Low-density Lipoprotein Cholesterol Measurement Research Articles

Achievement of low-density lipoprotein cholesterol goals in 18 countries outside Western Europe: The International ChoLesterol management Practice Study (ICLPS)

BackgroundLittle is known about the achievement of low density lipoprotein cholesterol (LDL-C) targets in patients at cardiovascular risk receiving stable lipid-lowering therapy (LLT) in countries outside Western Europe.MethodsThis cross-sectional observational study was conducted in 452 centres (August 2015−August 2016) in 18 countries in Eastern Europe, Asia, Africa, the Middle East and Latin America. Patients (n = 9049) treated for ≥3 months with any LLT and in whom an LDL-C measurement on stable LLT was available within the previous 12 months were included.ResultsThe mean±SD age was 60.2 ± 11.7 years, 55.0% of patients were men and the mean ± SD LDL-C value on LLT was 2.6 ± 1.3 mmol/L (101.0 ± 49.2 mg/dL). At enrolment, 97.9% of patients were receiving a statin (25.3% on high intensity treatment). Only 32.1% of the very high risk patients versus 51.9% of the high risk and 55.7% of the moderate risk patients achieved their LDL-C goals. On multivariable analysis, factors independently associated with not achieving LDL-C goals were no (versus lower dose) statin therapy, a higher (versus lower) dose of statin, statin intolerance, overweight and obesity, female sex, neurocognitive disorders, level of cardiovascular risk, LDL-C value unknown at diagnosis, high blood pressure and current smoking. Diabetes was associated with a lower risk of not achieving LDL-C goals.ConclusionsThese observational data suggest that the achievement of LDL-C goals is suboptimal in selected countries outside Western Europe. Efforts are needed to improve the management of patients using combination therapy and/or more intensive LLTs.

Treatment target re-classification of subjects comparing estimation of low-density lipoprotein cholesterol by the Friedewald equation and direct measurement of LDL-cholesterol

Aims: To compare low-density lipoprotein cholesterol (LDL-C) values calculated by the Friedewald equation with direct LDL-C in patient samples and assess the possible impact on re-classification of LDL-C target values for primary prevention or high cardiovascular disease (CVD) risk (<2.5 mmol/L) and secondary prevention or very high CVD risk (<1.8 mmol/L). LDL-C is an important CVD risk factor. Over the last decade, there has been a change in laboratory methodology from indirectly calculated LDL-C with the Friedewald equation to direct LDL-C measurements (dLDL-C).Methods: Reported results for plasma triglycerides, total cholesterol, high-density lipoprotein-cholesterol, and dLDL-C from 34,981 samples analyzed in year 2014 were extracted from the laboratory information system, Uppsala University Hospital, Uppsala, Sweden.Results: dLDL-C was approximately 10% lower than the corresponding LDL-C results calculated by the Friedewald equation in both men and women. In subjects with triglyceride concentrations above 4 mmol/L (n = 1250) the same discordant pattern was seen as for the entire study population. Altogether 5469 out of 18,051 men (30.3%) and 4604 out of 16,928 women (27.2%) were down-classified at least one CVD risk category. A very small number of subject was up-classified, in total 37 out of 18,051 men (0.2%) and 28 out of 16,928 women (0.2%).Conclusions: The two LDL-C methods had a high concordance, but the direct LDL-C measurement consistently gave approx. 10% lower values, and this caused one-third of subjects to be re-classified as having a lower cardiovascular disease risk in relation to recommended LDL-C target values and decision limits.

Outcomes of Secondary Prevention among Coronary Heart Disease Patients in a High-Risk Region in Finland.

Despite comprehensive national treatment guidelines, goals for secondary prevention of coronary heart disease (CHD) have not been sufficiently met everywhere in Finland. We investigated the recorded risk factor rates of CHD and their spatial differences in North Karelia Hospital District, which has a very high cardiovascular burden, in order to form a general view of the state of secondary prevention in a high-risk region. Appropriate disease codes of CHD-diagnoses and coding for percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) were used to identify from the electronic patient records the patient group eligible for secondary prevention. The cumulative incidence rate of new patients (n = 2556) during 2011–2014 varied from 1.9% to 3.5% between municipalities. The success in secondary prevention of CHD was assessed using achievement of treatment targets as defined in national guidelines. Health centres are administrated by municipalities whereupon the main reporting units were municipalities, together with composed classification of patients by age, gender and dwelling location. Health disparities between municipalities, settlement types and patient groups were found and are interpreted. Moreover, spatial high-risk and low-risk clusters of acute CHD were detected. The proportion of patients achieving the treatment targets of low-density lipoprotein cholesterol (LDL-C) varied from 21% to 38% between municipalities. Variation was also observed in the follow-up of patients; e.g., the rate of follow-up measurements of LDL-C in municipalities varied from 72% to 86%. Spatial variation in patients’ sociodemographic and neighbourhood characteristics and morbidity burden partly explain the differences in outcomes, but there are also very likely differences in the care process between municipalities which requires a study in its own right.

