Lower Low-density Lipoprotein Cholesterol Levels Research Articles

Efficacy and Safety of Lomitapide in Homozygous Familial Hypercholesterolaemia: A Systematic Review.

Homozygous familial hypercholesterolaemia (HoFH) patients have little or no low-density lipoprotein receptor (LDLR) function. HMG-CoA (3-hydroxy-3-methyl glutaryl coenzyme A) reductase inhibitors (statins) and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have limited lipid-lowering effects, therefore, there is an urgent need to develop new HoFH treatments. In 2012, the US Food and Drug Administration (FDA) approved the administration of lomitapide for lowering low-density lipoprotein cholesterol (LDL-C) levels. However, lomitapide is associated with various gastrointestinal disorders, elevated hepatic alanine aminotransferase (ALT) levels and other adverse reactions, thus, its long-term efficacy and safety in pediatrics and adults should be evaluated. A systematic review conducted in 2017 reported the efficacy and safety of lomitapide in Family hypercholesterolaemia (FH) patients. In this systematic review, we elucidate on the efficacy and safety of lomitapide in HoFH patients. A search was conducted in PubMed, Embase, Web of Science and Cochrane library databases to identify valid studies involving lomitapide-treated HoFH patients published before 11th August 2021. A total of 18 clinical studies involving 120 lomitapide-treated HoFH patients were identified. Lomitapide significantly suppressed LDL-C levels in HoFH patients. Clinical manifestations for lomitapide in children were comparable to those in adults. The most common adverse events were gastrointestinal disturbances and elevated ALT levels. However, most patients tolerated the treatment-associated adverse reactions. Low-fat diets and drug dose adjustments were appropriate measures for controlling the treatment-associated adverse reactions. In pediatric and adult HoFH patients, lomitapide significantly suppresses LDL-C levels, therefore, it is an important option for HoFH treatment. The most common adverse events of lomitapide treatment include gastrointestinal disorders and elevated hepatic ALT levels. Despite the limitations, lomitapide is feasible for long-term treatment of HoFH patients, with dietary and safety monitoring. CRD42021284425.

Advancements in the Treatment of Homozygous Familial Hypercholesterolemia.

Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder with extreme elevations of low-density lipoprotein cholesterol (LDL-C) leading to premature atherosclerotic cardiovascular disease (ASCVD) as early as in childhood. Management of HoFH centers around aggressive and adequate reduction of LDL-C levels to slow the trajectory of ASCVD development. Historically, lowering LDL-C levels in HoFH has been challenging because of both the markedly elevated LDL-C levels (often ＞400 mg/dL) and reduced response to treatment options, such as statins, for which the mechanism of action requires a functional LDL receptor. However, the treatment landscape for HoFH has rapidly progressed over the last decade. While statins and ezetimibe remain first-line treatment, patients often require addition of multiple therapies to achieve goal LDL-C levels. The PCSK9 inhibitors are an important recent addition to the available treatment options, along with lomitapide, bile acid sequestrants, and, possibly, bempedoic acid. Additionally, ANGPTL3 has emerged as an important therapeutic target, with evinacumab being the first available ANGPTL3 inhibitor on the market for the treatment of patients with HoFH. For patients who cannot achieve adequate LDL-C reduction, lipoprotein apheresis may be necessary, with the added benefit of reducing lipoprotein(a) levels that carries an added risk if also elevated in patients with HoFH. Finally, gene therapy and genome editing using CRISPR/Cas-9 are moving through clinical development and may dramatically alter the future landscape of treatment for HoFH.

Potential Gains in Life Expectancy Associated With Achieving Treatment Goals in US Adults With Type 2 Diabetes

