Individual Low-density Lipoprotein Cholesterol Research Articles

Low density lipoprotein cholesterol and cardiovascular disease risk in patients with absence of coronary artery calcification: a multicenter cohort study

Abstract Background Low-density lipoprotein cholesterol (LDL-C) plays a central role in the development of coronary heart disease (CHD). Absence of coronary artery calcification (CAC 0), as assessed by coronary computed tomography angiography (CCTA), is associated with a favorable outcome as it indicates a low burden of atherosclerosis. However, questions remain regarding the risk of non-calcified plaque and CHD in younger patients with CAC zero, as atherosclerosis tends to be non-calcified in earlier stages. Purpose To assess if LDL-C is associated with presence of non-calcified plaque and future cardiovascular events in patients with CAC zero across the age spectrum. Methods This observational multicenter cohort study included patients aged 18 years or more who underwent CCTA between January 2008 and May 2021 with CAC zero. LDL-C was measured prior to CCTA. Patients were followed from date of CCTA to occurrence of cardiovascular event, death, or 1st of October 2022. No patients were lost to follow-up. We assessed the association between LDL-C and presence of non-calcified plaque on CCTA as adjusted odds ratios, and risk for myocardial infarction and CHD (myocardial infarction or coronary revascularization) as adjusted hazard ratios using Cox regression analyses, across different age groups. Results A total of 23,776 patients with CAC zero were included in the study. Median age was 54 years (IQR 47-61) and 14,605 (61%) were women. During median follow-up of 5.5 years, 165 (0.7%) and 427 (1.8%) experienced myocardial infarction and CHD, respectively. Overall, the prevalence of non-calcified plaque was 11.1% (n=2,650). Higher LDL-C was associated with presence of non-calcified plaque with an odds ratio of 1.21 (95% CI 1.16-1.27) per 1 mmol/L higher LDL-C. Individuals aged ≤45 years had a higher odds ratio for non-calcified plaque per 1 mmol/L higher LDL-C compared to individuals aged 46-60 and >60 years; 1.36 (95% CI 1.22-1.52), 1.22 (95% CI 1.15-1.30) and 1.13 (95% CI 1.04-1.22), respectively, p value for interaction between the youngest and oldest age group was <0.05. Overall, LDL-C was associated with higher risk for myocardial infarction and CHD with hazard ratios of 1.29 (95% CI 1.10-1.52) and 1.26 (95% CI 1.14-1.39) per 1 mmol/L higher LDL-C, despite CAC zero. Conclusions Particularly in younger patients with absence of CAC, elevated LDL-C is associated with presence of non-calcified plaque and increased risk for future cardiovascular events. These data are important for clinical practice, as they demonstrate the importance of managing LDL-C in younger individuals over the long-time horizon despite CAC zero.

Discordance of Circulating Non-HDL Cholesterol with LDL Cholesterol Concerning Long-Term Prognosis in Statin-Treated Individuals with Acute Coronary Syndrome and Previous Coronary Artery Bypass Grafting Undergoing Percutaneous Coronary Intervention.

Some individuals who maintain desirable low-density lipoprotein cholesterol (LDL-C) levels still experience the progression of atherosclerosis, which may eventually lead to cardiovascular events. Non-high-density lipoprotein cholesterol (non-HDL-C) levels are quantified to assess residual risk in statin-treated patients with coronary heart disease. The study aimed to estimate the predictive performance of discordance between non-HDL-C and LDL-C on clinical prognosis in statin-treated patients with previous coronary artery bypass grafting (CABG). 468 statin-treated patients with previous CABG undergoing percutaneous coronary intervention (PCI) as a secondary coronary treatment due to acute coronary syndrome (ACS) were retrospectively enrolled in this study. The definition of major adverse cardiovascular events (MACEs) was a composite endpoint of cardiovascular death, recurring myocardial infarction, and a need for repeat revascularization. Cox proportional hazards modeling, restricted cubic splines regression, and discordance analysis were conducted to the association between all lipid parameters and the occurrence of MACEs. Discordant values were defined as LDL-C concentrations 1.8 mmol/L accompanied by non-HDL-C 2.6 mmol/L. MACEs occurred in 95 patients over a median follow-up period of 744.5 days. Cox models demonstrated that increased concentrations of non-HDL-C and LDL-C levels were independent risk indicators of MACEs (p 0.001). The restricted cubic spline analysis revealed a linear relationship between non-HDL-C concentrations and MACEs (p-nonlinear: 0.26), whereas a nonlinear relationship was observed between LDL-C concentrations and MACEs (p 0.01). In the subgroup analysis, the spline curves revealed that the odds of the individuals with desirable LDL-C levels suffering MACEs emerged when non-HDL-C levels were above 2.07 mmol/L. Individuals who exhibited discordance involving high non-HDL-C/low LDL-C levels had an elevated risk of experiencing MACEs compared to those with concordantly low LDL-C and low non-HDL-C levels [hazard ratios (HRs) = 2.44, 95% confidence interval (CI) = 1.14-5.22, p = 0.02]. Non-HDL-C levels could predict the residual risk of MACEs in ACS patients with previous CABG and statin therapy that underwent percutaneous coronary intervention. A discordance between non-HDL-C and LDL-C in individuals with desirable LDL-C levels could be useful in identifying those with a residual risk of cardiovascular complications.