Number of Patients Eligible for PCSK9 Inhibitors Based on Real-world Data From 2.5 Million Patients

Introduction and objectivesPCSK9 inhibitors (PCSK9i) are safe and effective lipid-lowering drugs. Their main limitation is their high cost. The aim of this study was to estimate the number of patients eligible for treatment with PCSK9i according to distinct published criteria. MethodsData were obtained from the Information System for the Development of Research in Primary Care. Included patients were equal to or older than 18 years and had at least 1 low-density lipoprotein cholesterol measurement recorded between 2006 and 2014 (n = 2 500 907). An indication for treatment with PCSK9i was assigned according to the following guidelines: National Health System, Spanish Society of Arteriosclerosis, Spanish Society of Cardiology, National Institute for Health and Care Excellence, and the European Society of Cardiology/European Atherosclerosis Society Task Force. Lipid-lowering treatment was defined as optimized if it reduced low-density lipoprotein levels by ≥ 50% and adherence was > 80%. ResultsAmong the Spanish population aged 18 years or older, the number of possible candidates to receive PCSK9i in an optimal lipid-lowering treatment scenario ranged from 0.1% to 1.7%, depending on the guideline considered. The subgroup of patients with the highest proportion of potential candidates consisted of patients with familial hypercholesterolemia, and the subgroup with the highest absolute number consisted of patients in secondary cardiovascular prevention. ConclusionsThe number of candidates to receive PCSK9i in conditions of real-world clinical practice is high and varies widely depending on the recommendations of distinct scientific societies.

Abstract P011: Cardiovascular Risk Factors and Longevity

Introduction: Cardiovascular disease is the leading cause of mortality in old age, yet there is limited research on the patterns of cardiovascular risk factors that predict survival to 90 years. Hypothesis: The patterns of cardiovascular risk factors that portend longevity will differ from those that confer low cardiovascular risk. Methods: We examined repeated measures of blood pressure, LDL-cholesterol, and BMI from age 67 and survival to 90 years in the Cardiovascular Health Study (CHS). CHS is a prospective study of 5,888 black and white adults in two waves (1989-90 and 1992-93) from Medicare eligibility lists in four counties in the U.S. We restricted to participants aged 67 to 75 years at baseline to control for birth cohort effects and examined repeated measures of cardiovascular risk factors throughout the late-life course. We fit logistic regression models to predict survival to age 90 using generalized estimating equations, and modeled the risk factors as linear, a linear spline, and clinically relevant categories. Models were adjusted for demographics and medication use, and we also examined whether the association of each risk factor with longevity varied by the age of risk factor measurement. Best fit models are presented. Results: Among 3,645 participants in the birth cohort, 1,160 (31.8%) survived to 90 by June 16 th , 2015. Higher systolic blood pressure in early old age was associated with reduced odds for longevity, but there was an interaction with age such that the association crossed the null at 80 years. (Table) Among those with LDL-cholesterol &lt;130 mg/dL, higher LDL-cholesterol was associated with greater longevity; at levels above 130 mg/dL there was no association between LDL-cholesterol and longevity. BMI had a u-shaped association with longevity. Conclusions: In summary, the patterns of risk factors that predict longevity differ from that considered to predict low cardiovascular risk. The risk of high systolic blood pressure appears to depend on the age of blood pressure measurement.

