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  • The polygenic nature of mild-to-moderate hypertriglyceridemia
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2020-01-14
    Jacqueline S. Dron; Jian Wang; Adam D. McIntyre; Henian Cao; Robert A. Hegele

    Background Patients with mild-to-moderate hypertriglyceridemia (HTG) are thought to share specific genetic susceptibility factors that are also present in severe HTG patients, but no data have been reported on this issue. Objective To characterize genetic profiles of mild-to-moderate HTG patients and compare them to patients with severe HTG. Methods DNA from patients with mild-to-moderate HTG was sequenced using our targeted sequencing panel, “LipidSeq”. For each patient, we assessed: 1) rare variants disrupting five TG metabolism genes; and 2) the accumulation of 16 common SNPs using a polygenic risk score. The genetic profiles for these patients were then compared to normolipidemic controls and to patients with severe HTG. Results Across 134 mild-to-moderate HTG patients, 9.0% carried heterozygous rare variants and 24.6% had an excess accumulation of common SNPs. Mild-to-moderate HTG patients were 2.38-times (95% CI [1.13-4.99]; P=0.021) more likely to carry a rare variant and 3.26-times (95% CI [2.02-5.26]; P<0.0001) more likely to have an extreme polygenic risk score compared to the 1000 Genomes Project. In addition, severe HTG patients were 1.86-times (95% CI [0.98-3.51]; P=0.032) more likely to carry a rare variant and 1.63-times (95% CI [1.07-2.48]; P=0.013) more likely to have an extreme polygenic risk score compared to mild-to-moderate HTG patients. Conclusions We report an increased prevalence of genetic determinants in patients with an increased severity of the HTG phenotype when considering either rare variants disrupting TG metabolism genes or an excess accumulation of common SNPs. As well, the findings confirm that the most prevalent genetic contributor to HTG, regardless of severity, is polygenic SNP accumulation.

  • Efficacy and safety of alirocumab in statin-intolerant patients over 3 years: Open-label treatment period of the ODYSSEY ALTERNATIVE trial
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2020-01-13
    Patrick M. Moriarty; Paul D. Thompson; Christopher P. Cannon; John R. Guyton; Jean Bergeron; Franklin J. Zieve; Eric Bruckert; Terry A. Jacobson; Marie T. Baccara-Dinet; Jian Zhao; Stephen Donahue; Shazia Ali; Garen Manvelian; Robert Pordy
  • Skeletal muscle area and density are associated with lipid and lipoprotein cholesterol levels: The Multi-Ethnic Study of Atherosclerosis
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2020-01-13
    Chantal A. Vella; Megan C. Nelson; Jonathan T. Unkart; Iva Miljkovic; Matthew A. Allison

    Background Loss of muscle mass with age may be a key player in metabolic dysregulation. Objective To examine associations between abdominal muscle area and density with lipids and lipoproteins. Methods 1868 adults completed health history and physical activity questionnaires, provided venous blood samples for lipids and inflammatory biomarkers, and underwent computed tomography to quantify body composition. Associations between muscle area and density with multiple lipid measures were assessed with multivariable linear and logistic regression. Results The mean age and body mass index of participants was 65 years and 28 kg·m2, respectively, and 50% were female. After adjustment for demographics, cardiovascular disease risk factors, lipid-lowering medications, physical activity, sedentary behavior, inflammatory biomarkers and central obesity, a 1-standard deviation (SD) increase in total abdominal, stability, and locomotor muscle areas were associated with a 13%, 11%, and 8% lower high-density lipoprotein cholesterol level, respectively (p<0.05). With similar adjustment, a 1-SD increase in total abdominal and stability muscle area was associated with a 13% and 12% lower total cholesterol level, respectively (p<0.01). Compared to the lowest quartiles of total, stability and locomotor muscle area, those in the higher quartiles of muscle area had over a 40% reduction in the odds of triglyceride levels greater than 150 mg/dl (p<0.05). Total abdominal muscle density was positively associated with total cholesterol (p<0.05) but was not associated with the other lipid outcomes. Conclusion Maintaining adequate skeletal muscle mass with age may decrease specific lipid levels related to hyperlipidemia and development of cardiometabolic disease.

  • Genetic analysis of familial hypercholesterolemia in Asian Indians: a single center study
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2020-01-09
    Nitika Setia; Sireesha Movva; Prahlad Balakrishnan; Ishpreet K. Biji; J.P.S. Sawhney; Raman Puri; Anjali Arora; Ratna D. Puri; Renu Saxena; Sanghamitra Mishra; Sanika Apte; Samarth Kulshrestha; V.L. Ramprasad; Ishwar C. Verma

    Background Familial Hypercholesterolemia (FH), an autosomal co-dominant disorder characterized by very high LDL cholesterol, is strongly associated with premature coronary artery disease. Objectives Molecular landscape of FH in Asian Indians is not well studied, although this ethnic group comprises a large proportion of the world population. Knowledge of mutations in these groups is useful for identifying persons affected with FH, saving their lives and cascade screening in their relatives. Methods Potential cases of FH (n=100), were identified by criteria adapted for the Indian population from Dutch Lipid Clinic Network (DLCN) criteria. Pathogenic variants were analyzed in LDLR, APOB 100 (exons 26 and 29), PCK9 and APOE genes using Sanger sequencing, and MLPA technique. Cases in whom there were no pathogenic variants were tested by Next Generation Sequencing (NGS) using a targeted panel of genes. Results Thirty-eight pathogenic variants were identified in 47 of 100 unrelated probands. Of these variants, 33 were in LDLR, 3 in APOB and 2 in PCSK9 genes. Ten pathogenic variants were novel. Mutations were detected in 91.4% of those subjects classified as Definite, 40% as Probable and in 18.8% as Possible FH cases based on modified DLCN criteria. A likely founder mutation in intron 10 (c.1587-1G>A) of LDLR gene was observed in 6 North Indian families. The conventional pathogenic variants in APOB and PCSK9 genes, and those previously reported in LDLR gene among Asian Indians were not detected in this cohort. Conclusion This study demonstrates genetic heterogeneity of FH in India. The variants observed were different from those described in Western populations. NGS technology helped to identify new mutations in APOB gene, suggesting that in less studied populations it is better to sequence the whole gene rather than test for specific mutations.

