Remnant-like Particle Cholesterol Levels Research Articles

Association of Remnant-like Particle Cholesterol with Major Adverse Cardiovascular Events in Subjects with Different Levels of Proprotein Convertase Subtilisin/Kexin 9: A 9.5-year Follow-up Study in a Beijing Community Population

Objective: The purpose of this study was to determine the relationship between remnant-like particle cholesterol (RLP-C) and major adverse cardiovascular events (MACEs) in patients with different levels of proprotein convertase subtilisin/kexin 9 (PCSK9). Methods: From September 2007 to January 2009, 1,859 subjects in Pingguoyuan communities in Beijing were initially screened. After excluding those with bedridden status, mental illness, severe systemic diseases, and missing data, 1,680 subjects were recruited for follow up. All recruited subjects were followed up from February 2013 to September 2013 (181 subjects were lost to follow-up) and from June 2017 to September 2018 (174 subjects were lost to follow up). Finally, 1,325 subjects were included in the study. General demographic characteristics, lifestyle and behaviors, disease history and use of medication was collected. Levels of total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, fast blood glucose, RLP-C, low-density lipoprotein triglycerides and PCSK9 were measured. The levels of RLP-C (low: RLP-C ≤ 157 mg/L; high: RLP-C > 157 mg/L) and PCSK9 (low: PCSK9 ≤ 135.87 μg/L; high: PCSK9 > 135.87 μg/L) were represented using quartiles. Subjects were categorized into 4 groups according to their RLP-C and PCSK9 levels: Q4, high levels of RLP-C with high levels of PCSK9; Q3, high levels of RLP-C with low levels of PCSK9; Q2, low levels of RLP-C with high levels of PCSK9; and Q1, low levels of RLP-C with low levels of PCSK9. The association of RLP-C with MACEs in subjects with different PCSK9 levels was evaluated. Results: After a median follow-up of 9.5 years, 1,325 subjects were included in the study and a total of 191 MACEs had occurred. The incidence of MACEs was higher in the RLP-C > 157 mg/L group than the RLP-C ≤ 157 mg/L group (18.40% vs. 10.42%). Cox proportional hazards regression model analysis showed that increased RLP-C levels were associated with an increased risk of MACEs (hazard ratio: 1.405; 95% confidence interval: 1.005–1.964; P < 0.005). The incidence of MACEs was higher in the high RLP-C/PCSK9 group vs. the low RLP-C/PCSK9 group (20.68% vs. 8.76%). Cox proportional hazards regression model analysis showed that RLP-C was associated with an increased risk of MACEs in subjects with high PCSK9 levels independent of traditional risk factors (hazard ratio: 1.791; 95% confidence interval: 1.168–2.825; P = 0.001), but not in those with low PCSK9 levels. Conclusions: RLP-C was identified as a risk factor for MACEs, particularly in subjects with high PCSK9 levels. Lowering PCSK9 levels may reduce residual risk in subjects with elevated plasma RLP-C levels.

Remnant-Like Particle Cholesterol and the Risk of Major Adverse Cardiovascular Events: A Systematic Review and Meta-Analysis.

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.

Increased estimated remnant-like particle cholesterol is associated with impaired coronary collateralization in patients with coronary chronic total occlusions

AimsThis study intends to explore whether, or to what extent, the estimated remnant-like particle cholesterol was associated with coronary collateralization in patients with chronic total occlusion lesions.Methods792 patients with at least one coronary chronic total occlusion lesion were enrolled. Serum level of lipid profiles were determined and the estimated remnant-like particle cholesterol was calculated. The development of coronary collateralization was graded as low (Rentrop score 0–1) or high (Rentrop score 2–3) collateralization according to the Rentrop classification system and then the association between the estimated remnant-like particle cholesterol and collateralization was assessed.Results222 participants were classified into low collateralization group. The estimated remnant-like particle cholesterol level was significantly higher in low collateralization (P < 0.001) and type 2 diabetes mellitus (P = 0.009) group. To further explore the association between the estimated remnant-like particle cholesterol and the development of coronary collateralization, these patients were divided into 3 groups based on the estimated remnant-like particle cholesterol tertiles. The prevalence of low collateralization increased stepwise with the tertile groups (T1 12.5% vs. 27.1% vs. 45.3%, P < 0.001). Multivariate logistic regression analysis showed that the estimated remnant-like particle cholesterol was independently associated with the under-developed collateralization, with an OR and 95%CI of 2.34 (1.46–3.74) and 4.91 (3.01–8.02) in the T2 and T3 group, respectively. The following receiver-operating characteristic analysis indicated that the diagnostic value of estimated remnant-like particle cholesterol for the low collateralization was 0.696, with a cut-off value of 0.485, and its sensitivity was 82.88%. Besides, the addition of the estimated remnant-like particle cholesterol into the baseline model consisting of traditional risk factors could improve the incremental value of the discrimination of impaired collateralization only in overall and type 2 diabetes mellitus populations.ConclusionsThe increased estimated remnant-like particle cholesterol is independently associated with impaired collateralization in patients with coronary chronic total occlusion lesions. Therapies targeting at remnant-like particle cholesterol may be needed in advanced coronary artery disease patients with type 2 diabetes mellitus not suitable for vascular revascularization.