Validation of the Friedewald formula for the estimation of low density lipoprotein cholesterol in a sub-Saharan African population

Introduction : low density lipoprotein cholesterol (LDL-C) levels are used to estimate cardiovascular disease (CVD) risk and to guide prescriptions. To circumvent the challenges of direct LDL-C measurement, guidelines recommend the use of Friedewald formula derived LDL-C levels. Despite reported limitations of this formula, its validity in sub-Saharan Africans has not been adequately investigated. The objective was to assess the validity of the Friedewald formula derived against directly measured LDL-C in adult Cameroonians. Methods : we reviewed the fasting lipid profiles of 2500 patients, performed between March 2012 and January 2016 using enzymatic colorimetric method (reference), at the Douala General Hospital laboratory. The Friedewald formula was used to calculate LDL-C from total cholesterol, high density lipoprotein cholesterol and triglyceride levels. Calculated LDL-C values were compared to the reference values and clinical significance of differences between the two methods was assessed using total error allowable (TEa). Results : the difference between means of Friedewald-calculated and the reference LDL-C values was neither statistically nor clinically significant (3.33±1.51 vs. 3.33 ± 1.25 mmol/l; p = 0.704). The calculated LDL-C correlated positively with the measured LDL-C value (r = 0.749) and both methods showed a good agreement on Bland-Altman plot. Conversely, there was only moderate agreement (kappa=0.478, 95% CI: 0.455-0.502) between the two values in the stratification of cardiovascular risk according to the National Cholesterol Education Programme/Adult Treatment Panel III. Consequently, 40.6% of the participants were misclassified. Conclusion : Friedewald formula is technically accurate but has a modest clinical accuracy which can translate into a substantial misclassification of patients’ cardiovascular risk and subsequent inappropriate therapeutic decisions.

Visit-to-visit variability of lipid measurements as predictors of cardiovascular events

Higher visit-to-visit variability in risk factors such as blood pressure and low-density lipoprotein (LDL)-cholesterol are associated with an increase in cardiovascular (CV) events. The purpose of this study was to determine whether variability in high-density lipoprotein cholesterol (HDL-C) and triglyceride levels predicted coronary and CV events in a clinical trial population with known coronary disease. We assessed intraindividual variability in fasting high-density lipoprotein (HDL)-cholesterol, triglyceride, and LDL-cholesterol measurements among 9572 patients in the Treating to New Targets trial and correlated the results with coronary events over a median follow-up of 4.9years. In the fully adjusted Cox model, 1 standard deviation of average successive variability, defined as the average absolute difference between successive values, was associated with an increased risk of a coronary event for HDL-cholesterol (hazard ratio [HR] 1.16, 95% confidence interval [CI] 1.11-1.21, P<.0001), for triglycerides (HR 1.09, 95% CI 1.04-1.15, P=.0005), and for LDL-cholesterol (HR 1.14, 95% CI 1.09-1.19, P<.0001). Similar results were found for the 3 other measures of variability, standard deviation, coefficient of variability, and variability independent of the mean. Similar results were seen for CV events, stroke, and nonfatal myocardial infarction. Higher variability in triglyceride and LDL-cholesterol, but not HDL-cholesterol, was predictive of incident diabetes. The correlation among the variability of the 3 lipid measurements was weak. Visit-to-visit variability in fasting measurements of HDL-cholesterol, triglycerides, and LDL-cholesterol are predictive of coronary events, CV events, and for triglyceride and low-density lipoprotein cholesterol variability, incident diabetes. The mechanisms accounting for these associations remain to be determined.

Newly-developed De Cordova’s Formula for Calculation of LDL Cholesterol in Bangladeshi Population

