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Objective: To explore the causal association of glucose-lipid metabolism and obesity indicators with myocardial infarction by a two-sample Mendelian randomization analysis. Methods: Single nucleotide polymorphisms (SNPs) related to phenotypes were obtained from genome-wide association study databases. The body mass index (BMI) and glycated hemoglobin dataset includes 99 998 samples and 8 126 035 SNPs; the waist-to-hip ratio dataset includes 224 459 samples and 2 562 516 SNPs; the waist circumference and hip circumference dataset includes 462 166 samples and 9 851 867 SNPs; the fasting glucose dataset includes approximately 12 million SNPs; the low-density lipoprotein cholesterol (LDL-C) dataset includes 201 678 samples and 12 321 875 SNPs; the high-density lipoprotein cholesterol (HDL-C), and triglycerides dataset includes 156 109 samples and 15 784 414 SNPs; and the body fat percentage, whole-body fat mass, trunk fat percentage, and trunk fat mass dataset includes 454 588 samples and 9 851 867 SNPs. This study primarily used inverse-variance weighted method to analyze the associations between various exposure factors and outcomes. Heterogeneity among SNPs was assessed using Cochran's Q test, and horizontal pleiotropy of SNPs was examined using the MR-Egger method. Additionally, a multivariable MR approach was used to adjust for BMI, further validating associations between exposure factors and the risk of myocardial infarction. Results: Higher BMI ( OR= 1.070, 95% CI : 1.041-1.100), waist-to-hip ratio ( OR =1.366, 95% CI : 1.113-1.677), LDL-C ( OR =1.638, 95% CI : 1.488-1.803), triglycerides ( OR =1.445, 95% CI : 1.300-1.606), waist circumference ( OR =1.841, 95% CI : 1.650-2.055), hip circumference ( OR =1.247, 95% CI : 1.132-1.372), body fat percentage ( OR =1.795, 95% CI : 1.568-2.055), whole-body fat mass ( OR =1.519, 95% CI: 1.381-1.670), trunk fat percentage ( OR =1.538, 95% CI : 1.374-1.723), and trunk fat mass ( OR =1.421, 95% CI : 1.294-1.561), as well as lower HDL-C ( OR =0.799, 95% CI : 0.729-0.875), have causal effects on myocardial infarction (all P <0.05). After adjusting for BMI, hip circumference, trunk fat percentage, and trunk fat mass were no longer associated with myocardial infarction. However, waist-to-hip ratio ( OR =1.457, 95% CI : 1.132-1.877), fasting glucose ( OR =1.191, 95% CI : 1.024-1.383), glycated hemoglobin ( OR =1.129, 95% CI : 1.034-1.233), LDL-C ( OR =1.592, 95% CI : 1.314-1.929), triglycerides ( OR =1.410, 95% CI : 1.279-1.553), waist circumference ( OR =1.922, 95% CI : 1.448-2.551), body fat percentage ( OR =1.421, 95% CI : 1.072-1.884), and whole-body fat mass ( OR =1.295, 95% CI : 1.031-1.626) remained positively associated with myocardial infarction, while HDL-C ( OR =0.809, 95% CI : 0.729-0.897) remained negatively associated. Conclusions: Abdominal obesity and dysregulation of glucose-lipid metabolism are risk factors for myocardial infarction. Screening for glucose-lipid metabolism (fasting glucose, HDL-C, LDL-C, triglycerides) and obesity-related indicators (waist circumference, waist-to-hip ratio, body fat percentage, and whole-body fat mass) is of great importance for the primary prevention of myocardial infarction.

The risk of atherosclerotic cardiovascular diseases (ASCVDs) can be reduced by lowering low-density lipoprotein cholesterol (LDL-C) concentrations. Nevertheless, ASCVDs still cause most deaths worldwide. Here, we discuss the prevention of ASCVD and the event risk with a focus on heart-healthy diets, i.e., low intakes of saturated and trans-fatty acids and cholesterol, and high intakes of unsaturated fatty acids, viscous fibre, and dietary phytostanols as fatty acid esters, according to international dyslipidaemia treatment guidelines. Calculations based on both FINRISK and Cholesterol Treatment Trialists' Collaborators regression equations indicate that heart-healthy diets combined with phytostanol ester reduce LDL-C concentrations to such an extent that the 10-year estimated reduction in the incidence of coronary artery disease would be 23%. This information can be used, in particular, to prevent the development of subclinical atherosclerosis in healthy middle-aged populations and the progression of atherosclerosis to ASCVD. The outcome of simple and feasible dietary changes, and, when needed, combined with statins, can be significant: reduced mortality, an increased number of healthy life-years, and reduced healthcare costs., (© 2024. The Author(s).)

Dyslipidemia is the most significant risk factor for cardiovascular diseases (CVDs) Secondary dyslipidemia: its treatments and association with atherosclerosis. Glob Health Med, Efficacy and safety of saroglitazar for the management of dyslipidemia: A systematic review and meta-analysis of interventional studies. The current treatment strategies for managing dyslipidemia focus on reducing low-density lipoprotein cholesterol (LDL-C) to minimize the risks of atherosclerosis and myocardial infarction (MI). Homozygous Familial Hypercholesterolemia (HoFH) is an inherited autosomal dominant disease caused by a mutation in the LDL receptor (LDLr), which can lead to extremely high levels of LDL-C The Beneficial Effect of Lomitapide on the Cardiovascular System in LDLr(-/-) Mice with Obesity, The microsomal triglyceride transfer protein inhibitor lomitapide improves vascular function in mice with obesity. Although statin therapy has been the primary treatment for dyslipidemia, HoFH patients do not respond well to statins, requiring alternative therapies. Microsomal triglyceride transfer protein (MTP) inhibition has emerged as a potential therapeutic target for treating HoFH. MTP is primarily responsible for transferring triglyceride and other lipids into apolipoprotein B (ApoB) during the assembly of very low-density lipoprotein (VLDL) particles in the liver. Lomitapide, an inhibitor of MTP, has been approved for treatingof HoFH adults. Unlike statins, lomitapide does not act on the LDLr to reduce cholesterol. Instead, lomitapide lowers the levels of ApoB-containing proteins, primarily VLDL, eventually decreasing LDL-C levels. Studies have shown that lomitapide can reduce LDL-C levels by more than 50% in patients with HoFH who have failed to respond adequately to other treatments. Lowering LDL-C levels is important for preventing atherosclerosis, reducing cardiovascular risk, improving endothelial function, and promoting overall cardiovascular health, especially for patients with HoFH Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. This review paper focuses on research findings regarding the therapeutic benefits of lomitapide, highlighting its effectiveness in lowering cholesterol levels and reducing the risk of CVDs The microsomal triglyceride transfer protein inhibitor lomitapide improves vascular function in mice with obesity., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Background and Aims: The criteria for the use of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) more restrictive than those approved were established in Catalonia by the Health System (CatSalut) to improve their efficiency, with different LDL-C values from which to start treatment according to risk factors. The aim of the study is to analyse adherence to these criteria and results., Methods: A retrospective study of patients treated with PCSK9i at Vall d'Hebron University Hospital between 2016 and 2021 was performed using data from the Registry of Patients and Treatments and medical records. The degree of agreement with the CatSalut criteria, LDL-C-responders (decrease ≥30%), cardiovascular events and discontinuations were analysed., Results: A total of 193 patients treated with PCSK9i were followed for a median of 27 months (IQR 23). The median age was 61 (IQR 15); 62.7% were men. Seventy percent of the patients had non-familial hypercholesterolemia. Treatment was for secondary prevention of cardiovascular disease in 82.4% of cases. The median LDL-C decreased from 139 (IQR 52) to 59 (IQR 45) mg/dL. The percentage of LDL-C reduction was 61.0% (IQR 30). In 72.5% of patients, all CatSalut criteria for starting treatment were met. The rate of responders was 85.4%. During follow-up, 19 patients (9.8%) had a cardiovascular event, and 15 (7.7%) discontinued treatment, in two cases due to toxicity., Conclusion: PCSK9i were used according to CatSalut criteria in three out of four cases. In this high-risk population, incidence of cardiovascular events was similar to that in clinical trials., (Copyright © 2024 Elsevier España, S.L.U. All rights reserved.)

A lower mortality rate from coronary artery disease (CAD) and a more favourable lipid profile have been reported in Afro-Caribbeans compared with people of European ancestry. The aim of this study was to determine whether common lipid variants identified in other populations are associated with lipid levels and CAD in Afro-Caribbeans. We studied 705 Afro-Caribbeans (192 with CAD) who were genotyped for 13 lipid-associated variants. We calculated three polygenic risk scores (PRSs) for elevated LDL (LDL-PRS), decreased HDL (HDL-PRS), and elevated triglycerides (TG-PRS). LDL-PRS, HDL-PRS, and TG-PRS were associated with LDL, HDL, and TG levels, respectively. The LDL-PRS was positively associated with LDL > 2.6 mmol/L and with LDL > 3.0 mmol/L with ORs (odds ratios) of 1.33 (95% confidence interval (CI) = 1.14-1.56) and 1.40 (CI = 1.21-1.62), respectively. The HDL-PRS was associated with a low HDL category (HDL < 1.03 mmol/L) with an OR of 1.3 (CI = 1.04-1.63) and inversely associated with a high HDL category (HDL > 1.55 mmol/L) with an OR of 0.79 (CI = 0.65-0.96). The LDL-PRS was positively associated with CAD after adjustment for age, gender, hypertension, diabetes, and smoking with an OR of 1.27 (CI = 1.06-1.51) but not the HDL-PRS nor the TG-PRS. Results of the present study indicate that common lipid variants are associated with lipid levels and prevalent CAD in Afro-Caribbeans.

To determine the potential causal association between serum lipid levels and sarcoidosis, and to investigate the potential impact of lipid lowering agents on sarcoidosis. Two-sample Mendelian randomization (TSMR) was used to investigate the association between lipid levels (including LDL-c, HDL-c, TG, and TC) and sarcoidosis risk. In addition, we used Mendelian drug target randomization (DMR) to analyze the relationship between drug targets for lowering LDL-c levels (HMGCR, PCSK9, and NPC1L1) and drug targets for lowering TG levels (LPL and APOC3) and the risk of sarcoidosis. According to the TSMR analysis, a positive correlation was observed between the serum LDL-c concentration and sarcoidosis incidence (n = 153 SNPs, OR = 1.232, 95% CI = 1.018-1.491; p = 0.031). Similarly, serum TG concentration was found to be positively associated with sarcoidosis (n = 52 SNPs, OR = 1.287, 95% CI = 1.024-1.617; p = 0.03). The DMR results demonstrated a positive correlation between PCSK9-mediated serum LDL-c levels and sarcoidosis (n = 35 SNPs, OR = 1.681, 95% CI = 1.220-2.315; p = 0.001). Similarly, serum TG levels mediated by LPL were positively associated with sarcoidosis (n = 28 SNPs, OR = 1.569, 95% CI = 1.223-2.012; p = 0.0003). This study suggested that elevated serum TG and LDL-c levels may increase the risk of sarcoidosis. PCSK9-mediated reduction of LDL-C levels (simulating the effects of PCSK9 inhibitors) and LPL-mediated reduction of TG levels (simulating the effects of LPL-related lipid lowering drugs) can decrease the risk of developing sarcoidosis., (© 2024. The Author(s).)

