Elevated Low-density Lipoprotein Cholesterol Research Articles

PCSK9 Inhibitors: Focus on Evolocumab and Its Impact on Atherosclerosis Progression

This paper investigates the therapeutic use of PCSK9 inhibitors, particularly Evolocumab, as monoclonal antibodies for the treatment of atherosclerosis based on recent literature reviews. PCSK9 is an outstanding example of a breakthrough in medical science, with advancements in understanding its biological function driving substantial progress in atherosclerosis treatment. Atherosclerotic cardiovascular disease (ASCVD) is a leading global cause of mortality, imposing substantial financial burdens on healthcare systems. Elevated low-density lipoprotein cholesterol (LDL-C), a modifiable risk factor, plays a pivotal role in the development of ASCVD. Emerging treatments such as PCSK9 inhibitors are now being introduced to combat this issue, with the goal of reducing ASCVD risk by directly targeting LDL-C levels. This discovery highlighted the potential of monoclonal antibodies to inhibit PCSK9, thereby enhancing LDL-C receptor activity. This breakthrough led to the development of Alirocumab and Evolocumab inhibitors, which typically reduce LDL-C levels by approximately 50%. This research underscores the importance of PCSK9 inhibitors in treating ASCVD, drawing on evidence from various randomized controlled trials such as FOURIER, ODYSSEY OUTCOMES, and VESALIUS-CV. These trials have also shown that PCSK9 inhibitors are effective and safe for the treatment of several cardiovascular disorders. PCSK9 inhibitors are therefore useful in patients who do not reach their target LDL-C levels when on the highest doses of statins or patients with very high cardiovascular risk who cannot tolerate statins at all.

Statin-Associated Muscle Symptoms: Identification and Recommendations for Management.

Statins are first-line pharmacotherapy for the treatment of elevated low-density lipoprotein cholesterol and are generally well-tolerated. However, some patients may experience statin-associated muscle symptoms (SAMS). This paper reviews recommendations for identification and management of patients with SAMS. The National Lipid Association and other professional societies have issued guidance to assist clinicians in identifying and managing patients with partial or complete statin intolerance. The most common reason for intolerance is SAMS. This review discusses strategies to achieve therapeutic objectives for atherogenic lipoprotein management in patients with SAMS. Many patients who experience SAMS can tolerate some degree of statin therapy and non-statin medications are available as adjunctive or alternative treatments. With a thorough clinician-patient discussion and shared decision-making, a treatment plan can be identified to achieve therapeutic objectives and reduce the risk of atherosclerotic cardiovascular disease.

The effectiveness of liver transplantation in reducing lipid levels in Saudi children with homozygous familial hypercholesterolemia

IntroductionThe lipid profiles of patients aged <15 years who have been diagnosed with homozygous familial hypercholesterolemia (HoFH) at King Faisal Specialist Hospital & Research Center (Riyadh) were examined.MethodsThe total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels of 17 patients were measured on initial presentation and compared with the levels measured after pharmacological treatment and then again after liver transplantation.ResultsAt the end of the pharmacological treatment, the total cholesterol levels decreased by an average of 3.79 mmol/L (reduced by 15.40%) (P < 0.001), and LDL-C levels decreased on average by 2.73 mmol/L (reduced by 13.46%) (P = 0.014). However, in two patients, LDL-C levels increased by 5.42% and 9.03% after pharmacological treatment. Conversely, the lipid values measured after liver transplantation decreased significantly nearly to within normal and borderline limits. The post-transplant total cholesterol and LDL-C levels declined by a mean of 19.96 mmol/L (reduced by 81.04%) and 17.47 mmol/L (reduced by 84.27%), respectively (P < 0.001 for both).DiscussionThese findings suggest that liver transplantation provides a more effective means to reduce elevated total cholesterol and LDL-C levels in patients with HoFH. Although liver transplantation is considered a better treatment for FHoH, risks, complications, and donor organ shortage may present problems.

Toxicity and efficacy study of a combination of two retinoic acids in an ApoE knockout mouse model of atherosclerosis.