Improvements in control of factors associated with diabetes risk in the US have stalled and remain suboptimal. The benefit of continually improving goal achievement has not been evaluated to date. To quantify potential gains in life expectancy (LE) among people with type 2 diabetes (T2D) associated with lowering glycated hemoglobin (HbA1c), systolic blood pressure (SBP), low-density lipoprotein cholesterol (LDL-C), and body mass index (BMI) toward optimal levels. In this decision analytical model, the Building, Relating, Assessing, and Validating Outcomes (BRAVO) diabetes microsimulation model was calibrated to a nationally representative sample of adults with T2D from the National Health and Nutrition Examination Survey (2015-2016) using their linked short-term mortality data from the National Death Index. The model was then used to conduct the simulation experiment on the study population over a lifetime. Data were analyzed from January to October 2021. The study population was grouped into quartiles on the basis of levels of HbA1c, SBP, LDL-C, and BMI. LE gains associated with achieving better control were estimated by moving people with T2D from the current quartile of each biomarker to the lower quartiles. Life expectancy. Among 421 individuals, 194 (46%) were women, and the mean (SD) age was 65.6 (8.9) years. Compared with a BMI of 41.4 (mean of the fourth quartile), lower BMIs of 24.3 (first), 28.6 (second), and 33.0 (third) were associated with 3.9, 2.9, and 2.0 additional life-years, respectively, in people with T2D. Compared with an SBP of 160.4 mm Hg (fourth), lower SBP levels of 114.1 mm Hg (first), 128.2 mm Hg (second), and 139.1 mm Hg (third) were associated with 1.9, 1.5, and 1.1 years gained in LE in people with T2D, respectively. A lower LDL-C level of 59 mg/dL (first), 84.0 mg/dL (second), and 107.0 mg/dL (third) were associated with 0.9, 0.7, and 0.5 years gain in LE, compared with LDL-C of 146.2 mg/dL (fourth). Reducing HbA1c from 9.9% (fourth) to 7.7% (third) was associated with 3.4 years gain in LE. However, a further reduction to 6.8% (second) was associated with only a mean of 0.5 years gain in LE, and from 6.8% to 5.9% (first) was not associated with LE benefit. Overall, reducing HbA1c from the fourth quartile to the first is associated with an LE gain of 3.8 years. These findings can be used by clinicians to motivate patients in achieving the recommended treatment goals and to help prioritize interventions and programs to improve diabetes care in the US.

Effect of Lipoprotein(a) on Stroke Recurrence Attenuates at Low LDL-C (Low-Density Lipoprotein) and Inflammation Levels.

Lp(a) (lipoprotein(a)) contributes to cardiovascular disease mainly through proatherogenic and proinflammatory effects. Here, we aimed to evaluate whether a residual stroke risk of Lp(a) would remain when the LDL-C (low-density lipoprotein cholesterol) and inflammatory levels are maintained low. This prospective cohort study included 9899 patients with ischemic stroke or transient ischemic attack from the Third China National Stroke Registry who had measurements of plasma Lp(a) and were followed up for 1 year. Cutoffs were set at the 50 mg/dL for Lp(a). LDL-C was corrected for Lp(a)-derived cholesterol (LDL-Cc [LDL-C corrected]) and cutoffs were set at 55 and 70 mg/dL.The threshold values of IL-6 (interleukin 6) and hsCRP (high-sensitive C-reactive protein) were the median 2.65 ng/L and 2 mg/L. Multivariable-adjusted hazard ratio (HR) were calculated using Cox regression models for each category to investigate the associations of Lp(a) with stroke recurrence within 1 year. Among all patients, those with Lp(a) ≥50 mg/dL were at higher stroke recurrence risk than those with Lp(a) <50 mg/dL (11.5% versus 9.4%; adjusted HR, 1.20 [95% CI, 1.02-1.42]). However, the risk associated with elevated Lp(a) was attenuated in patients with LDL-Cc <55 mg/dL (high Lp(a) versus low Lp(a): 8.9% versus 9.0%; adjusted HR, 0.92 [95% CI, 0.65-1.30]) or IL-6 <2.65 ng/L (9.0% versus 7.8%; adjusted HR, 1.14 [95% CI, 0.87-1.49]). Notably, in the group with both low LDL-Cc and inflammation levels, the rate of patients with high Lp(a) did not significantly different from the rate of patients with low Lp(a; LDL-Cc <55 mg/dL and IL-6 <2.65 ng/L: 6.2% versus 7.1%; adjusted HR, 0.86 [95% CI, 0.46-1.62]; LDL-Cc <55 mg/dL and hsCRP <2 mg/L: 7.7% versus 7.6%; adjusted HR, 0.97 [95% CI, 0.57-1.66]). However, there was no interaction between the LDL-Cc, IL-6, hsCRP, and Lp(a) levels on stroke recurrence risk. Increased Lp(a) was significantly associated with stroke recurrence risk in patients with ischemic stroke/transient ischemic attack. However, at low LDL-Cc or IL-6 levels, the elevated Lp(a) -associated stroke recurrence risk was attenuated in a secondary prevention setting.

Novel Pharmaceutical and Nutraceutical-Based Approaches for Cardiovascular Diseases Prevention Targeting Atherogenic Small Dense LDL.