Raised serum LDL cholesterol is an important modifiable risk factor for the development of atherosclerosis and cardiovascular disease. So the management of dyslipidaemia is mostly based on the concentration of LDL cholesterol. Friedewald’s formula is commonly used method to estimate LDL cholesterol in most clinical laboratories. However, this formula cannot reflect the actual figure of LDL cholesterol. In 2013, de Cordova developed a new simple formula to calculate LDL cholesterol without using serum TG which is said to be more accurate than Friedewald’s formula. The present study was designed to compare the formula-based calculated LDL cholesterol (Friedewald’s formula and de Cordova’s formula) with direct homogenous estimation. The objective of the present study was to evaluate of applicability of de Cordova’s formula for calculation of LDL cholesterol. By using non-probability sampling technique, 460 individuals were enrolled in the study who were attending in the one-point collection centre of BSMMU for lipid profile estimation. Subjects were categorized as normolipidaemic individuals and dyslipidaemic patients. Serum TC, TG, HDL cholesterol and LDL cholesterol were measured by direct automated method. LDL cholesterol was also calculated by Friedewald’s formula and de Cordova’s formula. Results were expressed as mean ± SD. Comparison was done by Pearson’s correlation test, agreement was done by BlandAltman agreement test between measured and calculated LDL cholesterol. The mean ± SD of measured LDL cholesterol was 132.99 ± 36.65 mg/ dL. LDL cholesterol calculated by Friedewald’s formula and de Cordova’s formula were 121.39 mg/dL and 116.81 mg/dL respectively. The limits of agreement between measured LDL cholesterol (direct method) and calculated LDL cholesterol by de Cordova’s formula were lowest and agreement was better for all dyslipidaemic subjects. de Cordova’s formula showed better agreement with measured LDL cholesterol (direct method) than Friedewald’s formula for approximate calculation of LDL cholesterol without using triglycerides.Keywords: LDL cholesterol, de Cordova’s formula, Friedewald’s formula

Número de pacientes candidatos a recibir inhibidores de la PCSK9 según datos de 2,5 millones de participantes de la práctica clínica real

Introduction and objectivesPCSK9 inhibitors (PCSK9i) are safe and effective lipid-lowering drugs. Their main limitation is their high cost. The aim of this study was to estimate the number of patients eligible for treatment with PCSK9i according to distinct published criteria. MethodsData were obtained from the Information System for the Development of Research in Primary Care. Included patients were equal to or older than 18 years and had at least 1 low-density lipoprotein cholesterol measurement recorded between 2006 and 2014 (n = 2 500 907). An indication for treatment with PCSK9i was assigned according to the following guidelines: National Health System, Spanish Society of Arteriosclerosis, Spanish Society of Cardiology, National Institute for Health and Care Excellence, and the European Society of Cardiology/European Atherosclerosis Society Task Force. Lipid-lowering treatment was defined as optimized if it reduced low-density lipoprotein levels by ≥ 50% and adherence was > 80%. ResultsAmong the Spanish population aged 18 years or older, the number of possible candidates to receive PCSK9i in an optimal lipid-lowering treatment scenario ranged from 0.1% to 1.7%, depending on the guideline considered. The subgroup of patients with the highest proportion of potential candidates consisted of patients with familial hypercholesterolemia, and the subgroup with the highest absolute number consisted of patients in secondary cardiovascular prevention. ConclusionsThe number of candidates to receive PCSK9i in conditions of real-world clinical practice is high and varies widely depending on the recommendations of distinct scientific societies.Full English text available from:www.revespcardiol.org/en

Reaching low-density lipoprotein cholesterol treatment targets in stable coronary artery disease: Determinants and prognostic impact

Low-density lipoprotein cholesterol (LDL-C) reduction is an integral part of the management of patients with coronary artery disease (CAD). To assess attainment of LDL-C goals during long-term treatment of patients with stable CAD, and to determine predictors of goal attainment and the prognostic impact of reaching LDL-C<70mg/dL (1.8mmol/L) in a real-life setting. Data were obtained for 4080 outpatients with stable CAD included in the multicentre CORONOR study. Five-year follow-up was achieved for 3991 (97.8%) patients. At inclusion, a recent (<1 year) measurement of LDL-C was available in 3757 (92.1%) patients. LDL-C<70mg/dL was reached by 885 (23.6%) patients. Independent predictors of LDL-C<70mg/dL were diabetes mellitus, statin treatment, treatment with renin-angiotensin system inhibitors, previous myocardial infarction and short time since last coronary event. The adjusted hazard ratio (HR) for the composite endpoint (cardiovascular death, myocardial infarction, ischemic stroke or coronary revascularization) during the 5-year follow-up was 1.31 (95% confidence interval [CI]: 1.09-1.58; P=0.004) for LDL-C≥70mg/dL versus<70mg/dL. When compared with patients with LDL-C<70mg/dL, the adjusted HRs for LDL-C 70-99mg/dL and ≥100mg/dL (2.6mmol/L) were 1.27 (95% CI: 1.05-1.55; P=0.016) and 1.38 (95% CI: 1.12-1.70; P=0.003), respectively. When LDL-C was used as a continuous variable, the adjusted HRs for increases of 10mg/dL (0.3mmol/L) and 1mmol/L were 1.05 (95% CI: 1.03-1.08) and 1.21 (95% CI: 1.10-1.33), respectively. In this observational study, only a minority of stable CAD patients had LDL-C<70mg/dL. The patients who reached their LDL-C goal had the lowest risk of cardiovascular events.