Atherosclerosis is a major contributor to cardiovascular disease, characterized by inflammation and lipid accumulation in arterial walls, leading to plaque formation. Elevated low-density lipoprotein cholesterol is a primary risk factor for atherosclerosis. All-trans retinoic acid (ATRA), a metabolite of vitamin A, has demonstrated anti-inflammatory effects and potential in regulating vascular injury. 9-cisretinoic acid (9cRA) is an active metabolite of vitamin A and activates the retinoid X receptor. This study investigates whether potassium retinoate (PA9RA), a synthetic combination of ATRA and 9cRA, offers superior efficacy in treating atherosclerosis compared to established treatments such as clopidogrel and atorvastatin. Male ApoE-/- mice were fed a Western-type diet and treated with PA9RA, clopidogrel, or atorvastatin for 10 weeks. The body weight, organ weight, serum biochemistry, and histopathology, including atherosclerotic lesion area and liver steatosis were assessed. PA9RA treatment led to a significant reduction in body weight and inguinal fat, with the 45 mg/kg/day dose showing marked efficacy in decreasing atherosclerotic lesion size and ameliorating liver steatosis. Histopathological evaluation revealed decreased foam cell formation and improved liver histology in PA9RA-treated groups compared to controls. Notable side effects included epidermal hyperplasia and gastric hyperplasia at high doses of PA9RA. PA9RA exhibits superior efficacy over clopidogrel and atorvastatin in ameliorating atherosclerosis and fatty liver in ApoE-/- mice. This study highlights PA9RA's potential as a promising therapeutic agent for atherosclerosis. Further research is needed to elucidate its mechanisms of action and assess long-term safety and efficacy.

Abstract 4114461: Low-density lipoprotein cholesterol, prevalence of cardiovascular disease risk factors, and predicted cardiovascular disease risk among young adults: National Health and Nutrition Examination Survey 2015-2020

Introduction: It is unclear if young adults with hyperlipidemia are also more likely to have non-lipid cardiovascular disease (CVD) risk-factors or higher long-term CVD risk. As such, we assessed associations between low-density lipoprotein cholesterol (LDL-C) levels and non-lipid CVD risk factors as well as 10- and 30-year risk of CVD in young adults. Methods: We included a nationally representative sample of adults 20-<40 years from the National Health and Nutrition Examination Survey (January 2015-March 2020). We described sociodemographic characteristics and CVD risk factors by LDL-C level. We used simple logistic regression to determine associations between LDL-C level and each CVD risk factor. We then calculated the median 10- and 30-year CVD risk by LDL-C category for each participant using the PREVENT risk estimating equations. Results: Among 2,133 (weighted estimation: 90.3 million) young adults, 51.0%, 32.6%, 12.5%, and 3.9% had an LDL-C <100 mg/dL, 100-<130 mg/dL, 130-<160 mg/dL, and 160-<190 mg/dL, respectively. Compared to participants with an LDL-C <100mg/dL, those with an LDL-C 100-<130 mg/dL, 130-<160 mg/dL, and 160-189 mg/dL were more likely to have metabolic syndrome, an enlarged waist, hypertension, elevated glucose, diabetes mellitus, high triglycerides, and high hs-CRP (Table). The median 10-year risk of CVD was approximately 1% across all baseline LDL-C levels. Over a 30-year time horizon, the median risk of incident CVD exceeded 5% only in the 130-<160mg/dL and 160-189mg/dL LDL-C categories (6.0% and 7.6%, respectively). LDL-C and the interaction between LDL-C and CVD risk enhancing factors were independently associated with 30-year predicted risk of CVD (p=0.006 and p=0.005, respectively). Discussion: Many young adults with an elevated LDL-C have concomitant high-risk CVD characteristics. The risk/benefit calculous for addressing this modifiable risk factor in these patients should be further explored.

Abstract 4113300: Targeting Liver Epsins Ameliorates Dyslipidemia in Atherosclerosis