  • Triglycerides, Hypertension, and Smoking Predict Cardiovascular Disease in Dysbetalipoproteinemia
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2019-12-24
    Martine Paquette; Sophie Bernard; Guillaume Paré; Alexis Baass

    Background Dysbetalipoproteinemia (DBL) is an autosomal recessive lipid disorder associated with a reduced clearance of remnant lipoproteins and is associated with an increased cardiovascular disease (CVD) risk. The genetic cause of DBL is apoE2 homozygosity in 90% of cases. However, a second metabolic hit must be present to precipitate the disease. However, no study has investigated the predictors of CVD, peripheral artery disease (PAD) and coronary artery disease (CAD) in a large cohort of DBL patients. Objective The objectives of this study were to describe the clinical characteristics of a DBL cohort and to identify the predictors of CVD, PAD and CAD in this population. Methods The inclusion criteria included age ≥ 18 years, apoE2/E2, triglycerides (TG) > 135 mg/dL and VLDL-C/ plasma TG ratio > 0.30. Results We studied 221 adult DBL patients, of which 51 (23%) had a history of CVD. We identified three independent predictors of CVD, namely hypertension (OR 5.68, 95% CI 2.13-15.16, p=0.001), pack year of smoking (OR 1.03, 95% CI 1.01-1.05, p=0.01) and TG tertile (OR 1.82, 95% CI 1.09-3.05, p=0.02). The CVD prevalence was 51% in patients with hypertension and 18% in those without hypertension (p=0.00001), and 30% in the highest TG tertile vs 15% in the lowest tertile (p=0.04). Similarly, the CVD prevalence was higher in heavy smokers compared to non-smokers (36% vs 13%, p=0.006). Conclusion Hypertension, smoking and triglycerides are independently associated with CVD risk in DBL patients. Aggressive treatment should be initiated in DBL patients due to the increased risk of CVD.

  • Blood lipid profiles and risk of atrial fibrillation: A systematic review and meta-analysis of cohort studies
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2019-12-20
    Bo Guan; Xintao Li; Wenqiang Xue; Gary Tse; Khalid Bin Waleed; Yichen Liu; Mengyi Zheng; Shouling Wu; Yunlong Xia; Yi Ding

    Background There is an increasing body of evidence associating traditional cardiovascular risk factors with atrial fibrillation (AF), but the relationship between blood lipid profiles and the risk of AF remains controversial. Objective To conduct a systemic review and meta-analysis of large cohort studies to evaluate the relationship between blood lipid profiles and incident AF. Methods PubMed and Embase were searched up to 31st January 2019 for cohort studies that reported the relationship between blood lipid levels and incident AF. The hazard ratios or odd ratios of the highest vs lowest categories of lipid levels were extracted to calculate pooled estimates. Sensitivity analysis and meta-regression were performed to explore potential sources of heterogeneity. Results Eleven studies were included in the meta-analysis, including nine studies for total cholesterol (TC), five for low-density lipoprotein cholesterol (LDL-c), eight for high-density lipoprotein cholesterol (HDL-c), and eight for triglyceride. Serum TC and LDL-c levels were inversely related to AF risk (RR = 0.81, 95% confidence interval [CI]: 0.72-0.92; RR = 0.79, 95% CI: 0.70-0.88, respectively). Likewise, elevated HDL-c levels were associated with a reduced AF risk (RR = 0.86, 95% CI: 0.76-0.97), while no significant association was observed between triglyceride levels and incident AF (RR = 1.02, 95% CI:0.90-1.17). Conclusions Our meta-analysis of large cohort studies found an inverse relationship between serum TC, LDL-c, and HDL-c levels and AF risk, while there was no significant association between TG levels and incident AF. Future studies regarding AF risk stratification may take these blood lipids into consideration and further efforts are needed to investigate the potential mechanisms.

  • Impact of PCSK9 inhibition with evolocumab on the postprandial responses of triglyceride-rich lipoproteins in type 2 diabetic subjects
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2019-12-12
    Marja-Riitta Taskinen; Elias Björnson; Linda Andersson; Juhani Kahri; Kimmo Porthan; Niina Matikainen; Sanni Söderlund; Kirsi Pietiläinen; Antti Hakkarainen; Nina Lundbom; Ralf Nilsson; Marcus Ståhlman; Martin Adiels; Paolo Parini; Chris Packard; Jan Borén

    Background —Monoclonal antibodies to proprotein convertase subtilisin/kexin type 9 (PCSK9) significantly lower the levels of LDL and very low-density lipoproteins, but their effect on postprandial lipoprotein metabolism in dyslipidemic subjects is unclear. Objective —To investigate the effects of evolocumab on postprandial lipid responses, ectopic fat depots, whole body cholesterol synthesis, hepatic lipogenesis, and fat oxidation in patients with type 2 diabetes. Methods —The trial was a single-phase, nonrandomized study of 12-week treatment with evolocumab 140 mg s.c. Q2W in 15 patients with type 2 diabetes on background statin therapy. Cardiometabolic responses to a high-fat mixed meal were assessed before and at the end of the intervention period. Results —Evolocumab treatment reduced significantly postprandial rises in plasma total triglyceride (by 21%, P<0.0001) and VLDL1-triglyceride (by 15%, P=0.018), but the increase in chylomicron-triglyceride following the meal was not significantly perturbed (P=0.053). There were reduced postprandial responses in plasma total apoC-III (by 14%, P<0.0001), apoB48 concentration (by 17%, P=0.0046) and in ‘remnant-like particles (RLP)’ cholesterol (by 29%, P<0.0001) on the PCSK9 inhibitor. Treatment reduced the steady state (i.e. fasting and postprandial) concentrations of VLDL2 cholesterol by 50% (P<0.0001) and VLDL2 triglyceride by 29% (P<0.0001), in addition to the 78% reduction of LDL cholesterol (P<0.001). The changes in apoC-III associated significantly with reduction in postprandial responses of RLP-cholesterol and TRL-cholesterol. Evolocumab therapy did not influence liver fat accumulation, hepatic de novo lipogenesis or fasting β-hydroxybutyrate, but did increase total body cholesterol synthesis (P<0.01). Conclusion —Evolocumab treatment improved postprandial responses of TRLs and measures of cholesterol-enriched remnant particles in type 2 diabetic subjects. These results indicate that postprandial phenomena need to be taken into account in assessing the full range of actions of PCSK9 inhibitors in dyslipidemic individuals.

  • Multiple tendon ruptures associated with statin therapy
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2019-12-05
    Shreyas D. Gowdar, Paul D. Thompson

    We present the case of a 44-year-old physician with familial heterozygous hypercholesterolemia who experienced multiple tendon ruptures during 19 years of statin therapy and no tendon injuries in the 5 years since statins were discontinued. Statins may deleteriously affect tendon extracellular matrix by inhibiting synthesis of matrix metalloproteinases and cell cycle regulatory proteins. Clinicians should be aware of this possible association between statins and tendinopathy.