Utilization of lipid-modifying therapy and low-density lipoprotein cholesterol goal attainment in patients at high and very-high cardiovascular risk: Real-world evidence from Germany

Background and aimsElevated low-density lipoprotein cholesterol (LDL-C) is a causal risk factor for cardiovascular (CV) events. European guidelines recommend reducing LDL-C as the primary lipid target to reduce CV risk, using lifestyle modifications and lipid-lowering therapy (LLT). Many European patients do not achieve guideline-recommended LDL-C levels. The present database analysis aimed to assess LLT treatment patterns and LDL-C threshold attainment in Germany in a large, real-world cohort of patients. MethodsPatients from the Cegedim Longitudinal Practice Database in Germany who met selection criteria were included: (a) LDL-C measurement in 2013; (b) ≥20 years of age; (c) high or very-high CV risk conditions: recent acute coronary syndrome (ACS), other coronary heart disease (CHD), ischemic stroke, peripheral arterial disease (PAD) (atherosclerotic cardiovascular disease [ASCVD]) or diabetes mellitus (DM) (non-ASCVD). LDL-C threshold attainment was assessed based on LDL-C targets from 2011 European guidelines. Results42,767 patients met the inclusion criteria; 35% received current statin treatment, and 30% achieved guideline-recommended LDL-C targets. Attainment of LDL-C goals among ASCVD hierarchical categories was 46.7% for recent ACS, 35.8% for ischemic stroke, 34.9% for other CHD, and 26.9% for PAD. Among patients in the non-ASCVD group with DM, 23.6% achieved LDL-C goals. Similar results were observed when patients were grouped by prevalence (patients assigned to every risk group for which they qualified). ConclusionsIn this high/very-high CV risk population in Germany, statin utilization was low; suggesting that LLTs are not prescribed as per European guidelines. These results highlight the need to increase LLT use among high-risk patients.

LDL-cholesterol measurement in diabetic type 2 patients: a comparison between direct assay and popular equations

BackgroundLow density lipoprotein –Cholesterol (LDL-C) is one of the main factors for assessment of cardiovascular disease risk and it is more important in diabetic patients. Various methods are currently used for LDL-C measurements which are compared in this study.MethodsThis study was conducted in Diabetes Research Center based on laboratory results of 1721 diabetic patients who referred to laboratory for regular follow-up of lipid profile. LDL-C was measured directly and also estimated according to Friedwald, Anandraja and Chen formulas.ResultsResults of direct LDL-C measurements were lower than all calculations at triglycerides (TG) levels less than 150 mg/dL while in higher TG levels direct measurement values were higher than Friedwald and Anandraja formula. Friedwald and Chen formula results had better correlation(r) with direct measurement than Anandraja in different levels of TG and also were able to define LDL-C > 100 mg/dL more accurately.ConclusionsAlthough we observed excellent correlation between the studied formulas with direct measurement, using the formula can misclassified diabetic patients with LDL-C values near threshold (100 mg/dL). However calculated LDL-C based on Chen and Friedwald formula can be a suitable alternative for direct measurement especially in regions with limited resources.

Lipid Metabolism, Abdominal Adiposity, and Cerebral Health in the Amish.

ObjectiveTo assess the association between peripheral lipid/fat profiles and cerebral grey matter (GM) and white matter (WM) in healthy, Old Order Amish (OOA).MethodsBlood lipids, abdominal adiposity, liver lipid contents and cerebral microstructure were assessed in OOA (N=64, 31 Males/33 Females, ages 18–77). Orthogonal factors were extracted from lipid and imaging adiposity measures. GM assessment used the Human Connectome Project protocol to measure whole-brain average cortical thickness. Diffusion weighted imaging derived WM fractional anisotropy and kurtosis anisotropy measurements.ResultsLipid/fat measures were captured by three orthogonal factors explaining 80% of the variance. Factor 1 loaded on cholesterol/LDL-C; Factor 2 on triglyceride/liver measurements; Factor 3 on abdominal fat measurements. A two-stage regression including age/sex (1st stage) and the three factors (2nd stage) examined the peripheral lipid/fat effects. Factors 2 and 3 significantly contributed to WM measures after Bonferroni corrections (p<0.007). No factor significantly contributed to GM. Blood pressure inclusion did not meaningfully alter the lipid/fat-WM relationship.ConclusionsPeripheral lipid/fat indicators significantly and negatively associated with cerebral WM rather than GM, independent of age and blood pressure. Dissecting the fat/lipid components contributing to different brain imaging parameters may open a new understanding of the body-brain connection through lipid metabolism.

