Modern Low-Density Lipoprotein Cholesterol Formulas Outperform Direct Methods in Patients with Hypertriglyceridemia and Low Levels of Low-Density Lipoprotein Cholesterol.

Aim Plasma low density lipoprotein cholesterol (LDL-C) is a unit measure of cholesterol mass & an estimate of circulating LDL-C. LDL-C is commonly calculated indirectly by Friedewald equation and not directly with enzymatic method. The Friedewald equation underestimates the LDLC compared to direct LDLC particularly in patients with low LDLC and high Triglycerides (TGL). Recently developed Sampson equation (2020) also estimates LDL-C indirectly but is less dependent on the TGL values. The present study compares directly measured LDL-C with above friedewald and sampsons equations. Methodology A Multicentric study (three health centers) measured LDL-C with direct enzymatic method in 8332 samples. The data was collected using electronic database and computed in Microsoft excel. Retrospective analysis was performed after ethical committee approval and waiver of consent. LDL-C values derived from Friedewald equation & Sampson equation was compared with LDL-C from direct enzymatic method. Subgroup analysis for accuracy was done among various direct LDL-C subgroups such as values less than 50 mg/dl, 50–70 mg/dl, 70–150 mg/dl and more than 150 mg/dl. The entire cohort was also subdivided into triglyceride subgroups <150 mg/dl, 150–450 mg/dl, >450 mg/dl and compared with direct LDL-C values. Results Our study results shows that mean direct LDL-C was 85.7mg/dl, mean calculated LDL-C by Sampson and Friedewald equation were 80mg/dl and 76mg/dl respectively. There was statistical significance in mean difference when direct LDL-C is compared with combined Sampson and Friedewald equation as per Games - Howell multiple comparison study in which mean difference was more with Friedewal's equation than with Sampson equation. The overall concordance upwards between Friedewald's equation versus direct LDL-C and Sampson LDL-C equation versus direct LDL-C was similar (81% and 83% respectively). The overall discordance upwards was more with Sampson LDL-C when compared with direct LDL-C (4%), unlike 1.5% when Friedewald's LDL-C compared with direct LDL-C. The overall discordance downwards was less with Sampson's LDL-C when compared with direct LDL-C (12%) unlike, 16% when Friedewald's LDL-C compared with direct LDL-C. Our study showed that mean LDL-C by Friedewald's equation is less accurate in comparison to the mean direct LDL-C values. But mean LDL-C by Sampson equation had close proximity to mean direct LDL-C values and less magnitude of discordance was noted in patients with low LDL-C & high TGL Conclusions Sampson's equation is better than friedewald's equation in estimation of LDL-C. Sampson's equation is ideal, better, easily calculated and incorporated. We have also developed a simple android application to estimate the LDL-C using both the Sampson and the Friedewald equation. We recommend that sampson's equation can be utilized in third world developing countries in planning low LDL-C targets during secondary prevention. Funding Acknowledgement Type of funding sources: None.

BackgroundWith the emergence of new lipid-lowering therapies, more patients are expected to achieve substantial lowering of low-density lipoprotein cholesterol (LDL-C). However, there are limited data examining the clinical experience of patients with low (<1.3 mmol/L) or very low (<0.65 mmol/L) levels of LDL-C. To provide information on patients with low LDL-C, we identified and characterized persons with low LDL-C using data from Danish medical databases.MethodsUsing a population-based clinical laboratory database, we identified adults with at least one LDL-C measurement in northern Denmark between 1998 and 2011 (population approximately 1.5 million persons). Based on the lowest measurement during the study period, we divided patients into groups with low (<1.3 mmol/L), moderate (1.3–3.3 mmol/L), or high (>3.3 mmol/L) LDL-C. We described their demographic characteristics, entire comorbidity history, and 90-day prescription history prior to the lowest LDL-C value measured. Finally, we further restricted the analysis to individuals with very low LDL-C (<0.65 mmol/L).ResultsAmong 765,503 persons with an LDL-C measurement, 23% had high LDL-C, 73% had moderate LDL-C, and 4.8% had low LDL-C. In the latter group, 9.6% (0.46% of total) had very low LDL-C. Compared with the moderate and high LDL-C categories, the low LDL-C group included more males and older persons with a higher prevalence of cardiovascular disease, diabetes, chronic pulmonary disease, ulcer disease, and obesity, as measured by hospital diagnoses or relevant prescription drugs for these diseases. Cancer and use of psychotropic drugs were also more prevalent. These patterns of distribution became even more pronounced when restricting to individuals with very low LDL-C.ConclusionUsing Danish medical databases, we identified a cohort of patients with low LDL-C and found that cohort members differed from patients with higher LDL-C levels. These differences may be explained by various factors, including prescribing patterns of lipid-lowering therapies.