  • Apolipoprotein B discordance with low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol in relation to coronary artery calcification in the Multi-Ethnic Study of Atherosclerosis (MESA)
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2019-11-29
    Jing Cao, Sarah O. Nomura, Brian T. Steffen, Weihua Guan, Alan T. Remaley, Amy B. Karger, Pamela Ouyang, Erin D. Michos, Michael Y. Tsai

    Background Discordant levels of apolipoprotein B (apo B) relative to low-density lipoprotein cholesterol (LDL-C) or non-high-density lipoprotein cholesterol (non-HDL-C) may be associated with subclinical atherosclerotic cardiovascular disease (ASCVD). Objective The present study investigated whether discordance between apo B and LDL-C or non-HDL-C levels was associated with subclinical ASCVD measured by coronary artery calcium (CAC). Methods This study was conducted in a subpopulation of the Multi-Ethnic Study of Atherosclerosis (MESA) cohort, aged 45 to 84 years, free of ASCVD, and not taking lipid-lowering medications at baseline (2000-2002) (prevalence analytic N=4,623; incidence analytic N=2,216; progression analytic N=3,947). Apo B discordance relative to LDL-C and non-HDL-C was defined using residuals and percentile rankings (>5/10/15 percentile). Associations with prevalent and incident CAC (CAC>0 vs. CAC=0) were assessed using prevalence ratio/relative risk regression and CAC progression (absolute increase/year) using multinomial logistic regression. Results Higher apo B levels were associated with CAC prevalence, incidence and progression. Apo B discordance relative to LDL-C or non-HDL-C was inconsistently associated with CAC prevalence and progression. Discordantly high apo B relative to LDL-C and non-HDL-C was associated with CAC progression. Associations for apo B discordance with non-HDL-C remained after further adjustment for metabolic syndrome components. Conclusion Apo B was associated with CAC among adults ≥45 years not taking statins, but provided only modest additional predictive value of apo B for CAC prevalence, incidence or progression beyond LDL-C or non-HDL-C. Apo B discordance may still be important for ASCVD risk assessment and further research is needed to confirm findings.

  • JCL roundtable: Pediatric lipidology
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2019-11-27
    Amy L. Peterson, Michele Mietus-Snyder, Don P. Wilson, John R. Guyton

    This JCL Roundtable discussion probes the knowledge of 3 experts in pediatric lipidology, an emerging discipline both in the United States and internationally. In the 1990s, only 3 US institutions could be said to have dedicated pediatric lipid clinics; that number has grown to 25 today. The Pediatric Atherosclerosis Prevention and Lipidology Group of the National Lipid Association has regular teleconferences to support advocacy and convey best practices. Guidelines for pediatric lipidology initially focused on low-density lipoprotein cholesterol in 1992 as part of the National Cholesterol Education Program. Today the most comprehensive coverage comes from the 2011 National Heart Lung and Blood Institute Pediatric Guidelines. Universal screening was recommended for children between ages 9 and 11 years and teenagers/young adults between 17 to 21 years, a position echoed as “may be recommended” by the 2018 AHA/ACC/Multisociety Cholesterol Guidelines. While pediatric lipidologists continue to treat uncommon genetic disorders, they increasingly confront an issue of epidemic proportions—dyslipidemia as the initial presentation of metabolic dysregulation associated with obesity. Consequences of such altered metabolism extend to atherosclerosis, diabetes, liver disease, and other serious problems in adult life. Pediatric lipid science and practice differ from adult experience in several ways, including importance of family and birth history as well as genetics/epigenetics, lack of general pediatricians’ familiarity with lipid drugs, value of family counseling, need for biomarkers of early metabolic dysregulation, and anticipation of endpoints in adult life not fully defined by randomized clinical trials in children.

  • Post-prandial remodeling of HDL following high saturated fat and high carbohydrate meals.
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2019-11-22
    Michelle Averill, Katya B. Rubinow, Kevin Cain, Jake Wimberger, Ilona Babenko, Jessica O. Becker, Karen E. Foster-Schubert, David E. Cummings, Andrew N. Hoofnagle, Tomas Vaisar

    Background Humans spend most of the time in the postprandial state, yet most knowledge about high-density lipoproteins (HDL) derives from the fasted state. HDL protein and lipid cargo mediate HDL’s antiatherogenic effects, but whether these HDL constituents change in the postprandial state and are affected by dietary macronutrients remain unknown. Objectives To assess changes in HDL protein and lipid composition after consumption of a high carbohydrate or high saturated fat (HSF) meal. Methods We isolated HDL from plasma collected during a randomized, cross-over study of metabolically healthy subjects. Subjects consumed isocaloric meals consisting predominantly of either carbohydrate or fat. At baseline and at 3 and 6 hours postprandial, we quantified HDL protein and lipid composition by liquid chromatography mass spectrometry. Results 15 subjects were included (60% female, ages 34±15 years, BMI 24.1±2.7 kg/m2). Consumption of the HSF meal led to HDL enrichment in total lipid (P=0.006), triglyceride (P=0.02) and phospholipid (P=0.008) content and a corresponding depletion in protein content. Following the HSF meal, 16 of the 25 measured phosphatidylcholine species significantly increased in abundance (P values range 0.027 to <0.001), along with several sphingolipids including ceramides (P<0.004), lactosylceramide (P=0.023), and sphingomyelin-14 (P=0.013). Enrichment in apolipoprotein A-I (P=0.001) was the only significant change in HDL protein composition following the HSF meal. The high carbohydrate meal conferred only minimal changes in HDL composition. Conclusion Meal macronutrient content acutely affects HDL composition in the postprandial state, with the HSF meal resulting in enrichment of HDL phospholipid content with possible consequences for HDL function.

  • Enhancing the value of PCSK9 monoclonal antibodies by identifying patients most likely to benefit. A consensus statement from the National Lipid Association
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2019-05-16
    Jennifer G. Robinson, Manju Bengularu Jayanna, Alan S. Brown, Karen Aspry, Carl Orringer, Edward A. Gill, Anne Goldberg, Laney K. Jones, Kevin Maki, Dave L. Dixon, Joseph J. Saseen, Daniel Soffer

    Acquisition costs and cost-effectiveness have limited access and recommendations to use proprotein convertase subtilisin/kexin type 9 (PCSK9)–inhibiting monoclonal antibodies (mAbs). Recently, prices were reduced by 60% for alirocumab and evolocumab. This statement systematically reviewed subgroup analyses from statin and PCSK9 mAb trials to identify higher risk groups for which PCSK9 mAbs at the new price could be considered a reasonable (

  • Association of baseline LDL-C with total and cardiovascular mortality in patients using proprotein convertase subtilisin-kexin type 9 inhibitors: A systematic review and meta-analysis
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2019-06-10
    Safi U. Khan, Haris Riaz, Hammad Rahman, Muhammad U. Khan, Muhammad Shahzeb Khan, Mohamad Alkhouli, Edo Kaluski, Thorsten M. Leucker, Michael J. Blaha