Lipoprotein subfractions in patients with sarcopenia and their relevance to skeletal muscle mass and function.

Loss of skeletal muscle mass is a characteristic of aging. Growing evidence suggests the role of fatty acids and their derived lipid intermediates in the regulation of skeletal muscle and function. However, the exact association between lipoprotein subfractions and sarcopenia in elderly individuals remains unclear. In this study, we aimed to investigate the levels of lipoprotein subfractions in sarcopenia patients and their relationship with skeletal muscle mass and function. A total of 84 elderly Chinese subjects aged ≥65years who did not have diseases that obviously affected lipid metabolism were included. Concentrations of lipoprotein subfractions, including total cholesterol (TC), high-density lipoprotein cholesterol (HDLC), HDL2, HDL3, low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), VLDL3, LDL-particle (LDL-P), lipoprotein(a) and remnant-like particle cholesterol (RLP-C), were determined by vertical auto profile. Triglyceride (TG) was measured by an enzymatic colorimetric assay. The skeletal muscle index (SMI) was assessed by bioelectrical impedance analysis. Handgrip strength was measured using a hand-held dynamometer. The levels of TC, TG, LDL-C, LDL-P, IDL, VLDL, VLDL3, RLP-C and C-reactive protein were significantly higher in sarcopenia patients than in controls (p<0.05). Pearson Product-Moment Correlation Coefficient analysis showed that the TC, TG, LDL-C, IDL, VLDL, VLDL3, and RLP-C levels were negatively associated with the SMI; The TG, IDL, VLDL, VLDL3, and RLP-C were negatively correlated with handgrip strength. In multivariate stepwise regression analysis, the VLDL and RLP-C levels were significantly correlated with the SMI. The sensitivity and specificity of the combined measurement of VLDL and RLP-C in predicting sarcopenia were 69.8% and 92.5% (AUC: 0.831; 95% CI:(0.739, 0.924); p<0.05). The occurrence of sarcopenia is associated with disorders of lipid metabolism, particularly VLDL and RLP-C.

Does remnants-like particle cholesterol is elevated in FH?

Background and Aims: Familial hypercholesterolemia (FH) is often associated with mildly increased triglyceride levels, probably because remnant-like particles can also be catabolized by LDL receptor. Remnant-like particles cholesterol (RLP-C) has been associated with coronary artery disease in the general population. Few data exist regarding this issue in patients with FH. Aim: to evaluate RLP-C levels in severe hypercholesterolemic patients with clinical and genetic diagnosis for FH.

Abstract 15567: Residual Cholesterol and Cardiovascular Events in Patients With Coronary Artery Disease Under Different Glucose Metabolism Status

Introduction: The atherogenicity of residual cholesterol (RC) has been underlined by recent guidelines, which was linked to coronary artery disease (CAD), especially for patients with diabetes mellitus (DM). Hypothesis: This study aimed to examine the prognostic value of plasma RC, clinically presented as triglyceride-rich lipoprotein-cholesterol (TRL-C) or remnant-like lipoprotein particles-cholesterol (RLP-C), in CAD patients with different glucose metabolism status. Methods: Fasting plasma TRL-C and RLP-C levels were directly calculated or measured in 4331 patients with CAD. Patients were followed for incident MACEs for up to 8.6 years and categorized according to both glucose metabolism status [DM, pre-DM, normal glycaemia regulation (NGR)] and RC levels. Cox proportional hazards model was used to calculate hazard ratios (HRs) with 95% confidence intervals. Results: During a mean follow-up of 5.1 years, 541 (12.5%) MACEs occurred. The risk for MACEs was significantly higher in patients with elevated RC levels after adjustment for potential confounders. No significant difference in MACEs was observed between pre-DM and NGR groups (p&gt;0.05). When stratified by status of glucose metabolism and RC levels, highest levels of RLP-C, calculated and measured TRL-C were significant and independent predictors of developing MACEs in pre-DM (HR: 2.10, 1.98, 1.92, respectively; all p&lt;0.05) and DM (HR: 2.25, 2.00, 2.16, respectively; all p&lt;0.05). Conclusions: In this large cohort study with long-term follow-up, data firstly demonstrated that higher RC levels were significantly associated with the worse prognosis in DM and pre-DM patients with CAD, suggesting RC might be a target for patients with impaired glucose metabolism.