Compelling evidence supports the causative link between increased levels of low-density lipoprotein cholesterol (LDL-C) and atherosclerotic cardiovascular disease (CVD) development. For that reason, the principal aim of primary and secondary cardiovascular prevention is to reach and sustain recommended LDL-C goals. Although there is a considerable body of evidence that shows that lowering LDL-C levels is directly associated with CVD risk reduction, recent data shows that the majority of patients across Europe cannot achieve their LDL-C targets. In attempting to address this matter, a new overarching concept of a lipid-lowering approach, comprising of even more intensive, much earlier and longer intervention to reduce LDL-C level, was recently proposed for high-risk patients. Another important concern is the residual risk for recurrent cardiovascular events despite optimal LDL-C reduction, suggesting that novel lipid biomarkers should also be considered as potential therapeutic targets. Among them, small dense LDL particles (sdLDL) seem to have the most significant potential for therapeutic modulation. This paper discusses the potential of traditional and emerging lipid-lowering approaches for cardiovascular prevention by targeting sdLDL particles.

Cholesterol-lowering drugs: Focus on Ezetimibe: Cholesterol-lowering drugs: Focus on ezetimibe

Ezetimibe is an intestinal cholesterol/sterol inhibitor. It is generally well-tolerated, and except for coadministration with cyclosporin (which increases concentration of both ezetimibe and cyclosporin), has limited drug interactions. Clinical trial data suggests that ezetimibe 10 mg orally once a day reduces low density lipoprotein cholesterol (LDL-C) levels about 15-25% as monotherapy or when added to statins, depending on the patient and individual clinical trial. Ezetimibe also reduces lipoprotein remnants. Due to its additive effects to statins, international lipid guidelines recommend ezetimibe as an option for patients who do not achieve LDL-C treatment goals with statins alone. The Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) trial demonstrated that when added to statin therapy, ezetimibe incrementally lowered LDL-C levels and modestly improved cardiovascular outcomes. Ezetimibe is formulated as monotherapy, or as a fixed-dose combination with statins or bempedoic acid. Finally, ezetimibe is the only pharmacotherapy approved for treatment of beta-sitosterolemia, which is a rare autsomal recessive disorder resulting in enhanced intestinal cholesterol absorption, increased circulating sterols, and tendinous and cutaneous xanthomas, arthritis or arthralgia, and premature cardiovascular disease.

Combination therapy in the guidelines: from high-intensity statins to high-intensity lipid-lowering therapies

The causal role of cholesterol in atherosclerosis was established more than 100 years ago. Along with the fact that the higher the cholesterol, the greater the risk of atherosclerotic cardiovascular diseases (ASCVD), many randomized controlled trials (RCT) have shown that lowering LDL cholesterol (LDL-C) is associated with a lower incidence of ASCVD. This impact of lipid-lowering therapies on cardiovascular risk is independent of the drug used, as shown by several meta-analyses and Mendelian randomization studies. Therefore, the concept of using “high-intensity statins” should be changed to “high-intensity lipid-lowering therapies” that go beyond the use of statins. Recent RCTs using non-statin lipid-lowering therapies has provided scientific evidence that the lower the LDL-C, the better in terms of cardiovascular events. Based on these observations, current guidelines recommend achieving very low LDL-C levels in patients with high and very-high cardiovascular risk. To achieve these demanding goals, the physician must use the full spectrum of lipid-lowering therapies, beyond high-intensity, high-dose statins. Oral combination therapies and, when necessary, subcutaneous treatments become the new standard of care for hypercholesterolemia. However, the number of patients achieving LDL-C goals is unacceptably low. This is due in part to insufficient prescription and insufficient treatment. To improve the efficacy of therapy, several strategies have been proposed, step by step, planning therapy and maximizing treatment, based on the needs of the patient. A wider use of lipid-lowering

Low cholesterol is not associated with depression: data from the 2005-2018 National Health and Nutrition Examination Survey