Evolving Management of Low-Density Lipoprotein Cholesterol: A Personalized Approach to Preventing Atherosclerotic Cardiovascular Disease Across the Risk Continuum.

Management of elevated low-density lipoprotein cholesterol (LDL-C) is central to preventing atherosclerotic cardiovascular disease (ASCVD) and key to reducing the risk of ASCVD events. Current guidelines on the management of blood cholesterol recommend statins as first-line therapy for LDL-C reduction according to an individual's ASCVD risk and baseline LDL-C levels. The addition of nonstatin lipid-lowering therapy to statins to achieve intensive LDL-C lowering is recommended for patients at very high risk of ASCVD events, including patients with familial hypercholesterolemia who have not achieved adequate LDL-C lowering with statins alone. Despite guideline recommendations and clinical trial evidence to support the use of lipid-lowering therapies for ASCVD risk reduction, most patients at high or very high risk do not meet LDL-C thresholds. This review explores the challenges associated with LDL-C lowering in contemporary clinical practice and proposes a framework for rethinking the binary definition of ASCVD, shifting from "primary" versus "secondary" prevention to a "continuum of risk." The approach considers the role of plaque burden and progression in subclinical disease and emphasizes the importance of early risk assessment and treatment for preventing first cardiovascular events. Patients at high risk of ASCVD events who require significant LDL-C lowering should be considered for combination therapies comprising statin and nonstatin agents. Practical guidance for the pharmacological management of elevated LDL-C, both now and in the future, is provided.

Type 1 diabetes management: Room for improvement.

Optimal diabetes care and risk factor management are important to delay micro- and macrovascular complications in individuals with type 1 diabetes (T1D). Ongoing improvement of management strategies requires the evaluation of target achievement and identification of risk factors in individuals who do (or do not) achieve these targets. Cross-sectional data were collected from adults with T1D visiting six diabetes centers in the Netherlands in 2018. Targets were defined as glycated hemoglobin (HbA1c) <53 mmol/mol, low-density lipoprotein-cholesterol (LDL-c) <2.6 mmoL/L (no cardiovascular disease [CVD] present) or <1.8 mmoL/L (CVD present), or blood pressure (BP) <140/90 mm Hg. Target achievement was compared for individuals with and without CVD. Data from 1737 individuals were included. Mean HbA1c was 63 mmol/mol (7.9%), LDL-c was 2.67 mmoL/L, and BP 131/76 mm Hg. In individuals with CVD, 24%, 33%, and 46% achieved HbA1c, LDL-c, and BP targets respectively. In individuals without CVD these percentages were 29%, 54%, and 77%, respectively. Individuals with CVD did not have any significant risk factors for HbA1c, LDL-c, and BP target achievement. In comparison, individuals without CVD were more likely to achieve glycemic targets if they were men and insulin pump users. Smoking, microvascular complications, and the prescription of lipid-lowering and antihypertensive medication were negatively associated with glycemic target achievement. No characteristics were associated with LDL-c target achievement. Microvascular complications and antihypertensive medication prescription were negatively associated with BP target attainment. Opportunities for improvement of diabetes management exist for the achievement of glycemic, lipid, and BP targets but may differ between individuals with and without CVD.