Changes in serum levels of angiopoietin-like protein-8 and glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 after ezetimibe therapy in patients with dyslipidemia

Changes in serum levels of angiopoietin-like protein-8 (ANGPTL8) and glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 (GPIHBP1) in patients with dyslipidemia after ezetimibe therapy remain to be elucidated. Thirty-eight patients who initially received ezetimibe and were followed for 16 weeks were enrolled. Various parameters were investigated before and after 16 weeks of ezetimibe treatment in all patients. In addition, the patients were also divided into metabolic syndrome (MetS) (n = 22) and Non-MetS (n = 16) groups, and various parameters were compared between these groups. ANGPTL8 was significantly positively correlated with triglyceride (TG) and negatively correlated with high-density lipoprotein cholesterol (HDL-C) before treatment in all patients and in the MetS group. After treatment, TC and LDL-C were significantly decreased in all patients, and in both the MetS and Non-MetS groups, whereas there were no changes in TG or HDL-C. Serum levels of remnant-like particle cholesterol (RLP-C) significantly decreased in all patients and in the MetS group. The ANGPTL8 level before treatment was significantly positively associated with TG and negatively correlated with HDL-C in all patients and in the MetS group. ANGPTL8 and GPIHBP1were significantly decreased after treatment in all patients. GPIHBP1 was also significantly decreased after treatment in both groups. In conclusion, this is the first report to support the possibility of a new effect of ezetimibe therapy. Ezetimibe significantly decreased the serum level of LDL-C, but not TG or HDL-C, while reducing ANGPTL8 and GPIHBP1 in all patients with dyslipidemia. In addition, ezetimibe significantly decreased RLP-C levels in the MetS group.

Prognostic impact of estimated remnant-like particle cholesterol in patients with differing glycometabolic status: an observational cohort study from China

BackgroundIt is uncertain whether estimated remnant-like particle cholesterol (RLP-C) could predict residual risk in patients with different glycometabolic status. This study aimed to evaluate the relationship between estimated RLP-C and adverse prognosis in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) treated with percutaneous coronary intervention (PCI) and to identify the potential impact of glycometabolism on the predictive value of estimated RLP-C.MethodsThe study assessed 2419 participants with NSTE-ACS undergoing PCI at Beijing Anzhen Hospital from January to December 2015. Estimated RLP-C was calculated as follows: total cholesterol (TC) minus low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C). The adverse events included all-cause death, non-fatal myocardial infarction (MI), and ischemia-driven revascularization.ResultsEstimated RLP-C was prominently associated with adverse prognosis in the total population [hazard ratio (HR) 1.291 per 1-SD increase, 95% confidence interval (CI) 1.119–1.490, P <  0.001], independent of confounding risk factors. However, subgroup analysis showed that increasing estimated RLP-C was related to a higher risk of adverse events in the diabetic population only [HR 1.385 per 1-SD increase, 95% CI 1.183–1.620, P <  0.001]. Estimated RLP-C failed to be a significant determinant of adverse prognosis in non-diabetic and pre-diabetic subgroups. The addition of estimated RLP-C to a baseline model including traditional risk factors enhanced the predictive performance both in total and diabetic populations.ConclusionsHigh estimated RLP-C level is a significant predictor for recurrent adverse events in patients with diabetes and NSTE-ACS treated with PCI.

Improvement of endothelial dysfunction is mediated through reduction of remnant lipoprotein after statin therapy in patients with coronary artery disease

