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• Remnant cholesterol was positively associated with ASCVD. • Remnant cholesterol was positively associated with HF. • Remnant cholesterol was inversely associated with AF. It remains unclear if remnant cholesterol is associated with atherosclerotic cardiovascular disease (ASCVD) (myocardial infarction, angina pectoris and stroke), heart failure (HF), and atrial fibrillation (AF) under primary prevention settings. We aimed to clarify this issue among a general population without a history of ASCVD, HF or AF. Analyses were conducted with a nationwide health claims database collected in the JMDC Claims Database between 2005 and 2022 (n = 1,313,722; median age, 42 years; 54.6% men). We assessed the associations between remnant cholesterol calculated as total cholesterol minus HDL cholesterol minus LDL cholesterol and composite CVD outcomes, including, ASCVD, HF, and AF using Cox proportional hazard model, dividing the individuals into tertiles of remnant cholesterol (T1–T3). The mean follow-up duration was 3.0 years. In total, 43,755 events were recorded. Remnant cholesterol was significantly associated with composite CVD outcomes after adjustments (T3 vs T1: hazard ratio [HR]; 1.07, 95% confidence interval [CI]: 1.04–1.10, p-trend<0.001). Remnant cholesterol was associated with myocardial infarction (T3 vs T1:HR: 1.20, 95% CI: 1.06–1.34, p-trend=0.002), angina pectoris (T3 vs T1:HR: 1.09, 95% CI: 1.05–1.14, p-trend<0.001), stroke (T3 vs T1:HR: 1.08, 95% CI: 1.02–1.14, p-trend=0.007), and HF (T3 vs T1:HR: 1.08, 95% CI: 1.04–1.12, p-trend<0.001), while we found a marginal inverse association between remnant cholesterol and AF (T3 vs T1:HR: 0.92, 95% CI: 0.86–1.00, p-trend=0.054). Remnant cholesterol was positively associated with ASCVD and HF, while we found a marginal inverse association between remnant cholesterol and AF. [ABSTRACT FROM AUTHOR]

• Homozygosity for mutation Q384K in the APOB gene causes hypobetalipoproteinemia. • Mutation Q384K disrupts the structure of the large lipid transfer (LLT) module of apoB. • Secretion of apoB-100 from the liver was markedly reduced. • Secretion of apoB-48 from the intestine was normal. • Abnormal structure of LLT module affects lipidation of apoB-100. Molecular genetic testing of patients with hypobetalipoproteinemia may identify a genetic cause that can form the basis for starting proper therapy. Identifying a genetic cause may also provide novel data on the structure-function relationship of the mutant protein. To identify a genetic cause of hypobetalipoproteinemia in a patient with levels of low density lipoprotein cholesterol at the detection limit of 0.1 mmol/l. DNA sequencing of the translated exons with flanking intron sequences of the genes adenosine triphosphate-binding cassette transporter 1, angiopoietin-like protein 3, apolipoprotein B, apolipoprotein A1, lecithin-cholesterol acyltransferase, microsomal triglyceride transfer protein and proprotein convertase subtilisin/kexin type 9. The patient was homozygous for mutation Q384K (c.1150C>A) in the apolipoprotein B gene, and this mutation segregated with hypobetalipoproteinemia in the family. Residue Gln 384 is located in the large lipid transfer module of apoB that has been suggested to be important for lipidation of apolipoprotein B through interaction with microsomal triglyceride transfer protein. Based on measurements of serum levels of triglycerides and apolipoprotein B-48 after an oral fat load, we conclude that the patient was able to synthesize apolipoprotein B-48 in the intestine in a seemingly normal fashion. Our data indicate that mutation Q384K severely reduces the secretion of apolipoprotein B-100 in the liver without reducing the secretion of apolipoprotein B-48 in the intestine. Possible mechanisms for the different effects of this and other missense mutations affecting the large lipid transfer module on the two forms of apoB are discussed. [ABSTRACT FROM AUTHOR]

• Nonalcoholic fatty liver disease (NAFLD) severity on liver biopsy has an inverse relationship with Lp(a) level. Patients with non-alcoholic steatohepatitis (NASH) on histology had 50% lower Lp(a) compared to patients with nonalcoholic fatty liver (NAFL). • Conversely, NAFLD severity has a direct relationship with other markers of atherogenic dyslipidemia, including HDL-C, triglycerides, apolipoprotein-B (ApoB), and low-density lipoprotein particle concentration (LDL-P). • This relationship may have implications for prognosticating cardiovascular disease risk in patients with NAFLD. Nonalcoholic fatty liver disease (NAFLD) is associated with atherogenic dyslipidemia and an increased risk of cardiovascular events. Previous studies have suggested an inverse relationship between NAFLD severity and lipoprotein(a) [Lp(a)] level, but contemporary data from the U.S. are lacking. Lp(a), lipid profile, apolipoproteins, and nuclear magnetic resonance-based lipoprotein particle concentrations were measured in 151 patients with biopsy-proven NAFLD. Levels were compared between those with nonalcoholic fatty liver (NAFL) on histology and non-alcoholic steatohepatitis (NASH). Median age was 55 [48, 62] years, 67% of patients were women, 83% were White, 43% had NAFL, and 57% had NASH. Triglyceride level was higher and high-density lipoprotein-cholesterol (HDL-C) was lower among those with NASH as compared with NAFL. Circulating apolipoprotein-B (ApoB) and low-density lipoprotein particle concentration (LDL-P) were 9% and 17% higher in the NASH group as compared with NAFL, respectively. Contrastingly, Lp(a) concentration was 50% lower in NASH relative to NAFL group. Hepatocyte ballooning, lobular inflammation, and fibrosis on histology were inversely associated with Lp(a) concentration. NAFLD severity has a discordant association with Lp(a) and other markers of atherogenic dyslipidemia. This relationship may have implications for prognosticating cardiovascular disease risk in patients with NAFLD. [ABSTRACT FROM AUTHOR]

• In FD, PCSK9 mAbs in particular reduce smaller and cholesterol-rich lipoproteins. • PCSK9 mAbs do not affect CM metabolism. • PCSK9 mAbs probably achieve their effects by increased hepatic clearance. Proprotein convertase subtilisin kexin type 9 (PCSK9) monoclonal antibodies (mAbs) reduce fasting and post fat load cholesterol in non-HDL and intermediate density lipoprotein (IDL) in familial dysbetalipoproteinemia (FD). However, the effect of PCSK9 mAbs on the distribution and composition of atherogenic lipoproteins in patients with FD is unknown. To evaluate the effect of the PCSK9 mAb evolocumab added to standard lipid-lowering therapy in patients with FD on fasting and post fat load lipoprotein distribution and composition. Randomized placebo-controlled double-blind crossover trial comparing evolocumab (140 mg subcutaneous every 2 weeks) with placebo during two 12-week treatment periods. Patients received an oral fat load at the start and end of each treatment period. Apolipoproteins (apo) were measured with ultracentrifugation, gradient gel electrophoresis, retinyl palmitate and SDS-PAGE. PCSK9 mAbs significantly reduced particle number of all atherogenic lipoproteins, with a stronger effect on smaller lipoproteins than on larger lipoproteins (e.g. IDL-apoB 49%, 95%confidence interval (CI) 41–59 and very low-density lipoprotein (VLDL)-apoB 33%, 95%CI 16-50). Furthermore, PCSK9 mAbs lowered cholesterol more than triglyceride (TG) in VLDL, IDL and low-density lipoprotein (LDL) (e.g. VLDL-C 48%, 95%CI 29–63%; and VLDL-TG 20%, 95%CI 6.3–41%). PCSK9 mAbs did not affect the post fat load response of chylomicrons. PCSK9 mAbs added to standard lipid-lowering therapy in FD patients significantly reduced lipoprotein particle number, in particular the smaller and more cholesterol-rich lipoproteins (i.e. IDL and LDL). PCSK9 mAbs did not affect chylomicron metabolism. It seems likely that the observed effects are achieved by increased hepatic lipoprotein clearance, but the specific working mechanism of PCSK9 mAbs in FD patients remains to be elucidated. [Display omitted] [ABSTRACT FROM AUTHOR]