Objective: Although abnormal lipid metabolism is one of the major risk factors for diabetes, the correlation between lipids and glucose is rarely discussed in the general population. The differences in lipid-glucose correlations across gender and ethnicity have been even more rarely studied. We examined the association between fasting blood glucose (FBG) and lipids, including triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and apolipoprotein B (ApoB), using 6,093 participants aged 20 years or older from the National Health and Nutrition Examination Survey (NHANES)., Methods: Analyses were performed using multiple logistic regression and generalised additive models., Results: When other confounders were considered, we found that fasting glucose was positively correlated with triglycerides and negatively correlated with HDL-C, whereas total cholesterol, LDL-C cholesterol, and fasting glucose were related to each other in a U-curve fashion, with inflection points of 5.17 mmol/L and 2.3 mmol/L, respectively.This relationship persisted in subgroups of different sexes and races. A positive correlation was found between fasting glucose and ApoB, but subgroup analyses revealed that this relationship was not correlated across gender and race., Conclusion: In the general population, fasting blood glucose levels were positively correlated with TG, negatively correlated with HDL-C, and U-shaped with total cholesterol and LDL-C. The likelihood of developing diabetes was 40% higher when LDL-C was greater than 2.3 mmol/L than in patients with LDL-C less than 2.3 mmol/L., (© 2024. The Author(s).)

Background: The atherogenic effect of remnant cholesterol is being increasingly acknowledged. This study aimed to explore the association of discordance between remnant cholesterol and low-density lipoprotein cholesterol with stroke onset using 2 Chinese national cohorts., Methods and Results: We studied 11 139 participants from CHARLS (China Health and Retirement Longitudinal Study) and 5993 participants from CHNS (China Health and Nutrition Survey) aged 45 years or older. The discordance between remnant cholesterol and low-density lipoprotein cholesterol was defined using the difference in percentile units (>15 units). There were 988 (8.9%) and 128 (2.1%) stroke events reported during follow-up in the 2 cohorts. Elevated remnant cholesterol was significantly associated with a higher risk of total stroke in 2 cohorts. After adjusting for remnant cholesterol level, the discordantly high remnant cholesterol group was significantly associated with an increased stroke risk (CHARLS: subdistribution hazard ratio [sHR], 1.31 [95 CI, 1.10-1.55]; CHNS: sHR, 1.84 [95 CI, 1.15-3.08]) compared with the discordantly low group. Consistent results were shown even among those with optimal low-density lipoprotein cholesterol level., Conclusions: The discordance between remnant cholesterol and low-density lipoprotein cholesterol, representing the intraindividual discrepancy, is significantly associated with stroke onset among Chinese adults.

Background: The trans intestinal cholesterol excretion (TICE) pathway is a potential therapeutic target to reduce plasma low-density lipoprotein (LDL) cholesterol levels. TICE encompasses the direct excretion of cholesterol by enterocytes into feces. In mice, TICE has been shown to be stimulated by a hydrophilic bile acid pool, resulting in increased fecal neutral sterol loss and reduced plasma cholesterol levels. We investigated whether treatment with a hydrophilic bile acid, ursodeoxycholic acid (UDCA), would increase fecal neutral sterols in humans as a proxy for TICE., Methods and Results: We performed a randomized, double-blind, placebo-controlled, cross-over trial in 20 male participants aged >18 years, with plasma LDL cholesterol levels ≥2.6 mmol/L. After a run-in period of ezetimibe 20 mg once daily for 3 weeks, patients were randomized to UDCA 600 mg or placebo orally once daily for 2 weeks. After a 3 week washout, patients underwent the alternate treatment. At baseline, mean (SD) age, body mass index, and plasma LDL cholesterol were 59±11.3 years, 26.4±3.1 kg/m 2 , and 3.9±0.8 mmol/L, respectively. After UDCA treatment, the plasma bile acid hydrophobicity index was reduced compared with placebo (-118.7% versus +2.3%, P <0.001). The fecal neutral sterols did not change (-5.8% versus +18.8%, P =0.51) and treatment with UDCA increased LDL cholesterol with 0.39 mmol/L (+8.1% versus -3.64%, P =0.002) when compared with placebo., Conclusions: UDCA in combination with ezetimibe increased plasma bile acid hydrophilicity in healthy subjects with LDL cholesterol levels >2.6 mmol/L but did not result in increased fecal neutral sterols or decreased LDL cholesterol. This suggests that TICE is not stimulated by an increase in the hydrophilicity of the bile acid pool in humans.

Background: The relationship between serum lipids and sarcopenia remains unclear due to conflicting results in previous studies., Objective: To explore the associations and potential causality between serum lipids, including high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and total cholesterol (TC), and sarcopenia., Methods: Data from the National Health and Nutrition Examination Survey (NHANES) were analysed using multivariable regression and restricted cubic splines (RCSs) to assess the associations between serum lipids and sarcopenia. Bidirectional Mendelian randomization (MR) was employed to investigate the causal relationships with sarcopenia-related traits such as appendicular lean mass (ALM), hand grip strength, and usual walking pace., Results: Serum HDL-C and TG levels were inversely associated with ALMBMI, with each 1-unit increase linked to a 0.13 % and 1.32 % decrease, respectively. Elevated TG, but not HDL-C, LDL-C, or TC levels, was significantly associated with an increased risk of sarcopenia (P for trend = 0.001). RCS analysis revealed a log-shaped dose-response relationship between TG and sarcopenia risk (P overall <0.001, P non-linear <0.001), with a cutoff value of 92.75 mg/dL. Genetically predicted HDL-C, LDL-C, and TG were associated with ALM. Conversely, ALM showed an inverse causal relationship with all four serum lipids. Additionally, genetically predicted usual walking pace influenced HDL-C and TG levels (P < 0.001)., Conclusion: The study reveals a nonlinear association between TG levels and sarcopenia risk, and a bidirectional association between lipid profiles and muscle mass, underscoring the need for further research to elucidate these mechanisms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Lipids are associated with atherosclerosis, and novel lipid indices have been recently identified to be closely linked to cardiovascular diseases. This study explored the association between four novel lipid indices and the white matter hyperintensities (WMHs) in patients diagnosed with cerebral small vessel disease (CSVD)., Methods: Between January 2023 and February 2024, 219 patients were recruited, including 165 patients with CSVD WMHs and 54 healthy controls. Based on WMHs severity, patients with CSVD were categorised into mild and moderate-to-severe cohorts using the Fazekas rating scale. The plasma levels of four novel lipid indices (low-density lipoprotein cholesterol/high-density lipoprotein cholesterol ratio [LDL-C/HDL-C], triglyceride/high-density lipoprotein cholesterol ratio [TG/HDL-C], total cholesterol/high-density lipoprotein cholesterol ratio [TC/HDL-C], and non-high-density lipoprotein cholesterol [Non-HDL-C]), were rigorously monitored in the enrolled patients., Results: A total of 165 patients with CSVD WMHs were enrolled, including 94 with mild WMHs and 71 with moderate-to-severe WMHs. Multivariable logistic regression analysis revealed that LDL-C/HDL-C, TG/HDL-C, TC/HDL-C, and Non-HDL-C levels were significantly associated with WMHs (all P ≤ 0.001). Receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic performance of plasma lipid levels for WMHs in patients with CSVD. The novel lipid indicators outperformed traditional lipid indicators in assessing the diagnostic capability of WMHs. The combined index of the four blood lipid indices had an optimal cutoff point (OCP) of 0.489, with 88.3% sensitivity and 60.6% specificity. The area under the curve (AUC) is 0.800 (95% confidence interval [CI], 0.731-0.869; P < 0.001). Compared with males (OR = 1.126, 95% CI = 0.779-1.628), females (OR = 2.484, 95% CI = 1.398-4.414; P for interaction = 0.023) had a higher risk of developing WMHs., Conclusion: This study demonstrates a significant association between four novel lipid indices and the cerebral WMHs in CSVD, highlighting the potential of these markers as novel plasma biomarkers and predictive indicators for assessing CSVD progression and guiding clinical management., (© 2024. The Author(s).)