A More Valid Measurement of Low-Density Lipoprotein Cholesterol in Diabetic Patients

2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.

Exon Skipping of Hepatic APOB Pre-mRNA With Splice-switching Oligonucleotides Reduces LDL Cholesterol In Vivo

Relationship among low cholesterol levels, depressive symptoms, aggression, hostility, and cynicism

Background The reference method of low density lipoprotein cholesterol (LDL-C) measurement is beta-quantification, composing of three step including ultracentrifugation, precipitation and cholesterol measurement by Abell-Kendall method. The method is time-consuming, laborious and demands large volume of samples, which limits its use in clinical laboratories. Consequently, Friedewald equation for LDL-C estimation has been widely used owing to its simplicity and usefulness in routine and epidemiologic use. Direct homogenous methods for LDL-C, performed rapidly without preparation and fully automated, were also developed and are widely implicated in routine uses. Although direct measurement can be a good alternative, the reliability of the method has been challenged since some reagents also detect a part of cholesterol presented in the chylomicron and very-low density lipoprotein, also known as remnant cholesterol. In this study, we aimed to investigate the effect of remnant cholesterols on the results of LDL-C measured by homogenous methods. Methods This study used 41 commutable frozen serum samples which were produced following Clinical and Laboratory Standards Institute C37-A guideline. These 41 samples were used for the Korean quality assurance program of manufacturers for lipid assays during 2023-2024. In this program, the Korea Disease Control and Prevention Agency (KDCA) provide two vials of each sample to participating manufacturers. The manufacturers measure total cholesterol (TC), LDL-C, high density lipoprotein cholesterol (HDL-C), and triglyceride (TG) from each vial in two different days in triplicate and submit the results to KDCA. Roche, Beckman Coulter, Siemens, Abbott, Fujifilm Wako, Minaris, Sekisui, and Diasys participated this program and submitted the result of TC, HDL-C, LDL-C, and TG in the 41 samples. These manufacturers are anonymized as A, B, C, D, E, F, G, and H, respectively. The reference value of TC, HDL-C, LDL-C, and TG were also determined by reference methods. Remnant cholesterol levels were calculated from reference values using the formula: Remnant cholesterol = TC – HDL-C – LDL-C. The LDL-C measurement bias (%) of each manufacturer relative to the reference value was calculated for each sample. The relationship between the remnant cholesterol/LDL-C ratio and LDL-C %bias was assessed using Spearman’s correlation analysis. Results The mean remnant cholesterol/LDL-C ratio of 41 samples was 0.22, with individual ratios ranging from 0.08 to 0.68. Correlation analyses were performed to assess the relationship between the remnant cholesterol/LDL-C ratio and direct LDL-C measurement %bias (Figure 1). Statistically significant positive correlations were observed in six of the eight manufacturers (Figure 1. B–E, G, H). For samples with a remnant cholesterol/LDL-C ratio of &amp;lt; 0.25 (n=31), directly measured LDL-C demonstrated showed minimal bias. In contrast, for samples with a remnant cholesterol/LDL-C ratio of 0.25 or higher (n=10), most reagents exhibited greater %bias. Conclusion This study underscores that remnant cholesterol can serve as a significant source of positive bias in direct LDL-C measurement, which varies by reagents. Clinical laboratories should be aware of this potential interference, especially in samples with elevated remnant cholesterol levels. In addition, the reagents that exhibited notable bias associated with remnant cholesterol should prioritize refining their methodologies to minimize remnant cholesterol interference.