Low-density lipoprotein cholesterol goal attainment in patients with clinical evidence of familial hypercholesterolemia and elevated Lp(a)

BackgroundAlthough potent lipid-lowering therapies are available, patients commonly fall short of recommended low-density lipoprotein cholesterol (LDL-C) levels. The aim of this study was to examine the relationship between familial hypercholesterolemia (FH) and elevated lipoprotein(a) [Lp(a)] and LDL-C goal attainment, as well as the prevalence and severity of coronary artery disease (CAD). Moreover, we characterized patients failing to meet recommended LDL-C goals.MethodsWe performed a cross-sectional analysis in a cohort of patients undergoing cardiac catheterization. Clinical FH was determined by the Dutch Clinical Lipid Network Score, and Lp(a) ≥ 50 mg/dL (≈ 107 nmol/L) was considered elevated.ResultsA total of 838 participants were included. Overall, the prevalence of CAD was 72%, and 62% received lipid-lowering treatment. The prevalence of clinical FH (probable and definite FH) was 4%, and 19% had elevated Lp(a) levels. With 35%, LDL-C goal attainment was generally poor. Among the participants with clinical FH, none reached their LDL-C target. Among patients with elevated Lp(a), LDL-C target achievement was only 28%. The prevalence and severity of CAD were higher in participants with clinical FH (86% prevalence) and elevated Lp(a) (80% prevalence).ConclusionMost participants failed to meet their individual LDL-C goals according to the ESC 2016 and 2019 guidelines. In particular, high-risk patients with clinical FH or elevated Lp(a) rarely met their target for LDL-C. The identification of these patients and more intense treatment approaches are crucial for the improvement of CAD primary and secondary prevention.

Comparison of Methods to Estimate Low-Density Lipoprotein Cholesterol in Patients With High Triglyceride Levels

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.

Targeting dyslipidemia with antioxidative vitamins C, D, and E; a systematic review of meta-analysis studies: Dyslipidemia and antioxidative vitamins.

There is controversial evidence for the beneficial effects of antioxidative vitamins (vits) on dyslipidemia. In this regard, we aimed to systematically review all meta-analyses of trials on this topic. We comprehensively searched PubMed, Web of Science, Scopus, and Cochrane Library databases until January 2021 to explore the published English meta-analyses of trials conducted to assess the effects of single or combined vits C, D and E consumption on lipid profile. The meta-analyses of observational, in vivo/in vitro, or case-report studies were excluded. Search results were reported based on the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) flowchart. Overall, 25 meta-analyses including 32,177 individuals with different underlying disorders met our inclusion criteria. Numerous studies had assessed supplementation with Vit-D or its combination with other agents on lipid profile. Consumption of 400IU/day (d) to 50,000IU/week (w) Vit-D for at least eight weeks improved the levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) in type 2 diabetes mellitus or polycystic ovary syndrome (PCOS) patients. This treatment reduced the levels of TC and TG in patients with chronic kidney disease. A significant increase in high-density lipoprotein cholesterol (HDL-C) levels was only observed in coronary artery disease patients. Sole intake of 500-2000mg/d Vit-C for at least 3weeks improved LDL-C and TG values in hypercholesterolemic patients. Nevertheless, sole intake of Vit-E had controversial effects on lipid profile. The combination of 400-1800IU/d omega-3 free fatty acid (FFA) and 400IU/d Vit-E significantly reduced the levels of LDL-C and TG in overweight individuals, without any significant effect on other components. A significant improvement of TG values was observed after consumption of 1000-2000mg/d omega-3 FFA plus 400IU/d Vit-E along with 50,000IU/each 2w Vit-D for at least 6weeks in diabetic patients. The beneficial effects of antioxidative vitamins (C, D, E) or their combination with other agents on lipid profile varied based on their dosage, intake duration, and the health status of the individuals. The online version contains supplementary material available at 10.1007/s40200-021-00919-8.

Population pharmacokinetics and exposure-response modeling for evinacumab in homozygous familial hypercholesterolemia.