• Discordant Apo B was defined by both residuals and cut-off values. • Discordant Apo B was associated with intra-/extra-cranial atherosclerotic plaques. • Discordant Apo B may be a risk factor for cerebrovascular atherosclerosis. Data are limited on associations between apolipoprotein B (Apo B) and cerebral atherosclerosis. Our study aimed to estimate associations between discordant Apo B with low-density lipoprotein cholesterol (LDL-C) or non-high-density lipoprotein cholesterol (Non-HDL-C) and the odds of the presence and burden of intra-/extra-cranial atherosclerotic plaques. This cross-sectional study was based on the baseline survey from the PolyvasculaR Evaluation for Cognitive Impairment and vaScular Events (PRECISE) study, a population-based prospective cohort study. Participants with complete baseline data but without taking lipid-lowering medication were included in this analysis. Discordant Apo B with LDL-C or Non-HDL-C were defined by residuals and cut-off values (LDL-C: 3.4 mmol/L, Non-HDL-C: 4.1 mmol/L). We used binary and ordinal logistic regression models to explore associations between discordant Apo B with LDL-C or Non-HDL-C and the presence and burden of intra-/extra-cranial atherosclerotic plaques. A total of 2,943 participants were enrolled in this study. Discordantly high Apo B with LDL-C was associated with an increased odds of the presence of intracranial atherosclerotic plaque [odds ratio (OR),1.28; 95%CI,1.01-1.61], intracranial atherosclerotic burden [common odds ratio (cOR), 1.31; 95%CI,1.04-1.64], the presence of extracranial atherosclerotic plaque (OR, 1.37; 95%CI,1.14-1.66), and extracranial atherosclerotic burden (cOR, 1.32; 95%CI,1.10-1.58) compared with the concordant group. Discordantly low Apo B with Non-HDL-C was associated with decreased odds of the presence and burden of intra-/extra-cranial atherosclerotic plaques. Discordantly high Apo B with LDL-C or Non-HDL-C were associated with an increased odds of the presence and burden of intra-/extra-cranial atherosclerotic plaques. This demonstrated that discordantly high Apo B might be important for early assessment of risk of cerebral atherosclerotic plaques in addition to LDL-C and Non-HDL-C. [ABSTRACT FROM AUTHOR]

BackgroundIn hemodialysis (HD) patients, higher lipid levels are associated with lower mortality. Lipid-lowering therapy does not reduce all-cause mortality or cardiovascular (CV) mortality. Lipoproteins play a role in the innate immune system. Our objective was to determine whether protection from infection might counterbalance adverse CV outcomes associated with lipoproteins.MethodsWe examined associations between serum apolipoprotein (Apo) A1, B, C2, C3, high-density lipoprotein and low-density lipoprotein (LDL) cholesterol and triglyceride levels and infectious mortality or hospitalization, CV mortality or hospitalization, and all-cause mortality in 433 prevalent HD patients. Cox models with time-varying apolipoprotein concentrations collected every 6 months for up to 2 years were used for analyses.ResultsMedian follow-up time for all-cause mortality was 2.7 years (25th-75th percentile range: 2.2-3.4 years). One hundred seventy-nine (41%) patients had an infection-related event. In multivariable models, higher Apo B and LDL were associated with lower risks of infection-related outcomes (hazard ratio Apo B 0.92 [95% confidence interval 0.86-0.99 per 10 mg/dL, P = .03]; hazard ratio LDL 0.93 [95% confidence interval 0.87-1.00 per 10 mg/dL, P = .05]). Sixty-three (15%) participants had a CV-related event. No significant associations were observed between lipoproteins and CV outcomes. Eighty-seven (20%) participants died. Higher Apo A1, Apo B, and Apo C3 were associated with lower risks of all-cause mortality. There was no interaction between the use of lipid-lowering medication and any of the outcomes.ConclusionAssociations of lipoproteins with lower risk of serious infection accompanied by no significant association with CV events may help to explain the paradoxical association between lipids and survival and lack of benefit of lipid-lowering therapies in HD.

Objective: The importance of any enhanced atherogenicity of triglyceride (TG)-rich lipoproteins (TRLs) will depend on the relative abundance of these particles compared with LDL or total apolipoprotein (apo)B. Accordingly, we determined the contribution that TRLs make to total apoB as TG or apoB concentrations increase. We also describe compositional changes in TRLs as TG or apoB increase to assess whether VLDL-C is a valid proxy for VLDL-apoB., Methods: We used sequential ultracentrifugation to separate lipoprotein fractions in plasma samples from 1940 dyslipidemic patients not on lipid-lowering medication, and measured apoB, cholesterol and TG in the plasma and in each subfraction. We analyzed this data in quartiles of TG or apoB., Results: There was wide variance in all parameters in all quartiles of both TG and apoB. Although VLDL-apoB accounted for almost all the increase in total apoB across TG quartiles, LDL-apoB still accounted for 80 % of the total in TG quartile 4. In contrast, LDL-apoB accounted for 90 % of the increase in apoB across apoB quartiles. As TG increases, the increase in VLDL-C is explained more by increased VLDL-C/apoB when TG is moderately elevated, and more by increased VLDL-apoB when TG is very high., Conclusions: In conclusion, VLDL-apoB only becomes a substantial component of total apoB with extreme hypertriglyceridemia and VLDL-C is not an appropriate proxy for VLDL-apoB., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2024. Published by Elsevier Inc.)

This National Lipid Association (NLA) Expert Clinical Consensus provides an overview of the physiologic and clinical considerations regarding the role of apolipoprotein B (apoB) measurement to guide clinical care based on the available scientific evidence and expert opinion. ApoB represents the total concentration of atherogenic lipoprotein particles in the circulation and more accurately reflects the atherogenic burden of lipoproteins when compared to low-density lipoprotein cholesterol (LDL-C). ApoB is a validated clinical measurement that augments the information found in a standard lipoprotein lipid panel; therefore, there is clinical value in using apoB in conjunction with a standard lipoprotein lipid profile when assessing risk and managing lipid-lowering therapy (LLT). ApoB has been shown to be superior to LDL-C in risk assessment both before and during treatment with LLT. In individuals, there can be discordance between levels of LDL-C and apoB, as well as LDL-C and non-high-density lipoprotein cholesterol (non-HDL-C), despite high levels of population-wide correlation. When there is discordance between LDL-C and apoB, or LDL-C and non-HDL-C, atherosclerotic cardiovascular disease risk generally aligns better with apoB or non-HDL-C. Additionally, apoB can be used in tandem with standard lipoprotein lipid measurements to diagnose distinct lipoprotein phenotypes. ApoB testing can inform clinical prognosis and care, as well as enable family cascade screening, when an inherited lipoprotein syndrome is identified. The NLA and other organizations will continue to educate clinicians about the role of apoB measurement in improving clinical risk assessment and dyslipidemia management. An urgent need exists to improve access and reimbursement for apoB testing., (Copyright © 2024. Published by Elsevier Inc.)