BackgroundAlthough high serum cholesterol is widely recognized as a major risk factor for heart disease, the health effects of low cholesterol are less clear. Several studies have found a correlation between low cholesterol and depression, but the results are inconsistent.MethodsData from the National Health and Nutrition Examination Survey (NHANES) 2005-2018 were utilized in this cross-sectional study. The analysis of the relationship between cholesterol and depression was performed at three levels: low total cholesterol, low high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol. The inclusion criteria were as follows: (1) people with low (<4.14 mmol/L) or normal (4.14-5.16 mmol/L) total cholesterol for Sample 1; people with low (<1 mmol/L) or normal (≥1 mmol/L) HDL cholesterol levels for Sample 2; and people with low (<1.8 mmol/L) or normal (1.8-3.4 mmol/L) LDL cholesterol levels for Sample 3; and (2) people who completed the Patient Health Questionnaire-9 depression scale. Age, sex, educational level, race, marital status, self-rated health, alcohol status, smoking status, body mass index (BMI), poverty income ratio, physical function, comorbidities, and prescription use were considered potential confounders. The missing data were handled by multiple imputations of chained equations. Logistic regression was used to assess the relationship between low cholesterol and depression.ResultsAfter controlling for potential confounding factors in the multivariate logistic regression, no association was observed between depression and low total cholesterol (OR=1.0, 95% CI: 0.9-1.2), low LDL cholesterol (OR=1.0, 95% CI: 0.8-1.4), or low HDL cholesterol (OR=0.9, 95% CI: 0.8-1.1). The results stratified by sex also showed no association between low total cholesterol, low LDL cholesterol, low HDL cholesterol and depression in either men or women.ConclusionThis population-based study did not support the assumption that low cholesterol was related to a higher risk of depression. This information may contribute to the debate on how to manage people with low cholesterol in clinical practice.

PCSK9 inhibition in patients with acute stroke and symptomatic intracranial atherosclerosis: protocol for a prospective, randomised, open-label, blinded end-point trial with vessel-wall MR imaging

IntroductionDual antiplatelet therapy and high-intensity statins are the mainstay treatment in patients with acute stage, symptomatic intracranial atherosclerotic stenosis (ICAS). Alirocumab is a monoclonal antibody that can inhibit proprotein convertase...

Infection with the hepatitis C virus causes viral genotype-specific differences in cholesterol metabolism and hepatic steatosis

Lipids play essential roles in the hepatitis C virus (HCV) life cycle and patients with chronic HCV infection display disordered lipid metabolism which resolves following successful anti-viral therapy. It has been proposed that HCV genotype 3 (HCV-G3) infection is an independent risk factor for hepatocellular carcinoma and evidence suggests lipogenic proteins are involved in hepatocarcinogenesis. We aimed to characterise variation in host lipid metabolism between participants chronically infected with HCV genotype 1 (HCV-G1) and HCV-G3 to identify likely genotype-specific differences in lipid metabolism. We combined several lipidomic approaches: analysis was performed between participants infected with HCV-G1 and HCV-G3, both in the fasting and non-fasting states, and after sustained virological response (SVR) to treatment. Sera were obtained from 112 fasting patients (25% with cirrhosis). Serum lipids were measured using standard enzymatic methods. Lathosterol and desmosterol were measured by gas-chromatography mass spectrometry (MS). For further metabolic insight on lipid metabolism, ultra-performance liquid chromatography MS was performed on all samples. A subgroup of 13 participants had whole body fat distribution determined using in vivo magnetic resonance imaging and spectroscopy. A second cohort of (non-fasting) sera were obtained from HCV Research UK for comparative analyses: 150 treatment naïve patients and 100 non-viraemic patients post-SVR. HCV-G3 patients had significantly decreased serum apoB, non-HDL cholesterol concentrations, and more hepatic steatosis than those with HCV-G1. HCV-G3 patients also had significantly decreased serum levels of lathosterol, without significant reductions in desmosterol. Lipidomic analysis showed lipid species associated with reverse cholesterol transport pathway in HCV-G3. We demonstrated that compared to HCV-G1, HCV-G3 infection is characterised by low LDL cholesterol levels, with preferential suppression of cholesterol synthesis via lathosterol, associated with increasing hepatic steatosis. The genotype-specific lipid disturbances may shed light on genotypic variations in liver disease progression and promotion of hepatocellular cancer in HCV-G3.

Efficacy and safety of bempedoic acid in patients not receiving statins in phase 3 clinical trials