Molecular effects of leptin on peroxisome proliferator activated receptor gamma (PPAR-γ) mRNA expression in rat's adipose and liver tissue.

Leptin is a 16-kDa peptide hormone secreted by adipose tissue that participates in the regulation of energy homeostasis. The aim of this study was to determine the effect of leptin injection on mRNA expression of peroxisome proliferator-activated receptor gamma (PPAR-γ) and comparison of PPAR-γ mRNA expression in rat's adipose and liver tissue. Twenty adult male rats were divided into the following groups: Group 1asa control (n=10) that did not receive any treatment. Group 2as a treatment (n=10) that received leptin (30 µg ⁄ kg BW) intraperitoneally (ip) for two successive days. Blood samples were taken before and one day after second leptin injection for triglyceride (TG), Free Fatty Acid (FFA), HLD-cholesterol, and LDL-cholesterol measurement. Total RNA was extractedfrom the adipose tissue and liver tissues of rats. Adipose and liver tissue cells' cDNA was synthesized to characterize the expression of PPAR-γ. Gene expression of PPAR-γ mRNA was tested by RT- PCR technique. Results show leptin decreases expression of PPAR-γ on rat. Low levels of PPAR-γ mRNA were detected in adipose and liver tissues of treatment rats in comparison to control group. In treatment group, the level of PPAR-γ mRNA in liver tissue was very lower than the adipose tissue. The levels of HDL and FFA in treatment rats were increased whereas serum levels TG, VLDL and LDL were not changed. It is concluded that leptin signal with suppressing of PPAR-γ mRNA expression in rat's adipose and liver tissues can result in lipolysis instead of lipogenesis.

Familial hypercholesterolemia in a European Mediterranean population—Prevalence and clinical data from 2.5 million primary care patients

Familial hypercholesterolemia (FH), the most frequent hereditary cause of premature coronary heart disease (CHD), is underdiagnosed and insufficiently treated. The objectives of the study were to estimate the prevalence of the FH phenotype (FH-P) and to describe its clinical characteristics in a Mediterranean population. Data were obtained from the Catalan primary care system's clinical records database (Catalan acronym: SIDIAP). Patients aged >7years with at least 1 low-density lipoprotein cholesterol measurement recorded between 2006 and 2014 (n=2,554,644) were included. Heterozygous FH-P and homozygous FH-P were defined by untreated low-density lipoprotein cholesterol plasma concentrations. The presence of cardiovascular diseases and risk factors was defined by coded medical records from primary care and hospital discharge databases. The age- and sex-standardized prevalence of heterozygous FH-P and homozygous FH-P were 1/192 individuals and 1/425,774 individuals, respectively. In the group aged 8 to 18years, 0.46% (95% confidence interval: 0.41-0.52) had FH-P; overall prevalence was 0.58% (95% confidence interval: 0.58-0.60). Among patients with FH-P aged >18years, cardiovascular disease prevalence was 3.5 times higher than in general population, and CHD prevalence in those aged 35 to 59years was 4.5 times higher than in those without FH-P. Lipid-lowering therapy was lacking in 13.5% of patients with FH-P, and only 31.6% of men and 22.7 of women were receiving high or very high-intensity lipid-lowering therapy. Prevalence of FH-P was higher than expected, but underdiagnosed and suboptimally treated, especially in women. Moreover, treatment started late considering the high CHD incidence associated with this condition.

Performance of Calculated and Directly Measured Low-Density Lipoprotein Cholesterol in a Pediatric Population.