• Patients with no apo B-containing lipoproteins can develop severe complications. • We have followed three such patients for >40 years. • All three patients are clinically and particularly neurologically stable. • A liver biopsy in one patient showed minimal pathology. • Adhering to high dose fat soluble vitamins was associated with favorable outcomes. Complete deficiency of apolipoprotein (apo) B-containing lipoproteins can result from both abetalipoproteinemia (ABL) and homozygous hypobetalipoproteinemia (HoHBL), caused by bi-allelic loss-of-function variants in the MTTP and APOB genes encoding microsomal triglyceride transfer protein and apolipoprotein (apo) B, respectively. Both conditions are associated with failure to assemble and secrete apo B-containing lipoproteins from intestine and liver, resulting in absence of chylomicrons, very low-density lipoproteins and remnants, and low-density lipoproteins. Because absorption and transport of fat soluble vitamins requires intact production of apo B-containing lipoproteins, untreated patients develop fat soluble vitamin deficiencies, with associated clinical features including atypical retinitis pigmentosa, osteopenia, neuromyopathy and coagulopathy. Other features include acanthocytosis on the peripheral blood film, fat malabsorption and hepatosteatosis. We describe two patients with ABL and one with HoHBL who have each been on high dose oral fat soluble vitamin replacement under the care of the same physician for more than four decades. Each patient has remained clinically stable. A recent liver biopsy from an ABL patient showed mild macrovesicular steatosis, patchy microvesicular steatosis and mild fibrosis. These observations add to our understanding of the long term trajectory of ABL and HoHBL, and emphasize the importance of compliance to treatment and follow up. [ABSTRACT FROM AUTHOR]

Background: Case-control, intervention and laboratory studies have demonstrated a link between apolipoprotein B-containing lipoproteins and clot structure and thrombosis. There is, however, limited evidence on population level., Objectives: We determined the cross-sectional relationship between lipoprotein(a) (Lp(a)), low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B (ApoB) with fibrinogen and plasma clot properties in 1 462 Black South Africans, a population with higher fibrinogen and Lp(a) levels compared with individuals of European descent., Methods: Data were obtained from participants in the South African arm of the Prospective Urban and Rural Epidemiology study. Clot properties analysed included lag time, slope, maximum absorbance, and clot lysis time (turbidity). Lp(a) was measured in nM using particle-enhanced immunoturbidimetry. General linear models (GLM) were used to determine the associations between ApoB and ApoB-containing lipoproteins with fibrinogen and plasma clot properties. Stepwise regression was used to determine contributors to clot properties and Lp(a) variance., Results: GLM and regression results combined, indicated fibrinogen concentration and rate of clot formation (slope) had the strongest association with Lp(a); clot density associated positively with both Lp(a) and LDL-C; time to clot formation associated negatively with ApoB; and CLT demonstrated strong positive associations with both ApoB and LDL-C, while its association with Lp(a) was fibrinogen concentration dependent., Conclusion: These findings suggest that ApoB and the lipoproteins carrying it contribute to prothrombotic clot properties in Africans on epidemiological level and highlight potential novel prothrombotic roles for these (apo)lipoproteins to be considered for the development of targeted therapeutic approaches to address thrombotic conditions related to clot properties., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: This work was supported by the North-West University, South African National Research Foundation, Population Health Research Institute, and the South African Medical Research Council (SAMRC-RFA-EMU-1-0-2020). None of the funding bodies was involved in the design of the study, collection, analysis, or interpretation of the data or in writing of this manuscript. Opinions expressed and conclusions arrived at are those of the authors and are not to be attributed to the funding sources., (Copyright © 2024. Published by Elsevier Inc.)

Background: Blood lipid levels were associated with chronic kidney disease (CKD) in patients with type 2 diabetes (T2D), but the genetic basis and causal nature remains unclear., Objective: This study aimed to investigate the relationships of lipids and their fractions with CKD in patients with T2D., Methods: Our prospective analysis involved 8,607 White participants with T2D but no CKD at baseline from the UK Biobank. Five common lipid traits were included as exposures. Weighted genetic risk scores (GRSs) for these lipid traits were developed. The causal associations between lipid traits, as well as lipid fractions, and CKD were explored using linear or nonlinear Mendelian randomization (MR). The 10-year predicted probabilities of CKD were evaluated via integrating MR and Cox models., Resutls: Higher GRS of apolipoprotein B (ApoB) was associated with an increased CKD risk (HR[95 % CI]:1.07[1.02,1.13] per SD;P = 0.008) after adjusting for potential confounders. Linear MR indicated a positive association between genetically predicted ApoB levels and CKD (HR[95 % CI]:1.53[1.12,2.09];P = 0.008), but no evidence of associations was found between other lipid traits and CKD in T2D. Regarding 12 ApoB-contained lipid fractions, a significant causal association was found between medium very-low-density lipoprotein particles and CKD (HR[95 % CI]:1.16[1.02,1.32];P = 0.020). Nonlinear MR did not support nonlinearity in these causal associations. The 10-year probability curve showed that ApoB levels was positively associated with the risk of CKD in patients with T2D., Conclusion: Lower ApoB levels were causally associated with a reduced risk of CKD in patients with T2D, positioning ApoB as a potential therapeutic target for CKD prevention in this population., Competing Interests: Declaration of competing interest The authors declare there is no conflict of interests., (Copyright © 2024. Published by Elsevier Inc.)

• Evolocumab was well tolerated in patients aged ≥12 and <80 years with HoFH in India. • Evolocumab was generally associated with reduction in LDL-C. • Lipid-lowering efficacy of evolocumab varied by age and baseline LDL-C. • Pharmacogenetic testing of HoFH patients may identify responders to evolocumab. Evolocumab is a fully human monoclonal antibody inhibitor of proprotein convertase subtilisin/kexin type 9 approved in India for treatment of homozygous familial hypercholesterolemia (HoFH) in patients aged ≥12 years. RAMAN (NCT03403374) was a single-country, open-label, phase 4 study evaluating the safety and tolerability of evolocumab in patients with HoFH in India. Patients ≥12 to ≤80 years of age on stable lipid-lowering therapy with fasting low-density lipoprotein cholesterol (LDL-C) >3.4 mmol/L (>130 mg/dL) received evolocumab 420 mg subcutaneously monthly (every 2 weeks if on apheresis). The primary endpoint was patient incidence of treatment-emergent adverse events. Secondary endpoints included percent changes at week 12 in LDL-C and other lipids. Of 30 enrolled patients, 13 were <18 years of age. Mean±SD baseline levels of LDL-C, apolipoprotein B, and lipoprotein(a) were 12.3 ± 3.5 mmol/L (473.5 ± 135.2 mg/dL), 2.8 ± 0.7 g/L (275.3 ± 69.1 mg/dL), and 201.3 ± 177.6 nmol/L, respectively. Ten patients (33%) reported treatment-emergent adverse events, with 2 (7%) serious adverse events and none leading to discontinuation; no deaths occurred during evolocumab treatment. At week 12, mean (SE) percent changes from baseline in LDL-C, apolipoprotein B, and lipoprotein(a) were −6.4% (4.2), −6.0% (3.7), and −0.2% (4.9), respectively. Reductions in LDL-C among individual patients were variable and greatest in patients ≥18 years of age and with baseline LDL-C <13 mmol/L (<500 mg/dL). Evolocumab was safe and well tolerated in patients with HoFH in India with smaller reductions in LDL-C and other lipids than those observed in previous studies with HoFH and different populations. [Display omitted] [ABSTRACT FROM AUTHOR]