BackgroundDespite the high incidence of patients with statin tolerance problems, randomized evaluations of nonstatin oral treatment options for lowering of low-density lipoprotein cholesterol (LDL-C) in this population are sparse. ObjectiveTo assess the LDL-C lowering effect of bempedoic acid in patients not taking statins. MethodsThis was a pooled analysis of data from patients enrolled in four phase 3 bempedoic acid studies (12 to 52 weeks in duration) who were not taking concomitant statins (Phase 3 No Statin Cohort) and a phase 3 bempedoic acid plus ezetimibe fixed-dose combination study (BA+EZE FDC No Statin Cohort). The primary endpoint for all studies was the percent change from baseline to week 12 in LDL-C levels. Safety and tolerability were assessed by laboratory values and adverse events. ResultsIn the Phase 3 No Statin Cohort, bempedoic acid (n = 394) lowered LDL-C levels at week 12 significantly more than placebo (n = 192; −26.5% [95% CI, −29.7%, −23.2%]; P<0.001). The fixed-dose combination of bempedoic acid with ezetimibe lowered LDL-C by 39.2% (95% CI, −51.7% to −26.7%; P<0.001). Muscle-related disorders occurred at a rate of 26.4 and 28.6 per 100 person-years with bempedoic acid and placebo, respectively. ConclusionsIn patients with hypercholesterolemia unable to take statins, bempedoic acid lowered LDL-C levels by a mean of 26.5% vs placebo and bempedoic acid + ezetimibe fixed-dose combination lowered LDL-C by 39.2%. The treatments were generally well tolerated, suggesting that bempedoic acid may be efficacious and well tolerated in this challenging-to-treat patient population.

Abstract EP32: Low Density Lipoprotein Cholesterol Associations With The Risk Of Coronary Heart Disease And Stroke Among Middle-aged Japanese Workers: Analysis Using Inverse Probability Weighting

Introduction: Low density lipoprotein cholesterol (LDL-C) is an established causal factor for coronary heart disease (CHD) and ischemic stroke. A positive linear association between LDL-C and risk of CHD or ischemic stroke was reported from western populations but among Japanese the evidence still insufficient especially on the risk of ischemic stroke. This study used a longitudinal data from the Aichi Worker’s Cohort Study to explore the associations of LDL-C levels with the incidence of CHD, and stroke subtypes. Methods: Pooled data of 6325 adults (5001 men and 1324 women) who responded to the second (2002) and third (2007) wave surveys of the study were used for the current analysis. Propensity scores for LDL-C categories were generated using multinomial logistic regression that included age, sex, smoking, alcohol drinking, physical activity, body mass index, high-density lipoprotein cholesterol, triglycerides, history of diabetes and hypertension, antihypertensive medication, taking dyslipidemia medication and survey year. Hazard ratios (HRs) and the 95% confidence intervals (95% CIs) were estimated from inverse probability weighted (IPW) cox proportional hazards model for LDL-C categories associations with risks of CHD, stroke and its subtypes, and CVD. We also used restricted cubic spline to examine the possible nonlinear relationship. Results: During a median of 14 years of follow-up, 73 strokes (40 ischemic stroke, 30 hemorrhagic stroke and 3 unknown) and 60 CHD were observed. In comparison with LDL-C &lt; 120 mg/ dl, LDL-C ≥160 mg/dl was significantly associated with the increased risk of CVD (HR 1.79, 95% CI: 1.12-2.86) and CHD (HR 3.82, 95% CI: 1.80-8.06), but not with stroke (HR 1.05, 95% CI: 0.54-2.06), hemorrhagic stroke (HR 0.47, 95% CI: 0.13-1.67) or ischemic stroke (HR 1.56, 95% CI: 0.66-3.68). The results of restricted cubic spline analysis showed that the risks of CVD and CHD gradually increased from LDL-C of 120 mg/dl. On the other hand, the risk of ischemic stroke was flat until around LDL-C of 160 mg/dl and then increased afterward. The risk of hemorrhagic stroke was flat from LDL-C of 120 mg/dl or above, but showed an increased risk trend towards lower levels of LDL-C. Conclusions: Based on this recent, long-term prospective study among middle-aged Japanese workers and by applying the IPW method to adjust for several confounding variables, we found that LDL-C was linearly and positively associated with CHD incidence while higher LDL-C levels tended to be at an increased risk of ischemic stroke, though non-significant.

Impact of Low-density Lipoprotein Cholesterol Levels on Outcomes in Nonvalvular Atrial Fibrillation: Results from the China Atrial Fibrillation Registry Study.