Rationale: Low density cholesterol receptor (LDLR) in the liver is critical for the clearance of low-density lipoprotein cholesterol (LDL-C) in the blood. In atherogenic conditions, proprotein convertase subtilisin/kexin 9 (PCSK9) binds to LDLR on the surface of hepatocytes, preventing its recycling and enhancing its degradation in lysosomes, resulting in reduced LDL-C clearance. Our recent studies demonstrate that epsins, a family of ubiquitin-binding endocytic adaptors, are critical regulators of atherogenicity. Given the fundamental contribution of circulating LDL-C to atherosclerosis, we hypothesize that liver epsins promote atherosclerosis by controlling PCSK9-triggered LDLR endocytosis and degradation. Objective: We will determine the role of liver epsins in promoting PCSK9-mediated LDLR degradation and hindering LDL-C clearance to propel atherosclerosis. Methods and Results: We generated double knockout mice using albumin Cre in which both genes of epsin, namely, epsin 1 and epsin 2, are specifically deleted in the liver (Liver-DKO) on an ApoE -/- background. We discovered that western diet (WD)-induced atherogenesis was greatly inhibited, along with diminished blood cholesterol and triglyceride levels. Mechanistically, using scRNA-seq analysis on hepatocyte-derived data revealed elevated pathway involved in LDL particle clearance under WD treatment in ApoE -/- /Liver-DKO, which was coupled with diminished plasma LDL-C levels. Further analysis using the MEBOCOST algorithm revealed enhanced communication score between LDLR and cholesterol, suggesting elevated LDL-C clearance in the ApoE -/- Liver-DKO mice. In addition, we showed that loss of epsins in the liver upregulates of LDLR protein level. We further showed that epsins bind LDLR via the ubiquitin-interacting motif (UIM), and PCSK9-triggered LDLR degradation was abolished by depletion of epsins, preventing atheroma progression. Finally, our therapeutic strategy, which involved targeting liver epsins with nanoparticle-encapsulated siRNAs, was highly efficacious at inhibiting dyslipidemia and impeding atherosclerosis. Conclusions: Liver epsins promote atherogenesis by mediating PCSK9-triggered degradation of LDLR, thus raising the circulating LDL-C levels. Targeting epsins in the liver may serve as a novel therapeutic strategy to treat atherosclerosis by suppression of PCSK9-mediated LDLR degradation.

Abstract 4136273: A Machine Learning Approach to Simplify Risk Stratification of Patients with Atherosclerotic Cardiovascular Disease

Introduction: The 2018 AHA/ACC/Multisociety Blood Cholesterol Guideline recommends that patients with atherosclerotic cardiovascular disease (ASCVD) be classified as very high-risk (VHR) or not very high-risk (NVHR). This designation is based on the presence of > 2 major ASCVD events (recent acute coronary syndrome [ACS], history of myocardial infarction [MI], history of ischemic stroke, symptomatic peripheral artery disease [PAD]) or 1 major ASCVD event and > 2 high-risk conditions (age ≥65 years, heterozygous familial hypercholesterolemia, history of coronary revascularization, diabetes, hypertension, chronic kidney disease, current smoking, persistently elevated LDL-cholesterol [LDL-C], history of heart failure). While this approach was initially instituted to better predict future ASCVD events alone, more intensive LDL-C lowering is now recommended for those at VHR (LDL-C treatment threshold of 55 mg/dL for VHR patients vs 70 mg/dL for NVHR patients). We aimed to simplify ASCVD risk stratification in patients with clinical ASCVD using machine learning models. Methods: We used electronic health record data (Providence Health system) from 2022 to identify patients with ASCVD based on ICD-10 codes. Patient demographics, comorbidities, and laboratory data stratified patients as VHR or NVHR. Then, a classification and regression tree analysis was performed, with the outcome being VHR classification. Patients were randomly assigned to either the testing or training dataset in equal proportion. Variables in the model included age, sex, race, ethnicity, and the Guideline criteria. Model performance was assessed using misclassification rate and area under the receiver operative curve (AUC). Results: A total of 491,514 patients with ASCVD were included, of which 56% were male, 77% were white, and the mean (SD) age was 72.5 (13.0) years. Over half of patients (59%) were VHR. Those with recent ACS, history of MI, history of ischemic stroke, or PAD were classified as VHR 93%, 92%, 84%, and 91%, respectively. Presence of hypertension in these patients increased the likelihood of being VHR to 97%, 97%, 94%, and 98%, respectively. The misclassification rate and AUC for the testing set were 6.8% and 96.2%, respectively. Conclusions: Most patients with a major ASCVD event and hypertension were found to be VHR. Relying on these two factors alone can help simplify risk assessment. This approach may also help increase use of guideline-recommended LDL-C lowering therapy.

Association analysis of gut microbiota with LDL-C metabolism and microbial pathogenicity in colorectal cancer patients