• It is acceptable to screen with nonfasting lipids. • It is recommended to follow up abnormal results with fasting levels. • Non-HDL cholesterol levels can effectively guide ASCVD prevention. • Advanced lipoprotein tests may guide therapeutic decisions in select patients. • Better harmonization of advanced lipid measurement methods is needed. • Recommendations for lipids in clinical care. Lipoprotein measurements are pivotal in the management of patients at risk for atherosclerotic coronary heart disease (CHD) with myocardial infarction and coronary death as the main outcomes, and for atherosclerotic cardiovascular disease (ASCVD), which includes CHD and stroke. Recent developments and changes in guidelines affect optimization of using lipid measures as cardiovascular biomarkers. This scientific statement reviews the pre-analytical, analytical, post-analytical, and clinical aspects of lipoprotein measurements. Highlights include the following: i) It is acceptable to screen with nonfasting lipids. ii) non-high-density lipoprotein HDL-cholesterol (non-HDL-C) is measured reliably in either the fasting or the nonfasting state and can effectively guide ASCVD prevention. iii) low density lipoprotein cholesterol (LDL-C) can be estimated from total cholesterol, high density lipoprotein cholesterol (HDL-C), and triglyceride (TG) measurements. For patients with LDL-C>100 mg/dL and TG ≤150 mg/dL it is reasonable to use the Friedewald formula. However, for those with TG 150-400 mg/dL the Friedewald formula for LDL-C estimation is less accurate. The Martin/Hopkins method is recommended for LDL-C estimation throughout the range of LDL-C levels and up to TG levels of 399 mg/dL. For TG levels ≥400 mg/dL LDL-C estimating equations are currently not recommended and newer methods are being evaluated. iv) When LDL-C or TG screening results are abnormal the clinician should consider obtaining fasting lipids. v) Advanced lipoprotein tests using apolipoprotein B (apoB), LDL Particle Number (LDL-P) or remnant cholesterol may help to guide therapeutic decisions in select patients, but data are limited for patients already on lipid lowering therapy with low LDL-C levels. Better harmonization of advanced lipid measurement methods is needed. Lipid measurements are recommended 4-12 weeks after a change in lipid treatment. Lipid laboratory reports should denote desirable values and specifically identify extremely elevated LDL-C levels (≥190 mg/dL at any age or ≥160 mg/dL in children) as severe hypercholesterolemia. Potentially actionable abnormal lipid test results, including fasting triglycerides (TG) ≥500 mg/dL, should be reported as hypertriglyceridemia. Appropriate use and reporting of lipid tests should improve their utility in the management of persons at high risk for ASCVD events. [ABSTRACT FROM AUTHOR]

Severe hypertriglyceridemia (HTG) is a common cause of acute pancreatitis, although even moderate HTG may elevate this risk. Identifying patients who are prone to hypertriglyceridemic pancreatitis (HTGP) can facilitate early, preventative interventions. To examine advanced lipoprotein profile (ALP) of hypertriglyceridemic patients with and without HTGP to identify lipid and lipoprotein parameters which may help improve risk stratification. This was a retrospective cohort study of adult patients with serum triglycerides (TGs) ≥ 500 mg/dL who underwent ALP testing. Chart reviews were conducted to identify those who developed HTGP or not. Comparisons of lipid profiles of patients with and without HTGP were performed using chi-square or rank-sum tests. ROC curves were generated to identify lipid and lipoprotein parameters which helped improve prediction of HTGP beyond serum TG levels. Fifty-eight subjects were included in the analysis. Twenty had at least one documented episode of HTGP. Among patients with HTGP, median serum TG concentrations were 2832 mg/dL vs. 978 mg/dL in the non-pancreatitis group (p < 0.001). Chylomicron TG/total TG, chylomicron TG/VLDL TG, chylomicron TG/apoB, total TG/total Cholesterol, and total TG/apoB were significantly higher among the pancreatitis group. Total serum TG/apoB had the best discriminant value for predicting HTGP with an AUC-ROC of 0.87 (p < 0.001). A cutoff of >10.6 was associated with a sensitivity of 90% and specificity of 75%. Measurement of serum apoB levels and calculation of s erum TG/apoB ratio may help identify hypertriglyceridemic patients at risk for HTGP. • Acute pancreatitis (AP) is a serious complication of hypertriglyceridemia. • Whether other lipid parameters besides serum TG predict risk for AP is not known. • Serum TG/apoB ratio improves risk estimation for AP beyond serum TG. [ABSTRACT FROM AUTHOR]

Non-high density lipoprotein cholesterol (non-HDLC) represents the cholesterol in triglyceride-rich lipoproteins (TRL) and low-density lipoproteins (LDL). Apolipoprotein B (apoB) reflects the number of TRL and LDL particles. In hypertriglyceridemia (HTG), there is triglyceride (TG) enrichment of TRLs, and also a substantial increase of cholesterol in larger TRLs that considerably augments the non-HDLC value. Therefore, in HTG, non-HDLC could increase disproportionately with respect to apoB. We aimed to compare the relative effect of the full range of mild, moderate, and severe HTG on the status of non-HDLC and apoB as cardiovascular disease (CVD) risk markers. Analysis of lipid profile data from 4347 patients in a Lipid Clinic cohort with baseline fasting lipid profiles documented prior to starting lipid-lowering medications. The correlation between non-HDLC and apoB was assessed in intervals of increasing TG. Non-HDLC and apoB were analyzed at each TG level using comparative CVD risk equivalent categories and assessed for divergence and discordance. With increasing TG levels: (1) the correlation between non-HDLC and apoB diminished progressively, (2) non-HDLC levels increased continuously, whereas apoB levels plateaued after an initial increase up to TG of ~ 4.0-5.0 mmol/L (~354-443 mg/dL), (3) there was divergence in the stratification of non-HDLC and apoB into CVD risk equivalent categories. Non-HDLC and apoB should not be viewed as interchangeable CVD risk markers in the presence of severe HTG. This has never been tested. With increasing HTG severity, discordance between non-HDLC and apoB can cause clinically important divergence in CVD risk categorization. • As TG increases, the correlation between non-HDLC and apoB decreases progressively. • In HTG, discordant non-HDLC and apoB causes divergence in CVD risk categorization. • Non-HDLC and apoB should not be viewed as interchangeable CVD risk markers in HTG. [ABSTRACT FROM AUTHOR]