BackgroundLow-density lipoprotein cholesterol (LDL-C) reduction improves cardiovascular outcomes. This study investigates the relationship between lipid levels and outcomes in patients with nonvalvular atrial fibrillation by LDL-C quarters.Material/MethodsPatients with atrial fibrillation were enrolled from 31 typical hospitals in China. Of 19 515 patients, 6775 with nonvalvular atrial fibrillation (NVAF) were followed for 5 years or until an event occurred.ResultsHyperlipidemia was not an independent risk factor for stroke/thromboembolism and cardiovascular mortality among patients with NVAF (hazard ratio 0.82, 95% CI 0.7–0.96, P=0.82). When patients were divided into quartiles according to LDL-C levels at the time of enrollment (Q1, <1.95; Q2, 1.95–2.51; Q3, 2.52–3.09; and Q4, >3.09 mmol/L), as LDL-C increased, events tapered off according to Kaplan-Meier curves for patients who were without oral anticoagulants and off statins (non-OAC; log-rank=8.3494, P=0.0393) and for those with oral anticoagulants (OAC; log-rank=6.7668 P=0.0797). This relationship was stronger for patients who were without OAC treatment and off statins than for those with OAC treatment. The relationship was not significant in patients with or without OAC and on statins (log-rank=2.5080, P=0.4738). This relationship also existed in patients with CHA2DS2-VASc scores <2 (log-rank=5.893, P=0.1167). For those with CHA2DS2-VASc scores ≥2 (log-rank=6.6163, P=0.0852), the relationship was stronger.ConclusionsIn patients with NVAF using standard or no lipid-lowering medication, low plasma LDL-C levels were related to an increased risk of stroke/thromboembolism and cardiovascular mortality.

Relationship Between Blood Lipid Levels and Mortality in Hospitalized COVID-19 Patients.

People with comorbid conditions are at increased risk of developing severe/fatal coronavirus disease 2019 (COVID-19). We aimed to investigate the relationship between lipid levels and mortality in patients hospitalized for COVID-19 infection. In this retrospective study, we collected the details of 5274 COVID-19 patients who were diagnosed using the polymerase chain reaction and/or computed tomography and were hospitalized between March and November 2020. Patients (n = 4118) whose blood lipid levels were checked within the first 24 h after hospitalization were included in the study. Multivariable cox proportional hazards regression was used to assess the relationship between lipid variables such as low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG) and death. There was a statistically significant association between LDL-C, HDL-C, and TG levels and the risk of death (P =.002, <.001, and .035, respectively). Low and high LDL-C, low HDL-C, and high TG levels were negatively associated with COVID-19-related mortality. Blood lipid levels may be useful predictors of mortality in COVID-19 patients.

Discordance Between Standard Equations for Determination of LDL Cholesterol in Patients With Atherosclerosis

BackgroundAccurate estimation of low-density lipoprotein cholesterol (LDL-C) is important for guiding cholesterol-lowering therapy. Different methods currently exist to estimate LDL-C. ObjectivesThis study sought to assess discordance of estimated LDL-C using the Friedewald, Sampson, and Martin/Hopkins equations. MethodsElectronic health record data from patients with atherosclerotic cardiovascular disease and triglyceride (TG) levels of <400 mg/dL between October 1, 2015, and June 30, 2019, were retrospectively analyzed. LDL-C was estimated using the Friedewald, Sampson, and Martin/Hopkins equations. Patients were categorized as concordant if LDL-C was <70 mg/dL with each pairwise comparison of equations and as discordant if LDL-C was <70 mg/dL for the index equation and ≥70 mg/dL for the comparator. ResultsThe study included 146,106 patients with atherosclerotic cardiovascular disease (mean age: 68 years; 56% male; 91% White). The Martin/Hopkins equation consistently estimated higher LDL-C values than the Friedewald and Sampson equations. Discordance rates were 15% for the Friedewald vs Martin/Hopkins comparison, 9% for the Friedewald vs Sampson comparison, and 7% for the Sampson vs Martin/Hopkins comparison. Discordance increased at lower LDL-C cutpoints and in those with elevated TG levels. Among patients with TG levels of ≥150 mg/dL, a >10 mg/dL difference in LDL-C was present in 67%, 27%, and 23% of patients when comparing the Friedewald vs Martin/Hopkins, Friedewald vs Sampson, and Sampson vs Martin/Hopkins equations, respectively. ConclusionsClinically meaningful differences in estimated LDL-C exist among equations, particularly at TG levels of ≥150 mg/dL and/or lower LDL-C levels. Reliance on the Friedewald and Sampson equations may result in the underestimation and undertreatment of LDL-C in those at increased risk.

Safety Issues Associated With the Clinical Application of PCSK9 Inhibitors: Current Findings.