Evinacumab, an angiopoietin‐like protein 3 (ANGPTL3) inhibitor, has been shown to significantly reduce low‐density lipoprotein cholesterol (LDL‐C) in patients with homozygous familial hypercholesterolemia (HoFH). This work characterized the population pharmacokinetics (PK)/pharmacodynamics (PD) of evinacumab using pooled phase III clinical data. Total evinacumab PK were described by a two‐compartment model with combined linear and saturable (Michaelis–Menten) elimination, and first‐order absorption. At clinically relevant concentrations, plasma drug concentrations were mainly influenced by the linear clearance pathway. Although the maximum target‐mediated rate of elimination (Vmax) parameter for the saturable pathway was found to be positively related to baseline ANGPLTL3, variability in body weight contributed more to the variability in evinacumab exposure than variability in ANGPTL3. An effect of HoFH versus healthy volunteers on Vmax was also identified. Weight‐based dosing regimens resulted in consistent evinacumab exposure across weight ranges. An indirect exposure–response model adequately described the relationship between evinacumab and LDL‐C, where drug concentration is assumed to inhibit LDL‐C production. The final population PK/PD model included two nonclinically significant covariates (race and baseline body weight) on the maximum drug‐induced inhibitory effect (Imax) and one (baseline LDL‐C) on the evinacumab concentration inducing 50% of Imax (IC50). A smaller IC50 was observed in patients with higher baseline LDL‐C, suggesting greater sensitivity to treatment. Population exposure–response analysis permitted estimation of derived PD parameters and individual LDL‐C levels over time for patients with HoFH. The model accurately predicted the proportion of patients with HoFH achieving prespecified LDL‐C goals with evinacumab during the ELIPSE HoFH study, further supporting a dosing strategy.

Atherosclerotic cardiovascular risk and simulation of lipid-lowering therapy in China

Abstract Background Lipid-lowering therapy is a key strategy to reduce atherosclerotic cardiovascular disease (ASCVD) risk. However, little is known about the burden of lipid-lowering therapy in China. Purpose We aim to simulate the proportion of individuals in need of different lipid-lowering therapy regimens to reach diverse low-density lipoprotein cholesterol (LDL-C) goals based on the ASCVD risk stratification. Methods We used the data from China PEACE Million Persons Project, a national screening project covering 31 provinces in China. The ASCVD risk stratifications and LDL-C goals were based on the 2016 Chinese Guideline for the Management of Dyslipidemia in Adults. Stepwise lipid-lowering therapy (atorvastatin 20 mg, add-on ezetimibe and add-on evolocumab) was simulated by a Monte Carlo model based on individual's LDL-C level. Results We included 2,876,272 participants (89.7% of the screened) who were not receiving lipid-lowering therapy (mean age 55.8±9.9 years; 60.5% women). The proportion of participants at low, moderate, high and very high ASCVD risk were 57.9%, 17.5%, 22.3% and 2.3%, respectively. In individuals at low or moderate risk, 10.5% did not reach the goal of LDL-C&amp;lt;3.4mmol/L; after statin simulation, 99.8% met the goal. In high-risk patients, 49.0% did not reach LDL-C&amp;lt;2.6mmol/L; after statin monotherapy (82.7%), add-on ezetimibe (10.6%) and add-on evolocumab (6.7%), 99.7% met the goal. In very-high-risk patients, 72.2% did not reach LDL-C&amp;lt;1.8mmol/L; while 99.1% met the goal after all patients received the simulation: statin monotherapy (76.5%), add-on ezetimibe (13.0%) and add-on evolocumab (10.5%). In a total of 609,489 participants (21.2% of the overall participants) needing lipid-lowering therapy, 88.5% required statin monotherapy and 11.5% additional non-statin therapy (Figure). Conclusions Moderate-intensity statin therapy is pivotal in the lipid-lowering therapy in China; nearly 10% in need of lipid-lowering therapy required additional non-statin therapy. Funding Acknowledgement Type of funding sources: None.

Bempedoic Acid: A First-in-Class Agent for Lowering Cholesterol Levels.