    Background The objective of this study was to investigate whether baseline low-density lipoprotein cholesterol (LDL-C) levels influence total and cardiovascular mortality reduction associated with proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor therapy. Methods In this meta-analysis, 9 randomized controlled trials were selected using Medline, Embase, and CENTRAL until November 2018. Analyses were stratified by mean baseline LDL-C (<100 mg/dL and ≥ 100 mg/dL). Stepwise prespecified sensitivity analyses were performed after excluding the SPIRE trials and by regrouping ODYSSEY OUTCOME mortality data according to the baseline LDL-C (< and ≥100 mg/dL). Results In 83,321 patients, PCSK9 inhibitor therapy was not associated with a reduction in the risk of all-cause mortality (relative risk [RR], 0.94, 95% confidence interval [CI], 0.81–1.09, P = .41). These results remained consistent after excluding the SPIRE trials (RR, 0.89, 95% CI, 0.75–1.05, P = .18). However, the RR varied by baseline LDL-C, with significant RR reduction only in patients with LDL-C ≥ 100 mg/dL (RR, 0.39, 95% CI, 0.20–0.76) (P-interaction = .01). Meta-regression showed RR of 0.97 for all-cause mortality per 1 mg/dL higher baseline LDL-C (95% CI, 0.94–0.99). PCSK9 inhibitor therapy showed no significant effect on cardiovascular mortality, with no effect when excluding the SPIRE trials. However, after regrouping ODYSSEY OUTCOME estimates, there was a significant reduction in cardiovascular mortality restricted to patients with LDL-C ≥ 100 mg/dL (RR, 0.67, 95% CI, 0.51–0.87) (P-interaction = .006). Conclusion PCSK9 inhibitor therapy on a background statin treatment may reduce the risk of total and cardiovascular mortality in patients with baseline LDL-C ≥ 100 mg/dL. These results support current guidelines reserving PCSK9 inhibitors for high-risk patients with residually high LDL-C.

  • Novel mutations of SAR1B gene in four children with chylomicron retention disease
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2019-05-30
    Maria Luisa Simone, Claudio Rabacchi, Zarife Kuloglu, Aydan Kansu, Arzu Ensari, Arzu Meltem Demir, Gulin Hizal, Enza Di Leo, Stefano Bertolini, Sebastiano Calandra, Patrizia Tarugi

    Background Intestinal lipid malabsorption, resulting from an impaired formation or secretion of chylomicrons and associated with severe hypobetalipoproteinemia (HBL), may be due to biallelic mutations in APOB (homozygous FHBL type-1), MTTP (abetalipoproteinemia), or SAR1B (chylomicron retention disease). Objective We investigated four children, each born from consanguineous parents, presenting with steatorrhea, malnutrition, accumulation of lipids in enterocytes, and severe hypocholesterolemia with an apparent recessive transmission. Methods We sequenced a panel of genes whose variants may be associated with HBL. Results Case 1, a 9-month-old male, was found to be homozygous for a SAR1B variant (c.49 C>T), predicted to encode a truncated Sar1b protein devoid of function (p.Gln17*). Case 2, a 4-year-old male, was found to be homozygous for a SAR1B missense variant [c.409 G>C, p.(Asp137His)], which affects a highly conserved residue close to the Sar1b guanosine recognition site. Case 3, a 6-year-old male, was found to be homozygous for an ∼6 kb deletion of the SAR1B gene, which eliminates exon 2; this deletion causes the loss of the ATG translation initiation codon in the SAR1B mRNA. The same homozygous mutation was found in an 11-month-old child (case 4) who was related to case 3. Conclusions We report 4 children with intestinal lipid malabsorption were found to have chylomicron retention disease due to 3 novel variants in the SAR1B gene.

  • Current trends in non–HDL cholesterol and LDL cholesterol levels in adults with atherosclerotic cardiovascular disease
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2019-05-27
    Gloria Lena Vega, Scott M. Grundy

    Background Low-density lipoprotein cholesterol (LDL-C) and non–high-density lipoprotein cholesterol (non–HDL-C) are targets for prevention of atherosclerotic cardiovascular disease (ASCVD). The American Heart Association and American College of Cardiology recently modified recommendations for clinical management of cholesterol in secondary and primary prevention. Accordingly, the present article examines the need for cholesterol-lowering drugs in the U.S. population with ASCVD. Objective This study examines trends in non–HDL-C and LDL-C levels in a free living population of ASCVD subjects between 1999 and 2016. Methods National Health and Nutrition Examination Surveys database included 4920 adults with ASCVD aged 40 to 85 years. Complete data were available for 4226. Trend analysis of changes in lipids is shown in box plots. Results Mean age was 67 years with 57% males. Over 17 years, LDL-C decreased significantly by 24% and non–HDL-C by 21%. Over the period of study, reported intake of cholesterol-lowering drugs rose from 37% in 1999-2000 to 69% in 2015 to 2016. Over this same period, serum triglycerides decreased by 29% (P < .001) and HDL-C rose by 6%. Conclusions The changes in LDL-C and non–HDL-C in patients with ASCVD over a 17-year period probably are related to increased treatment with statins. However, the changes are too small to be explained by widespread use of high-intensity statins, which is the current recommendation for patients with ASCVD. These findings pose a challenge for professional education to support implementation of current guidelines for cholesterol-lowering therapies.

  • Complementary low-density lipoprotein-cholesterol lowering and pharmacokinetics of adding bempedoic acid (ETC-1002) to high-dose atorvastatin background therapy in hypercholesterolemic patients: A randomized placebo-controlled trial
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2019-05-13
    Narendra D. Lalwani, Jeffrey C. Hanselman, Diane E. MacDougall, Lulu R. Sterling, Clay T. Cramer

    Background Bempedoic acid is an oral, once-daily, first-in-class medication being developed to treat hypercholesterolemia. Objective The aim of the study was to assess the low-density lipoprotein cholesterol (LDL-C)–lowering efficacy of bempedoic acid added to stable high-intensity atorvastatin background therapy and multiple-dose plasma pharmacokinetics of atorvastatin alone and combined with steady-state bempedoic acid. Methods This was a phase 2 study in patients with hypercholesterolemia (NCT02659397). Patients received once-daily open-label atorvastatin 80 mg for 4 weeks then were randomized 2:1 at baseline to receive double-blind bempedoic acid 180 mg (n = 45) or placebo (n = 23) plus open-label atorvastatin 80 mg for 4 weeks. Efficacy was assessed 4 weeks after randomization. Atorvastatin and metabolites' steady-state levels were analyzed before first dosing with bempedoic acid and after 2 weeks of treatment. Results The 4-week stabilization phase with 80 mg atorvastatin resulted in approximately 40% lowering of LDL-C values from screening. The placebo-adjusted least squares mean lowering of LDL-C from baseline to Day 29 with bempedoic acid was 22% (P = .003). Placebo-adjusted reductions from baseline with bempedoic acid also were significant for total cholesterol (−10%; P = .014), non–high-density lipoprotein cholesterol (−13%; P = .015), apolipoprotein B (−15%; P = .004), and high-sensitivity C-reactive protein (−44%; P = .002). Point estimates of bempedoic acid effects on steady-state atorvastatin and ortho-hydroxy atorvastatin area under the curve were <30% and not clinically meaningful. Conclusions Bempedoic acid 180 mg added to stable high-dose atorvastatin therapy effectively lowers LDL-C in patients with hypercholesterolemia without causing clinically important increases in atorvastatin exposure.