An assessment of methods for the accurate measurement of low-density lipoprotein cholesterol (LDL-C) at decreased concentrations has not yet been carried out. We evaluated the performance of the Friedewald equation, a direct enzymatic assay, and a novel equation for determining LDL-C levels in a pediatric population with elevated triglycerides and reduced LDL-C levels. LDL-C concentrations of 127 pediatric patients were determined by the Friedewald equation, a direct enzymatic assay, and a novel equation. The bias of each approach was assessed at selected LDL-C cutoffs and after stratifying samples by triglyceride content. The concordance of each approach, relative to the reference method, was determined at LDL-C cut-points of less than 70, 70 to 99, and 100 to 129 mg/dL. The Friedewald equation substantially underestimated pediatric LDL-C concentrations below 100 mg/dL in the presence of elevated triglycerides. The Ortho Clinical Diagnostics (Raritan, NJ) direct LDL assay was positively biased at low LDL-C levels. The novel equation most effectively reduced the bias of the Friedewald equation at all LDL-C concentrations and increased the concordance of sample classification to the reference method. The novel equation should be used for accurate measurement of pediatric LDL-C when the concentration is below 100 mg/dL in the presence of elevated triglycerides (150-399 mg/dL).

Underestimation of Low Density Lipoprotein-Cholesterol With the Friedewald Equation Versus a Direct Homogenous Low Density Lipoprotein-Cholesterol Assay.

Low-density lipoprotein cholesterol (LDL-C) concentrations are the primary therapeutic target in patients with atherosclerotic cardiovascular disease (ASCVD). However, at low LDL-C concentrations, there is a significant underestimation using the Friedewald equation compared with ultracentrifugation. In this pilot study, we compared LDL-C concentrations obtained using the Friedewald equation (LDL-F) vs those concentrations from a direct LDL-C (LDL-D) assay in 152 consecutive specimens from patients with triglyceride levels between 200-399 mg/dL and LDL-F <100 mg/dL. Also, we compared LDL-F and LDL-D results to the novel formula (LDL-N). The LDL-F value was significantly lower than that of LDL-D when LDL concentrations were 70-99 mg/dL (P <.001, 14% negative bias), and this decrease was accentuated in specimens with LDL <70 mg/dL, (P <.001, 27% negative bias). When compared with the LDL-N value, LDL-F and LDL-D values showed a 17% and 2% negative bias for specimens with LDL-C values of 70-99 mg/dL and 36% and 1% negative bias, respectively, at LDL-C <70 mg/dL (P <.001 for comparisons of LDL-F and LDL-N values). To provide accurate LDL-C levels in patients at high risk for ASCVD, if beta quantification by ultracentrifugation is unavailable and if LDL-C is <100 mg/dL and triglycerides are 200-399 mg/dL, laboratories should revert to direct LDL-C measurements or use the novel formula. Although LDL-N is more cost-effective, LDL-D can be run on most platforms, does not require a specimen from a fasting individual, is standardized, and has the advantage of being validated in large trials such as the Heart Protection Study.

Discordant response of low-density lipoprotein cholesterol and lipoprotein(a) levels to monoclonal antibodies targeting proprotein convertase subtilisin/kexin type 9

Clinical trials testing proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) have demonstrated an unanticipated but significant lipoprotein (a) (Lp(a))-lowering effect, on the order of 25% to 30%. Although the 50% to 60% reduction in low-density lipoprotein (LDL)-cholesterol (LDL-C) achieved by PCSK9i is mediated through its effect on LDL receptor (LDLR) preservation, the mechanism for Lp(a) lowering is unknown. We sought to characterize the degree of concordance between LDL-C and Lp(a) lowering because of PCSK9i in a standard of care patient cohort. Participants were selected from our Center for Preventive Cardiology, an outpatient referral center in a tertiary academic medical center. Subjects were included in this study if they had (1) at least 1 measurement of LDL-C and Lp(a) before and after initiation of the PCSK9i; (2) baseline Lp(a)>10mg/dL; and (3) continued adherence to PCSK9i therapy. They were excluded if (1)they were undergoing LDL apheresis; (2) pre- or post-PCSK9i LDL-C or Lp(a) laboratory values were censored; or (3) subjects discontinued other lipid-modifying therapies. In total, 103 subjects were identified as taking a PCSK9i and 26 metall inclusion and exclusion criteria. Concordant response to therapy was defined as an LDL-C reduction >35% and an Lp(a) reduction >10%. The cohort consisted of 26 subjects (15 females, 11 males, mean age 63±12years). Baseline mean LDL-C and median Lp(a) levels were 167.4±72mg/dL and 81mg/dL (interquartile range 38-136mg/dL), respectively. The average percent reductions in LDL-C and Lp(a) were 52.8% (47.0-58.6) and 20.2% (12.2-28.1). The correlation between %LDL and %Lp(a) reduction was moderate, with a Spearman's correlation of 0.56 (P<.01). All subjects except for 1 had a protocol-appropriate LDL-C response to therapy. However, only 16 of the 26 (62%; 95% confidence interval 41%-82%) subjects had a protocol-concordant Lp(a) response. Although some subjects demonstrated negligible Lp(a) reduction associated with PCSK9i, there were some whose Lp(a) decreased as much as 60%. In this standard-of-care setting, we demonstrate moderate correlation but large discordance (∼40%) in these 2 lipid fractions in response to PCSK9i. The results suggest that pathways beyond the LDLR are responsible for Lp(a) lowering and indicate that PCSK9i have the potential to significantly lower Lp(a) in select patients, although confirmation in larger multicenter studies is required.