Despite statin therapy being the cornerstone for the treatment of hypercholesterolemia, a significant number of patients do not tolerate statin therapy because of muscle-related adverse effects or cannot achieve their individual low-density lipoproteincholesterol (LDL-C) goals with statin therapy alone. Several nonstatin agents have been evaluated for the management of LDL-C levels and reduction of cardiovascular (CV) risk in these patients, but there are some limitations with their use. Bempedoic acid is a novel nonstatin agent for the management of lipid disorders, via the inhibition of adenosine triphosphate citrate lyase (ACL). It was recently approved by the US Food and Drug Administration based on several phase III trials which showed promising results regarding safety and efficacy. Though CV outcome data are not available yet, bempedoic acid may be a useful adjunct therapy for select patients. The purpose of this review is to evaluate the major findings in these clinical trials and discuss the potential role of bempedoic acid in clinical practice and its use in older people.

Bempedoic Acid: A First-in-Class Agent for Lowering Cholesterol Levels

Despite statin therapy being the cornerstone for the treatment of hypercholesterolemia, a significant number of patients do not tolerate statin therapy because of muscle-related adverse effects or cannot achieve their individual low-density lipoproteincholesterol (LDL-C) goals with statin therapy alone. Several nonstatin agents have been evaluated for the management of LDL-C levels and reduction of cardiovascular (CV) risk in these patients, but there are some limitations with their use. Bempedoic acid is a novel nonstatin agent for the management of lipid disorders, via the inhibition of adenosine triphosphate citrate lyase (ACL). It was recently approved by the US Food and Drug Administration based on several phase III trials which showed promising results regarding safety and efficacy. Though CV outcome data are not available yet, bempedoic acid may be a useful adjunct therapy for select patients. The purpose of this review is to evaluate the major findings in these clinical trials and discuss the potential role of bempedoic acid in clinical practice and its use in older people.

Drug related metabolites and genetic polymorphisms predict low low-density lipoprotein cholesterol response to atorvastatin treatment in patients with coronary heart disease

Abstract Background There is considerable individual variation in the low-density lipoprotein cholesterol (LDL-C) reduction at all classes and doses of statins. Knowledge of the determinants of individual variation LDL-C response upon statin treatment may pave the way for personalized and optimized statin treatment. Purpose We aimed to determine clinical and drug related predictors of variability of LDL-C response to atorvastatin 40 mg in patients with coronary heart disease. Methods This is an explorative study among 70 patients enrolled in the MUscle Side-Effects of atorvastatin in coronary patients (MUSE) randomized double blinded cross-over trial. Absolute and relative changes in LDL-C after 7 weeks treatment with atorvastatin 40 mg/day and 7 weeks treatment with placebo, were calculated for each patient. Linear regression analyses were applied to investigate the association between clinical (10 variables) and drug related (atorvastatin and/or metabolites, 18 variables) predictors and changes in LDL-C. Results Adherence to allocated treatment was high as confirmed by atorvastatin levels in blood and a mean proportion of days covered of 99% (range 91–100%). Mean reduction in LDL-C on atorvastatin treatment (LDL-C atorvastatin – LDL-C placebo) was 2.1 (SD 0.7, range 0.3 to 3.4) mmol/L. Mean percentage reduction in LDL-C was 51.1 (SD 11.2, range 29 to 60)%, and 37 patients (52.9%) had &amp;lt;50% LDL-C reduction. Genetic polymorphisms in SLCO1B1 or CYP3A (B 0.06, 95% CI 0.01 to 0.12, p=0.026), increasing number of coronary events (B 0.06, 95% CI 0.002 to 0.10, p=0.005), increasing trough concentration of 4-OH atorvastatin lactone (B 0.05, 95% CI 0.01 to 0.08, p=0.005) and increasing trough concentration of 4-OH atorvastatin acid (B 0.05, 95% CI 0.01 to 0.08, p=0.006) were the significant determinants of lower relative change (%) in LDL-C, in adjusted analyses. Age, gender, somatic comorbidity, cardiovascular risk factors, statin dependent muscle side-effects and other clinical and drug related determinants were not associated with changes in LDL-C. Conclusions There is considerable inter-individual variation in the LDL-C response upon treatment with atorvastatin despite confirmed high statin adherence. This is the first study reporting that genetic polymorphisms involved in the metabolism of statins and atorvastatin metabolites predict lower LDL-C response. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): National Association of Health, Grant/Award