Background and Aims: Non-HDL-C provides an estimate of lipid-associated risk and is a secondary treatment target after myocardial infarction (MI). The aim was to study the relationship between non-HDL-C levels after MI and risk of adverse outcomes., Methods: From the SWEDEHEART registry, 56 262 patients with MI were included. Outcomes were major adverse cardiovascular event (MACE: death, MI, and ischaemic stroke), death, and non-fatal MI. Non-HDL-C was assessed at admission, 2 months, and 1 year. Target achievement (<2.2 mmol/L) of non-HDL-C, timing thereof, and outcomes were assessed., Results: During median follow-up of 5.4 years, 9549 had MACE, 5427 died, and 3946 had MI. Long-term hazard ratio (HR) for MACE in the lowest vs. the highest quartile of achieved non-HDL-C at 1 year was 0.76 [95% confidence interval (CI) 0.71-0.81]. Short-term results were consistent also when assessing non-HDL-C levels at 2 months, including early events up to 1 year (HR 0.80, 95% CI 0.68-0.92). Similar results were observed for all outcomes. Patients achieving both early and sustained targets had lowest risk of outcomes (HR 0.80, 95% CI 0.74-0.86) vs. patients achieving target early or late (HR for both 0.86, 95% CI 0.79-0.93)., Conclusions: The lowest achieved levels both at 2 months and at 1 year of non-HDL-C were associated with better outcome. The lowest risk was observed when target was achieved within 2 months of MI and sustained thereafter. These findings challenge the current stepwise approach for cholesterol lowering after MI, which inevitably results in delaying goal attainment and possible harm., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Data describing the long-term efficacy and tolerability of inclisiran are limited. This was explored in ORION-8, an open-label extension of preceding Phase 2 and Phase 3 placebo-controlled and open-label extension trials., Methods and Results: Following completion of the parent trial, adult patients with atherosclerotic cardiovascular disease (ASCVD), ASCVD risk equivalent, or heterozygous familial hypercholesterolaemia received open-label inclisiran twice yearly (after initial and 3-month doses) until Day 990, followed by an end-of-study visit at Day 1080 or ≥ 90 days after the last dose. The study endpoints included the proportion of patients achieving pre-specified low-density lipoprotein cholesterol (LDL-C) goals [ASCVD: < 1.8 mmol/L (< 70 mg/dL); ASCVD risk equivalent: < 2.6 mmol/L (< 100 mg/dL)], percentage and absolute changes in LDL-C at end-of-study, and safety of inclisiran. Of 3274 patients, 2446 (74.7%) were followed until end-of-study. Mean age was 64.9 ± 9.9 years, 82.7% (n = 2709) had ASCVD, and mean baseline LDL-C was 2.9 ± 1.2 mmol/L. Mean cumulative exposure to inclisiran (including parent trials) was 3.7 years; maximum exposure was 6.8 years. With inclisiran, 78.4% [95% confidence interval (CI): 76.8, 80.0] of patients achieved pre-specified LDL-C goals and mean percentage change in LDL-C was -49.4% (95% CI: -50.4, -48.3). No attenuation of LDL-C lowering over time was observed. Treatment-emergent adverse events at injection site (all mild/moderate) occurred in 5.9% of the patients. Inclisiran-associated anti-drug antibodies were infrequent (5.5%) and had no impact on the efficacy or safety of inclisiran. No new safety signals were identified., Conclusion: In the largest and longest follow-up to date with >12 000 patient-years exposure, inclisiran demonstrated consistent and effective LDL-C lowering with a favourable long-term safety and tolerability profile., Trial Registration Number: ClinicalTrials.gov identifier: NCT03814187., Competing Interests: Conflict of interest: R.S.W. reports receiving advisory board fees from Boehringer Ingelheim and past fees for consulting on lipid issues with The Medicines Company; F.J.R. reports receiving advisory board fees and lecture fees from Amgen, Sanofi-Aventis, Regeneron Pharmaceuticals, Novartis, and LIB Therapeutics; W.K. reports receiving consulting fees and lecture fees from AstraZeneca, Novartis, and Amgen; consulting fees from Pfizer, The Medicines Company, Novartis, DalCor Pharmaceuticals, Kowa, Corvidia Therapeutics, Esperion, Genentech, OMEICOS, Novo Nordisk, LIB Therapeutics, Daiichi Sankyo, New Amsterdam Pharma, and TenSixteen Bio; lecture fees from Berlin-Chemie, Bristol-Myers Squibb, and Sanofi; and grant support and provision of reagents from Singulex, Abbott, Roche Diagnostics, and Dr Beckmann Pharma; U.L. reports receiving grant support from Amgen, Bayer, and Novartis and advisory board fee from Novartis; L.A.L. reports grant support paid to his institution and advisory board fees and fees for CME from Amgen and Novartis; grant support paid to his institution and fees for serving on a steering committee from Kowa, The Medicines Company and Novartis; and advisory board fees and fees for CME from Amarin, AstraZeneca, HLS, Merck, New Amsterdam, Pfizer, and Sanofi; G.G.S. reports receiving research support paid to his institution from AstraZeneca, Sanofi, Silence Therapeutics, and The Medicines Company and a patent (62/806313) on a method for reducing cardiovascular risk assigned in full to the University of Colorado; K.K.R. reports receiving support from the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre; his institution (Imperial College London) receives support from the NIHR Applied Research Collaboration Northwest London. K.K.R. also reports receiving lecture fees from Aegerion Pharmaceuticals, Kowa, Cipla, Algorithm, and Zuelling Pharma; grant support paid to his institution; lecture fees and advisory board fees from Amgen, Regeneron Pharmaceuticals/Sanofi, and Pfizer; lecture fees and fees for serving on steering committees for trials from AstraZeneca and Eli Lilly; fees for serving on steering committees for trials from Cerenis Therapeutics, The Medicines Company, and Esperion; advisory board fees from Akcea Therapeutics, Novartis, Silence Therapeutics, Bayer, and Daiichi Sankyo; lecture fees and advisory board fees from Takeda, Boehringer Ingelheim, and Dr Reddy’s Laboratories; grant support and advisory board fees from Merck Sharp & Dohme; fees for serving on a clinical events adjudication committee from AbbVie; and fees for serving as principal investigator for a trial from Resverlogix; Z.T., S.V., and X.Z. are all employees of Novartis Pharmaceuticals Corp, East Hanover, New Jersey, USA and hold shares in Novartis; A.L. is employee of Novartis Pharma AG, Basel, Switzerland; P.M. was an employee of Novartis Pharma AG, Basel, Switzerland, at the time of conducting this study., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Fat-binding nutraceutical supplements have gained considerable attention as potential cholesterol-lowering strategies to address dyslipidemia in overweight and obese individuals. This study aimed to evaluate the effects of a polysaccharide-rich compound containing β-glucan/chitin-chitosan (βGluCnCs) on lipid profiles and lipoprotein function. In a prospective, two-arm clinical trial, 58 overweight and obese individuals were randomized to receive either 3 g/day of βGluCnCs or a placebo (microcrystalline cellulose) for 12 weeks. Serum lipids and lipoprotein functions were assessed at baseline and at 4-week intervals throughout the study. The administration of βGluCnCs led to a significant increase in HDL cholesterol (HDLc) levels and improved HDLc/non-HDLc and HDLc/total cholesterol (TC) ratios, while reducing apolipoprotein B (ApoB) levels ( p < 0.05). However, the intervention did not affect HDL particle diameter, particle number, or lipoprotein functionality. Women demonstrated greater sensitivity to changes in HDLc during βGluCnCs supplementation, whereas men exhibited a significant reduction in ApoB levels. When stratified by baseline LDL cholesterol (LDLc) levels (cut-off: 130 mg/dL), the increase in HDLc and the ApoA1/ApoB ratio was found in the low-LDL group. In contrast, the high-LDL group experienced a significant reduction in atherogenic non-LDLc and LDLc, along with an improvement in HDL's antioxidant capacity after βGluCnCs intervention. These changes were not statistically significant in the placebo group. In conclusion, our study demonstrated that daily supplementation with βGluCnCs significantly improved lipid profiles, with effects that varied based on sex and baseline LDLc levels.

Background: Antipsychotic drugs may have adverse effects on the components of metabolic syndrome. Previous studies have shown that changes in the intestinal microbiome are associated with metabolic disturbances in patients with schizophrenia. The objective of this study was to determine the effects of synbiotics on the components of metabolic syndrome as primary outcomes in patients with schizophrenia. Secondary outcomes were HbA1c, insulin resistance, LDL-c, and anthropometric measurements., Methods: In this double-blind, placebo-controlled trial, seventy patients with schizophrenia receiving antipsychotic drugs who had at least two criteria of metabolic syndrome were randomly divided into two groups to receive either two capsules of a synbiotic supplement or a placebo daily for 8 weeks. Anthropometric indices and biochemical parameters were measured at baseline and after the intervention., Results: Fifty-five patients completed the study. The synbiotic supplement significantly decreased waist circumference and HbA1C compared to placebo (-2.66 ± 4.20 vs. 3.03 ± 4.50 and - 0.26 ± 0.54 vs. 0.20 ± 0.75, respectively). Although BMI did not change significantly in the synbiotic + antipsychotic group, it increased in the placebo + antipsychotic group (-0.37 ± 1.00 vs. 0.61 ± 1.09 P < 0.5). LDL-c and triglyceride (TG) levels decreased significantly in the synbiotic + antipsychotic group, but the change was not significantly different from that of the placebo + antipsychotic group. FBS, HDL-c, systolic and diastolic blood pressure, insulin resistance, and total cholesterol were not significantly different between the two groups after intervention., Conclusion: Synbiotic supplement may decrease waist circumference, HbA1c, LDL and TG and prevent BMI increase in patients receiving antipsychotic drugs., Trial Registration: Iranian Registry of Clinical Trials (IRCT Number: IRCT20090901002394N45), Date: 26-12-2019., (© 2024. The Author(s).)

Background and Objectives : The proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors evolocumab and alirocumab are recently developed promising drugs used for treatment of familial hypercholesterolemia (FH). This systematic review and meta-analysis aimed to thoroughly evaluate the efficacy and safety of evolocumab and alirocumab among pediatric patients with FH. Materials and Methods : A comprehensive search was conducted in PubMed, Embase, CENTRAL (Cochrane Central Register of Controlled Trials), and ClinicalTrials.gov from inception through July 2024 to identify primary interventional studies among pediatric patients with FH. Meta-analyses were performed if appropriate. Statistics were analyzed using Review Manager version 5.4 and Stata version 16.0. Results : Fourteen articles reporting nine unique studies were included. There were three randomized controlled trials (RCTs) assessing evolocumab or alirocumab involving a total of 320 pediatric patients, one cross-over trial and five single-arm or observational studies. Pooled results showed significant efficacy of evolocumab/alirocumab in reducing low-density lipoprotein cholesterol (LDL-C) (weighted mean difference [WMD]: -37.92%, 95% confidence interval [CI]: -43.06% to -32.78%; I 2 = 0.0%, p = 0.60), apolipoprotein B (WMD: -33.67%, 95% CI: -38.12% to -29.22%; I 2 = 0.0%, p = 0.71), and also lipoprotein(a) (WMD: -16.94%, 95% CI: -26.20% to -7.69%; I 2 = 0.0%, p = 0.71) among pediatric patients with FH. The efficacies of evolocumab/alirocumab on LDL-C reduction within pediatric patients with heterozygous FH (HeFH) were consistent between studies, whereas in patients with homozygous FH (HoFH), it varied dramatically. Pediatric patients with the null/null variant may respond to the treatment. PCSK9 inhibitors were generally well tolerated within most pediatric patients, in line with previous studies among adult populations. Conclusions : The PCSK9 inhibitors evolocumab/alirocumab significantly reduced LDL-C and some other lipid parameters, such as apolipoprotein B, in pediatric patients with HeFH. These drugs may be appropriate as a potential therapy for pediatric patients with HoFH who cannot achieve LDL-C targets with other treatments. Evolocumab/alirocumab was generally well tolerated in the pediatric population.