BackgroundColorectal cancer (CRC) is the most common gastrointestinal malignancy worldwide, with obesity-induced lipid metabolism disorders playing a crucial role in its progression. A complex connection exists between gut microbiota and the development of intestinal tumors through the microbiota metabolite pathway. Metabolic disorders frequently alter the gut microbiome, impairing immune and cellular functions and hastening cancer progression.MethodsThis study thoroughly examined the gut microbiota through 16S rRNA sequencing of fecal samples from 181 CRC patients, integrating preoperative Low-density lipoprotein cholesterol (LDL-C) levels and RNA sequencing data. The study includes a comparison of microbial diversity, differential microbiological analysis, exploration of the associations between microbiota, tumor microenvironment immune cells, and immune genes, enrichment analysis of potential biological functions of microbe-related host genes, and the prediction of LDL-C status through microorganisms.ResultsThe analysis revealed that differences in α and β diversity indices of intestinal microbiota in CRC patients were not statistically significant across different LDL-C metabolic states. Patients exhibited varying LDL-C metabolic conditions, leading to a bifurcation of their gut microbiota into two distinct clusters. Patients with LDL-C metabolic irregularities had higher concentrations of twelve gut microbiota, which were linked to various immune cells and immune-related genes, influencing tumor immunity. Under normal LDL-C metabolic conditions, the protective microorganism Anaerostipes_caccae was significantly negatively correlated with the GO Biological Process pathway involved in the negative regulation of the unfolded protein response in the endoplasmic reticulum. Both XGBoost and MLP models, developed using differential gut microbiota, could forecast LDL-C levels in CRC patients biologically.ConclusionsThe intestinal microbiota in CRC patients influences the LDL-C metabolic status. With elevated LDL-C levels, gut microbiota can regulate the function of immune cells and gene expression within the tumor microenvironment, affecting cancer-related pathways and promoting CRC progression. LDL-C and its associated gut microbiota could provide non-invasive markers for clinical evaluation and treatment of CRC patients.

Serum Low-Density Lipoprotein Cholesterol Levels are Associated with Relapse in Neuromyelitis Optica Spectrum Disorder.

The relationship between serum low-density lipoprotein cholesterol (LDL-C) and the risk of relapse in neuromyelitis optica spectrum disorder (NMOSD) remains uncertain. We aimed to examine the association between serum LDL-C level and relapse in NMOSD patients. We conducted an analysis of the prospective observational NMOSD cohort study with consecutive 184hospitalized NMOSD patients from department of neurology. Blood samples were collected to measure LDL-C level upon admission. Primary and relapse were evaluated during hospitalization. The relationship between serum LDL-C level and relapse were analyzed by linear curve fitting analyses. Crude and adjusted odds ratios (OR) of LDL-C for relapse with 95% confidence intervals were analyzed using multiple logistic regression models. ROC curve analysis was used to identify the target lipid-lowering value of LDL-C and the probability of relapse was evaluated by the Kaplan-Meier Plot. Over a mean disease course of 100±87 days, 59.24% (n=109) participants developed relapse with higher LDL-C than the primary group (n=75) (p<0.001). Adjusted smoothed plots suggested that there were linear relationships between serum LDL-C level and relapse (p< 0.001). The OR (95% CI) between serum LDL-C level and relapse were 2.67 (1.76-4.04, p<0.001), and 2.38 (1.48-3.83, p<0.001) respectively in NMOSD patients before and after adjusting for potential confounders. The target LDL-C lowering values were 2.795mmol/L with potential benefits to prevent relapse in NMOSD. In this sample of NMOSD patients, we found that the elevated serum LDL-C was independently and positively associated with the relapse, and serum LDL-C should be well-controlled to prevent the relapse of NMOSD.

Long-Term Benefits and Safety of Statins in Patients with Kidney Failure: A Target Trial Emulation Study.

Patients with kidney failure are at elevated risk of cardiovascular diseases. Although statins were commonly used to mitigate cardiovascular disease risk among the population with high risk, the evidence for initiating statin therapy among patients with kidney failure remains inconclusive. This study aimed to investigate the long-term benefits and risks associated with statin therapy in patients with kidney failure. Using territory-wide public electronic health records in Hong Kong, 3,019 statin-eligible individuals with kidney failure and elevated LDL cholesterol ≥ 100 mg/dL from Jan 2008 to Dec 2015 were included for analysis. The framework of target trial emulation was adopted to investigate the risk of the major cardiovascular diseases (i.e., a composite of myocardial infarction, heart failure and stroke), all-cause mortality, as well as the major adverse events (i.e., myopathies and liver dysfunction) between statin initiators and statin non-initiators. The pooled logistic model was used to obtain the hazard ratio (HRs) for the outcomes of interest in both intention-to-treat (ITT) analysis and per-protocol (PP) analysis. Significant risk reduction associated with statin therapy (HR [95%CI]) was observed for major cardiovascular diseases (ITT: 0.78 [0.62, 0.98]; PP: 0.66 [0.50, 0.87]) and all-cause mortality (ITT: 0.80 [0.68, 0.95]; PP: 0.60 [0.48, 0.76]). The standardised 5-year and 10-year absolute risk reduction in per-protocol analysis was 7% (3%, 11%) and 11% (4%, 18%), respectively. No significant risks for the major adverse events were observed. Statin therapy was associated with lower risks of cardiovascular diseases and all-cause mortality in patients with kidney failure without a higher risk of major adverse events.