Reduction in low-density lipoprotein cholesterol levels is the cornerstone of treatment and prevention of atherosclerotic cardiovascular diseases. Currently, high-intensity statins are being used as the first-line therapy to lower low-density lipoprotein cholesterol levels, as they improve the prognosis of patients with atherosclerotic cardiovascular disease and those in high-risk groups. However, in some patients, the expected reduction in cholesterol is not achieved despite aggressive treatment with statins. Moreover, some patients cannot tolerate the dosage or show poor response or compliance to statins. Therefore, combination therapies with statins and other medications should be considered. Recently, several clinical trials have shown that the use of proprotein convertase subtilisin/kexin type 9 inhibitors with or without statins and/or other lipid-lowering drugs can significantly reduce low-density lipoprotein cholesterol levels, sometimes to extremely low levels. Therefore, to facilitate appropriate prescription of these new lipid-lowering drugs, we systemically evaluated the safety issues associated with these inhibitors and extremely low low-density lipoprotein cholesterol levels.

Worldwide experience of homozygous familial hypercholesterolaemia: retrospective cohort study

Homozygous familial hypercholesterolaemia (HoFH) is a rare inherited disorder resulting in extremely elevated low-density lipoprotein cholesterol levels and premature atherosclerotic cardiovascular disease (ASCVD). Current guidance about its management and prognosis stems from small studies, mostly from high-income countries. The objective of this study was to assess the clinical and genetic characteristics, as well as the impact, of current practice on health outcomes of HoFH patients globally. The HoFH International Clinical Collaborators registry collected data on patients with a clinical, or genetic, or both, diagnosis of HoFH using a retrospective cohort study design. This trial is registered with ClinicalTrials.gov, NCT04815005. Overall, 751 patients from 38 countries were included, with 565 (75%) reporting biallelic pathogenic variants. The median age of diagnosis was 12·0 years (IQR 5·5-27·0) years. Of the 751 patients, 389 (52%) were female and 362 (48%) were male. Race was reported for 527 patients; 338 (64%) patients were White, 121 (23%) were Asian, and 68 (13%) were Black or mixed race. The major manifestations of ASCVD or aortic stenosis were already present in 65 (9%) of patients at diagnosis of HoFH. Globally, pretreatment LDL cholesterol levels were 14·7 mmol/L (IQR 11·6-18·4). Among patients with detailed therapeutic information, 491 (92%) of 534 received statins, 342 (64%) of 534 received ezetimibe, and 243 (39%) of 621 received lipoprotein apheresis. On-treatment LDL cholesterol levels were lower in high-income countries (3·93 mmol/L, IQR 2·6-5·8) versus non-high-income countries (9·3 mmol/L, 6·7-12·7), with greater use of three or more lipid-lowering therapies (LLT; high-income 66% vs non-high-income 24%) and consequently more patients attaining guideline-recommended LDL cholesterol goals (high-income 21% vs non-high-income 3%). A first major adverse cardiovascular event occurred a decade earlier in non-high-income countries, at a median age of 24·5 years (IQR 17·0-34·5) versus 37·0 years (29·0-49·0) in high-income countries (adjusted hazard ratio 1·64, 95% CI 1·13-2·38). Worldwide, patients with HoFH are diagnosed too late, undertreated, and at high premature ASCVD risk. Greater use of multi-LLT regimens is associated with lower LDL cholesterol levels and better outcomes. Significant global disparities exist in treatment regimens, control of LDL cholesterol levels, and cardiovascular event-free survival, which demands a critical re-evaluation of global health policy to reduce inequalities and improve outcomes for all patients with HoFH. Amsterdam University Medical Centers, Location Academic Medical Center; Perelman School of Medicine at the University of Pennsylvania; and European Atherosclerosis Society.

Optimal Low-Density Lipoprotein Cholesterol Levels in Adults Without Diabetes Mellitus: A Nationwide Population-Based Study Including More Than 4 Million Individuals From South Korea.

BackgroundAlthough the strong association between low-density lipoprotein cholesterol (LDL-C) and cardiovascular disease (CVD) is well-known, the threshold LDL-C level at which the risk of CVD begins to increase in individuals without diabetes mellitus (DM) remains unknown. We aimed to evaluate the association between incident CVD and serum LDL-C levels with or without statin use in individuals without DM.MethodsWe identified 4,182,117 individuals without previous CVD who underwent a health screening examination in 2009 and 2011 from the Korean National Health Insurance Cohort database. The primary endpoint was a composite of cardiovascular deaths, myocardial infarction (MI) cases, and ischemic stroke cases.ResultsDuring the median follow-up of 6 years, there were 51,961 CVD events that included 17,392 MI cases, 33,779 ischemic stroke cases, and 2,039 cardiovascular deaths. The LDL-C levels that were associated with an increased risk of CVD were ≥100 mg/dL in non-statin users and ≥130 mg/dL in statin users. However, even in individuals with lower LDL-C levels, all those with fasting plasma glucose (FPG) levels ≥110 mg/dL had a significantly higher risk of CVD.ConclusionsWe demonstrated that LDL-C levels ≥100 mg/dL were correlated with an increased risk of CVD in individuals without DM and a history of CVD. We found that a glucose, cholesterol interaction increased CVD risk, and modestly elevated FPG levels (110–125 mg/dL) were associated with a higher CVD risk even in individuals with well-controlled LDL-C levels.