Background/objectives: Genetic factors contribute to the physiopathology of obesity and its comorbidities. This study aimed to investigate the association of the SNPs ABCA1 (rs9282541), ADIPOQ (rs2241766), FTO (rs9939609), GRB14 (rs10195252), and LEPR (rs1805134) with various clinical, anthropometric, and biochemical variables., Methods: The study included 396 Mexican mestizo individuals with obesity and 142 individuals with normal weight. Biochemical markers were evaluated from peripheral blood samples, and SNP genotyping was performed using PCR with TaqMan probes. A genetic risk score (GRS) was computed using an additive model., Results: No significant associations were found between the SNPs ABCA1 , ADIPOQ , FTO , and LEPR with obesity. However, the T allele of the GRB14 SNP was significantly associated with obesity (χ 2 = 5.93, p = 0.01; OR = 1.52; 95% CI: 1.08-2.12). A multivariate linear regression model (adjusted R-squared: 0.1253; p < 0.001) predicting LDL-c levels among all participants (n = 538) identified significant ( p < 0.05) beta coefficients for several anthropometric and biochemical variables, as well as for the GRS. Additionally, the interaction between the GRS and the waist-to-hip ratio (WHR) showed a negative beta coefficient (BC = -26.5307; p = 0.014). Participants with a WHR < 0.839 showed no effect of GRS on LDL-c concentration, while those with a WHR > 0.839 exhibited a greater effect of GRS (~9) at lower LDL-c concentrations (~50 mg/dL) and a lesser effect of GRS (~7) at higher LDL-c concentrations (~250 mg/dL)., Conclusions: A significant interaction between genetics and WHR influences LDL-c in Mexicans, which may contribute to the prevention and clinical management of dyslipidemia and cardiovascular disease.

Background: Chronic kidney disease (CKD) patients face the risk of rapid kidney function decline leading to adverse outcomes like dialysis and mortality. Lipid metabolism might contribute to acute kidney function decline in CKD patients. Here, we utilized the Mendelian Randomization approach to investigate potential causal relationships between drug target-mediated lipid phenotypes and rapid renal function decline., Methods: In this study, we utilized two methodologies: summarized data-based Mendelian randomization (SMR) and inverse variance-weighted Mendelian randomization (IVW-MR), to approximate exposure to lipid-lowering drugs. This entailed leveraging expression quantitative trait loci (eQTL) for drug target genes and genetic variants proximal to drug target gene regions, which encode proteins associated with low-density lipoprotein (LDL) cholesterol, as identified in genome-wide association studies. The objective was to investigate causal associations with the progression of rapid kidney function decline., Results: The SMR analysis revealed a potential association between high expression of PCSK9 and rapid kidney function decline (OR = 1.11, 95% CI= [1.001-1.23]; p = 0.044). Similarly, IVW-MR analysis demonstrated a negative association between LDL cholesterol mediated by HMGCR and kidney function decline (OR = 0.74, 95% CI = 0.60-0.90; p = 0.003)., Conclusion: Genetically predicted inhibition of HMGCR is linked with the progression of kidney function decline, while genetically predicted PCSK9 inhibition is negatively associated with kidney function decline. Future research should incorporate clinical trials to validate the relevance of PCSK9 in preventing kidney function decline., (© 2024. The Author(s).)

Background: We assessed long-term real-world effectiveness and safety of lomitapide in patients with homozygous familial hypercholesterolemia (HoFH)., Methods: Retrospective case series of six patients with HoFH treated with lomitapide in an Italian clinic. Changes in low-density lipoprotein cholesterol (LDL-C) during lomitapide treatment were assessed. The effect on LDL-C of PCSK9 inhibitors, apheresis and lomitapide was evaluated. Additionally, high-density lipoprotein cholesterol (HDL-C), gastrointestinal tolerability, hepatic steatosis/elasticity, transaminases, and cardiovascular events and symptoms were assessed., Results: Median age at HoFH clinical and molecular diagnoses was 25 (range 2-49) and 40 (29-71) years, respectively. Five (83.3%) had prior cardiovascular events. One patient received apheresis, which was subsequently discontinued. All patients received PCSK9 inhibitors but discontinued due to minimal effectiveness. Median (range) age at lomitapide initiation was 44 (28-73) years, with a median 47 (18-85) months' treatment (mean dose 17.5 [5-40] mg/day). Mean (SD) baseline LDL-C was 263.2 (148.1) mg/dL, which decreased by 80% at nadir (52.8 [19.2] mg/dL) and 69% at last follow-up (81.3 [30.5] mg/dL). Four patients (66.7%) achieved LDL-C < 70 mg/dL sometime during follow-up, all of whom also achieved LDL-C < 55 mg/dL. Adverse events (AEs) were generally mild to moderate, hepatic steatosis was either absent or mild/moderate and hepatic elasticity remained normal in all but two patients (> 70 years old). All patients with reported cardiovascular symptoms had improvements in symptoms, and all patients reported stabilization or regression of intima-media thickness and atheromatous plaques., Conclusions: These long-term, real-world data demonstrate that lomitapide substantially reduced LDL-C for up to seven years. Most patients achieved LDL-C goal at some point, consistent with published Phase III trial and real-world evidence data. No patient discontinued lomitapide treatment. Further long-term follow-up in a larger patient population will be important to determine cardiovascular and other outcomes., (© 2024. The Author(s).)

Background: Cholestasis is characterized by the accumulation of bile in the liver or biliary system due to obstruction or impaired flow, necessitating lipid profiling to assess lipid metabolism abnormalities. Intrahepatic cholestasis, being the most significant type of cholestasis, further complicates the assessment of lipid abnormalities. However, the accuracy of low-density lipoprotein cholesterol (LDL-C) measurement in intrahepatic cholestasis patients remains uncertain., Objective: This study aimed to evaluate the consistency of the homogeneous assay and the Friedewald formula in detecting LDL-C levels and identify factors influencing LDL-C test results in intrahepatic patients with cholestasis., Methods: Retrospective analysis of laboratory data was conducted on intrahepatic cholestatic patients. Correlations between LDL-C values obtained using the homogeneous method (LDL-C(D)) and the Friedewald formula (LDL-C(F)), as well as associations between high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A1 (ApoA1), LDL-C(D) and LDL-C(F), and apolipoprotein B (ApoB), were analyzed. Logistic regression analyses were employed to identify diagnostic indicators for inaccurate LDL-C measurements in intrahepatic cholestatic patients., Results: Compared to patients with intrahepatic cholestasis without jaundice, the correlation between LDL-C(F) and LDL-C(D) was weaker in those with jaundice. Additionally, HDL-C exhibited a strong correlation with ApoA1 in both jaundice and non-jaundice cholestasis cases. Elevated non-HDL-C to APOB ratio (NH-C/B Ratio) levels (>4.5) were identified as a reliable predictor of inaccurate LDL-C measurements in patients with chronic intrahepatic cholestasis accompanied by jaundice., Conclusions: LDL-C measurement reliability is moderately weaker in patients with intrahepatic cholestasis accompanied by jaundice. Elevated levels of the NH-C/B ratio serve as a significant predictor of inaccurate LDL-C measurements in this chronic patient population, highlighting its clinical relevance for diagnostic assessments., Competing Interests: The authors declare that they have no competing interests., (© 2024 Cheng et al.)

Aims: Examine whether the low-density lipoprotein cholesterol (LDL -C) determination method influences the rate of statin initiation for primary prevention of cardiovascular disease., Methods and Results: We conducted a register-based retrospective study in the Region of Southern Denmark. Two hospital-based laboratories in the region directly measure LDL -C whereas four laboratories calculate LDL -C using Friedewald's formula. Physicians do not choose which method is used. We included all statin-naïve patients ≥40 years with no history of cardiovascular disease, diabetes, or chronic kidney disease, who had their LDL -C determined during 2018-2019. There were 202 807 people who had LDL -C determined during the study period (median age 59 years, 44% women) of which 37% had a direct LDL -C measurement. The median reported LDL -C was 3.40 mmol/L [interquartile range (IQR) 2.90-4.00] for those with a direct measurement vs. 3.00 mmol/L (IQR 2.40-3.50) for those with calculated LDL -C. For those with direct measurement, re-calculated LDL -C (using Friedewald's formula) was 0.35 mmol/L lower than the reported direct LDL -C measurement. Among those with directly measured LDL -C, 3.6% initiated statins compared with 2.7% of those with a calculated LDL -C. Direct LDL -C measurement led to higher odds of having a statin initiated compared with calculated LDL -C (adjusted odds ratio 1.23, 95% CI 1.17-1.30); for those with triglycerides >1.7 mmol/L the adjusted odds ratio was 1.41 (95% CI 1.30-1.52)., Conclusion: Differences in the reporting of LDL -C from laboratories using different methods have a substantial influence on physician's decisions to prescribe statins., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Cardiovascular diseases, including coronary heart disease (CHD), are currently positioned among the leading causes of mortality globally. Risk factors of CHD include, among others, hypercholesterolemia and elevations in systemic inflammation. Functional foods enriched with compounds showing cholesterol-lowering effects are considered one among various dietary and lifestyle intervention strategies to tackle this problem. A CHD-preventive effect of dietary plant sterols has been broadly discussed, not only due to their ability to reduce blood cholesterol level, but also to their proven anti-inflammatory potential. Palm oil is one of the most widely consumed edible oils in the world. Despite its widespread use, especially in Asian countries, no study has been conducted using palm oil as a vehicle for plant sterols. Methods: The aim of the placebo-controlled double-blinded trial presented here was, therefore, to evaluate the effect of palm oil enriched with plant sterols, used as a cooking oil, on lipid profile and systemic inflammation marker in 100 adult hyperlipidemic residents of Bogor, Indonesia. Results: The study has shown a significant reduction in total cholesterol and LDL cholesterol level in study subjects consuming plant sterol-enriched palm oil as a replacement for usual palm oil for cooking, with no similar effect on CRP levels. Conclusions: The study suggests that, along with a healthy diet and lifestyle promotion, incorporating plant sterols in palm oil used for cooking may be an effective strategy to reduce cardiovascular risks in hyperlipidemic individuals.