  • Impact of PCSK9 inhibitors on plasma lipoprotein(a) concentrations with or without a background of niacin therapy
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2019-04-26
    Bruce A. Warden, Jessica Minnier, Gerald F. Watts, Sergio Fazio, Michael D. Shapiro

    Background Lipoprotein(a) [Lp(a)] is an atherogenic lipoprotein associated with atherosclerotic cardiovascular disease. Niacin and proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) both lower Lp(a). Objective The objective of the study was to determine if addition of PCSK9i to background niacin therapy further lowers Lp(a). Methods This study is a retrospective analysis of patients who met the following inclusion criteria: initiated PCSK9i therapy, had Lp(a) measurements before and after initiation of PCSK9i, and for the combination therapy group, PCSK9i was added on top of baseline niacin monotherapy. Of the 150 patients included in this study, 136 were on monotherapy (PCSK9i) and 14 were on combination therapy (niacin + PCSK9i). Lp(a) values were assessed in both groups before and after the addition of PCSK9i. Results Median percent and absolute Lp(a) reductions in the niacin + PCSK9i combination therapy group were −15.3% (interquartile range [IQR] −31.8, −1) and −9 mg/dL (IQR −37.2, −0.5), respectively, from a baseline Lp(a) of 95 mg/dL (IQR 20.5, 171). These reductions were statistically significant or nearly so (P = .04 and P = .05, respectively). Median percent and absolute Lp(a) reductions in the PCSK9i monotherapy group were −17.3% (IQR −34.4, 0) and −6 mg/dL (IQR −16, 0), respectively, from a baseline Lp(a) of 39.5 mg/dL (IQR 15, 117.5). There was no difference in median percent and absolute change in Lp(a) between monotherapy and combination therapy groups (P = .84 and P = .54, respectively). Conclusions Our study demonstrates that the addition of PCSK9i to background of niacin therapy is associated with ∼15% reduction in Lp(a) beyond that achieved with background niacin monotherapy.

  • Alirocumab efficacy and safety by race and ethnicity: Analysis from 3 ODYSSEY phase 3 trials
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2019-06-27
    Keith C. Ferdinand, Terry A. Jacobson, Andrew Koren, Joseph Elassal, Desmond Thompson, Prakash Deedwania
  • Low-density lipoprotein cholesterol goal achievement in patients with familial hypercholesterolemia in countries outside Western Europe: The International ChoLesterol management Practice Study
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2019-05-14
    Dirk J. Blom, Wael Almahmeed, Khalid Al-Rasadi, Joseph Azuri, Veronique Daclin, Meral Kayikcioglu, Florence Mercier, Alvaro J. Ruiz, Raul D. Santos
  • Prevalence, risk factor burden, and severity of coronary artery disease in patients with heterozygous familial hypercholesterolemia hospitalized for an acute myocardial infarction: Data from the French RICO survey
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2019-06-21
    Michel Farnier, Clémence Salignon-Vernay, Hermann Yao, Frédéric Chague, Philippe Brunel, Maud Maza, Damien Brunet, Florence Bichat, Jean-Claude Beer, Yves Cottin, Marianne Zeller

    Background Individuals with heterozygous familial hypercholesterolemia (FH) are at high risk of early myocardial infarction (MI). However, coronary artery disease (CAD) burden of FH remains not well described, especially for French patients. Objective The objective of this study was to assess the prevalence of FH and severity of CAD from a large database of a French regional registry of acute MI. Methods All consecutive patients hospitalized for an acute MI in a multicenter database from 2001 to 2017 were considered. FH was diagnosed using an algorithm adapted from the Dutch Lipid Clinic Network criteria. The prevalence and clinical features of FH and the severity of CAD were assessed. Results Among the 11,624 patients included in the study, the proportion of “probable/definite”, “possible”, and “unlikely” FH in patients with MI was 2.1% (n = 249), 20.7% (n = 2405), and 77.2% (n = 8970), respectively. When compared with patients with “unlikely” FH, patients with “probable/definite” FH were 20 years younger (51 vs 71, P < .001), with a lower rate of diabetes (17% vs 25%, P = .007) and a higher prevalence of personal and familial history of CAD. Chronic statin treatment was only used in 48% of FH patients and ezetimibe in 8%. After adjustment for age, sex, and diabetes, patients with FH were characterized by increased extent of CAD (SYNTAX score 11 vs 7, P < .001) and multivessel disease (55% vs 40%, P < .001). Conclusions In this large cohort of French individuals, FH was common in patients with MI, associated with markedly early age of MI and severity of CAD burden and limited use of preventive lipid-lowering therapy.

  • A cross-national investigation of cardiovascular survival in homozygous familial hypercholesterolemia: The Sino-Roman Study
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2019-05-12
    Claudia Stefanutti, Jing Pang, Serafina Di Giacomo, Xue Wu, Xumin Wang, Claudia Morozzi, Gerald F. Watts, Jie Lin

    Background Homozygous familial hypercholesterolemia (hoFH) is a rare inherited disorder characterized by extreme elevation of low-density lipoprotein (LDL) cholesterol, accelerated coronary artery disease, and premature death. Aggressive LDL-lowering therapies are important for survival, but these are not available worldwide. Objective The aim of the study was to compare and contrast cardiovascular outcomes and mortality of hoFH patients in 2 countries with disparate use of lipoprotein apheresis (LA) and modern therapies for lowering LDL cholesterol. Methods A retrospective study was undertaken comparing cardiovascular disease (CVD)-free survival and mortality in 44 hoFH patients who were treated with statins but not LA, from a center in Beijing, China, and 18 hoFH patients who were treated with LA and novel therapies from an early age, from a center in Rome, Italy. Results CVD-free survival and survival were significantly reduced in Chinese patients compared with the Italian patients after 30 years of follow-up (log-rank P < .01). In a pooled analysis, cardiovascular survival was significantly increased with earlier age at treatment, longer duration of treatment, and lower on-treatment LDL cholesterol concentrations (P < .05). In addition, the probability of a CVD event and death were increased in patients that carried a null mutation in the LDLR or had elevated lipoprotein(a). Conclusions We show that coronary artery disease outcomes in patients with hoFH can be significantly improved with earlier and potent LDL cholesterol lowering with pharmacotherapies and LA. This has major implications for countries, such as China, where the models of care for hoFH remains underdeveloped.