Impact of addressing modifiable risk factors on the 10-year risk of cardiovascular disease in individuals with familial hypercholesterolemia: a causal analysis utilising UK biobank

Abstract Background Familial hypercholesterolemia (FH) is a prevalent autosomal dominant disorder characterised by elevated low-density lipoprotein cholesterol (LDL-C) levels from birth. These elevated LDL-C levels significantly amplify the lifetime risk of cardiovascular disease (CVD). While the impact of early and effective initiation of lipid-lowering medication (LLM) on CVD risk is well documented in genetically confirmed FH, the additional impact of addressing modifiable lifestyle risk factors (MLRF) in that patient population remains largely unquantified. Methods This study quantified the potential effects of successfully managing 4 MLRF (smoking, obesity, alcohol consumption, and low physical activity) on the 10-year incidence of a first CVD diagnosis in adults with genetically confirmed FH treated with LLM within the UK Biobank. The synthesised causal estimates of these 4 MLF were obtained using two recent causal analysis frameworks, namely the doWhy causal calculus framework and the Causal Forest Double Machine Learning Method. Results In 660 FH individuals (mean age 56±8 years; 60.15% women), smoking cessation and reducing body mass index below 30 kg/m2 delivered the most substantial risk reductions (pooled estimates, adjusted for the 3 other MLRF: -6.5% and -3.2%, respectively; both p&amp;lt;0.001), followed by initiating moderate or high physical activity (-1.7%; p&amp;lt;0.001; Figure). Notably, cessation of alcohol consumption significantly increased CVD risk (+2.5%; p&amp;lt;0.001), aligning with existing literature. Conclusion In over 10 years, reductions in CVD risk ranging from 1.7% to 6.5% were achievable through smoking cessation, BMI reduction, and enhanced physical activity in FH individuals. Leveraging causal inference methodologies facilitates the discernment of which risk factors offer the most pronounced additional benefits beyond lipid-lowering interventions in this high-risk population.Forest Plot of Causal Effect Estimates

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 &amp;gt;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 &amp;lt;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.

The difference between guideline based lipid optimisation and real-world practice in a very high risk population

Abstract Background Elevated low-density lipoprotein cholesterol (LDL-C) is an important risk factor for the progression of cardiovascular disease and early optimisation of lipid lowering therapy following an acute coronary syndrome (ACS) or stroke is associated with improved outcomes. Recent guidelines have advocated the use of combination lipid-lowering therapy and achieving very low LDL-C concentrations.Purpose To identify if optimal lipid management in high risk patients has occurred. Methods A retrospective analysis of high-risk patients with a prior history of ACS or stroke presenting with a further subsequent ACS/stroke from January 2022 to December 2022 in a UK District General Hospital was performed. Lipid lowering therapy in primary care in the 18 months leading up admission, inpatient admission and subsequent 12 month post admission (delivered through the cardiac rehabilitation service post ACS and via primary care post stroke) was compared to our regional secondary prevention lipid lowering pathway. This patient group, with recurrent events, was selected as represents the "very high risk group" and had been through various clinicians multiple times increasing the opportunity to treat to guidance. Results 102 very high risk patients were admitted within the 12 month period. Only 79/102 patients had lipid profile in preceding 18 months and only 19% were compliant with the standard secondary prevention guidelines (20/102 patients high intensity statins), mainly due to reduced intensity statin doses (60%) and no lipid lowering medications (15%). A significant proportion of patients did not have any lipid blood tests during their index admission (no lipid profile 21% in stroke group vs 77% in ACS group) and whilst there was a significant inpatient escalation in lipid therapy this was mainly confined to high dose statins, and seen more clearly in the ACS group (ACS 65% vs stroke 21%). During the 12 months following admission a significant number of patients had no further lipid profiles (21% ACS vs 57% stroke) and minimal further optimisation of lipid management. Further escalation following high intensity statins were rare with only 5 / 102 patients receiving high intensity statin plus ezetimibe, 1 patient receiving statin/ ezetimibe/ PCSK9 inhibitor. Only 45% of patients achieved the guideline target of LDL &amp;lt; 1.8 mmol/L and only 18% achieved the ESC target of LDL &amp;lt;1.4 during 1 year follow up. Conclusion Although lipid guidelines have changed in recent year’s clinical real-world practice locally has not reflected these important developments, even in a very high-risk group patients are not benefiting from established evidence-based interventions. A majority of our ACS patients did not have a lipid profile blood test during their admission highlighting the fact that whilst guidelines have progressed significantly over the last few years the clinical importance of lipid optimisation in practice has not been appreciated by many of the cliniciansResults