Cardiometabolic risk factors in siblings from a statewide screening program

The Coronary Artery Risk Detection in Appalachian Communities (CARDIAC) Project is a state-wide risk factor screening program that operated in West Virginia for 19years and screened more than 100,000 5th graders for obesity, hypertension, and dyslipidemia. We investigated siblings in the CARDIAC Project to assess whether cardiometabolic risk factors (CMRFs) correlate in siblings. We identified 12,053 children from 5752 families with lipid panel, blood pressure, and anthropometric data. A linkage application (LinkPlus from the U.S. Centers for Disease Control and Prevention) matched siblings based on parent names, addresses, telephone numbers, and school to generate a linkage probability curve. Graphical and statistical analyses demonstrate the relationships between CMRFs in siblings. Siblings showed moderate intraclass correlation coefficient of 0.375 for low-density lipoprotein cholesterol (LDL-C), 0.34 for high-density lipoprotein cholesterol (HDL-C), and 0.22 for triglyceride levels. The body mass index (BMI) intraclass correlation coefficient (0.383) is slightly better (2%) than LDL-C or HDL-C, but the standardized beta values from linear regression suggest a 3-fold impact of sibling LDL-C over the child's own BMI. The odds ratio of a second sibling having LDL-C < 110mg/dL with a first sibling at that level is 3.444:1 (Confidence Limit 3.031-3.915, P<.05). The odds ratio of a sibling showing an LDL-C ≥ 160mg/dL, given a first sibling with that degree of elevated LDL-C is 29.6:1 (95% Confidence Limit: 15.54-56.36). The individual LDL-C level correlated more strongly with sibling LDL-C than with the individual's own BMI. Seventy-eight children with LDL-C > 160mg/dL and negative family history would have been missed, which represents more than half of those with LDL-C > 160mg/dL (78 vs 67 or 54%). Sibling HDL-C levels, LDL-C levels, and BMIs correlate within a family. Triglyceride and blood pressure levels are less well correlated. The identified CMRF relationships strengthen the main findings of the overall CARDIAC Project: an elevated BMI is not predictive of elevated LDL-C and family history of coronary artery disease poorly predicts cholesterol abnormality at screening. Family history does not adequately identify children who should be screened for cholesterol abnormality. Elevated LDL-C (>160mg/dL) in a child strongly suggests that additional siblings and parents be screened if universal screening is not practiced.

Baseline, delta, and achieved low-density lipoprotein cholesterol levels and cardiovascular risk in patients on statin therapy: A post-hoc resampling mediation analysis of treating new targets [TNT] trial.

Clinical guidelines for monitoring low-density lipoprotein cholesterol (LDL-C) after statin therapy do not clearly define the clinical roles of baseline LDL-C, ΔLDL-C, and achieved LDL-C according to statin intensity. We performed post-hoc analysis of the Treating to New Target (TNT) study to evaluate individual LDL-C parameters after statin therapy. Primary outcome was the risk for total major adverse cardiovascular events (MACE). We use resampling multilevel mediation analysis to analyze complex relationships among LDL-C parameters based on similar statin intensities. Tertiles for resample A (matched baseline LDL-C; distinct achieved LDL), resample B (matched ΔLDL-C; distinct baseline LDL-C), and resample C (matched achieved LDL-C; distinct ΔLDL-C) were analyzed using Cox proportional hazard ratios. In original data analysis, the incidence of MACE was reduced in those with lower achieved LDL-C in total, low, and high intensity statin users (hazard ratios [HRs]=0.990, 0.992, 0.992; respectively; all P-values<.001). In mediation analysis, resample A showed consistently high incidence for MACE in the middle tertile (HR=1.237; 95% confidential interval [CI]=1.008-1.517; P-value=.041) and highest tertile (HR=1.275; 95% CI=1.021-1.592; P-value=.032) compared to the lowest tertile. However, resamples B and C did not show consistent differences. Similarly, no consistent statistical difference in MACE according to statin intensity. Lower achieved LDL-C decreased MACE in participants with a similar baseline LDL-C after statin therapy. However, the change in absolute values of ΔLDL-C and achieved LDL-C should be interpreted in an individualized manner due to their complex collinearity, and statin intensity should also be taken into consideration.

Effects of a Novel Nutraceutical Combination (Aquilea Colesterol®) on the Lipid Profile and Inflammatory Biomarkers: A Randomized Control Trial.