  • The island of Gran Canaria: A genetic isolate for familial hypercholesterolemia
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2019-05-08
    Rosa M. Sánchez-Hernández, Antonio Tugores, Francisco J. Nóvoa, Yeray Brito-Casillas, Ana B. Expósito-Montesdeoca, Paloma Garay, Ana M. Bea, Marta Riaño, Miguel Pocovi, Fernando Civeira, Ana M. Wägner, Mauro Boronat

    Background Genetic diagnosis of familial hypercholesterolemia (FH) has not been universally performed in the Canary Islands (Spain). Objectives This study aimed to genetically characterize a cohort of patients with FH in the island of Gran Canaria. Methods Study subjects were 70 unrelated index cases attending a tertiary hospital in Gran Canaria, with a clinical diagnosis of FH, according to the criteria of the Dutch Lipid Clinic Network. Given that 7 of the first 10 cases with positive genetic study were carriers of a single mutation in the LDLR gene [p.(Tyr400_Phe402del)], a specific polymerase chain reaction-based assay was developed for the detection of this variant as a first screening step on the remaining subjects. In those without this mutation, molecular diagnosis was completed using a next-generation sequencing panel including LDLR, APOB, PCSK9, LDLRAP1, APOE, STAP1, and LIPA genes and incorporating copy number variation detection in LDLR. Results On the whole, 44 subjects (62%) had a positive genetic study, of whom 30 (68%) were heterozygous carriers of the p.(Tyr400_Phe402del) variant. Eleven subjects carried other mutations in LDLR, including the novel mutation NM_000527.4: c.877dupG; NP_000518.1: p.(Asp293Glyfs*8). An unclassified PCSK9 gene variant was found in one subject [(NM_174936.3:c.1496G>A; NP_777596.2: p.(Arg499His)]. Other single patients had mutations in APOB (heterozygous) and in LIPA (homozygous). All identified variants co-segregated with the disease phenotype. Conclusions These findings suggest a founder effect for the p.(Tyr400_Phe402del) LDLR mutation in Gran Canaria. A cost-effective local screening strategy for genetic diagnosis of FH could be implemented in this region.

  • Comparing different assessments of remnant lipoprotein cholesterol: The very large database of lipids
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2019-06-11
    Kamil F. Faridi, Renato Quispe, Seth S. Martin, Aditya D. Hendrani, Parag H. Joshi, Eliot A. Brinton, Daniel E. Cruz, Maciej Banach, Peter P. Toth, Krishnaji Kulkarni, Steven R. Jones

    Background Remnant lipoprotein cholesterol (RLP-C) is a risk factor for atherosclerotic cardiovascular disease, but there is no standard method for measurement. Some studies have used very low-density lipoprotein cholesterol estimated by the Friedewald equation to approximate RLP-C using a basic lipid panel, whereas others have attempted to measure RLP-C with ultracentrifugation. Objective The aim of the study was to compare RLP-C levels estimated from basic lipid parameters to those measured by ultracentrifugation. Methods We analyzed 1,350,908 individuals from the Very Large Database of Lipids, comparing one estimate of RLP-C using basic lipid parameters (RLP-Cestimated = non–high-density lipoprotein cholesterol − Friedewald-estimated low-density lipoprotein cholesterol for triglycerides <355 mg/dL [4 mmol/L], or non–high-density lipoprotein − directly measured low-density lipoprotein for triglycerides ≥355 mg/dL) to levels measured by vertical auto profile ultracentrifugation (RLP-Cmeasured = dense subfraction of very low-density lipoprotein cholesterol + intermediate-density lipoprotein cholesterol). We calculated correlations between RLP-Cestimated and RLP-Cmeasured along with median within-subject differences between RLP-Cestimated and RLP-Cmeasured across quintiles of RLP-Cestimated. We also assessed correlations with RLP-C estimated from basic lipid parameters using a novel method of calculating low-density lipoprotein cholesterol with a patient-specific conversion factor (RLP-Cestimated-N). Results Our cohort was 48% male, and median (interquartile range) age was 59 (49–69) years. Median (interquartile range) RLP-Cestimated and RLP-Cmeasured were 23 (16.4–33.2) and 24 (19–32) mg/dL, respectively. The correlation between RLP-Cestimated and RLP-Cmeasured was 0.76. Based on the specified definition of RLP-Cestimated, the correlation between RLP-Cestimated and triglyceride/5 for triglyceride < 355 mg/dL was exactly 1.0. RLP-Cestimated was lower than RLP-Cmeasured in the first and second quintiles of RLP-Cestimated but greater in the highest quintile. The correlations with RLP-Cestimated-N were 0.98 and 0.81 for RLP-Cestimated and RLP-Cmeasured, respectively. Conclusions A previously used estimate of RLP-C using basic lipid parameters correlates weakly with remnants measured by ultracentrifugation. Our findings emphasize the need to standardize definitions and measurements of RLP-C.

  • LPA genotype is associated with premature cardiovascular disease in familial hypercholesterolemia
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2019-04-23
    Martine Paquette, Sophie Bernard, George Thanassoulis, Alexis Baass

    Background In recent years, lipoprotein (a) (Lp(a)) has been recognized as an important risk factor for cardiovascular disease (CVD). A variant in the LPA gene, rs10455872, has been associated with higher concentrations of Lp(a), as well as an increased risk of CVD in the general population. Objective The objective of the present study is to compare the predictive value of an LPA variant, rs10455872, as well as Lp(a) concentration on the prevalence of CVD and on the age of the first CVD event in a cohort of genetically confirmed heterozygous patients with familial hypercholesterolemia (FH). Methods Lp(a) total particle mass was measured by an enzyme-linked immunoassay kit. The rs10455872 genotype has been obtained via an exome chip genotyping method. Results The cohort comprised 88 carriers and 580 noncarriers of the rs10455872. The Lp(a) concentration (g/L) was significantly higher in carriers than in noncarriers (0.41 [0.33–0.60] vs 0.12 [0.05–0.27], respectively, P < .0001). There was a significant association between rs10455872 and prevalent CVD in a model corrected for classical CVD risk factors (odds ratio 1.97, 95% confidence interval 1.05–3.68, P = .04). There was a significant association between rs10455872 and the age of the first CVD event in a model corrected for all cardiovascular risk factors including Lp(a) levels (39.7 vs 43.9 years in carriers vs noncarriers, respectively, P = .02). Conclusion Our results suggest that the LPA variant rs10455872 is a good predictor of premature CVD risk in FH. This also suggest that targeting Lp(a) in FH subjects could be associated with further reduction in CVD risk.