Background: Dyslipidemia is an important risk factor for acute myocardial infarction. However, real-world data on its prevalence and lipid management trends for Korean patients with acute myocardial infarction are limited. This study aimed to determine the 10-year temporal trends in dyslipidemia prevalence and lipid management in this patient population., Methods and Findings: The study used a merged database of two nationwide observational cohorts (2011-2020) that included 26,751 participants. The primary endpoints were the achievement rates of the (1) absolute low-density lipoprotein cholesterol (LDL-C) target of <70 mg/dL (<1.8 mmol/L), (2) relative LDL-C target reduction of >50% from the baseline, (3) absolute or relative LDL-C target (American target), and (4) both absolute and relative LDL-C targets (European target). The dyslipidemia prevalence increased from 11.1% to 17.1%, whereas the statin prescription rate increased from 92.9% to 97.0% from 2011 to 2020. The rate of high-intensity statin use increased from 12.80% in 2012 to 69.30% in 2020. The rate of ezetimibe use increased from 4.50% in 2016 to 22.50% in 2020. The high-intensity statin and ezetimibe prescription rates (0.20% to 9.30% from 2016 to 2020) increased gradually. The absolute and relative LDL-C target achievement rates increased from 41.4% and 20.8% in 2012 to 62.5% and 39.5% in 2019, respectively. The American (45.7% in 2012 to 68.6% in 2019) and European (16.5% in 2012 to 33.8% in 2019) target achievement rates also increased., Conclusions: The adoption of lipid management guidelines in clinical practice has improved. However, continued efforts are needed to reduce the risk of recurrent ischemic events., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Oh et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Abnormal lipid metabolism is linked to intervertebral disc degeneration (IVDD), sciatica, and low back pain (LBP), but it remains unclear whether targeted interventions can prevent these issues. This study investigated the causal effects of lipid-lowering drug use on IVDD, sciatica, and LBP development., Methods: Single-nucleotide polymorphisms (SNPs) linked to total cholesterol (TC), low-density-lipoprotein cholesterol (LDL-C), and non-high-density-lipoprotein cholesterol (non-HDL-C) were obtained from the Global Lipids Genetics Consortium's genome-wide association study (GWAS). Genes near HMGCR, PCSK9, and NPC1L1 were selected to represent therapeutic inhibition targets. Using Mendelian randomization (MR) focusing on these drug targets, we identified causal effects of PCSK9, HMGCR, and NPC1L1 on the risk of developing IVDD, sciatica, and LBP, with coronary heart disease risk serving as a positive control. Using summary data from Mendelian randomization (SMR) analysis, we evaluated potential therapeutic targets for IVDD, sciatica, and LBP through protein quantitative trait loci (pQTL). The genetic associations with IVDD, sciatica, LBP, and coronary heart disease were derived from FinnGen (discovery) and UK Biobank (replication). Additionally, a cross-sectional observational study was performed using data from the National Health and Nutrition Examination Survey (NHANES) to further investigate the connection between LBP and statin use, with a sample size of 4343 participants. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated to assess the outcomes., Results: The NHANES-based cross-sectional study indicated that non-statin use was associated with an increased risk of developing LBP (OR = 1.29, 95% CI [1.04, 1.59], P = 0.019). Moreover, Inverse-variance weighting (IVW) analysis revealed that NPC1L1-mediated reductions in TC, LDL-C, and non-HDL-C concentrations were associated with a decreased risk of developing IVDD (P = 9.956E-03; P = 3.516E-02; P = 1.253E-04). Similarly, PCSK9-mediated reductions in LDL-C and TC concentrations were linked to a lower risk of developing sciatica (P = 3.825E-02; P = 2.709E-02). Sensitivity analysis confirmed the stability and reliability of the MR results. MST1 (macrophage stimulating 1) levels was inversely associated with IVDD, sciatica, and LBP risks., Conclusion: The results of cross-sectional study suggested that non-use of statins was positively correlated with LBP. The results of Mendelian randomization study suggest that NPC1L1 could lower the risk of developing IVDD by reducing TC, LDL-C, and non-HDL-C levels. Additionally, PCSK9 may reduce the risk of developing sciatica by lowering LDL-C and TC levels. In contrast, HMGCR appears to have no significant effect on IVDD, sciatica, or LBP development. Nonetheless, further research is needed to verify these preliminary results. MST1 warrants further exploration as a potential therapeutic target. It is necessary to do further research to validate these findings., (© 2024. The Author(s).)

Statin-associated muscle symptoms are frequently reported and often lead to discontinuation of statin therapy with an increased risk of cardiovascular events. In vitro studies suggest that statin-mediated inhibition of the mevalonate pathway leads to muscle cell toxicity. We aimed to determine the relationship between mevalonate, LDL-cholesterol, and atorvastatin metabolites in patients with coronary heart disease and self-perceived muscle side effects. Furthermore, we assessed the correlation between mevalonate in blood and muscle and the relationship to statin intolerance due to muscle symptoms. We used blood plasma from a randomized crossover trial (n = 70) and muscle biopsies and plasma from a subgroup in a subsequent open intervention study (n = 26). Both studies tested atorvastatin 40 mg/day. Seven patients did not tolerate ≥3 statins throughout the follow-up and were classified as statin-intolerant. Mevalonate in blood plasma decreased during atorvastatin treatment (median difference -38%, range -77% to 43%, p < 0.001), whereas mevalonate in muscle tissue was not lowered (0.05%, range -47% to 145%). Mevalonate correlated poorly with LDL-cholesterol and atorvastatin metabolites (Spearman's rho -0.28 to 0.10). The statin-intolerant patients had a smaller reduction in circulating mevalonate compared with the tolerant patients; median difference -8.1 (-22 to 3.5) nmol/L versus -25 (-93 to 12) nmol/L, p = 0.028. A similar observation was made for LDL-cholesterol. Cutoffs based on these biomarkers classified >50% correctly as tolerant. Inhibition of the mevalonate pathway does not appear to be the mechanism underlying statin intolerance in the present study. Further studies of mevalonate as a biomarker for statin tolerance are needed to clarify the potential., (© 2024 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Recent studies have suggested that adverse events associated with lipoprotein(a) [Lp(a)] might be modified by low-density lipoprotein cholesterol (LDL-C) or high-sensitivity C-reactive protein (hs-CRP) levels, but whether LDL-C and hs-CRP jointly mediate the outcome of Lp(a) remains unknown in patients with coronary artery disease., Methods and Results: A prospective study was conducted, enrolling consecutive 10 724 patients with percutaneous coronary intervention (PCI) in 2013. The endpoint event was all-cause death. A total of 10 000 patients with complete baseline data were finally included. During a median follow-up of 5.1 years, Lp(a) ≥ 30 mg/dL was an independent risk factor of all-cause death in the overall population, LDL-C ≥ 70 mg/dL, and hs-CRP ≥ 2 mg/L population, respectively. According to concurrent LDL-C (70 mg/dL) and hs-CRP (2 mg/L) levels, further analysis revealed that when LDL-C < 70 mg/dL regardless of hs-CRP levels, Lp(a) ≥ 30 mg/dL was not an independent predictor of all-cause death. However, when LDL-C ≥ 70 mg/dL, Lp(a) ≥ 30 mg/dL was independently associated with a higher risk of all-cause death in hs-CRP ≥ 2 mg/L (HR: 1.488, 95% CI: 1.059‒2.092), but not in hs-CRP < 2 mg/L (HR: 1.303, 95% CI: 0.914‒1.856)., Conclusion: Among PCI patients, Lp(a)-associated outcome was jointly affected by LDL-C and hs-CRP. As long as LDL-C is well controlled, the adverse effects of increased Lp(a) on cardiovascular risk seem to be weakened, and only when LDL-C and hs-CRP increase at the same time, elevated Lp(a) is associated with poorer long-term outcome., (© 2024 The Author(s). Clinical Cardiology published by Wiley Periodicals, LLC.)

Objective: Sex differences in lipid metabolism associated with prevalent small dense (S-) low-density lipoprotein (LDL) cholesterol particles are not elucidated. An LDL to apolipoprotein B (ApoB) ratio < 1.2 can estimate how prevalent S-LDL particles are and, thus, reflect cardiovascular risk. The aim of this study was to evaluate the sex distribution of LDL/ApoB ratio among patients with type 2 diabetes (DM) and to assess, in both sexes, the correlations between key lipid parameters and LDL/ApoB < 1.2., Subjects and Methods: The study included 190 Caucasian participants (mean age 51.8 ± 6.4 years) with DM (DM group) or without DM (control group) divided into subgroups according to sex. The participants were examined for levels of several lipid parameters, selected lipid-related oxidative stress markers, and estimated S-LDL prevalence., Results: An LDL/ApoB < 1.2 (p < 0.05) was observed in 67% of male and female patients with DM. Although triglyceride levels did not differ between men and women, women had higher levels of total cholesterol (p < 0.05) and LDL cholesterol (p < 0.01) than men. Among women with LDL/ApoB < 1.2, strong correlations were observed between values of lipid hydroperoxides (LOOH) and atherogenic index of plasma (p < 0.005) and between levels of triglycerides and LOOH (p < 0.005) and ApoB (p < 0.0001)., Conclusions: The findings indicate that women with LDL/ApoB < 1.2 tend to have a higher cardiovascular risk than men. Additionally, LDL/ApoB < 1.2 can be a surrogate marker for estimating the S-LDL prevalence in individuals with potentially increased cardiovascular risk., Competing Interests: Disclosure: no potential conflict of interest relevant to this article was reported.

Background: Coronary heart disease (CHD) patients are considered high cardiovascular risks. Guidelines recommend low-density lipoprotein cholesterol (LDL-C) target levels below 55 mg/dl with > 50% reduction from baselines. These levels can be reached by a combination of statins, ezetimibe, and anti-protein convertase subtilisin/kexin type 9 (anti-PCSK9) agents. Our clinical impression was that CHD patients do not reach LDL-C target levels, despite the wide availability., Objectives: To evaluate whether hospitalization would result in changes in lipid lowering regimens and short-term compliance., Methods: We conducted a retrospective cohort study using data of CHD patients who were admitted to internal medicine wards at Clalit Health Services medical centers because of anginal syndrome during 2020-2022. The data were evaluated for demographic and clinical characteristics; LDL-C level at admission, 6 months previously, and 3 months and 6-9 months after discharge; rates of reaching LDL-C target levels; and lipid lowering treatment at admission, discharge, and 6-9 months after., Results: The cohort included 10,540 patients. One-third and three-quarters did not have lipids level measurements up to 6 months before and during hospitalization, respectively. Only one-fifth of the patients reached LDL-C values before and during admission (median LDL-C 72 mg/dl; range 53-101). Approximately half were treated with high-dose potent statins. Only 10% were treated with ezetimibe. Hospitalization did not have a clinically significant effect on short-term lipid lowering treatment or LDL-C levels., Conclusions: Gaps were noted between guidelines and clinical practice for reaching LDL-C target levels. Further education and strict policy are needed.

