of 1.40 [95% CI, 1.08-1.83] and 1.77 [95% CI, 1.35-2.33], respectively), and Apo-AI levels in the middle and lowest tertiles (HRs of 1.77 [95% CI, 1.02-1.74] and 1.77 [95% CI, 1.36-2.32], respectively). LDL-C level was not significantly associated with the ASCVD outcome in this population (HR, 1.00 [95% CI, 0.77-1.30] for the highest tertile). LIMITATIONS: Associations based on observational data do not permit inferences about causal associations. CONCLUSIONS: Higher VLDL-C and Apo-B levels, as well as lower HDL-C and Apo-AI levels, are associated with increased risk for ASCVD. These findings support future investigations into pharmacologic targeting of lipoproteins beyond LDL-C, such as triglyceride-rich lipoproteins, to reduce residual risk for ASCVD among individuals with CKD.

Extreme Atherosclerotic Cardiovascular Disease (ASCVD) Risk Recognition.

PURPOSE OF REVIEW: To distinguish extreme and very high atherosclerotic cardiovascular disease (ASCVD) event risk based on prospective epidemiological studies and clinical trial results. RECENT FINDINGS: Clinical practice guidelines have categorized patients with either a history of one or more "clinical ASCVD" events or "coronary heart disease (CHD) risk equivalency" to be at "very high risk" for a recurrence or a first event, respectively. A 20% or greater 10-year ASCVD risk for a composite 3-point "major" atherosclerotic cardiovascular event (MACE) of non-fatal myocardial infarction (MI), non-fatal stroke, or cardiovascular death can serve as an arbitrary definition of those at "very high risk." Exclusion of stroke may underestimate risk of "hard" endpoint 10-year ASCVD risk and addition of other potential endpoints, e.g., hospital admission for unstable angina or revascularization, a 5-point composite MACE, may overinflate the risk definitions and categorization. "Extreme" risk, a descriptor for even higher morbidity and mortality potential, defines a 30% or greater 10-year 3-point MACE (ASCVD) risk. In prospective, epidemiological studies and randomized clinical trial (RCT) participants with an initial acute coronary syndrome (ACS) within several months of entry into the study meet the inclusion criteria assignment for extreme risk. In survivors beyond the first year of an ASCVD event, "extreme" risk persists when one or more comorbidities are present, including diabetes, heart failure (HF), stage 3 or higher chronic kidney disease (CKD), familial hypercholesterolemia (FH), and poorly controlled major risk factors such as hypertension and persistent tobaccoism. "Extreme" risk particularly applies to those with progressive or multiple clinical ASCVD events in the same artery, same arterial bed, or polyvascular sites, including unstable angina and transient ischemic events. Identifying asymptomatic individuals with extensive subclinical ASCVD at "extreme" risk is a challenge, as risk engine assessment may not be adequate; individuals with genetic FH or those with diabetes and Agatston coronary artery calcification (CAC) scores greater than 1000 exemplify such threatening settings and opportunities for aggressive primary prevention. Heterogeneity exists among individuals at risk for clinical ASCVD events; identifying those at "extreme" risk, a more ominous ASCVD category, associated with greater morbidity and mortality, should prompt the most effective global cardiometabolic risk reduction.

A longitudinal study of the association of the eicosapentaenoic acid/arachidonic acid ratio derived from fish consumption with the serum lipid levels: a pilot study.

It has been demonstrated that regular fish consumption is associated with a reduced mortality from atherosclerotic cardiovascular disease (ASCVD). However, data are scarce regarding the correlation between the changes in the serum eicosapentaenoic acid/arachidonic acid (EPA/AA) ratio associated with regular fish consumption and the changes in the serum lipid profile variables. This study was designed as a hospital-based longitudinal study to investigate the relationship between the changes in the serum EPA/AA ratio and changes of the serum lipid levels in patients with one or more risk factors for ASCVD. In 475 patients followed-up for at least 1 year, univariable and multivariable regression analyses conducted after adjustments for the risk factors of ASCVD revealed that the absolute change of the EPA/AA ratio (∆EPA/AA ratio) was independently and significantly associated with the changes of the serum levels of low-density lipoprotein cholesterol (LDL-C) (ß = - 0.129, p = 0.005), triglyceride (TG) (ß = - 0.108, p = 0.019), non-high-density lipoprotein cholesterol (non-HDL-C) (ß = - 0.149, p = 0.001), and TG/HDL-C ratio, a marker of the LDL particle size (ß = - 0.104, p = 0.02), while not being correlated with any other lipid parameters. On the other hand, while the ∆ docosahexaenoic acid (DHA)/AA ratio was inversely correlated with the changes of the serum HDL-C level and positively correlated with the changes of the TG/HDL-C ratio, possibly serving to promote development of atherosclerosis. The results suggest that an increase of the EPA/AA ratio might be associated with decrease of the serum levels of LDL-C, TG and non-HDL-C levels, as well as with an increase of the TG/HDL-C ratio, which represents increased LDL particle size, all of which play a role in the development of ASCVD. A high EPA/AA ratio, but not DHA/AA ratio, derived from fish consumption might reduce the risk of ASCVD through reducing the risk of development of atherosclerosis.Clinical Trial Registration Information: UMIN ( http://www.umin.ac.jp/ ), Study ID: UMIN000010603.

A Clinical Guide to Combination Lipid-Lowering Therapy.