BackgroundRemnant lipoproteinemia with high levels of low-density lipoprotein cholesterol (LDL-C) is a high risk for endothelial dysfunction. Statins are the first-line lipid-lowering drugs for this combined hyperlipidemia. However, it remains undetermined whether reduction of remnant lipoprotein mediates the relationship between improvement in endothelial dysfunction and reduction of LDL-C level after statin treatment. MethodsA total of 122 coronary artery disease (CAD) patients with impaired flow-mediated dilation (FMD; <5.5%), high levels of LDL-C (≥100 mg/dL), and remnant-like lipoprotein particle cholesterol (RLP-C) (≥5 mg/dL) were examined in this study. The lipid profiles and FMD were measured before and after 6–9 months of statin treatment. The association between changes in LDL-C levels and its relationship with changes in FMD was investigated. Furthermore, mediation analysis was performed to assess the changes in RLP-C level as a mediator of the relationship between the reduction in LDL-C level and improvement of FMD. ResultsTreatment with statins improved FMD in 69 (56.5%) patients. Patients with improved FMD showed lower percent changes of LDL-C, triglyceride (TG), RLP-C, RLP-C/TG, and C-reactive protein (CRP) levels, and higher percent change of HDL-C level, compared to patients who did not show improved FMD. The percent changes in FMD levels had a significant inverse correlation with the percent changes in LDL-C, (r = −0.18, p = 0.03), RLP-C (r = −0.39, p < 0.001), RLP-C/TG (r = −0.34, p < 0.001), and CRP (r = −0.27, p < 0.01). Mediation analysis showed that the relationship between reduction in LDL-C and improvement of FMD was mediated by reduction of RLP-C (34.5%), RLP-C/TG (24.4%), and CRP (24.9%) levels. ConclusionImprovement of remnant lipoproteinemia may be an important mediator for the relationship between improvement of endothelial dysfunction and LDL-lowering after statin treatment in patients with CAD.

Association between plasma essential amino acids and atherogenic lipid profile in a Chinese population: A cross-sectional study

Background and aimsThe association between amino acids and small dense low-density lipoprotein cholesterol (sdLDL-C) and remnant-like particle cholesterol (RLP-C) remains poorly understood. This study aims to investigate the association between plasma essential amino acids (EAAs) and atherogenic lipid profiles. MethodsPlasma amino acid levels of 475 individuals were measured using liquid chromatography-mass spectrometry. SdLDL-C, RLP-C, and other lipid components were evaluated. Associations between EAAs and lipid components or dyslipidemia were determined using correlation analysis and multivariate logistic regression. ResultsConcentrations of plasma branched-chain amino acid (BCAA) were positively correlated with sdLDL-C, RLP-C, and triglycerides (TG) levels, but inversely correlated with high-density lipoprotein cholesterol (HDL-C). In contrast, threonine concentration was inversely correlated with sdLDL-C, RLP-C, and TG. Compared with the lowest tertile, individuals in the highest tertile of plasma total BCAAs level had an odds ratio (OR) of 2.33 (95% confidence interval [CI]: 1.35, 4.03) for the risk of high sdLDL-C, 3.63 (95%CI: 1.69, 7.80) for the risk of high RLP-C, 3.10 (95%CI: 1.66, 5.80) for the risk of high TG, and 3.67 (95%CI: 2.00, 6.73) for atherogenic lipid triad (all p < 0.01). In contrast, compared with the lowest tertile, individuals in the highest plasma threonine tertile had a 43% lower OR for high sdLDL-C, 56% lower OR for high TG, and 55% lower OR for lipid triad risk (all p < 0.05). ConclusionsAmong the EAAs evaluated, elevated plasma BCAAs were significantly associated with increased risk of atherogenic lipid profile. In contrast, elevated threonine was associated with reduced risk of atherogenic lipid profile.

Remnant lipoproteins play an important role of in-stent restenosis in type 2 diabetes undergoing percutaneous coronary intervention: a single-centre observational cohort study

BackgroundIncreasing evidence has suggested that the presence of remnant lipoproteins is a significant risk factor for atherosclerosis. Remnant lipoproteins are lipoproteins that are rich in triglycerides (TGs), and the main components include very-low-density lipoprotein (VLDL) in the fasting state. Diabetic patients often have hypertriglyceridemia with elevated levels of VLDL cholesterol but normal levels of low-density lipoprotein cholesterol (LDL-C). The aim of the present study was to elucidate the potential role of remnant lipoproteins-induced atherosclerosis in the occurrence and development of in-stent restenosis (ISR) in diabetic patients with coronary artery disease.MethodsThe present study enrolled 2312 patients with type 2 diabetes mellitus who underwent percutaneous coronary intervention from January 2013 to December 2014 and who were followed up by angiography. Patients were divided into two groups based on the presence or absence of ISR, and multivariate Cox’s proportional hazards regression modelling showed that remnant-like particle cholesterol (RLP-C) was an independent risk factor for ISR. According to the receiver operating characteristic curve, the optimal cutoff point of the RLP-C was identified, and the patients were further divided into 2 groups. Propensity score matching analysis was performed, and 762 pairs were successfully matched. Log-rank tests were used to compare Kaplan–Meier curves for overall follow-up to assess ISR.ResultsThe multivariate Cox’s proportional hazards regression analysis showed that RLP-C was independently associated with ISR, and the baseline RLP-C level at 0.505 mmol/L was identified as the optimal cutoff point to predict ISR. Patients were divided into 2 groups by RLP levels. After propensity score matching analysis, a total of 762 pairs matched patients were generated. Kaplan–Meier curves showed that the estimated cumulative rate of ISR was significantly higher in patients with RLP-C levels ≥ 0.505 mmol/L (log-rank P < 0.001; HR equal to 4.175, 95% CI = 3.045–5.723, P < 0.001) compared to patients with RLP-C levels < 0.505 mmol/L.ConclusionsThe present study emphasized the importance of remnant-like particle cholesterol in cardiovascular pathology in diabetic patients. Physicians should take measures to control RLP-C below the level of 0.505 mmol/L to better prevent of in-stent restenosis in diabetic patients.