Visit-to-Visit Low-Density Lipoprotein Cholesterol Variability Is an Independent Determinant of Carotid Intima-Media Thickness in Patients With Type 2 Diabetes.

BackgroundStudies demonstrated that visit-to-visit variability in low-density lipoprotein cholesterol (LDLC) is an independent predictor of cardiovascular events in subjects with coronary artery disease. Whether visit-to-visit variability in LDLC levels affects subclinical atherosclerosis is unknown. This study sought to evaluate the role of visit-to-visit variability in LDLC levels on subclinical atherosclerosis.MethodsWe evaluated 162 type 2 diabetic patients with measurement of carotid intima-media thickness (IMT). Intrapersonal mean and standard deviation (SD) of six measurements of LDLC during 12 months were calculated. Multivariate linear regressions assessed the independent correlates of carotid IMT.ResultsThe mean and SD of LDLC were 112 ± 22 and 15 ± 10 mg/dL, respectively, and 43.2% of patients were on hypolipidemic drugs. Age (standardized β = 0.355, P < 0.001), male sex (standardized β = 0.234, P = 0.002) and SD-LDLC (standardized β = 0.201, P = 0.009) emerged as independent determinants of carotid maximum IMT independently of mean LDLC levels, body mass index (BMI), waist circumference, duration and treatment of diabetes, means and SDs of glycemic and other lipid variables, and uses of hypolipidemic and anti-hypertensive medications (R2 = 0.15). Results did not change when mean IMT was used instead of maximum IMT. After controlling for age and sex, maximum IMT was thicker in patients with the highest compared to those with other three quartiles of SD-LDLC combined (1.14 ± 0.04 (SE) vs. 1.01 ± 0.02 mm, P = 0.01). Independent determinants of SD-LDLC were mean LDLC, use of hypolipidemic drugs, fasting triglyceride and visit-to-visit variability in HbA1c.ConclusionsConsistency of LDLC levels may be important to subclinical atherosclerosis in real-world patients with type 2 diabetes. It may be important for patients on lipid-lowering drugs to prevent non-compliance.

All-Cause Mortality Risk in Australian Women with Impaired Fasting Glucose and Diabetes

Aims Impaired fasting glucose (IFG) and diabetes are increasing in prevalence worldwide and lead to serious health problems. The aim of this longitudinal study was to investigate the association between impaired fasting glucose or diabetes and mortality over a 10-year period in Australian women. Methods This study included 1167 women (ages 20–94 yr) enrolled in the Geelong Osteoporosis Study. Hazard ratios for all-cause mortality in diabetes, IFG, and normoglycaemia were calculated using a Cox proportional hazards model. Results Women with diabetes were older and had higher measures of adiposity, LDL cholesterol, and triglycerides compared to the IFG and normoglycaemia groups (all p < 0.001). Mortality rate was greater in women with diabetes compared to both the IFG and normoglycaemia groups (HR 1.8; 95% CI 1.3–2.7). Mortality was not different in women with IFG compared to those with normoglycaemia (HR 1.0; 95% CI 0.7–1.4). Conclusions This study reports an association between diabetes and all-cause mortality. However, no association was detected between IFG and all-cause mortality. We also showed that mortality in Australian women with diabetes continues to be elevated and women with IFG are a valuable target for prevention of premature mortality associated with diabetes.