Unveiling homozygous familial hypercholesterolemia in Greece: a comprehensive analysis of baseline traits and LDL goal achievement in adults from the HELLAS-FH Registry

Abstract Background Homozygous familial hypercholesterolemia (HoFH) is a severe genetic disorder characterized by markedly elevated low-density lipoprotein cholesterol (LDL-C) levels. This study aimed to analyze demographic characteristics, lipid profile, and rate in achieving LDL-C targets in adult HoFH patients in Greece. Methods This is a cross-sectional analysis of the Hellenic Familial Hypercholesterolemia Registry (HELLAS-FH). Adults with genetically or clinically diagnosed HoFH were included. Median LDL-C levels were assessed during HoFH diagnosis and enrollment. Results Seventeen HoFH adults (mean age 41 years and mean age at diagnosis 31 years, men 58.8%). Genetic confirmation of HoFH was available in 10 patients, while the remaining were diagnosed based on clinical criteria. Family history of atherosclerotic cardiovascular disease was documented in 70.5% of patients. Clinical presentations varied, with 47.0% exhibiting tendon xanthomas, 17.6% xanthelasmas, 23.5% corneal arcus, and 52.9% premature coronary artery disease (CAD). Predominant treatment involved statins (88.2%), ezetimibe (58.8%),PCSK9i (23.5%), lomitapide (29.4%), while LDL apheresis was utilized in 23.5%. Median LDL-C levels were 407 mg/dL (10.53 mmol/L) at diagnosis and 226 mg/dL (5.84 mmol/L) at enrollment. None of the patients achieved the LDL-C target set by the 2019 EAS/ESC Guidelines. Conclusion The challenges of delayed diagnosis, undertreatment, and unattained LDL-C targets persist in HoFH management in Greece, emphasizing the critical need for effective lipid-lowering interventions to mitigate cardiovascular risk.

LDL-C target attainment and statin use in patients with ASCVD, familial hypercholesterolaemia, and those otherwise at moderate/high-risk of ASCVD in australian general practice (SCOPE-GP)

Abstract Background The proportion of Australian general practice patients not attaining low-density lipoprotein cholesterol (LDL-C) goals is not well described. The SCOPE-GP study evaluated duration of LDL-C exceeding treatment goals, statin use and discontinuation rates in patients with atherosclerotic cardiovascular disease (ASCVD), without ASCVD events but at moderate/high-risk, and familial hypercholesterolemia (FH). Methods This population-based retrospective cohort study used de-identified medical records of adult patients captured in the IQVIA GP-EMR database. Patients were indexed at the earliest date of ASCVD, FH, or hyperlipidemia diagnosis from January 1, 2010 to June 30, 2022, with a variable follow-up period from index to June 30, 2022. Ascertainment of study cohort was based on the 2021 ESC/EAS guidelines and Framingham Risk Equation. LDL-C test result levels were extracted per patient, summarised and analysed. Patients were stratified based on their test results at latest results/closest to censor date. Average time above target levels is the proportion of number of days above LDL-C target levels over total number of follow-up days for each patient. A Poisson distribution was fitted to estimate 95% confidence interval. Lipid lowering therapies (LLT) were stratified by (ASCVD, FH and moderate/high risk of CVD) at last visit/censor date. Combination of LLT were defined as prescriptions for fixed dose combinations or ≥2 separate scripts of LLT from different classes within 180 days from last visit/censor date (look back period). Discontinuation is defined as no statins were prescribed again after the last script for 270 days or more, limited to the first occurrence. Results The average time with LDL-C levels above target was 1077.5 days in ASCVD patients (n=2,688), 938.6 days in moderate-risk ASCVD (n=37,003), 980.9 days in high-risk ASCVD (n=85,199), and 900.8 days in FH (n=279). The proportion of days above target level for all four cohorts is described in Figure 1. Among 107,552 patients with recorded LDL-C levels ≥1.8mmol/L at their last visit/censor date, 30.9% were on statin monotherapy and 1.0% were on statin+ezetimibe. Statin use was highest in ASCVD patients (65.4%), followed by FH (49.5%), high risk (40.0%) and moderate risk subjects (29.5%) (Table 1). Statin discontinuation rates were 60.3%, 76.3, 66.1%, and 65.8% in these groups, respectively. The predominant reason for statin discontinuation was non-specific adverse drug reactions (12.2% ASCVD, 11.7% moderate-risk, 13.2% high-risk and 17.9% FH). The proportion of subjects contraindicated to statins was highest in moderate risk subjects (0.05%). Conclusions Prolonged periods of elevated LDL-C and high statin discontinuation rates were prevalent among at-risk individuals in Australian primary care. This underscores a significant ASCVD burden that could be prevented with more active lipid management.