P2721Serum levels of remnant-like particle cholesterol play an important role in the pathogenesis of coronary spasm

P2721Serum levels of remnant-like particle cholesterol play an important role in the pathogenesis of coronary spasm

Post-prandial Remnant Lipoprotein Metabolism in Sitosterolemia

Aim: We aimed to clarify post-prandial accumulation of remnant-like particles (RLP) in patients with sitosterolemia.Methods: Oral fat tolerance test cream (Jomo Shokuhin, Takasaki, Japan) 50 g was given per body surface area (m2); blood sampling was performed at 2 h intervals up to 6 h. Plasma lipoprotein fractions and RLP fractions were determined in four sitosterolemic subjects with double mutations in ATP-binding cassette (ABC) sub-family G member 5 or member 8 (ABCG5 or ABCG8) gene (mean age = 18 yr, median low-density lipoprotein cholesterol [LDL-C] = 154 mg/dL), six heterozygous carriers (mean age = 31 yr, median LDL-C = 105 mg/dL), and five subjects with heterozygous familial hypercholesterolemia (FH, mean age = 32 yr, median LDL-C = 221 mg/dL). The incremental area under curve (iAUC) of lipids, including LDL-C, apolipoprotein B-48 (apoB48), RLP cholesterol (RLP-C), and RLP triglyceride (RLP-TG) were evaluated.Results: After oral fat load, there was no significant difference of the iAUC of LDL-C between sitosterolemia and heterozygous FH, whereas the iAUC of apoB48 was significantly larger in the sitosterolemic subjects compared with that of heterozygous FH (2.9 µg/mL × h vs. 1.3 µg/mL × h, p < 0.05). Under these conditions, the iAUCs of RLP-C and RLP-TG levels were significantly larger in the sitosterolemic subject compared with those of heterozygous FH (9.5 mg/dL × h vs. 5.7 mg/dL × h, p < 0.05; 149 mg/dL × h vs. 40 mg/dL × h, p < 0.05, respectively), whereas those of heterozygous carriers were comparable with those with heterozygous FH.Conclusions: Post-prandial lipoprotein metabolism in sitosterolemia appeared to be impaired, leading to their elevation in serum sterol levels. (UMIN Clinical Trials Registry number, UMIN000020330)

Remnant-Like Particle Cholesterol, Low-Density Lipoprotein Triglycerides, and Incident Cardiovascular Disease

BackgroundHypertriglyceridemia is associated with increased remnant-like particle cholesterol (RLP-C) and triglycerides in low-density lipoprotein (LDL-TG). Recent studies have focused on atherogenicity of RLP-C, with few data on LDL-TG. ObjectivesThe aim of this study was to examine associations of RLP-C and LDL-TG with incident cardiovascular disease (CVD) events and genetic variants in the ARIC (Atherosclerosis Risk In Communities) study. MethodsFasting plasma RLP-C and LDL-TG levels were measured in 9,334 men and women without prevalent CVD. Participants were followed for incident CVD events (coronary heart disease and ischemic stroke) for up to 16 years. Associations between LDL-TG and RLP-C levels and genetic variants were assessed by whole-exome sequencing using single-variant analysis for common variants and gene-based burden tests for rare variants; both an unbiased and a candidate gene approach were explored. ResultsRLP-C and LDL-TG levels were correlated with triglyceride levels (r = 0.85 and r = 0.64, p < 0.0001). In minimally adjusted analyses, RLP-C and LDL-TG were associated with CVD risk, but in models adjusted for traditional risk factors including lipids, only LDL-TG was associated with incident CHD (hazard ratio: 1.28; 95% confidence interval: 1.10 to 1.50) and stroke (hazard ratio: 1.47; 95% confidence interval: 1.13 to 1.92). A common APOE variant, rs7412, had the strongest association with LDL-TG and RLP-C (p < 5 × 10−8). ConclusionsRLP-C and LDL-TG levels were predictive of CVD and associated with APOE variants. LDL-TG may represent a marker of dysfunctional remnant lipoprotein metabolism associated with increased CVD risk. Further research is needed to determine whether LDL-TG plays a causal role in CVD and may be a target for therapy.