A 22-year-old woman presented with elevated low-density lipoprotein (LDL) cholesterol and clinically suspected familial hypercholesterolemia. Initial genetic analysis by Sanger sequencing found no causal variants in LDLR or other familial hypercholesterolemia genes. More than a decade later, her 9-year-old daughter was also found to have elevated LDL cholesterol. Re-analysis using current genetic methodology detected a novel whole-gene duplication of APOB in both individuals, which was tentatively assumed to explain their elevated LDL cholesterol based mainly on biological plausibility. However, on further assessment with cascade screening and cosegregation analysis involving multiple family members, the APOB duplication was eventually discounted as being causative. This case illustrates the risk of assuming pathogenicity of a novel genetic variant without undertaking corroborative diagnostic measures. It further highlights the time and skill required for accurate variant analysis and emphasizes the challenges faced by clinicians who are increasingly expected to rapidly interpret such results without sufficient time or resources to pursue supportive or corroborating evidence. • Familial hypercholesterolemia is a complex trait influenced by monogenic, polygenic, and environmental factors. • Many patients with elevated low-density lipoprotein (LDL) cholesterol have no identifiable genetic cause. • DNA variant interpretation requires strong foundational knowledge of genetics. • Cosegregation analysis provides additional evidence for novel DNA variants. [ABSTRACT FROM AUTHOR]

Dysbetalipoproteinemia (DBL) is a disease of remnant lipoprotein accumulation caused by a defective apolipoprotein (apo) E and is associated with a considerable atherogenic burden. However, there exists confusion concerning the diagnosis of this disorder, and as a consequence, misdiagnosis is frequent. The objective of the present study is to propose an algorithm for the diagnosis of DBL using simple clinical variables. In a large cohort of 12,434 dyslipidemic patients, 4891 patients presented with mixed dyslipidemia (total cholesterol ≥ 5.2 mmol/L [200 mg/dL] and triglycerides ≥ 2.0 mmol/L [175 mg/dL]), and 188 DBL patients were identified based on the presence of an elevated very-low-density lipoprotein cholesterol/triglyceride ratio and were carriers of apoE2/E2. The APOE genotype or phenotype as well as the lipoprotein ultracentrifugation results were available for all patients. Among the laboratory variables associated with the lipid profile, the non-high-density lipoprotein cholesterol (HDL-C)/apoB ratio was the best predictor of DBL diagnosis based on the C-statistic. Previous proposed criteria had either low sensitivity or low specificity for the diagnosis of DBL. Using a non-HDL-C/apoB cut point of 3.69 mmol/g (1.43 in conventional units) followed by the presence of apoE2/E2 resulted in a good sensitivity (94.8%), negative predictive value (99.8%), specificity (99.6%), positive predictive value (88.5%), accuracy (99.4%), and area under the curve (0.97 [0.95–0.99]) for the prediction of DBL. We therefore propose a 3-step algorithm for the diagnosis of DBL using total cholesterol and triglycerides as a first step, the non-HDL-C/apoB ratio as a second screening criterion and finally the APOE genotype, lipoprotein ultracentrifugation, or electrophoresis as a confirmatory test. • Misdiagnosis of dysbetalipoproteinemia (DBL) is frequent among dyslipidemic patients • The non-HDL-C/apoB ratio ≥ 3.69 mmol/g is a good screening criterion for DBL • Confirmation of the DBL diagnosis by APOE genotype offered excellent performance [ABSTRACT FROM AUTHOR]

Familial hypercholesterolemia is characterized by high levels of low-density lipoprotein cholesterol (LDL-C), and causes of familial hypercholesterolemia include apolipoprotein B (APOB) loss-of-function mutations (LOFm) and proprotein convertase subtilisin/kexin type 9 (PCSK9) gain-of-function mutations (GOFm). The aim of this study was to compare the pharmacokinetics and pharmacodynamics of alirocumab between patients with APOB LOFm vs PCSK9 GOFm. Patients (6 APOB LOFm and 17 PCSK9 GOFm carriers) with LDL-C ≥70 mg/dL on maximally tolerated lipid-lowering therapies received alirocumab 150 mg at Weeks 0, 2, 4, and 6, placebo at Week 8, alirocumab at Week 10, placebo at Weeks 12 and 14, then completed a follow-up period at Week 22. At Week 8, mean ± standard error (SE) alirocumab concentration was lower in APOB LOFm carriers compared with PCSK9 GOFm carriers (12.12 ± 1.81 vs 16.74 ± 2.53 mg/L). APOB LOFm carriers had higher mean ± SE total PCSK9 (6.56 ± 0.73 mg/L) and lower mean ± SE free PCSK9 (0.025 ± 0.016 mg/L) at Week 8 compared with PCSK9 GOFm carriers (4.21 ± 0.35 and 0.11 ± 0.035 mg/L for total and free PCSK9, respectively). Despite this observed greater PCSK9 suppression, mean ± SE percent LDL-C reduction was lower in APOB LOFm (55.3 ± 1.0%) compared with PCSK9 GOFm carriers (73.1 ± 0.9%). Treatment-emergent adverse events occurred in 16 patients (94.1%) in the PCSK9 GOFm group and 5 patients (83.3%) in the APOB LOFm group. Overall, PCSK9 inhibition with alirocumab results in clinically meaningful reductions in LDL-C in both APOB LOFm and PCSK9 GOFm carriers, although reductions were greater in the PCSK9 GOFm carriers. The results indicate a possible underlying contributor to hypercholesterolemia other than PCSK9 in patients with APOB LOFm. NCT01604824; clinicaltrials.gov. • For the apolipoprotein B (APOB) loss-of-function mutations (LOFm) group, mean low-density lipoprotein cholesterol reduction from baseline was 55.3% at Week 8. • For the proprotein convertase subtilisin/kexin type 9 (PCSK9) gain-of-function mutations (GOFm) group, mean low-density lipoprotein cholesterol reduction from baseline was 73.1% at Week 8. • At Week 8, alirocumab levels were lower in APOB LOFm vs PCSK9 GOFm carriers. • PCSK9 suppression by alirocumab was greater in APOB LOFm vs PCSK9 GOFm carriers. • Treatment-emergent adverse events occurred in 94.1% and 83.3% of PCSK9 GOFm and APOB LOFm groups, respectively. [ABSTRACT FROM AUTHOR]