PURPOSE OF REVIEW: We provide an overview of our current understanding of combination lipid-lowering therapies intended for dyslipidemia treatment and cardiovascular disease prevention. First, we analyze recent statin and non-statin combination therapy guidelines and clinical studies since the publication of 2013 American College of Cardiology Cholesterol Guidelines. Second, we examine the clinical utility of non-statin agents alone and in combination in terms of LDL-C lowering and ASCVD risk reduction. RECENT FINDINGS: Medical societies, including the American College of Cardiology (ACC), National Lipid Association (NLA), and American Association of Clinical Endocrinologists (AACE), have released guidelines to address the appropriate use of non-statin therapies. The guidelines incorporated new evidence, including the IMPROVE-IT and FOURIER clinical trials, which demonstrate that the combination of statin therapy with other non-statin agents such as ezetimibe and PCSK9 inhibitors has a significant clinical benefit. Increasing evidence that aggressive low-density lipoprotein cholesterol (LDL-C) lowering leads to lower cardiovascular disease risk supports the need for continued exploration of the role of combination lipid-lowering therapies. A review of guidelines and clinical trials evaluating non-statin agents illuminates the growing base of evidence and expert opinion supporting the use of combination lipid-lowering therapies. While the majority of clinical trial data utilizes dyslipidemia monotherapy, especially statins, combination therapies represent an opportunity for individualized, patient-centered approach to LDL-C lowering and atherosclerotic cardiovascular disease (ASCVD) risk reduction. The overview provides a perspective on lipid management intended for clinicians who seek additional information and guidance on the use of combination therapies.

The Association of Statin Therapy with Incident Diabetes: Evidence, Mechanisms, and Recommendations.

PURPOSE OF REVIEW: Recent studies have demonstrated a higher risk of incident diabetes associated with statin use, causing concern among patients and clinicians. In this review, we will assess the evidence and proposed mechanisms behind statin therapy and its association with incident diabetes. We will then review the current recommendations for statin use in light of this association and suggest next steps for clinicians managing these patients and researchers exploring this phenomenon. RECENT FINDINGS: The annual risk of developing new-onset diabetes with statin treatment is approximately 0.1%. In comparison, the absolute risk reduction of major coronary events with statin use is approximately 0.42% annually. Statins are associated with the development of incident diabetes, particularly among those with predisposing risk factors for diabetes. However, the benefit of statin use among these patients in preventing major coronary events strongly favors statin use despite its risk of incident diabetes.

Role of Non-Statins, LDL-C Thresholds, and Special Population Considerations: A Look at the Updated 2016 ACC Consensus Committee Recommendations.

PURPOSE OF REVIEW: The 2013 ACC/AHA Cholesterol guidelines was a major paradigm shift in the management and treatment of dyslipidemia. The new guidelines outlined "statin benefit groups," highlighted weighing the benefit versus risks of statin therapy ("net benefit"), and discussed the importance of shared decision making between patients and providers in primary prevention. While there was widespread agreement on the main groups benefiting from statin therapy, there was significant controversy regarding LDL-C goals and thresholds, the role of non-statin therapy, and the use of statins in specific populations. The goal of this review is to understand the rationale for the updated 2016 ACC Expert Consensus on Non-Statins and to contrast it with the 2015 NLA Recommendations on the Management of Dyslipidemia. RECENT FINDINGS: The findings of the ACC Expert Consensus Panel were largely influenced by the results of several new clinical trials using non-statin therapy in combination with moderate to high intensity statin therapy. The IMPROVE-IT trial demonstrated that ezetimibe on top of statin therapy lowered ASCVD risk in patients with acute coronary syndromes whose LDL was driven below the previous LDL-C target of <70 mg/dL. In addition, preliminary data assessing the safety of evolocumab and alirocumab on top of statin therapy suggested possible large reductions in ASCVD risk in post hoc analysis. Both the 2016 ACC Consensus Recommendations and the 2015 NLA Recommendations emphasize the importance of maximally tolerated statin therapy, the use of adjunctive non-statin LDL lowering therapy, and the use of LDL-C goals and thresholds to guide intensification of LDL lowering therapy. Although there are some important differences between the ACC Consensus and NLA recommendations in terms of treatment of special populations (i.e., CHF) and on the use of non-HDL-C goals and thresholds, both guidelines support a role for ezetimibe, bile acid sequestrants, and PCSK-9 inhibitors in patients on maximum tolerated statin therapy. The recent positive results of the FOURIER trial gives additional support to the non-statin recommendations of both the ACC and NLA.

Management of Dyslipidemias in Europe and the USA: Same Evidence, Different Conclusions? Can We Find Common Ground?

PURPOSE OF REVIEW: An examination of the current ACC/AHA and ESC/EAS Guidelines on the management of dyslipidemias for common ground and differences. RECENT FINDINGS: There is much common ground. Both note that ASCVD is, in most people, the product of a number of risk factors, notably tobacco exposure, hyperlipidemia, hypertension, inactivity, overweight and diabetes. They stress that risk calculators can help in the assessment of risk in apparently healthy persons. Persons with established ASCVD and many with diabetes or renal impairment are at high to very high risk and warrant intensive risk factor advice. The ACC/AHA Guidelines favor the universal use of statins in all high-risk subjects. In contrast, the ESC/EAS Guidelines favor a goal approach based on total risk and baseline LDL cholesterol level. Perhaps the most important challenges are to stress similarities rather than differences and to simplify communications with both healthcare professionals and the public. Subjects with established vascular disease and renal impairment and many with diabetes are at high to very high risk and need intensive risk factor management. A risk chart or calculator is recommended to assess total risk in apparently healthy persons. The higher the risk, the more intense the risk factor management.