Remnant-like particles and coronary artery disease in familial hypercholesterolemia

BackgroundAlthough remnant-like particle cholesterol (RLP-C) has been associated with coronary artery disease (CAD) in the general population, few data exist regarding this issue in patients with familial hypercholesterolemia (FH). The aim of our study was to investigate the association between RLP-C and the presence of CAD in patients with FH. MethodsWe examined 282 patients with FH (144 males, mean age, 41 ± 17 years) whose RLP-C levels were measured. We assessed the baseline characteristics, including lipid levels, other conventional risk factors for cardiovascular events, the presence of CAD, and the serum RLP-C levels. ResultsSerum RLP-C levels significantly correlated with serum triglyceride (TG) levels (Pearson's r = 0.631, p < 0.001). We observed that a larger proportion of individuals in the higher tertiles of serum RLP-C had a larger number of diseased coronary arteries (p < 0.001 for the trend of multi-vessel disease). Logistic regression analysis, after adjusting for age, sex, hypertension, diabetes, smoking, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and lipoprotein (a) [Lp(a)], revealed that RLP-C was significantly associated with CAD [odds ratio (OR): 1.08, 95% confidence interval (CI): 1.00–1.16, p = 0.046]; however, adding serum TG levels into the logistic regression model nullified this association (OR: 1.07, 95% CI: 0.98–1.17, p = 0.141), whereas Lp(a) was independently associated with CAD (OR: 1.02, 95% CI: 1.00–1.03, p = 0.015). ConclusionsSerum RLP-C levels were significantly associated with the presence and severity of CAD in patients with FH. However, the clinical usefulness of measuring RLP-C levels beyond that of measuring TG levels should be further assessed.

Abstract 10851: Effect of Glycemic State on Postprandial Hyperlipidemia and Hyperinsulinemia in Patients With Coronary Artery Disease

Background: Both postprandial hyperlipidemia and hyperinsulinemia have been thought to play an important role in the development of atherosclerosis, and to be a potent risk factor for cardiovascular event. Methods: To examine effects of glycemic state on postprandial hyperlipidemia and hyperinsulinemia in patients with coronary artery disease (CAD), a total of 146 consecutive male patients with angiographically confirmed CAD were loaded with a high-fat and high-glucose test meal. CAD patients were divided into three groups as “non-diabetic”, “prediabetic”, and “diabetic” CAD groups. 28 male normoglycemic patients without CAD matched on age were served as control subjects. Results: The serum triglyceride (TG) and remnant-like particle cholesterol (RLP-C) levels at the 6th hour in diabetic CAD group showed significantly higher than non-diabetic CAD group, and the area under the curves (AUCs) of these levels in diabetic CAD group were significantly greater than non-diabetic CAD group (TG, P = 0.0287; RLP-C, P = 0.0386). There were no significant differences in the AUCs of TG or RLP-C between prediabetic and non-diabetic CAD group. The AUCs of plasma insulin levels or insulin resistance index (IRI): (AUCs of insulin) x (AUCs of glucose) as the insulin resistance marker were greater in diabetic CAD group than non-diabetic CAD group (insulin, P = 0.0311; IRI, P = 0.0235). The AUCs of serum TG or RLP-C levels showed a correlation with the AUCs of plasma insulin (AUC-TG, r = 0.4381, P &lt;0.0001; AUC-RLC-P, r = 0.3953, P &lt;0.0001), and they correlated well with the insulin resistance index (AUC-TG, r = 0.7194, P &lt;0.0001; AUC-RLC-P, r = 0.6621, P &lt;0.0001). Conclusions: We found that the insulin resistance showed a close relationship with postprandial hyperlipidemia in CAD patients. Diabetic, but not prediabetic state, may be a risk for postprandial impaired lipid metabolism.

Effect of Ezetimibe on LDL-C Lowering and Atherogenic Lipoprotein Profiles in Type 2 Diabetic Patients Poorly Controlled by Statins.