Adverse cardiovascular (CV) events have declined in Western countries due at least in part to aggressive risk factor control, including dyslipidemia management. The American and European (Western) dyslipidemia treatment guidelines have contributed significantly to the reduction in atherosclerotic cardiovascular disease (ASCVD) incidence in the respective populations. However, their direct extrapolation to Indian patients does not seem appropriate for the reasons described below. In the US, mean low-density lipoprotein cholesterol (LDL-C) levels have markedly declined over the last 2 decades, correlating with a proportional reduction in CV events. Conversely, poor risk factor control and dyslipidemia management have led to increased CV and coronary artery disease (CAD) mortality rates in India. The population-attributable risk of dyslipidemia is about 50% for myocardial infarction, signifying its major role in CV events. In addition, the pattern of dyslipidemia in Indians differs considerably from that in Western populations, requiring unique strategies for lipid management in Indians and modified treatment targets. The Lipid Association of India (LAI) recognized the need for tailored LDL-C targets for Indians and recommended lower targets compared to Western guidelines. For individuals with established ASCVD or diabetes with additional risk factors, an LDL-C target of <50 mg/dL was recommended, with an optional target of ≤30 mg/dL for individuals at extremely high risk. There are several reasons that necessitate these lower targets. In Indian subjects, CAD develops 10 years earlier than in Western populations and is more malignant. Additionally, Indians experience higher CAD mortality despite having lower basal LDL-C levels, requiring greater LDL-C reduction to achieve a comparable CV event reduction. The Indian Council for Medical Research-India Diabetes study described a high prevalence of dyslipidemia among Indians, characterized by relatively lower LDL-C levels, higher triglyceride levels, and lower high-density lipoprotein cholesterol (HDL-C) levels compared to Western populations. About 30% of Indians have hypertriglyceridemia, aggravating ASCVD risk and complicating dyslipidemia management. The levels of atherogenic triglyceride-rich lipoproteins, including remnant lipoproteins, are increased in hypertriglyceridemia and are predictive of CV events. Hypertriglyceridemia is also associated with higher levels of small, dense LDL particles, which are more atherogenic, and higher levels of apolipoprotein B (Apo B), reflecting a higher burden of circulating atherogenic lipoprotein particles. A high prevalence of low HDL-C, which is often dysfunctional, and elevated lipoprotein(a) [Lp(a)] levels further contribute to the heightened atherogenicity and premature CAD in Indians. Considering the unique characteristics of atherogenic dyslipidemia in Indians, lower LDL-C, non-HDL-C, and Apo B goals compared to Western guidelines are required for effective control of ASCVD risk in Indians. South Asian ancestry is identified as a risk enhancer in the American lipid management guidelines, highlighting the elevated ASCVD risk of Indian and other South Asian individuals, suggesting a need for more aggressive LDL-C lowering in such individuals. Hence, the LDL-C goals recommended by the Western guidelines may be excessively high for Indians and could result in significant residual ASCVD risk attributable to inadequate LDL-C lowering. Further, the results of Mendelian randomization studies have shown that lowering LDL-C by 5-10 mg/dL reduces CV risk by 8-18%. The lower LDL-C targets proposed by LAI can yield these incremental benefits. In conclusion, Western LDL-C targets may not be suitable for Indian subjects, given the earlier presentation of ASCVD at lower LDL-C levels. They may result in greater CV events that could otherwise be prevented with lower LDL-C targets. The atherogenic dyslipidemia in Indian individuals necessitates more aggressive LDL-C and non-HDL-C lowering, as recommended by the LAI, in order to stem the epidemic of ASCVD in India., (© Journal of the Association of Physicians of India 2024.)

Objective. Studies that have evaluated correlation between body mass index (BMI) and novel lipid indices such as triglycerides (TG)/high-density lipoprotein-cholesterol (HDL-C), total cholesterol (TC)/HDL-C, and low-density lipoprotein cholesterol (LDL-C)/HDL-C in type 2 diabetes mellitus (T2DM) are scarce. Hence, the aim of the present study was to explore the correlation between BMI and novel lipid indices in Bosnian patients with T2DM. Methods. Present study included 117 patients with T2DM (mean age: 66.51 years) and 68 controls (mean age: 68.37 years). BMI was calculated as weight/height². Lipids were measured by standard methods. TG/HDL-C, TC/HDL-C, and LDL-C/HDL-C ratios were separately calculated. The differences between the groups were assessed by Student's t-test or Man Whitney U test. Correlations were determined by Spearman's test. Results. In a total sample of T2DM patients, 41.0% were overweight and 44.4% were obese. In the control group, 51.5% of subjects were overweight and 25.0% were obese. In T2DM group, a significant correlation was observed between BMI and HDL-C, LDL-C, TG/HDL, TC/HDL-C, and LDL-C/HDL-C ratios. In the control group, there was a significant correlation found between BMI and HDL-C, TG, TG/HDL, TC/HDL-C, and LDL-C/HDL-C-ratios. Correlation between BMI and other lipid parameters in T2DM and the control group was not determined. Conclusion. The present study showed significant correlation between BMI and novel lipid indices in both T2DM patients and the control group of subjects. Possible explanation for the observed results might be prevalence of overweight and obese participants in this study sample. Since novel lipid indices are used in the prediction of cardiometabolic risk, results obtained in the present study have valuable clinical implications., (© 2024 Carla Devantier-Du Plessis et al., published by Sciendo.)

This study aimed to investigate the association between non-traditional lipid profiles and the risk of 1-year vascular events in patients who were already using statins before stroke and had admission LDL-C < 100 mg/dL. This study was an analysis of a prospective, multicenter, nationwide registry of consecutive patients with acute ischemic stroke patients who treated with statin before index stroke and LDL-C < 100 mg/dL on admission. Non-traditional lipid profiles including non-HDL, TC/HDL ratio, LDL/HDL ratio, and TG/HDL ratio were analyzed as a continuous or categorical variable. The primary vascular outcome within one year was a composite of recurrent stroke (either hemorrhagic or ischemic), myocardial infarction (MI) and all-cause mortality. Hazard ratios (95% Cis) for 1-year vascular outcomes were analyzed using the Cox PH model for each non-traditional lipid profiles groups. A total of 7028 patients (age 70.3 ± 10.8years, male 59.8%) were finally analyzed for the study. In unadjusted analysis, no significant associations were observed in the quartiles of LDL/HDL ratio and 1-year primary outcome. However, after adjustment of relevant variables, compared with Q1 of the LDL/HDL ratio, Q4 was significantly associated with increasing the risk of 1-year primary outcome (HR 1.48 [1.19-1.83]). For the LDL/HDL ratio, a linear relationship was observed (P for linearity < 0.001). Higher quartiles of the LDL/HDL ratio were significantly and linearly associated with increasing the risk of 1-year primary vascular outcomes. These findings suggest that even during statin therapy with LDL-C < 100 mg/dl on admission, there should be consideration for residual risk based on the LDL/HDL ratio, following stroke., (© 2024. The Author(s).)

Background: Nuts consumption is related to cardioprotective effects on primary cardiovascular prevention, but studies conducted in secondary prevention are small, scarce and controversial. The objective of this trial was to evaluate the effects of a regional and sustainable cardioprotective diet added or not with an affordable mixed nuts on cardiometabolic features in patients with previous myocardial infarction., Methods: DICA-NUTS study is a national, multi-center, and superiority-parallel randomized clinical trial. Males and females over 40 years old diagnosed with previous myocardial infarction in the last 2 to 6 months were included. Patients were allocated into two groups: the Brazilian Cardioprotective diet (DICA Br) supplemented with 30 g/day of mixed nuts (10 g of peanuts; 10 g of cashew; 10 g of Brazil nuts) (intervention group, n = 193); or only DICA Br prescription (control group, n = 195). The primary outcome was low-density lipoprotein cholesterol means (in mg/dL) after 16 weeks. Secondary outcomes were other lipid biomarkers, glycemic and anthropometric data and diet quality., Results: After adjustment for baseline values, participating study site, time since myocardial infarction and statin treatment regimen (high potency, moderate and low potency/no statins), no significant difference was found between the groups in low-density lipoprotein cholesterol concentrations (intervention-control difference: 3.48 mg/dL [-3.45 to 10.41], P = 0.32). Both groups improved their overall diet quality at the end of the study without differences between them after 16 weeks (intervention-control difference: 1.05 (-0.9 to 2.99); P = 0.29). Other lipids, glycemic profile and anthropometrics were also not different between study groups at the end of the study., Conclusion: Adding 30 g/day of mixed nuts to the DICA Br for 16 weeks did not change lipid, glycemic and anthropometric features in the post-myocardial infarction setting., Trial Registration: This study is registered on ClinicalTrials.gov website under number NCT03728127 and its World Health Organization Universal Trial Number (WHO-UTN) is U1111-1259-8105., (© 2024. The Author(s).)

Background: Blood lipid profiles are associated with various nutritional elements and dietary factors. This study aimed to explore the association between total dietary vitamin E intake and remnant cholesterol (RC), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) using data from the National Health and Nutrition Examination Survey (NHANES)., Methods: A cross-sectional analysis was conducted using NHANES 2007-2018 data. A total of 8,639 eligible participants (45.58% men and 54.42% women) with an average age of 46.12 ± 16.65 years were included in this study. Weighted multivariate linear regression and subgroup analyses were used to examine the association between vitamin E intake and RC, TC, HDL-C, and LDL-C. Smooth curve fitting was used to explore potential non-linear associations., Results: After adjusting for other covariates, multivariate linear regression analysis showed that higher vitamin E intake was negatively associated with plasma RC (β = -0.22, 95% CI: -0.27, -0.16), TC (β = -0.33, 95% CI: -0.51, -0.16), LDL-C (β = -0.25, 95% [confidence interval] CI: -0.40, -0.10) and positively associated with HDL-C (β = 0.13, 95% CI: 0.07, 0.20) in US adults. Subgroup analysis indicated that age may influence the association between vitamin E intake and RC. At the same time, gender may also affect the association between vitamin E intake and HDL-C., Conclusion: Higher vitamin E intake was negatively associated with plasma RC, TC, LDL-C and positively associated with HDL-C., (© 2024. The Author(s).)

Background: Dyslipidemia is prominently associated with adverse outcomes in patients with coronary artery disease (CAD). The non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR) is a novel comprehensive lipid index. However, limited evidence exists on the relationship of the NHHR with the risk of adverse outcomes in patients with CAD. This study aimed to explore the associations between the NHHR and adverse outcomes and identify the optimal NHHR ranges linked to the lowest adverse outcome risk in patients with CAD undergoing percutaneous coronary intervention (PCI)., Methods: Among 2253 patients with CAD undergoing PCI, 2251 with available total cholesterol and HDL-C levels were analyzed. Furthermore, all patients were classified into quintiles based on the NHHR. The primary outcome was the incidence of MACCEs, comprising cardiac mortality, acute myocardial infarction, stroke, and repeat revascularization. Multivariable logistic regression analysis was used to assess the relationship between the NHHR and MACCEs. Moreover, restricted cubic spline (RCS) analysis was performed to quantify nonlinearity. Lastly, the consistency between these associations was confirmed by conducting subgroup and interaction analyses., Results: A total of 270 patients experienced MACCEs over a median follow-up of 29.8 months (interquartile range, 25.6-34 months). After adjustment for confounding variables, the adjusted ORs (95% CIs) of the patients in quintiles 2, 3, 4, and 5 were 0.79 (0.52-1.20), 0.64 (0.42-0.99), 1.00 (0.67-1.48), and 1.17 (0.74-1.64), respectively (reference group: quintile 1). Additionally, RCS analysis demonstrated a U-shaped relationship between the NHHR and MACCEs, with an inflection point at an NHHR of 3.119 using a two-piecewise regression model. This relationship was consistent across the various subgroups, while significant interactions were not observed in these associations.The ORs and 95% CIs to the left and right of the inflection point were 0.734 (0.551-0.978) and 1.231 (1.038-1.460), respectively., Conclusions: This study reveals a U-shaped association between baseline NHHR and MACCE incidence in patients with CAD undergoing PCI., (© 2024. The Author(s).)