Intra-individual Variability in Lipoprotein(a) Levels: Findings from a Large Academic Health System Population.

Lipoprotein(a) [Lp(a)] levels are known to be mainly genetically determined. However, only scarce data are available on the intra-individual variability of Lp(a) levels across time. We included adult patients (≥18 years old) who had baseline and follow-up Lp(a) measurements (between 1997 and 2024) with a minimum of one year apart. Patients were categorized into three groups as follows: normal (<30 mg/dL), borderline (30 to 50 mg/dL) and high Lp(a) (≥50 mg/dL). Multivariable logistic regression was conducted to assess the predictors of the intra-individual changes in Lp(a) ≥10 mg/dL. A total of 11,669 individuals (median age: 54 years, 60% males) were included in our analysis, with median time between measurements of 4.5 years (IQR: 2.2, 10.6). The median Lp(a) was 16 mg/dL (IQR: 7, 52) at baseline, compared with 15 mg/dL (IQR: 7, 52) at follow-up. At follow-up, 96.4% of individuals with normal Lp(a) and 89.9% with high Lp(a) remained in their categories, while 51.2% with borderline Lp(a) changed their category. Of the included population, 24.9% had an intra-individual Lp(a) change ≥10 mg/dL. Female sex (p <0.001), history of ASCVD (p=0.003), statin therapy (p=0.003) and elevated low-density lipoprotein cholesterol (LDL-C) levels ≥100 mg/dL (p <0.001) were significantly associated with higher odds of intra-individual Lp(a) changes ≥10 mg/dL. Lipoprotein(a) levels were generally stable over time; however, patients with borderline levels may require more than one Lp(a) measurement, especially if they are females, have a history of ASCVD, have elevated LDL-C levels or are on statins therapy.

Rationale for Early Administration of PCSK9 Inhibitors in Acute Coronary Syndrome.

Acute coronary syndromes (ACSs) represent a significant global health challenge arising from atherosclerotic cardiovascular disease (ASCVD), with elevated low-density lipoprotein cholesterol (LDL-C) levels being a primary contributor. Despite standard statin therapy, individuals with ACS remain at high risk for recurrent cardiovascular events, particularly in the initial post-ACS period. Monoclonal antibodies targeting proprotein convertase subtilisin/kexin type 9 (PCSK9), such as evolocumab and alirocumab, offer a potential strategy to reduce LDL-C levels further and mitigate this residual risk. This review delves into the molecular mechanisms, effects on cholesterol metabolism, inflammatory modulation, and clinical outcomes associated with early administration of PCSK9 inhibitors following ACS.

Real-World Application of Evolocumab Among Patients with Hyperlipidemia in Korea: A Multicenter Prospective Study.

Elevated low-density lipoprotein cholesterol (LDL-C) is a major residual risk factor among patients with acute coronary syndrome (ACS). In the absence of sufficient real-world evidence, this observational (noninterventional) study investigated the effectiveness and safety of evolocumab in patients with hyperlipidemia treated with evolocumab for ACS in a real-world clinical setting in Korea. Between January 2022 and February 2023, patients from 10hospitals in Korea who initiated evolocumab within 24weeks of an ACS event were enrolled. Data collected at visit1 (evolocumab initiation) included patients' characteristics, comorbidities, and lipid-lowering therapies. LDL-C reduction from visit1 (week0) to visit2 (week8) was assessed. The primary outcome was the proportion of patients who achieved LDL-C < 1.4mmol/L (55mg/dL) at follow-up; the secondary outcome was the proportion who achieved LDL-C < 1.8mmol/L (70mg/dL) at follow-up. In this study, 89 out of 142 enrolled patients were included in the effectiveness analysis. The mean (SD) age of the included patients was 59.3 (12.3) years, with the majority being male (87.6%). Sixty-one patients received statin-ezetimibe combination therapy (68.5%). The median [Q1, Q3] LDL-C level at the start of the study was 2.5 [2.0, 3.0] mmol/L (98 [77, 115] mg/dL), which decreased to 1.3 [0.7, 1.7] mmol/L (49 [29, 67] mg/dL) after 8weeks of evolocumab treatment, resulting in an mean (SD) 50.9 (28.6) % reduction and 1.4 (1.0) mmol/L (55.1 (37.9) mg/dL) absolute reduction. At follow-up, 55.1% and 78.7% of patients achieved LDL-C goals of < 1.4mmol/L (55mg/dL) and < 1.8mmol/L (70mg/dL), respectively. No adverse or serious adverse drug reactions were reported. Evolocumab treatment was associated with significant LDL-C lowering and favorable safety and guideline-recommended LDL-C goal achievement rates among patients with ACS in the real-world clinical practice setting in South Korea.