Background Abetalipoproteinemia, a recessive disease resulting from deleterious variants in MTTP (microsomal triglyceride transfer protein), is characterized by undetectable concentrations of apolipoprotein B, extremely low levels of low-density lipoprotein cholesterol in the plasma, and a total inability to export apolipoprotein B–containing lipoproteins from both the intestine and the liver. Objective To study lipid absorption after a fat load and liver function in 7 heterozygous relatives from 2 abetalipoproteinemic families, 1 previously unreported. Results Both patients are compound heterozygotes for p.(Arg540His) and either c.708_709del p.(His236Glnfs*11) or c.1344+3_1344+6del on the MTTP gene. The previously undescribed patient has been followed for 22 years with ultrastructure analyses of both the intestine and the liver. In these 2 families, 5 relatives were heterozygous for p.(Arg540His), 1 for p.(His236Glnfs*11) and 1 for c.1344+3_1344+6del. In 4 heterozygous relatives, the lipid absorption was normal independent of the MTTP variant. In contrast, in 3 of them, the increase in triglyceride levels after fat load was abnormal. These subjects were additionally heterozygous carriers of Asp2213 APOB in-frame deletion, near the cytidine mRNA editing site, which is essential for intestinal apoB48 production. Liver function appeared to be normal in all the heterozygotes except for one who exhibited liver steatosis for unexplained reasons. Conclusion Our study suggests that a single copy of the MTTP gene may be sufficient for human normal lipid absorption, except when associated with an additional APOB gene alteration. The hepatic steatosis reported in 1 patient emphasizes the need for liver function tests in all heterozygotes until the level of risk is established. Highlights • Genetic, clinical, ultrastructural, and biological characteristics of a new abetalipoproteinemia (ABL) case. • Postprandial studies in the new ABL case and 7 heterozygous carriers. • Normal lipid absorption in MTTP heterozygotes except if additional APOB alteration. • Need for genetic cascade screening in ABL relatives. • Need for liver and lipid absorption monitoring in ABL heterozygotes. [ABSTRACT FROM AUTHOR]

Background Statin therapy is recommended in type 2 diabetes (T2DM) although views on treatment intensity and therapeutic targets remain divided. Objectives Our objectives were to compare the effects of high-intensity and moderate-intensity atorvastatin treatment on lipoprotein metabolism and inflammatory markers and how frequently treatment goals are met in high-risk T2DM patients. Methods Patients with T2DM and albuminuria (urinary albumin:creatinine ratio >5 mg/mmol, total cholesterol <7 mmol/L, proteinuria <2 g/d, creatinine <200 μmol/L) were randomized to receive atorvastatin 10 mg ( n = 59) or 80 mg ( n = 60) daily. Baseline and 1-year follow-up data are reported. Results Patients were at high cardiovascular disease risk (observed combined mortality and nonfatal cardiovascular disease annual event rate 4.8%). The non-high-density lipoprotein cholesterol (HDL-C) goal of <2.6 mmol/L was achieved in 72% of participants receiving high-dose atorvastatin, but only in 40% on low-dose atorvastatin ( P < .005). The proportion achieving apolipoprotein B (apoB) <0.8 g/L on high-dose and low-dose atorvastatin was 82% and 70%, respectively (NS). Total cholesterol, triglycerides, low-density lipoprotein (LDL) cholesterol, non-HDL-C, oxidized LDL, apoB, glyc-apoB, apolipoprotein E, and lipoprotein-associated phospholipase A2 decreased significantly, more so in participants on high-dose atorvastatin. Adiponectin increased and serum amyloid A decreased without dose dependency. Neither dose produced significant changes in HDL-C, cholesterol efflux, high-sensitivity C-reactive protein, glycated hemoglobin, serum paraoxonase-1, lecithin:cholesterol acyltransferase, or cholesteryl ester transfer protein. Conclusions High-dose atorvastatin is more effective in achieving non-HDL-C therapeutic goals and in modifying LDL-related parameters. Recommended apoB treatment targets may require revision. Despite the increase in adiponectin and the decrease in serum amyloid A, HDL showed no change in functionality. [ABSTRACT FROM AUTHOR]

Background Increased serum triglyceride and apolipoprotein B (apoB) levels and decreased high-density lipoprotein cholesterol (HDL-C) levels are risk factors for cardiovascular diseases. The major types of dyslipidemia in Chinese population are hypertriglyceridemia and low HDL-C. Objective This study aimed to evaluate the effect of HDL-C, triglyceride, and apoB levels on the risk of coronary heart disease (CHD) in a Chinese population undergoing coronary angiography. Methods This was a cross-sectional study. A total of 1941 consecutive patients who were referred to coronary angiography for the evaluation of suspected CHD were recruited. Lipid parameters were measured after an overnight fast. Patients were diagnosed with CHD and without CHD based on the findings of the coronary angiography. Results There were 1363 angiography confirmed CHD patients and 578 non-CHD patients. In nonstatin users, the major types of dyslipidemia were hypertriglyceridemia combined with low HDL-C, isolated low HDL-C, and isolated hypertriglyceridemia, accounting for 21.60%, 19.70%, and 14.99%, respectively. In statin users, a low to moderate-intensity statin was effective in lowering low-density lipoprotein cholesterol (LDL-C). The proportion of reaching an LDL-C goal <2.6 mmol/L and <1.8 mmol/L in statin users was 83.20% and 55.19%, respectively. In nonstatin users, the triglyceride and apoB levels were higher and the HDL-C levels were lower in CHD patients compared with non-CHD patients after the adjustment of age, sex, body mass index, diabetes, smoking, and alcohol drinking ( P = .002, .007, and .005, respectively). After adjusting for age, sex, body mass index, diabetes, hypertension, smoking and alcohol drinking, the quartiles of triglyceride, HDL-C, and apoB were associated with CHD ( P for trend = .001, .005, and .003, respectively). Conclusion Serum triglyceride, HDL-C, and apoB levels were independently associated with CHD in a Chinese population undergoing coronary angiography with a relatively low level of LDL-C and a high prevalence of hypertriglyceridemia and low HDL-C. [ABSTRACT FROM AUTHOR]

Background Both apolipoprotein B (apoB) and non–high-density lipoprotein cholesterol (non–HDL-C) are accepted as alternative risk factors or targets for lipid-lowering therapy, which correlate more strongly with cardiovascular events than low-density lipoprotein cholesterol. Objective The aim of this cross-sectional study was to evaluate the differences in plasma levels of plasminogen activator inhibitor-1 (PAI-1) and of von Willebrand factor (vWF) as endothelial hemostatic markers and carotid intima-media thickness (C-IMT) as a morphologic marker for atherosclerotic vascular disease among dyslipidemic individuals with apoB levels higher, estimated or lower based on regression equation of apoB vs non–HDL-C. Methods A total of 594 dyslipidemic subjects without atherosclerotic manifestation were divided into 3 groups (according to tertiles of apoB levels above, within, and below the line of identity): H-apoB ( n = 200), E-apoB ( n = 194), and L-apoB ( n = 200). PAI-1, vWF, C-IMT and lipids, anthropometric parameters, markers of insulin resistance, and inflammation were measured. Differences in variables between groups were analyzed using analysis of variance. Results There was a strong association between apoB and non–HDL-C. The correlations of apoB and of non–HDL-C with markers of endothelial damage and C-IMT were very similar. Despite these facts, individuals with higher apoB levels had significantly higher levels of PAI-1 compared with individuals with estimated ( P < .05) or lower apoB ( P < .001). There were no significant differences in vWF, C-IMT, markers of insulin resistance, obesity, and inflammation. Conclusion Individuals with apoB higher than predicted by non–HDL-C had significantly higher levels of PAI-1, which may contribute to the increased risk of future atherothrombotic events. [ABSTRACT FROM AUTHOR]