Secondary Prevention Using Cholesterol-Lowering Medications in Patients with Prior Atherosclerotic Cardiovascular Disease Events: A Retrospective Cohort Analysis.

Background: Secondary prevention with lipid-lowering medications in patients with atherosclerotic cardiovascular disease (ASCVD) is known to reduce the risk of clinical events and death. Current guidelines codify recommendations for implementing secondary prevention in appropriate patients. However, in real-world practice, secondary prevention is frequently initiated only after the patient experiences a cardiovascular-related hospitalization. The impact of these delays is not well known.Objectives: To estimate the effects of delaying treatment on the risk of cardiovascular-related hospitalization and on costs for patients who meet the criteria for secondary prevention as specified in the 2013 American College of Cardiology/American Heart Association (ACC/AHA) Guidelines for Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults.Methods: This is a retrospective cohort analysis using Humana data. Eligible patients were categorized by treatment group: (1) patients who initiated treatment before an ASCVD-related hospitalization and (2) patients who either did not initiate treatment until after an ASCVD hospitalization or never initiated treatment. The associations between the timely initiation of cholesterol-lowering medications for secondary prevention and (1) the risk for an ASCVD hospitalization and (2) health-care costs over one year, were estimated using multivariate regressions.Results: A total of 272 899 secondary prevention patients were identified who met study selection criteria. Early treatment was associated with significant reductions in the risk of an ASCVD hospitalization at any time following the identification of the patient’s eligibility for secondary prevention (by 33% compared to those treated late or never, P<.0001), but was significantly associated with higher total cost over the first post-index year (by US $509, P<.001). Patients whose low-density lipoprotein cholesterol (LDL-C) levels were >130 mg/dL experienced higher ASCVD hospitalization risks, and also larger risk reductions if treated before an ASCVD hospitalization compared to patients with lower LDL-C levels who were treated late or never treated.Conclusions: More widespread implementation of the treatment policies specified in the 2013 ACC/AHA Guidelines for secondary prevention should significantly reduce cardiovascular disease hospitalizations and reduce costs.

Secondary Prevention Using Cholesterol-Lowering Medications in Patients with Prior Atherosclerotic Cardiovascular Disease Events: A Retrospective Cohort Analysis

Background: Secondary prevention with lipid-lowering medications in patients with atherosclerotic cardiovascular disease (ASCVD) is known to reduce the risk of clinical events and death. Current guidelines codify recommendations for implementing secondary prevention in appropriate patients. However, in real-world practice, secondary prevention is frequently initiated only after the patient experiences a cardiovascular-related hospitalization. The impact of these delays is not well known. Objectives: To estimate the effects of delaying treatment on the risk of cardiovascular-related hospitalization and on costs for patients who meet the criteria for secondary prevention as specified in the 2013 American College of Cardiology/American Heart Association (ACC/AHA) Guidelines for Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults. Methods: This is a retrospective cohort analysis using Humana data. Eligible patients were categorized by treatment group: (1) patients who initiated treatment before an ASCVD-related hospitalization and (2) patients who either did not initiate treatment until after an ASCVD hospitalization or never initiated treatment. The associations between the timely initiation of cholesterol-lowering medications for secondary prevention and (1) the risk for an ASCVD hospitalization and (2) healthcare costs over one year, were estimated using multivariate regressions. Results: A total of 272 899 secondary prevention patients were identified who met study selection criteria. Early treatment was associated with significant reductions in the risk of an ASCVD hospitalization at any time following the identification of the patient’s eligibility for secondary prevention (by 33% compared to those treated late or never, P&lt;.0001), but was significantly associated with higher total cost over the first post-index year (by US $509, P&lt;.001). Patients whose low-density lipoprotein cholesterol (LDL-C) levels were &gt;130 mg/dL experienced higher ASCVD hospitalization risks, and also larger risk reductions if treated before an ASCVD hospitalization compared to patients with lower LDL-C levels who were treated late or never treated. Conclusions: More widespread implementation of the treatment policies specified in the 2013 ACC/AHA Guidelines for secondary prevention should significantly reduce cardiovascular disease hospitalizations and reduce costs.