  • Association between circadian preference and blood lipid levels using a 1:1:1 propensity score matching analysis
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2019-05-17
    Yu-Jin Kwon, Tae-Ha Chung, Hye Sun Lee, JuYoung Park, Ji-Youn Chung, Byoung-Kwon Lee, Ji-Won Lee

    Background Previous studies indicate that circadian preference is associated with various energy metabolism and metabolic disorders. However, little is known about the associations between a circadian rhythm and blood lipid levels, especially in humans. Objective The aim of the study was to investigate whether the circadian rhythm affects serum lipid levels in Korean adults. Methods We designed a cross-sectional study to evaluate the associations between circadian preference and blood lipid levels in Korean adults. A total of 1984 participants (range of age 19–81 years) were included in this study. Propensity scores were calculated using logistic regression with age, sex, and body mass index. A total of 435 subjects were evaluated by propensity score matching analysis, equally distributed into morningness, intermediate, and eveningness groups, each with 145 subjects. Circadian preference was evaluated by the Morningness-Eveningness Questionnaire. Results Participants with the evening preference had significantly higher levels of total cholesterol, triglyceride, low-density lipoprotein cholesterol, and non–high-density lipoprotein cholesterol (non–HDL-C) when compared with those with morning or intermediate preference, after adjusting for confounding variables. Regarding other lipid parameters, both total cholesterol/HDL-C and low-density lipoprotein cholesterol/HDL-C in the evening preference are significantly higher than those of other circadian preferences. Evening preference was also significantly associated with a higher atherogenic index of plasma. Conclusion Our study demonstrates that there is a significant association between circadian preference and blood lipid levels. Our findings suggest that individuals with evening preference could have a greater risk of atherosclerotic cardiovascular diseases.

  • High-density lipoprotein cholesterol is associated with multiple sclerosis fatigue: A fatigue-metabolism nexus?
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2019-06-18
    Richard W. Browne, Dejan Jakimovski, Nicole Ziliotto, Jens Kuhle, Francesco Bernardi, Bianca Weinstock-Guttman, Robert Zivadinov, Murali Ramanathan

    Background Fatigue is a frequent symptom in multiple sclerosis (MS). The role of cholesterol and lipids in MS fatigue has not been investigated. Objective To investigate the associations of cholesterol biomarkers and serum neurofilament light chain (sNfL) with fatigue in relapsing-remitting MS. Methods This cross-sectional study included 75 relapsing-remitting MS patients (69% female, mean age ± SD: 49.6 ± 11 years and median Expanded Disability Status Scale score: 2.0). Fatigue, disability, and depression were assessed with Fatigue Severity Scale (FSS), Expanded Disability Status Scale, and the Beck Depression Index–Fast Screen, respectively. sNfL was measured using single-molecule array technology. Plasma total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and an apolipoprotein panel data were obtained. Soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular adhesion molecule-1 (sVCAM-1), chemokine (C-C motif) ligand 5 (CCL5 or RANTES), and CCL18 levels were measured to assess inflammation. Results The mean FSS was 4.27 ± 1.73, and 57% had severe fatigue status (SFS, FSS ≥ 4.0). In regression analyses adjusted for age, sex, disability, and depression, lower FSS and SFS were associated with greater HDL-C (P = .006 for FSS, and P = .016 for SFS) and lower TC to HDL-C ratio (P = .011 for FSS, and P = .009 for SFS). Apolipoprotein A-II was also associated with FSS (P = .022). sNfL, CCL5, CCL18, sICAM-1, and sVCAM-1 levels were not associated with fatigue after adjusting for disability and depression. Conclusions TC to HDL-C ratio is associated with MS fatigue. Our results implicate a potential role for the HDL-C pathway in MS fatigue and could provide possible targets for the treatment of MS fatigue.

  • ODYSSEY EAST: Alirocumab efficacy and safety versus ezetimibe in high cardiovascular risk patients with hypercholesterolemia and on maximally tolerated statin in China, India, and Thailand
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2019-11-18
    Yaling Han, Jiyan Chen, Vijaykumar Chopra, Shuyang Zhang, Guohai Su, Changsheng Ma, Zhouqing Huang, Yingyan Ma, Zhuhua Yao, Zuyi Yuan, Qiang Zhao, Srun Kuanprasert, Marie T. Baccara-Dinet, Garen Manvelian, Jianyong Li, Rui Chen

    Background The proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab significantly reduces low-density lipoprotein cholesterol (LDL-C). Objective This study (ODYSSEY EAST) assessed the efficacy and safety of alirocumab versus ezetimibe in high cardiovascular risk patients from Asia. Methods Patients (n = 615) from China, India, and Thailand with hypercholesterolemia at high cardiovascular risk on maximally tolerated statin were randomized (2:1) to alirocumab (75 mg every 2 weeks [Q2W]; with dose increase to 150 mg Q2W at Week 12 if Week 8 LDL-C was >1.81 mmol/L [>70 mg/dL]) or ezetimibe (10 mg daily) for 24 weeks. The primary efficacy endpoint was percentage change in calculated LDL-C from baseline to Week 24. Safety was assessed throughout. Results Baseline data were similar in both groups. LDL-C levels were reduced from baseline to Week 24 by 56.0% and 20.3% in the alirocumab and ezetimibe groups, respectively (p < 0.0001 vs ezetimibe). Overall, 18.8% of alirocumab-treated patients received a dose increase to 150 mg Q2W. At Week 24, 85.1% of alirocumab-treated and 40.5% of ezetimibe-treated patients reached LDL-C <1.81 mmol/L (<70 mg/dL, p < 0.0001 vs ezetimibe). Treatment-emergent adverse events occurred in 68.5% of alirocumab-treated and 63.1% of ezetimibe-treated patients, with upper respiratory tract infection the most common (alirocumab: 13.3%; ezetimibe: 14.1%). Injection-site reactions occurred more frequently in alirocumab-treated patients (2.7%) than ezetimibe-treated patients (1.0%). Conclusions Alirocumab significantly reduced LDL-C vs ezetimibe in high cardiovascular risk patients from Asia and was generally well tolerated. These findings are consistent with previous ODYSSEY studies. Clinical Trial Registration NCT02715726

  • Association of extremely high levels of high-density lipoprotein cholesterol with endothelial dysfunction in men
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2019-06-20
    Yuji Takaeko, Shogo Matsui, Masato Kajikawa, Tatsuya Maruhashi, Shinji Kishimoto, Haruki Hashimoto, Yasuki Kihara, Eisuke Hida, Kazuaki Chayama, Chikara Goto, Yoshiki Aibara, Farina Mohamad Yusoff, Kensuke Noma, Ayumu Nakashima, Yukihito Higashi

    Background It is not clear whether a high level of high-density lipoprotein cholesterol (HDL-C) is associated with lower risk of atherosclerosis. It is likely that HDL-C is a double-edged sword for atherosclerosis. Objective The purpose of this study was to evaluate the relationship between HDL-C levels and endothelial function in men. Methods This was a cross-sectional study. We evaluated flow-mediated vasodilation (FMD) and serum levels of HDL-C in 5842 men aged 18 to 92 years who were not receiving lipid-lowering therapy. All participants were divided into four groups by HDL-C level: low HDL-C (<40 mg/dL), moderate HDL-C (40–59 mg/dL), high HDL-C (60–79 md/dL), and extremely high HDL-C (≥80 mg/dL). We were not able to evaluate the amount of alcohol intake because there was limited information on the amount of alcohol drinking in our database. Results FMD values were significantly smaller in the low group and the extremely high group than in the high group (P = .001 and P = .016, respectively). There was no significant difference in FMD between the low group and the extremely high group. Multiple logistic regression analysis revealed that extremely high HDL-C, but not low HDL-C, was independently associated with the lowest quartile of FMD (odds ratio: 1.39, 95% confidence interval: 1.09–1.77; P = .009). Conclusions An extremely high level of HDL-C in men (8.1% of this population) was associated with a significant reduction in FMD.