BackgroundThere exists a subpopulation of T2DM in whom first-line doses of statin are insufficient for optimally reducing LDL-C, representing a major risk of CVD. The RESEARCH study focuses on LDL-C reduction in this population along with modifications of the lipid profiles leading to residual risks.MethodsLipid changes were assessed in a randomized, multicenter, 12-week, open-label study comparing a high-potency statin (10mg of atorvastatin or 1mg of pitavastatin) plus ezetimibe (EAT: n = 53) with a double dose of statin (20mg of atorvastatin or 2mg of pitavastatin) (DST: n = 56) in DM subjects who had failed to achieve the optimal LDL-C targets. Lipid variables were compared with a primary focus on LDL-C and with secondary focuses on the percentage of patients who reached the LDL-C targets and changes in the levels of RLP-C (remnant like particle cholesterol) and sd-LDL-C, two characteristic atherogenic risks of DM.ResultsThe reduction of LDL-C (%), the primary endpoint, differed significantly between the two groups (-24.6 in EAT vs. -10.9 in DST). In the analyses of the secondary endpoints, EAT treatment brought about significantly larger reductions in sd-LDL-C (-20.5 vs. -3.7) and RLP-C (-19.7 vs. +5.5). In total, 89.4% of the patients receiving EAT reached the optimized treatment goal compared to 51.0% of the patients receiving DST. The changes in TC (-16.3 vs. -6.3) and non-HDL-C (-20.7 vs. -8.3) differed significantly between the two groups.ConclusionEzetimibe added to high-potency statin (10 mg of atorvastatin or 1 mg of pitavastatin) was more effective than the intensified-dose statin (20 mg of atorvastatin or 2 mg of pitavastatin) treatment not only in helping T2DM patients attain more LDL-C reduction, but also in improving their atherogenic lipid profiles, including their levels of sd-LDL-C and RLP-C.We thus recommend the addition of ezetimibe to high-potency statin as a first line strategy for T2DM patients with insufficient statin response.Trial RegistrationThe UMIN Clinical Trials Registry UMIN000002593

Comparison of the effects of low-dose rosuvastatin on plasma levels of cholesterol and oxidized low-density lipoprotein in 3 ultracentrifugally separated low-density lipoprotein subfractions

Plasma-oxidized (ox) low-density lipoprotein (LDL) is an atherogenic lipoprotein. The distribution of ox-LDL in plasma LDL subfractions and the effect of statins on this distribution have not been investigated in detail. We examined the distribution of cholesterol and ox-LDL in 3 ultracentrifugally separated plasma LDL subfractions and investigated the effects of a statin, rosuvastatin, on the levels of these lipoproteins. Thirty-one polygenic hypercholesterolemic subjects were included in this study. Levels of cholesterol and ox-LDL in 3 plasma LDL subfractions and plasma levels of remnant-like particle cholesterol, ox-LDL, and adiponectin were measured after 0, 3, 6, and 12 months of treatment with rosuvastatin. Sequential ultracentrifugation was performed to subfractionate plasma lipoproteins. The mean daily dose of rosuvastatin over the 12 months of treatment was 2.9 ± 1.0 mg (mean ± standard deviation). The cholesterol subfraction distribution was 43 ± 10% as low-density LDL, 46 ± 8% as medium-density LDL, and 13 ± 5% as high-density LDL. Similarly, the distribution of ox-LDL was 31 ± 10% as low-density LDL, 48 ± 7% as medium-density LDL, and 22 ± 8% as high-density LDL. After 12 months of treatment with rosuvastatin, the level of cholesterol was significantly reduced in all 3 subfractions (P < .0001), as was the level of ox-LDL (P < .0001). Furthermore, the plasma cholesterol level in high-density lipoprotein2 increased significantly. The distribution of ox-LDL in plasma LDL subfractions was more skewed toward the denser subfractions, compared with cholesterol. Rosuvastatin treatment significantly reduced plasma levels of cholesterol and ox-LDL in all LDL subfractions.