Dyslipidemia is one of the most important risk factors for the development of atherosclerotic disease and its control, through well-proven therapies, allows an optimal risk management over time. LDL-cholesterol targets are well defined by international guidelines and based on individual cardiovascular risk. As guidelines evolve, also laboratory reports need to do the same, including lipid reference values by cardiovascular risk classes, to avoid misunderstandings and inappropriate lipid-lowering therapy withdrawal. The aim of the present joint document from the Italian Society of Cardiology (SIC) and the Italian Society of Clinical Biochemistry and Clinical Molecular Biology - Lab Medicine (SIBioC) is to analyze the importance of cardiovascular risk estimation, therapeutical targets, and crucial elements about dyslipidemia in laboratory tests, as well as to suggest a shared proposal for the report of lipid profile parameters to be applied to all clinical scenarios of our daily practice.

Introduction: Cholesteryl ester transfer protein (CETP) plays an important role in lipid metabolism. Early interest in the development of CETP inhibitors proved to be disappointing. Recent interest has focused on the potential for CETP inhibition to reduce cardiovascular risk by lowering levels of low-density lipoprotein cholesterol (LDL-C)., Areas Covered: The data suggesting that low CETP activity may associate with lower levels of cardiovascular risk and early experience with CETP inhibitors focused on raising HDL-C levels. More recent data that suggests that any potential to reduce cardiovascular risk by inhibition of CETP is more likely to result from lowering levels of atherogenic lipid parameters. The development of obicetrapib, a potent CETP inhibitor, with robust lowering of apoB and LDL-C, will be summarized as a potential approach to the prevention of cardiovascular disease., Expert Opinion: Obicetrapib is a potent CETP inhibitor, with a demonstrated ability to lower levels of apoB and LDL-C as monotherapy and in addition to high intensity statin therapy. The ultimate impact of obicetrapib on cardiovascular events will be evaluated by ongoing clinical trials.

Background and Aims: We tested the association of polygenic risk scores (PRS) for low-density lipoprotein cholesterol (LDL-C) and coronary artery disease (CAD) with LDL-C and risk of ischemic heart disease (IHD) in the Danish general population., Methods: We included a total of 21,485 individuals from the Copenhagen General Population Study and Copenhagen City Heart Study. For everyone, LDL-PRS and CAD-PRS were calculated, each based on >400,000 variants. We also genotyped four rare variants in LDLR or APOB known to cause familial hypercholesterolemia (FH)., Results: Heterozygous carriers of FH-causing variants in APOB or LDLR had a mean LDL-C of 5.40 and 6.09 mmol/L, respectively, and an odds ratio for IHD of 2.27 (95 % CI 1.43-3.51) when compared to non-carriers. The LDL-PRS explained 13.8 % of the total variation in LDL-C in the cohort. Individuals in the lowest and highest 1 % of LDL-PRS had a mean LDL-C of 2.49 and 4.75 mmol/L, respectively. Compared to those in the middle 20-80 %, those in the lowest and highest 1 % of LDL-PRS had odds ratios for IHD of 0.58 (95 % CI, 0.38-0.88) and 1.83 (95 % CI, 1.33-2.53). The corresponding odds ratios for CAD-PRS were 0.61 (95 % CI, 0.41-0.92) and 2.06 (95 % CI, 1.49-2.85)., Conclusions: The top 1 % of LDL-PRS and CAD-PRS conferred effects on LDL-C and risk of IHD comparable to those seen for carriers of rare FH-causing variants in APOB or LDLR. These results highlight the potential value of implementing such PRS clinically., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Hyperlipidaemia is a major risk factor of atherosclerotic cardiovascular disease (ASCVD). Risk of cardiovascular events depends on cumulative lifetime exposure to low-density lipoprotein cholesterol (LDL-C) and, independently, on the time course of exposure to LDL-C, with early exposure being associated with a higher risk 1 . Furthermore, LDL-C fluctuations are associated with ASCVD outcomes 2-4 . However, the precise mechanisms behind this increased ASCVD risk are not understood. Here we find that early intermittent feeding of mice on a high-cholesterol Western-type diet (WD) accelerates atherosclerosis compared with late continuous exposure to the WD, despite similar cumulative circulating LDL-C levels. We find that early intermittent hyperlipidaemia alters the number and homeostatic phenotype of resident-like arterial macrophages. Macrophage genes with altered expression are enriched for genes linked to human ASCVD in genome-wide association studies. We show that LYVE1 + resident macrophages are atheroprotective, and identify biological pathways related to actin filament organization, of which alteration accelerates atherosclerosis. Using the Young Finns Study, we show that exposure to cholesterol early in life is significantly associated with the incidence and size of carotid atherosclerotic plaques in mid-adulthood. In summary, our results identify early intermittent exposure to cholesterol as a strong determinant of accelerated atherosclerosis, highlighting the importance of optimal control of hyperlipidaemia early in life, and providing insights into the underlying biological mechanisms. This knowledge will be essential to designing effective therapeutic strategies to combat ASCVD., (© 2024. The Author(s).)

Objective: We aim to explore the concept of distance and journey to goal, and consideration of these 2 elements a priori when choosing LLT., Methods: Modelling of expected % LDL-C reductions was carried out on a range of hypothetical patients' baseline LDL-C values prior to any LLT being commenced. Therapies were then added in a stepwise manner based on the pathway demonstrated in current national guidance and compared with goal achievement on a novel LLT optimization pathway implemented in Morecambe Bay NHS Trust., Results: Modelling of a stepwise lipid management pathway shows that high-intensity statin monotherapy is not sufficient in most modelled baseline LDL-C scenarios to achieve guideline-recommended goals. Furthermore, ezetimibe second line may preclude 3 rd line injectable prescribing and lead to "ezetimibe limbo" where the patient is now below the reimbursement threshold for injectable prescribing but still not achieving their LDL-C target. Overall goal achievement is poor across the spectrum of modelled LDL-C levels. In contrast, by following the Morecambe Bay pathway all patients on statin for the range of hypothetical baseline LDL-C levels can reach an LDL-C target of < 1.8 mmol/L., Conclusions: This study identifies a therapeutic gap when following a stepwise approach highlighted by recent national guidance. Our proposal of a novel pathway highlights that the order in which drugs are added is important in the context of national reimbursement thresholds and allows LDL-C goal to be reached in a timely manner, regardless of the starting baseline LDL-C level.

Background and Aims: We aimed to investigate the interplay between low-density lipoprotein-cholesterol (LDL-C) and coronary plaque in asymptomatic cohorts undergoing coronary tomography angiography (CCTA) assessment in the United States., Methods: A cross-sectional analysis of baseline data from 1808 statin-naïve participants in the Miami Heart Study was conducted. We assessed CCTA-detected atherosclerosis (any plaque, noncalcified plaque, maximal stenosis ≥50%, high-risk plaque) across LDL-C levels, coronary artery calcium (CAC) scores (0, 1-99, ≥100), and 10-year cardiovascular risk categories., Results: Atherosclerosis presence varied across LDL-C levels: 40% of those with LDL-C ≥190 mg/dL had no coronary plaque, while 33% with LDL-C <70 mg/dL had plaque (22.4% with noncalcified plaque). Among those with CAC 0, plaque prevalence ranged from 13.2% (LDL-C <70 mg/dL) to 28.2% (LDL-C ≥190 mg/dL), noncalcified plaque from 13.2% to 25.6%, stenosis ≥50% from 0 to 2.6%, and high-risk plaque from 0 to 5.1%. Conversely, with CAC ≥100, all had coronary plaque, with noncalcified plaque prevalence ranging from 25.0% (LDL-C <70 mg/dL) to 83.3% (LDL-C ≥190 mg/dL), stenosis ≥50% from 25.0% to 50.0%, and high-risk plaque from 0 to 66.7%. Among low-risk participants, 76.7% had CAC 0, yet 31.5% had any plaque and 18.3% had noncalcified plaque. Positive trends between LDL-C and any plaque (17.9%-45.2%) or noncalcified plaque (12.8%-23.8%) were observed in the low-risk group, but no clear trends were seen in higher-risk groups., Conclusions: Heterogeneity exists in subclinical atherosclerosis across LDL-C, CAC, and estimated cardiovascular risk levels. The value of CCTA in risk-stratifying asymptomatic adults should be further explored., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Nasir is on the advisory board of Amgen, Novartis, Novo Nordisk, his research is partly supported by the Jerold B. Katz Academy of Translational Research and is a member of the Steering Committee of the PAK-SEHAT study which is partly funded by an unrestricted research grant from Getz Pharma. Dr. Cainzos-Achirica is on the Steering Committee of the PAK-SEHAT Study, partially funded by an unrestricted research grant from Getz Pharma. Dr. Shapiro has served on Scientific Advisory Boards with Amgen, Ionis, Novartis, Precision BioScience and as a consultant for Ionis, Novartis, Regeneron, EmendoBio, Aidoc. Dr. Cury is a consultant to GE Healthcare, Covera Health and Cleerly., (Copyright © 2024. Published by Elsevier B.V.)

We herein report the first family of Japanese individuals with familial hypobetalipoproteinemia caused by the c.1468C>T mutation in apolipoprotein B (APOB). A 13-year-old boy with extremely low levels of low-density lipoprotein (LDL) cholesterol (24 mg/dL) was referred to our hospital. The patient had no secondary causes of hypobetalipoproteinemia. His father and grandmother also exhibited low LDL cholesterol levels. A genetic analysis confirmed that they all had this variant in APOB (c.1468C>T). None of the patients exhibited atherosclerotic cardiovascular diseases or any other complications associated with low LDL cholesterol levels, including fatty liver, neurocognitive disorders, and cerebral hemorrhaging.