Background: Cholesterol-lowering nutraceuticals are useful in the management of moderate hypercholesterolemia. Methods: In a parallel-group, randomized, placebo-controlled double-blind trial we evaluated the effects on plasma total cholesterol, low-density lipoprotein cholesterol (LDL-c), and inflammatory biomarkers of a nutraceutical combination (Aquilea Colesterol®) containing phytosterols (1.5 g), red yeast rice providing monacolin K (10 mg), hydroxytyrosol (5 mg), and plasma cholesterol values >5.17 mmol/L (>200 mg/dL) and LDL-c >2.97 mmol/L (>115 mg/dL). At baseline and at one and three months we recorded dietary habits; anthropometric parameters; blood pressure; lipid profile; fasting glucose; liver, renal, and muscle function tests, C-reactive protein (hs-CRP); and interleukin-6. Results: 13 men and 27 women (mean age 61.8 years) completed the trial; 20 participants received the nutraceutical and 20 received placebo. No adverse effects were noted. Compared to placebo, at one and three months the nutraceutical reduced total cholesterol by 11.4% and 14.1%, LDL-c by 19.8% and 19.7%, and apolipoprotein B by 12.4% and 13.5%, respectively (p < 0.001; all). hs-CRP decreased significantly (p = 0.021) in the nutraceutical group. Conclusion: The nutraceutical Aquilea Colesterol® is useful for reducing total cholesterol, LDL-c, and inflammation in individuals with moderate hypercholesterolemia.

Development of Novel DNA-Encoded PCSK9 Monoclonal Antibodies as Lipid-Lowering Therapeutics.

Elevated low-density lipoprotein cholesterol (LDL-C) is one of the major contributors to cardiovascular heart disease (CHD), the leading cause of death worldwide. Due to severe side effects of statins, alternative treatment strategies are required for statin-intolerant patients. Monoclonal antibodies (mAbs) targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) have shown great efficacy in LDL-C reduction. Limitations for this approach include the need for multiple injections as well as increased costs associated with patient management. Here, we engineered a DNA-encoded mAb (DMAb) targeting PCSK9 (daPCSK9), as an alternative approach to protein-based lipid-lowering therapeutics, and we characterized its expression and activity. A single intramuscular administration of mouse daPCSK9 generated expression in vivo for over 42 days that corresponded with a substantial decrease of 28.6% in non-high-density lipoprotein cholesterol (non-HDL-C) and 10.3% in total cholesterol by day 7 in wild-type mice. Repeated administrations of the DMAb plasmid led to increasing expression, with DMAb levels of 7.5 μg/mL at day 62. daPCSK9 therapeutics may provide a novel, simple, less frequent, cost-effective approach to reducing LDL-C, either as a stand-alone therapy or in combination with other LDL-lowering therapeutics for synergistic effect.

Atorvastatin therapy under clinical practice conditions - which LDL-C levels are achieved in patients at very high cardiovascular risk?

Current information on the utilisation of atorvastatin under clinical practice conditions is limited. The cross sectional study DISCOVER documented in the period from June until December 2014 dose and effects on lipids in ambulatory patients at very high cardiovascular risk, who were treated with atorvastatin monotherapy (original drug or generics). Of 2625 patients (mean age 66.1 ± 10.8 years, 62.1 % males), 47.0 % had coronary heart disease (CHD), 25.1 % type 2 diabetes mellitus (DM), and 27.9 % CHD plus concomitant DM. Mean treatment duration on atorvastatin was 92.6 ± 109.6 weeks, mean atorvastatin dose at time of documentation was 27.9 ± 15.8 mg/d. Low-density lipoprotein cholesterol (LDL-C) < 70 mg/dL was achieved by 10.5 % of the total cohort (7.5 % in DM, 9.3 % in CHD, and 15.2 % in CHD+DM). In contrast, according to physicians' subjective assessment, 62.7 % of patients reached their individual LDL-C target (with small differences between groups). In conclusion, the LDL-C target level < 70 mg/dL as recommended by current guidelines is achieved only in a minority of atorvastatin treated patients at very high cardiovascular risk.