Low-density lipoprotein cholesterol (LDL-C) is typically estimated with the Friedewald or Martin/Hopkins equation; however, if triglyceride levels are 400 mg/dL or greater, laboratories reflexively perform direct LDL-C (dLDL-C) measurement. The use of direct chemical LDL-C assays and estimation of LDL-C via the National Institutes of Health Sampson equation are not well validated, and data on the accuracy of LDL-C estimation at higher triglyceride levels are limited. To compare an extended Martin/Hopkins equation for triglyceride values of 400 to 799 mg/dL with the Friedewald and Sampson equations. This cross-sectional study evaluated consecutive patients at clinical sites across the US with patient lipid distributions representative of the US population in the Very Large Database of Lipids from January 1, 2006, to December 31, 2015, with triglyceride levels of 400 to 799 mg/dL. Data analysis was performed from November 9, 2020, to March 23, 2021. Accuracy in LDL-C classification according to guideline-based categories and absolute errors between estimated LDL-C and dLDL-C levels. Patients were randomly assigned 2:1 to derivation and validation data sets. Levels of dLDL-C were measured by vertical spin-density gradient ultracentrifugation. The LDL-C levels were estimated using the Friedewald method, with a fixed ratio of triglycerides to very low-density lipoprotein cholesterol (VLDL-C ratio of 5:1), extended Martin/Hopkins equation with a flexible ratio, and Sampson equation with VLDL-C estimation by multiple least-squares regression. A total of 111 939 patients (mean [SD] age, 52 [13] years; 65.0% male) with triglyceride levels of 400 to 799 mg/dL were included, representing 2.2% of 5 081 680 patients in the database. Across all individual guideline LDL-C classes (<40, 40-69, 70-99, 100-129, 130-159, 160-189, and ≥190), estimation of LDL-C by the extended Martin/Hopkins equation was most accurate (62.1%) compared with the Friedewald (19.3%) and Sampson (40.4%) equations. In classifying LDL-C levels less than 70 mg/dL across all triglyceride strata, the extended Martin/Hopkins equation was most accurate (67.3%) compared with Friedewald (5.1%) and Sampson (26.4%) equations. In addition, for classifying LDL-C levels less than 40 mg/dL across all triglyceride strata, the extended Martin/Hopkins equation was most accurate (57.2%) compared with the Friedewald (4.3%) and Sampson (14.4%) equations. However, considerable underclassification of LDL-C occurred. The magnitude of error between the Martin/Hopkins equation estimation and dLDL-C was also smaller: at LDL-C levels less than 40 mg/dL, 2.7% of patients had 30 mg/dL or greater differences between dLDL-C and estimated LDL-C using the Martin/Hopkins equation compared with the Friedewald (92.5%) and Sampson (38.7%) equations. In this cross-sectional study, the extended Martin/Hopkins equation offered greater LDL-C accuracy compared with the Friedewald and Sampson equations in patients with triglyceride levels of 400 to 799 mg/dL. However, regardless of method used, caution is advised with LDL-C estimation in this triglyceride range.

Identifying the potential sources of bias in the direct measurement of low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) is important. In this study, we aimed to investigate the effect of remnant cholesterol on LDL-C and HDL-C levels measured using homogenous methods. We obtained 41 commutable frozen serum samples and measured LDL-C and HDL-C levels. Eight measurement systems were used, and the degree of bias was obtained by comparing with the values obtained using the reference methods. Correlations among remnant cholesterol/LDL-C, remnant cholesterol/HDL-C, and bias were analyzed using Spearman's analysis. In all eight systems, samples with a positive bias >4 % had lower LDL-C levels and higher remnant cholesterol levels, as measured by the reference methods, compared to those with a bias≤4 %. A significant correlation between remnant cholesterol/LDL-C and a positive bias of LDL-C was observed in six of the eight systems evaluated. For HDL-C bias, three systems showed a positive correlation, and three systems showed a negative correlation. In some systems, LDL-C bias was higher in samples with remnant cholesterol/LDL-C≥0.25 than in those with remnant cholesterol/LDL-C <0.25. Remnant cholesterol has a potential effect on direct LDL-C and HDL-C measurements, which has been observed when several measurement systems are used. For these systems, manufacturers should improve the methods to reduce the interference of remnant cholesterol.