Background Ezetimibe added to statin therapy further reduces LDL-C and clinical atherosclerotic cardiovascular disease compared to statin alone. However, the number of effective and safe oral agents for patients not at LDL-C goal is limited. In prior clinical trials, gemcabene reduced LDL-C and was generally well-tolerated in nearly 900 patients treated for up to 12 weeks. Objective To evaluate the LDL-C lowering and safety of gemcabene as add-on to stable statin therapy in hypercholesterolemic patients. Methods This was an 8-week, double-blind, placebo-controlled, randomized, phase 2 study in men and postmenopausal women ≥18 and ≤65 years of age with LDL-C ≥130 mg/dL (3.4 mmol/L) while on low-intensity to high-intensity stable statin (the majority on moderate intensity) therapy. Sixty-six patients were randomized 1:1:1 to gemcabene 300 mg, 900 mg, or placebo QD. Results Gemcabene 300 mg and 900 mg produced a mean percent change in LDL-C of −23.4 ± 4.7% ( P = .005) and −27.7 ± 4.3% ( P < .001), respectively, vs −6.2 ± 4.3% for placebo. The median percent change in CRP was −26.1% ( P = .196) and −53.9% ( P < .001) for gemcabene 300 mg and 900 mg, respectively, vs −11.1% for placebo. Gemcabene 300 mg and 900 mg were well-tolerated with no significant difference in AEs compared to placebo. Conclusions Gemcabene as add-on to stable statin therapy demonstrated additional dose-dependent and statistically significant reductions in LDL-C of >20% and CRP >40% compared to placebo. The results support gemcabene-continued development for patients requiring LDL-C lowering beyond that provided by background statin therapy. [ABSTRACT FROM AUTHOR]

Background Apolipoprotein E (apoE) is a component of all major lipoprotein classes with multiple functions including clearance of circulating triglyceride-rich lipoprotein particles and hepatic production of triglyceride-rich lipoprotein, thus affording several avenues for apoE involvement in atherosclerosis development. ApoE has 3 isoforms (E2, E3, and E4) based on a common genetic polymorphism. Numerous studies have been performed assessing cardiovascular disease (CVD) risk relative to the 6 resulting genotypes; however, surprisingly, few studies have been performed assessing risk attributable to apoE plasma levels either alone or in addition also taking into account apoE genotypes. Objective To examine the role of apoE levels together with apoE genotypes on incident CVD risk in a large population-based cohort and also to afford preliminary characterization of atherogenic apoE-containing lipoprotein particles. Methods Cox multivariable proportional hazards modeling was performed on a cohort of the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study as a function of apoE levels and apoE genotypes adjusted for age, gender, and past history of CVD. Further modeling was performed with single addition of clinical and biomarker parameters to elucidate the nature of apoE-associated risk. Results High apoE levels were demonstrated to be associated with CVD risk (hazard ratio per apoE standard deviation, 1.20; 95% confidence interval, 1.11–1.31; P < .0001) both overall and within the high-frequency apoE genotype groups (ε2ε3, ε3ε3, and ε3ε4). Only on addition of apoB-containing lipoprotein parameters to models, did apoE levels lose association with risk. Conclusions ApoE levels positively associate with incident CVD risk with apoE-associated risk likely residing in apoB-containing lipoproteins. [ABSTRACT FROM AUTHOR]

Background Atherogenic dyslipidemia is highly prevalent in the Arabian Gulf. Non–high-density lipoprotein cholesterol (non-HDL-C) reduction has been proposed as an additional goal to low-density lipoprotein cholesterol (LDL-C) lowering to prevent atherosclerotic cardiovascular disease (ASCVD). Data on non–HDL-C goal attainment in patients with high triglycerides (TGs) on lipid-lowering drugs (LLDs) in the region is scarce. Objective Evaluate non–HDL-C target attainment according to the National Lipid Association in patients on LLDs stratified by TG (<150 [1.69], 150–200 [1.69–2.26], >200 [2.26] mg/dL [mmol/L]) levels in the Arabian Gulf. Methods Overall, 4383 patients on LLD treatment from 6 Middle Eastern countries participating in the Centralized Pan-Middle East Survey on the Undertreatment of Hypercholesterolemia study were evaluated. Patients were classified according to TG levels and ASCVD risk. Results The overall non–HDL-C goal attainment was 41% of the subjects. Non–HDL-C goal was less likely attained in patients with high TGs (12% vs 27% vs 55%; P < .001). Very high ASCVD risk patients with high TGs attained less their non–HDL-C targets compared with those with lower TG levels (8% vs 23% vs 51%; P < .001). Similarly, high ASCVD risk patients with high TGs also failed more in attaining non–HDL-C targets compared with those with lower TGs (26% vs 42% vs 69%; P < .001). In addition, those with high TG also succeeded less in attaining LDL-C and apolipoprotein B goals ( P < .001). Conclusions A large proportion of very high and high ASCVD patients on LLDs in the Arabian Gulf are not at recommended non–HDL-C targets and hence remain at a substantial residual risk. [ABSTRACT FROM AUTHOR]

Background Nonalcoholic fatty liver disease (NAFLD) is associated with a higher risk of cardiovascular disease, but the relationship has not been established in nonobese populations. Higher apolipoprotein B (apo B) levels and the apo B/A1 ratio and lower apo A1 levels are associated with an elevated risk of cardiovascular disease. We investigated the associations between apo B, apo A1, and the apo B/A1 ratio and the presence of metabolic syndrome and NAFLD in both normal-weight and overweight Koreans. Methods This cross-sectional study consisted of 8327 consecutive both normal-weight and overweight Koreans with NAFLD diagnosed by ultrasonography at the Samsung Medical Center in Korea from January 2008 to December 2010. Results The prevalence of NAFLD was 27.1% among the 8327 participants. Higher serum triglyceride levels and the apo B/A1 ratio and lower high-density lipoprotein cholesterol and apo A1 levels were significantly associated with higher prevalence of metabolic syndrome in both normal-weight group and overweight group. The multivariate-adjusted odds ratios (ORs) for NAFLD in normal-weight group after comparing the fourth vs the first quartiles of the triglyceride, HDL cholesterol, low-density lipoprotein (LDL) cholesterol, apo B, apo A1, and the apo B/A1 ratio data were 2.89 (95% confidence interval [CI], 2.19–3.83; P trend < .001), 0.60 (95% CI, 0.46–0.78; P trend < .001), 1.67 (95% CI, 1.33–2.11; P trend < .001), 1.88 (95% CI, 1.48–2.39; P trend < .001), 0.73 (95% CI, 0.58–0.93; P trend < .001), and 1.86 (95% CI, 1.45–2.38; P trend < .001), respectively. The corresponding adjusted ORs in the overweight group were 3.43 (95% CI, 2.60–4.54; P trend < .001), 0.89 (95% CI, 0.68–1.16; P trend = .221), 1.41 (95% CI, 1.11–1.78; P trend = .001), 1.58 (95% CI, 1.21–2.06; P trend < .001), 0.99 (95% CI, 0.77–1.27; P trend = .958), and 1.53 (1.16–2.01; P trend = .002), respectively. Conclusions Higher serum triglyceride, LDL cholesterol, apo B1 levels, and the apo B/A1 ratio were significantly associated with NAFLD independent of metabolic syndrome in both normal-weight and overweight Koreans. Lower serum HDL cholesterol and apo A1 levels were related to NAFLD in normal-weight participants. Our results suggest that the presence of NAFLD may be associated with increased risk for coronary artery disease in both normal-weight and overweight Koreans. [ABSTRACT FROM AUTHOR]