SLC12A3 variants modulate LDL cholesterol levels in the Mongolian population

BackgroundAbnormalities in lipid metabolism are crucial factors in the pathogenesis of cardiovascular disease (CVD). Variants of many genes have been verified to confer risk for lipid metabolism abnormalities. However, the relationship between genetic variants of the NCC-encoding SLC12A3 gene and lipid metabolism in the Mongolian population remains unclear. In the present study, we aimed to elucidate the effects of SLC12A3 variants on Mongolian lipid metabolism, including total cholesterol (TCHO), triglycerides (TG), low-density lipoprotein cholesterol (LDL-c), and high-density lipoprotein cholesterol (HDL-c).MethodsA randomly selected population of Mongolians (n = 331) from China underwent clinical testing. An ANOVA test, Kruskal-Wallis H test (K-W test) and haplotype analysis were used to evaluate the association between the levels of lipids (TCHO, TG, LDL-c, and HDL-c) and polymorphisms in SLC12A3 loci.ResultsWe identified three single nucleotide polymorphisms (SNPs) rs5803, rs2010501 and rs711746 in the SLC12A3 gene that were significantly associated with an individual’s serum LDL-c level. Haplotypes combining these SNPs also showed the same trend (all p values < 0.01). Furthermore, the influence of SLC12A3 genetic polymorphisms on differences in individual serum LDL-c levels remained significant, even after we controlled gender, and demographic and other non-genetic factors.ConclusionThese results suggest that variants of the SLC12A3 gene confer susceptibility to the abnormal serum LDL-c level in the Mongolian population.

Atorvastatin treatment and LDL cholesterol target attainment in patients at very high cardiovascular risk.

The use of atorvastatin is rapidly increasing among statins since the introduction of generics. However, only limited data are available on its current use and the effectiveness outside of randomised trials. The aim of the study was to assess low-density lipoprotein (LDL-C) levels in ambulatory patients at very high cardiovascular risk on atorvastatin therapy in physician’s offices. A total of 2625 high-risk patients on atorvastatin were included into this cross-sectional study by 539 office-based physicians between June and December 2014. 47.0 % of the patients had documented coronary heart disease (CHD), 25.1 % type 2 diabetes mellitus (DM), and 27.9 % CHD plus concomitant DM. The mean age was 66.1 ± 10.8 years, 62.1 % were male. Atorvastatin at the dose of 10, 20, 40 and 80 mg/day was administered in 15.6, 45.7, 33.9, and 4.8 % of the patients, respectively. The treatment duration was 92.6 ± 109.6 weeks. The mean atorvastatin dose at therapy start was 24.8 ± 15.2 mg/day and at time of documentation 27.9 ± 15.8 mg/day. Low-density lipoprotein cholesterol (LDL-C) <70 mg/dL was achieved by 10.5 % of the total cohort (7.5 % in DM, 9.3 % in CHD, and 15.2 % in CHD + DM). In contrast, according to physicians’ subjective assessment, 62.7 % of patients (with small differences between groups) had reached their individual LDL-C target. In summary, higher doses of atorvastatin are not frequently used in clinical practice. The LDL-C target level <70 mg/dL as recommended by current guidelines is achieved only in a minority of atorvastatin treated patients at very high cardiovascular risk.

GRP94 Regulates Circulating Cholesterol Levels through Blockade of PCSK9-Induced LDLR Degradation.

Clearance of circulating low-density lipoprotein cholesterol (LDLc) by hepatic LDL receptors (LDLR) is central for vascular health. Secreted by hepatocytes, PCSK9 induces the degradation of LDLR, resulting in higher plasma LDLc levels. Still, it remains unknown why LDLR and PCSK9 co-exist within the secretory pathway of hepatocytes without leading to complete degradation of LDLR. Herein, we identified the ER-resident GRP94, and more precisely its client-binding C-terminal domain, as a PCSK9-LDLR inhibitory binding protein. Depletion of GRP94 did not affect calcium homeostasis, induce ER stress, nor did it alter PCSK9 processing or its secretion but greatly increased its capacity to induce LDLR degradation. Accordingly, we found that hepatocyte-specific Grp94-deficient mice have higher plasma LDLc levels correlated with ∼ 80% reduction in hepatic LDLR protein levels. Thus, we provide evidence that, in physiological conditions, binding of PCSK9 to GRP94 protects LDLR from degradation likely by preventing early binding of PCSK9 to LDLR within the ER.