Evaluation of Lipid Profile Management in Coronary Artery Disease Patients on Statin Therapy: A Single-Centre, Retrospective, Observational Study.

Lipid control is crucial in managing coronary artery disease (CAD) to reduce cardiovascular risk. This study aimed to evaluate the effectiveness of lipid-lowering therapy, particularly statins, in achieving target lipid levels in patients with CAD. This single-center, retrospective, observational study was conducted at the Cardiology Outpatient Department of Dr. D. Y. Patil Medical College, Hospital and Research Centre, Pune, Maharastra, India. A sample size of 72 patients was included in this study. Adult patients receiving treatment for acute coronary syndrome (ACS), chronic stable angina (CSA), or unstable angina (UA) were included. Exclusion criteria were comorbidities affecting clinical decisions, HIV-positive status, pregnancy, or breastfeeding. Data on lipid profiles, including low-density lipoprotein (LDL) cholesterol (LDL-C), were collected, with LDL-C calculated using the Friedewald equation or measured directly. The primary outcome was the proportion of patients achieving LDL-C targets as per the 2019European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines. Statistical analysis was performed using chi-square tests, with significance set at p < 0.05. Of the enrolled patients, a substantial proportion did not achieve target LDL-C levels, with LDL-C remaining above the recommended thresholds in a significant number of patients. Despite ongoing statin therapy, lipid control was suboptimal in many cases, particularly among those with elevated LDL-C levels. A detailed analysis of lipid profiles and the achievement of target levels was done, highlighting areas where current treatment strategies may fall short. The study reveals that a significant number of patients with CAD on statin therapy do not achieve optimal lipid control, particularly in LDL-C management. This underscores the need for more aggressive or tailored lipid-lowering strategies to reduce residual cardiovascular risk in this high-risk population. Further studies are needed to explore the factors contributing to suboptimal lipid control and to develop interventions that can enhance the effectiveness of current therapies.

Serum levels of per- and poly-fluoroalkyl substances among middle-aged and elderly populations in Beijing and their association with dyslipidemia

Per- and poly-fluoroalkyl substances (PFAS), ubiquitous environmental pollutants, have been reported as possible contributors to human dyslipidemia. However, evidence for emerging PFAS remains scarce. Using a nested case-control study (n = 357) in a middle-aged and elderly population from Beijing, we investigated the serum concentrations of eight traditional and fourteen emerging PFAS and their potential links with dyslipidemia. Perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) were found to be the dominant PFAS. Serum levels of perfluorohexanesulfonic acid (PFHxS) and 6:2 chlorinated polyfluoroalkyl ether sulfonate (6:2 Cl-PFESA/F53B) were associated with higher risk of elevated low-density lipoprotein cholesterol (LDL-C) with odds ratios (OR) of 3.88 (95% CI: 1.44–10.51) and 2.71 (95% CI: 1.11–6.57), respectively. These compounds also positively correlated with high total cholesterol (TC). PFOA, perfluorodecanoic acid (PFDA), and 6:2 Fluorotelomer phosphate monoester (6:2 PAP) were linked to increased risk of high triglycerides (TG) with OR of 2.79 (95% CI: 1.30–6.01), 2.41 (95% CI: 1.27–4.60), and 1.53 (95% CI: 1.05–2.22), respectively. Conversely, perfluorooctane sulfonamidoacetic acid (FOSAA) was negatively associated with high TG levels. These findings indicate that both traditional and emerging PFAS may induce dyslipidemia, emphasizing the potentially serious impact of emerging PFAS on human health.