Background Icosapent ethyl (IPE) is a high-purity prescription form of eicosapentaenoic acid ethyl ester approved at a dose of 4 g/day as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe hypertriglyceridemia (TG ≥ 500 mg/dL). Objective In this prespecified exploratory analysis from the ANCHOR study of patients at high cardiovascular risk with TG ≥ 200 and <500 mg/dL despite statin control of low-density lipoprotein cholesterol, we assessed the effects of IPE on lipoprotein particle concentration and size and examined correlations of atherogenic particles with apolipoprotein B (ApoB). Methods Nuclear magnetic resonance spectroscopy was used to measure lipoprotein particle concentration and size. Results Compared with placebo (n = 211), IPE 4 g/day (n = 216) significantly reduced concentrations of: total (12.2%, P = .0002), large (46.4%, P < .0001), and medium (12.1%, P = .0068) very-low-density lipoprotein (VLDL) particles; total (7.7%, P = .0017) and small (13.5%, P < .0001) LDL particles; and total (7.4%, P < .0001) and large (31.0%, P < .0001) high-density lipoprotein particles. Atherogenic lipoprotein particles (total VLDL and total LDL) correlated with ApoB at baseline ( R 2 = 0.57) and week 12 ( R 2 = 0.65) as did total LDL particle concentration at baseline ( R 2 = 0.53) and week 12 ( R 2 = 0.59). Compared with placebo, IPE 4 g/day significantly reduced VLDL (7.7%, P < .0001) and high-density lipoprotein (1.2%, P = .0014) particle sizes with a modest but significant increase in LDL particle size (0.5%, P = .0031). Conclusions Compared with placebo, treatment with IPE 4 g/day for 12 weeks reduced key atherogenic lipoprotein particle concentrations. At both baseline and end of study, atherogenic lipoprotein concentrations correlated with ApoB. [ABSTRACT FROM AUTHOR]

Familial hypobetalipoproteinemia is a codominant disorder characterized by low plasma levels of low-density lipoprotein cholesterol and apolipoprotein B (apoB), which in ∼50% of the cases is due to mutations in APOB gene. In most cases, these mutations cause the formation of truncated apoBs of various sizes, which have a reduced capacity to bind lipids and form lipoprotein particles. Here, we describe 2 children with severe hypobetalipoproteinemia found to be homozygous for novel APOB gene mutations. The first case (HBL-201) was an asymptomatic 13-year-old boy incidentally found to have slightly elevated serum transaminases associated with hepatic steatosis. He was homozygous for a truncated apoB (2211 amino acids, apoB-48.74) whose size is similar to that of wild-type apoB-48 (2152 amino acids) produced by the intestine. ApoB-48.74 is expected to be incorporated into chylomicrons in the intestine but might have a reduced capacity to form secretion-competent very low–density lipoprotein in the liver. The second patient (HBL-96) was a 6-month-old girl suspected to have abetalipoproteinemia, for the presence of chronic diarrhea, failure to thrive, extremely severe hypobetalipoproteinemia, and low plasma levels of vitamin E and vitamin A. She was homozygous for a nonsense mutation (Gln513*) resulting in a short truncated apoB (apoB-11.30), which is not secreted into the plasma. In this patient, the impaired chylomicron formation is responsible for the severe clinical manifestations and growth retardation. In homozygous familial hypobetalipoproteinemia, the capacity of truncated apoBs to form chylomicrons is the major factor, which affects the severity of the clinical manifestations. [ABSTRACT FROM AUTHOR]

Background Because of variability in lipoprotein cholesterol content, low-density lipoprotein (LDL) cholesterol frequently underrepresents or overrepresents the number of LDL particles. Mipomersen is an antisense oligonucleotide that reduces hepatic production of apolipoprotein B–100, the sole apolipoprotein of LDL. Objective To characterize the effects of mipomersen on lipoprotein particle numbers as well as subclass distribution using nuclear magnetic resonance (NMR) spectroscopy. Methods We compared the tertiary results for the direct measurement of LDL particle numbers by NMR among 4 placebo-controlled, phase 3 studies of mipomersen that had similar study designs but different patient populations: homozygous familial hypercholesterolemia (HoFH), severe hypercholesterolemia, heterozygous familial hypercholesterolemia with established coronary artery disease, or hypercholesterolemia with high risk for coronary heart disease (HC-CHD). Results HoFH patients had the highest median total LDL particles at baseline compared with HC-CHD patients, who had the lowest. At baseline, the HoFH population uniquely had a greater mean percentage of large LDL particles (placebo, 60.2%; mipomersen, 54.9%) compared with small LDL particles (placebo, 33.1%; mipomersen, 38.9%). In all 4 studies, mipomersen was associated with greater reductions from baseline in the concentrations of small LDL particles compared with those of large LDL particles, and both total LDL particles and small LDL particles were statistically significantly reduced. Conclusions Mipomersen consistently reduced all LDL particle numbers and preferentially reduced the concentration of small LDL particles in all 4 phase 3 studies. [ABSTRACT FROM AUTHOR]

Background Low-density lipoprotein cholesterol (LDL-C) is the primary target of lipid-lowering therapy in people at risk for cardiovascular diseases. Mipomersen inhibits apolipoprotein B-100 (apoB) synthesis and causes reduction in LDL-C by reducing apoB. Objective We aimed to perform a meta-analysis of all published randomized controlled trials comparing safety and efficacy of mipomersen with placebo in adults with dyslipidemia. Methods We searched PUBMED, CENTRAL, and EMBASE from inception through March 2014 and used random-effects model to compute the effect size. Results We identified 8 randomized controlled trials (n = 462). Mipomersen compared with placebo significantly reduced LDL-C by 32.37% (95% confidence interval, 25.55–39.18; P < .00001), total cholesterol by 24.18% (18.54–29.83; P < .00001), very low–density lipoprotein cholesterol by 21.59% (9.16–34.02; P = .0007), non–high-density lipoprotein cholesterol (HDL-C) by 30.83% (23.92–37.74; P < .00001), and triglycerides by 36.26% (22–50.54; P < .00001). It also significantly reduced apoB, lipoprotein(a), and apolipoprotein A1. However, mipomersen did not significantly change HDL-C levels. In safety analysis, mipomersen compared with placebo increased the risks of injection-site reaction (risk ratio, 2.05; 95% confidence interval, 1.39–3.04; P = .0003), flu-like symptoms (1.63; 1.22–2.17; P = .0008), alanine aminotransferase ≥3X upper limit of normal (4.44; 1.67–11.86; P = .003), and hepatic steatosis (3.85, 1.39–10.67; P = .01). The risks of alanine aminotransferase ≥10X upper limit of normal did not reach statistical significance (1.57; 0.32–7.6, P = .58). Conclusion Mipomersen resulted in a significant improvement in lipid parameters except for HDL-C and increased the risks of injection-site reactions, flu-like symptoms, and hepatic steatosis compared with placebo. [ABSTRACT FROM AUTHOR]