Abstract 16803: Icosapent Ethyl (Eicosapentaenoic Acid Ethyl Ester): Effects on Remnant-Like Particle Cholesterol From the MARINE and ANCHOR Studies

Background: Remnant-like particle cholesterol (RLP-C) represents the cholesterol carried by partially catabolized triglyceride (TG)-rich lipoproteins such as very-low-density lipoproteins (VLDL) in the fasted state and chylomicron remnants in the post-prandial state. Increased RLP-C levels are atherogenic and may increase the risk of atherosclerotic cardiovascular disease. Long-chain polyunsaturated omega-3 fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid reduce RLP-C levels. Icosapent ethyl (IPE) is a high-purity prescription form of EPA ethyl ester approved to reduce TG levels in patients with severe (&gt;=500 mg/dL) hypertriglyceridemia. Objective: To evaluate the effects of IPE on RLP-C levels in patients from the MARINE and ANCHOR studies. Methods: MARINE (TG &gt;=500 and &lt;=2000 mg/dL; N=229) and ANCHOR (TG &gt;=200 and &lt;500 mg/dL despite statin control of low-density lipoprotein cholesterol; N=702) were both 12-week, phase 3, double-blind studies that randomized patients to IPE 4 g/day, 2 g/day, or placebo. This analysis assessed the median percentage change from baseline to study end in RLP-C levels compared with placebo. Serum RLP-C was measured with an immunoseparation assay (Polymedco). Results: In both the MARINE (n=218 with RLP-C data) and ANCHOR (n=252 with RLP-C data) studies, compared with placebo, IPE 4 g/day (Table) and 2 g/day reduced RLP-C levels. Compared with placebo, the approved IPE dose of 4 g/day also reduced RLP-C to a greater extent in subgroups with higher baseline TG levels, reduced RLP-C in statin-treated patients in the MARINE study, and reduced RLP-C in patients receiving moderate- to high-intensity statins in the ANCHOR study. Conclusions: Compared with placebo, IPE reduced RLP-C levels in patients in the MARINE and ANCHOR studies, including significant reductions in RLP-C in hypertriglyceridemic patients with TG &gt;=200 mg/dL or &gt;=500 mg/dL receiving statin therapy.

Bezafibrate improves insulin resistance evaluated using the glucose clamp technique in patients with type 2 diabetes mellitus: a small-scale clinical study.

BackgroundBezafibrate is mainly used to treat hypertriglyceridemia. Studies have reported that bezafibrate also improves type 2 diabetes mellitus, but the mechanism has not been fully elucidated. We performed euglycemic hyperinsulinemic clamps (glucose clamp) and meal tolerance tests (MTT) to examine the effects of bezafibrate on insulin resistance in patients with type 2 diabetes mellitus.MethodsTwelve Japanese patients with type 2 diabetes mellitus and dyslipidemia (mean age: 59.5 years; fasting plasma glucose: 7.95 mmol/L; hemoglobin A1c [HbA1c]: 7.3%; body mass index: 26.5 kg/m2) underwent a glucose clamp and MTT before and after 12 weeks of treatment with 400 mg/day bezafibrate. The glucose infusion rate was measured during the glucose clamp. The patients took a test meal (460 kcal) in the MTT. Plasma glucose and immunoreactive insulin levels were measured at 0 (fasting), 30, 60, 120, and 180 min. Serum C-peptide immunoreactivity, serum lipids, and liver function markers were also measured during the MTT.ResultsBezafibrate significantly increased the mean glucose infusion rate from 5.78 ± 1.94 to 6.78 ± 2.52 mg/kg/min (p < 0.05). HbA1c improved from 7.30 ± 0.55% to 7.02 ± 0.52% (p < 0.05). In the MTT, fasting plasma glucose decreased from 7.95 ± 1.15 to 6.98 ± 1.07 mmol/L (p < 0.05). The area under the plasma glucose curve from 0 to 180 min decreased significantly from 29.48 ± 5.07 to 27.12 ± 3.98 mmol/h/L (p < 0.05), whereas immunoreactive insulin was unchanged. Furthermore, bezafibrate also significantly improved serum lipids, with decreases in triglyceride levels from 1.84 ± 0.88 to 1.14 ± 0.41 mmol/L (p < 0.05), low-density lipoprotein cholesterol levels from 3.56 ± 0.83 to 2.92 ± 0.55 mmol/L (p < 0.05), and remnant-like particle cholesterol levels decreased from 0.25 ± 0.16 to 0.14 ± 0.06 mmol/L (p < 0.05), and increases in high-density lipoprotein cholesterol levels from 1.50 ± 0.24 to 1.66 ± 0.29 mmol/L (p < 0.05).ConclusionsBezafibrate improved glucose intolerance and peripheral insulin resistance in these Japanese patients with type 2 diabetes mellitus and dyslipidemia. Therefore, bezafibrate could be used to treat insulin resistance in patients with type 2 diabetes mellitus and dyslipidemia.Trial registrationUniversity Hospital Medical Information Network (UMIN) Clinical Trials Registry, UMIN000012462.