Purpose of Review: Globally, the prevalence of metabolic disorders is rising. Elevated low-density lipoprotein (LDL) cholesterol is a hallmark of familial hypercholesterolemia, one of the most prevalent hereditary metabolic disorders and another one is Diabetes mellitus (DM) that is more common globally, characterised by hyperglycemia with low insulin-directed glucose by target cells. It is still known that low-density lipoprotein cholesterol (LDL-C) increases the risk of cardiovascular disease (CVD). LDL-C levels are thought to be the main therapeutic objectives., Recent Findings: The primary therapy for individuals with elevated cholesterol levels is the use of statins and other lipid lowering drugs like ezetimibe for hypercholesterolemia. Even after taking statin medication to the maximum extent possible, some individuals still have a sizable residual cardiovascular risk. To overcome this proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors-monoclonal antibodies (mAbs) are a novel class of systemic macromolecules that have enhanced LDL-C-lowering efficacy. Along with this other inhibitor are used like Angiopoeitin like 3 inhibitors. Research on both humans and animals has shown that anti-CD3 antibodies can correct autoimmune disorders like diabetes mellitus. Individuals diagnosed with familial hypercholesterolemia (FH) may need additional treatment options beyond statins, especially when facing challenges such as statin tolerance or the inability of even the highest statin doses to reach the desired target cholesterol level. Here is the summary of PCSK9, ANGPTL-3 and CD3 inhibitors and their detailed information. In this review we discuss the details of PCSK9, ANGPTL-3 and CD3 inhibitors and the current therapeutic interventions of using the monoclonal antibodies in case of the metabolic disorder. We further present the present studies and the future prospective of the same., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Metabolic flexibility (MetF), defined as the ability to switch between fat and glucose oxidation, is increasingly recognised as a critical marker for assessing responses to dietary interventions. Previously, we showed that the consumption of multifibre bread improved insulin sensitivity and reduced low-density lipoprotein cholesterol (LDLc) levels in overweight and obese individuals. As a secondary objective, we aimed to explore whether our intervention could also improve MetF., Methods: In this study, 39 subjects at cardiometabolic risk participated in a double-blind, randomised, crossover trial lasting 8 weeks, repeated twice. During each phase, participants consumed either 150 g of standard bread daily or bread enriched with a mixture of seven dietary fibres. MetF response was assessed using a mixed-meal tolerance test (MMTT), analysing changes in respiratory quotient (∆RQ) measured using indirect calorimetry., Results: Although there were no significant differences in ∆RQ changes induced by dietary fibre between the two diets, these changes were positively correlated with postprandial triglyceride excursion (∆TG) at baseline. Subgroup analysis of baseline fasting and postprandial plasma metabolites was conducted to characterise MetF responders. These responders exhibited higher baseline fasting LDLc levels and greater post-MMTT ∆TG., Conclusion: In conclusion, although dietary fibres did not directly impact MetF in this study, our findings highlight potential determinants of MetF response, warranting further investigation in dedicated future interventions., (Journal of Human Nutrition and Dietetics© 2024 The Author(s). Journal of Human Nutrition and Dietetics published by John Wiley & Sons Ltd on behalf of British Dietetic Association.)

Background and Aims: Correction of calcium and protein undernutrition using milk, yoghurt, and cheese in older adults in aged care homes is associated with reduced fractures and falls. However, these foods contain potentially atherogenic fats. We aimed to determine whether this intervention that increased dairy consumption to recommended levels adversely affects serum lipid profiles., Method and Results: This was a sub-group analysis of a 2-year cluster-randomised trial involving 60 aged care homes in Australia. Thirty intervention homes provided additional milk, yoghurt, and cheese on menus while 30 control homes continued with their usual menus. A sample of 159 intervention and 86 controls residents (69% female, median age 87.8 years) had dietary intakes recorded using plate waste analysis and fasting serum lipids measured at baseline and 12 months. Diagnosis of cardiovascular disease and use of relevant medications were determined from medical records. Outcome measures were serum total, HDL and LDL cholesterol and ApoA-1 & B. Intervention increased daily dairy servings from 1.9 ± 1.0 to 3.5 ± 1.4 (p < 0.001) while controls continued daily intakes of ≤2 servings daily (1.7 ± 1.0 to 2.0 ± 1.0 (p = 0.028). No group differences were observed for serum total cholesterol/high-density lipoprotein-C (TC/HDL-C) ratio, Apoprotein B/Apoprotein A-1 (ApoB/ApoA-1) ratio, low-density lipoprotein-C (LDL-C), non-HDL-C, or triglycerides (TGs) at 12 months., Conclusion: Among older adults in aged care homes, correcting insufficiency in intakes of calcium and protein using milk, yoghurt and cheese does not alter serum lipid levels, suggesting that this is a suitable intervention for reducing the risk of falls and fractures., Clinical Trial Registry: Australian New Zealand Clinical Trials Registry (ACTRN12613000228785) 2012; https://www.anzctr.org.au., Competing Interests: Declaration of competing interest SI has received lecture fees from Abbott, Nestle Health Science, UK Dairy Baord, and European Milk Forum. CF, SP, JR, SV, DLH and ES have no conflicts of interest to declare., (Copyright © 2024. Published by Elsevier B.V.)

Background and Aims: Familial hypercholesterolemia (FH) is a genetic disorder marked by high LDL cholesterol and an increased premature coronary artery disease (CAD) risk. Current dichotomous classification of LDL receptor gene (LDLR) variants may inadequately capture patient variability in LDL cholesterol levels and CAD risk. This study assessed a novel approach for determining LDLR variant severity using variant-specific LDL cholesterol percentiles., Methods: Participants of the Dutch FH cascade screening program were screened for 456 LDLR variants. For each LDLR variant carrier, a sex- and age-specific LDL cholesterol percentile was derived from the LDL cholesterol level measured at study entry, i.e. generally from the blood drawn for DNA analysis. These percentiles were used to calculate the mean LDL cholesterol percentile for each variant. Based on the variant-specific LDL cholesterol percentiles, carriers were grouped into the following LDL cholesterol strata: <75th, 75th-88th, 88th-92nd, 92nd-96.5th, 96.5th-98th, and ≥98th percentile. Additionally, variants were categorized into class 1 (LDLR deficient) and non-class 1 (often LDLR defective) variants. CAD risk between carriers in the different LDL cholesterol strata and non-carriers was compared using a Cox proportional hazard model., Results: Out of 35,067 participants, 12,485 (36 %) LDLR variant carriers (mean age 38.0 ± 20.0 years, 47.7 % male) were identified. Carriers had a 5-fold higher CAD risk compared with non-carriers. Hazard ratios for CAD increased gradually from 2.2 (95%CI 0.97-5.0) to 12.0 (95%CI 5.5-24.8) across the LDL cholesterol strata. A 7.3-fold and 3.9-fold increased CAD risk was observed in carriers of class 1 and non-class 1 LDLR variants, respectively., Conclusions: This study presents a refined approach for classifying LDLR variants based on their impact on LDL cholesterol levels, allowing for more precise, genotype-specific CAD risk estimation in FH patients compared with traditional methods., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: LFR is cofounder of Lipid Tools and reports speakers fee from Ultragenyx, Novartis, and Daiichi Sankyo. JJPK is part time CSO of New Amsterdam Pharma and part time CMO of Staten Biotech and a consultant to AgBio, Scribe, Cincor, CSL Behring, CiVi Biopharma, Draupnir, Esperion Therapeutics, Madrigal, Menarini, Omeicos, Silence Therapeutics, Sirnaomics, TTxD and North Sea Therapeutics. GKH reports research grants from the Netherlands Organization for Scientific Research (vidi 016.156.445), CardioVascular Research Initiative, European Union and the Klinkerpad fonds, institutional research support from Aegerion, Amgen, AstraZeneca, Eli Lilly, Genzyme, Ionis, Kowa, Pfizer, Regeneron, Roche, Sanofi, and The Medicines Company; speaker's bureau and consulting fees from Amgen, Aegerion, Sanofi, and Regeneron until April 2019 (fees paid to the academic institution); and part-time employment and stock holder of at Novo Nordisk A/S, Denmark since April 2019. ESGS has received ad-board/lecturing fees, paid to the institution, from: Amgen, Sanofi, Astra-Zeneca, Esperion, Daiichi Sankyo, NovoNordisk, Ionis/Akcea, Amarin. The other authors report no disclosures., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose of Review: Although the clinical benefit of reducing low-density lipoprotein cholesterol (LDLc) in patients with coronary artery disease (CAD) is well-established, the impact on plaque composition and stability is less clear. Our narrative review aimed to assess the clinical effects of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors on coronary plaque characteristics specifically focusing from atheroma progression to regression and stabilization., Recent Findings: The combination of statin therapy and PCSK9 inhibitors (evolocumab and alirocumab) promotes plaque stability in patients following an acute coronary syndrome. The GLAGOV study highlighted the relationship between achieved LDLc levels and changes in percentage atheroma volume. Similarly, the PACMAN-AMI study concluded that the qualitative and quantitative changes in coronary plaque were associated with the levels of LDLc. Assessing the severity of coronary artery stenosis and the extent of atherosclerotic burden by means of imaging techniques (e.g., IVUS, OCT and near-infrared spectroscopic) have significantly advanced our understanding of the benefits from promoting plaque regression and achieving to features of plaque stabilization through increasingly intensive lipid-lowering strategies., (© 2024. The Author(s).)

Background: Among the Pentraxins, the long Pentraxin-3 (PTX-3) is associated with several processes, particularly in the earliest phases of the innate humoral response. Increased blood PTX-3 concentrations have been observed in a wide range of conditions, from infectious to cardiovascular disorders. Since its increase is more rapid than C-reactive protein (CRP), PTX-3 can be useful to detect and monitor early inflammation. To dissect its pathophysiological role in rheumatic diseases (RD), we conducted a systematic review and meta-analysis comparing blood PTX-3 concentrations in RD patients and healthy individuals and investigating possible associations with clinical, demographic, and study characteristics., Methods: We performed a search of published evidence until April 2024 in PubMed, Web of Science and Scopus, which led to the selection of 60 relevant manuscripts from a total of 1072 records., Results: Our synthesis revealed a statistically significant difference in PTX-3 concentrations between RD patients and controls (standard mean difference, SMD = 1.02, 95% CI 0.77-1.26, p < .001), that correlated with CRP concentrations. The effect size was associated with geographical region of study conduction, RD type, with a reduction of the observed heterogeneity in patients with low LDL-cholesterol and triglycerides concentrations., Conclusions: Our study has shown a significant increase in blood PTX-3 concentrations in RD patients, which was associated with specific patient characteristics. Nevertheless, additional studies are needed to better define the utility of measuring PTX-3 in the early phase of RD. Our study was conducted in compliance with the PRISMA 2020 statement (study protocol available at PROSPERO CRD42024516600)., (© 2024 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)