BackgroundPemafibrate, a selective PPARα modulator, has the beneficial effects on serum triglycerides (TGs) and very low density lipoprotein (VLDL), especially in patients with diabetes mellitus or metabolic syndrome. However, its effect on the low density lipoprotein cholesterol (LDL-C) levels is still undefined. LDL-C increased in some cases together with a decrease in TGs, and the profile of lipids, especially LDL-C, during pemafibrate administration was evaluated.MethodsPemafibrate was administered to type 2 diabetes patients with hypertriglyceridemia. Fifty-one type 2 diabetes patients (mean age 62 ± 13 years) with a high rate of hypertension and no renal insufficiency were analyzed. Pemafibrate 0.2 mg (0.1 mg twice daily) was administered, and serum lipids were monitored every 4–8 weeks from 8 weeks before administration to 24 weeks after administration. LDL-C was measured by the direct method. Lipoprotein fractions were measured by electrophoresis (polyacrylamide gel, PAG), and LDL-migration index (LDL-MI) was calculated to estimate small, dense LDL.ResultsPemafibrate reduced serum TGs, midband and VLDL fractions by PAG. Pemafibrate increased LDL-C levels from baseline by 5.3% (− 3.8–19.1, IQR). Patients were divided into 2 groups: LDL-C increase of > 5.3% (group I, n = 25) and < 5.3% (group NI, n = 26) after pemafibrate. Compared to group NI, group I had lower LDL-C (2.53 [1.96–3.26] vs. 3.36 [3.05–3.72] mmol/L, P = 0.0009), higher TGs (3.71 [2.62–6.69] vs. 3.25 [2.64–3.80] mmol/L), lower LDL by PAG (34.2 [14.5, SD] vs. 46.4% [6.5], P = 0.0011), higher VLDL by PAG (28.2 [10.8] vs. 22.0% [5.2], P = 0.0234), and higher LDL-MI (0.421 [0.391–0.450] vs. 0.354 [0.341–0.396], P < 0.0001) at baseline. Pemafibrate decreased LDL-MI in group I, and the differences between the groups disappeared. These results showed contradictory effects of pemafibrate on LDL-C levels, and these effects were dependent on the baseline levels of LDL-C and TGs.ConclusionsPemafibrate significantly reduced TGs, VLDL, midband, and small, dense LDL, but increased LDL-C in diabetes patients with higher baseline TGs and lower baseline LDL-C. Even if pre-dose LDL-C remains in the normal range, pemafibrate improves LDL composition and may reduce cardiovascular disease risk.

It is critical to reliably estimate Low Density Lipoprotein Cholesterol (LDL-C) in patients with concomitant hypertriglyceridemia and low LDL-C. We retrospectively compared the performances of the Friedewald (LDL-F), Martin-Hopkins (LDL-MH) and Sampson (LDL-SA) equations against a direct homogeneous LDL-C assay (dLDL-C) on observations presenting mild hypertriglyceridemia (triglycerides between 1.69 and 3.9 mmol/L) and low LDL-C (< 2.58 mmol/L). Observations were stratified according to their LDL-C. Agreement of the equations with dLDL-C was assessed using Intraclass Correlation Coefficients (ICC) with an agreement cut-off of 0.9, and analysis of Bland-Altman plots. Independently of the LDL-C stratum evaluated, the three equations failed to meet the 0.9 ICC cut-off, although their agreement with dLDL-C improves as LDL-C increases. Analysis of Bland-Altman plots shows a downwards discordance of LDL-F with dLDL-C, and an upwards discordance of LDL-MH and LDL-SA with direct LDL-C. LDL-MH resulted in the least observations outside the Bland-Altman limits of agreement. While no equation can be deemed satisfactory enough to replace direct assays in patients with low LDL-C and concomitant hypertriglyceridemia, LDL-MH seems to perform better than the other equations in estimating LDL-C in these patients.

Anti-Inflammatory Effects of Statins Beyond Cholesterol Lowering

BackgroundCardiac rehabilitation (CR) programs provide an opportunity to measure low density lipoprotein cholesterol (LDL-C) levels and optimise lipid lowering therapy (LLT) accordingly. New ESC guidelines released in August 2019 recommend...

Increased serum apolipoprotein (apo)B and associated LDL levels are well-correlated with an increased risk of coronary disease. ApoE⁻/⁻ and low density lipoprotein receptor (LDLr)⁻/⁻ mice have been extensively used for studies of coronary atherosclerosis. These animals show atherosclerotic lesions similar to those in humans, but their serum lipids are low in apoB-containing LDL particles. We describe the development of a new mouse model with a human-like lipid profile. Ldlr CETP⁺/⁻ hemizygous mice carry a single copy of the human CETP transgene and a single copy of a LDL receptor mutation. To evaluate the apoB pathways in this mouse model, we used novel short-interfering RNAs (siRNA) formulated in lipid nanoparticles (LNP). ApoB siRNAs induced up to 95% reduction of liver ApoB mRNA and serum apoB protein, and a significant lowering of serum LDL in Ldlr CETP⁺/⁻ mice. ApoB targeting is specific and dose-dependent, and it shows lipid-lowering effects for over three weeks. Although specific triglycerides (TG) were affected by ApoB mRNA knockdown (KD) and the total plasma lipid levels were decreased by 70%, the overall lipid distribution did not change. Results presented here demonstrate a new mouse model for investigating additional targets within the ApoB pathways using the siRNA modality.

Adverse cardiovascular (CV) events have declined in Western countries due at least in part to aggressive risk factor control, including dyslipidemia management. The American and European (Western) dyslipidemia treatment guidelines have contributed significantly to the reduction in atherosclerotic cardiovascular disease (ASCVD) incidence in the respective populations. However, their direct extrapolation to Indian patients does not seem appropriate for the reasons described below. In the US, mean low-density lipoprotein cholesterol (LDL-C) levels have markedly declined over the last 2 decades, correlating with a proportional reduction in CV events. Conversely, poor risk factor control and dyslipidemia management have led to increased CV and coronary artery disease (CAD) mortality rates in India. The population-attributable risk of dyslipidemia is about 50% for myocardial infarction, signifying its major role in CV events. In addition, the pattern of dyslipidemia in Indians differs considerably from that in Western populations, requiring unique strategies for lipid management in Indians and modified treatment targets. The Lipid Association of India (LAI) recognized the need for tailored LDL-C targets for Indians and recommended lower targets compared to Western guidelines. For individuals with established ASCVD or diabetes with additional risk factors, an LDL-C target of <50 mg/dL was recommended, with an optional target of ≤30 mg/dL for individuals at extremely high risk. There are several reasons that necessitate these lower targets. In Indian subjects, CAD develops 10 years earlier than in Western populations and is more malignant. Additionally, Indians experience higher CAD mortality despite having lower basal LDL-C levels, requiring greater LDL-C reduction to achieve a comparable CV event reduction. The Indian Council for Medical Research-India Diabetes study described a high prevalence of dyslipidemia among Indians, characterized by relatively lower LDL-C levels, higher triglyceride levels, and lower high-density lipoprotein cholesterol (HDL-C) levels compared to Western populations. About 30% of Indians have hypertriglyceridemia, aggravating ASCVD risk and complicating dyslipidemia management. The levels of atherogenic triglyceride-rich lipoproteins, including remnant lipoproteins, are increased in hypertriglyceridemia and are predictive of CV events. Hypertriglyceridemia is also associated with higher levels of small, dense LDL particles, which are more atherogenic, and higher levels of apolipoprotein B (Apo B), reflecting a higher burden of circulating atherogenic lipoprotein particles. A high prevalence of low HDL-C, which is often dysfunctional, and elevated lipoprotein(a) [Lp(a)] levels further contribute to the heightened atherogenicity and premature CAD in Indians. Considering the unique characteristics of atherogenic dyslipidemia in Indians, lower LDL-C, non-HDL-C, and Apo B goals compared to Western guidelines are required for effective control of ASCVD risk in Indians. South Asian ancestry is identified as a risk enhancer in the American lipid management guidelines, highlighting the elevated ASCVD risk of Indian and other South Asian individuals, suggesting a need for more aggressive LDL-C lowering in such individuals. Hence, the LDL-C goals recommended by the Western guidelines may be excessively high for Indians and could result in significant residual ASCVD risk attributable to inadequate LDL-C lowering. Further, the results of Mendelian randomization studies have shown that lowering LDL-C by 5-10 mg/dL reduces CV risk by 8-18%. The lower LDL-C targets proposed by LAI can yield these incremental benefits. In conclusion, Western LDL-C targets may not be suitable for Indian subjects, given the earlier presentation of ASCVD at lower LDL-C levels. They may result in greater CV events that could otherwise be prevented with lower LDL-C targets. The atherogenic dyslipidemia in Indian individuals necessitates more aggressive LDL-C and non-HDL-C lowering, as recommended by the LAI, in order to stem the epidemic of ASCVD in India.