  • Serum concentration of full-length- and carboxy-terminal fragments of endothelial lipase predicts future cardiovascular risks in patients with coronary artery disease
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2019-07-29
    Manabu Nagao, Kazuya Miyashita, Kenta Mori, Yasuhiro Irino, Ryuji Toh, Tetsuya Hara, Ken-ichi Hirata, Masakazu Shinohara, Katsuyuki Nakajima, Tatsuro Ishida

    Background Endothelial lipase (EL), a regulator of plasma high-density lipoprotein cholesterol (HDL-C), is secreted as a 68-kDa mature glycoprotein, and then cleaved by proprotein convertases. However, the clinical significance of the circulating EL fragments remains unclear. Objective The objective of this study was to analyze the impact of serum EL fragments on HDL-C levels and major adverse cardiovascular events (MACE). Methods Using novel monoclonal antibodies (RC3A6) against carboxy-terminal EL protein, we have established a new enzyme-linked immunosorbent assay (ELISA) system, which can detect both full-length EL protein (full EL) and carboxy-terminal truncated fragments (total EL) in serum. The previous sandwich ELISA detected only full EL. The full and total EL mass were measured in 556 patients with coronary artery disease. Among them, 272 patients who underwent coronary intervention were monitored for 2 years for MACE. Results There was a significant correlation between serum full and total EL mass (R = 0.45, P < .0001). However, the total EL mass showed a stronger inverse correlation with serum HDL-cholesterol concentration than the full EL mass (R = −0.17 vs −0.02). Kaplan-Meier analysis documented an association of serum total EL mass and MACE (log-rank P = .037). When an optimal cutoff value was set at 96.23 ng/mL, total EL mass was an independent prognostic factor for MACE in the Cox proportional hazard model (HR; 1.75, 95% CI; 1.10–2.79, P = .018). Conclusion Serum total EL mass could be a predictor for MACE in patients with coronary artery disease. This novel ELISA will be useful for further clarifying the impact of EL on HDL metabolism and atherosclerosis.

  • RAB18 modulates autophagy in human stellate cells
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2019-07-25
    Soumik BasuRay

    Background Macroautophagy (or autophagy) is a conserved degradative pathway that breaks down sequestered cytoplasmic proteins and organelles in specialized double-membrane compartments called autophagosomes that fuse with lysosomes. Several proteins orchestrate this process, specifically Rab GTPases that are master regulators of molecular trafficking. RAB18 GTPase, a known mediator of stellate cell activation, is known to modulate autophagic flux in fibroblasts. However, its role in autophagy is unexplored in hepatic stellate cells. Objective The aim of this study was to investigate the role of RAB18 in modulating autophagy in hepatic stellate cells. Methods Role of RAB18 was determined by genetic depletion, pharmacologic inhibition, and overexpression studies to monitor autophagy flux and proteostasis in human LX2 stellate cell line. Results RAB18 knockdown increases autophagy flux and regulates proteostasis. LX2 cells stimulated with transforming growth factor-beta robustly increases expression of profibrotic genes such as COL1A1 and ACTA2 along with RAB18 and its guanine nucleotide exchange factor, RAB3GAP1. Conclusion The study elucidates a role for RAB18 in autophagy and regulation of proteostasis in human stellate cells. Molecular insights into this process can provide therapeutic opportunities for intervention in liver fibrosis.

  • PCSK9 inhibition, atherosclerotic cardiovascular disease, and health economics: Challenges at the crossroads
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2019-07-24
    Lieven Annemans, Jane K. Stock, M. John Chapman

    Background Improved survival after a cardiovascular event has led to an expanding patient population at very high risk of recurrent events. Reduction in low-density lipoprotein cholesterol, and thus implicitly non–high-density lipoprotein cholesterol, to guideline-recommended goals is a key tenet of secondary prevention. Yet, standard-of-care treatment with statin (with or without ezetimibe) often leaves a high risk of preventable cardiovascular events. Inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9), highly efficacious lipid-lowering treatments that confer reduction in cardiovascular events and death, clearly have a role in the personalized management of these very-high-risk patients. Given budget constraints, however, their integration into the health care pathway merits health economic considerations. Consequently, it is important to identify challenges at the crossroads of the clinical and economic dimensions. Findings and conclusion Health economic analyses involve application of modeling scenarios integrating multiple parameters to ultimately yield values for quality-adjusted life-years and cost-effectiveness ratios. To date, these analyses have led to widely variable estimates of these benchmarks for PCSK9 inhibitors, causing confusion among stakeholders in the health care pathway. Clearly, a consensual approach to the conduct and reporting of health economic analyses involving all players, including noneconomists such as clinicians and patient advocates, is essential to bridge the gap between the clinical needs of patients and financial access to PCSK9 inhibition.

  • The economic burden of hypertriglyceridemia among US adults with diabetes or atherosclerotic cardiovascular disease on statin therapy
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2019-07-20
    Brian C. Case, Adam P. Bress, Paul Kolm, Sephy Philip, Jennifer S. Herrick, Craig B. Granowitz, Peter P. Toth, Wenjun Fan, Nathan D. Wong, Michael Hull, William S. Weintraub

    Background Hypertriglyceridemia (HTG) is associated with increased cardiovascular disease (CVD) risk. However, the cost burden of HTG-related CVD in high-risk US adults on statins has not been well characterized. Objective We estimated the HTG-related health care cost burden among US adults with CVD or diabetes taking statin therapy. Methods We estimated population sizes and annual health care costs among US adults aged ≥45 years with diabetes or CVD taking statin therapy with normal triglycerides (TGs) defined as TG < 150 mg/dL compared with those with HTG defined as TG ≥ 150 mg/dL. Population sizes were estimated from the 2007-2014 National Health and Nutrition Examination Surveys. Adjusted mean total annual health care costs in 2015 US dollars were estimated using the Optum Research Database. The annual total health care cost burden was estimated by multiplying the population size by the mean annual total incremental health care costs overall and within subgroups. Results There were 6.2 (95% confidence interval [CI], 5.4 - 7.1) million and 12.0 (95% CI, 11.1 – 12.9) million US adults aged ≥45 years with diabetes and/or CVD on statin therapy with TG ≥ 150 mg/dL and TG < 150 mg/dL, respectively. The mean adjusted incremental total one-year health care costs in adults with TG ≥ 150 mg/dL compared with those with TG < 150 mg/dL was $1730 (95% CI, $1160 - $2320). This leads to a projected annual incremental cost burden associated with HTG in patients with diabetes or CVD on statins of $10.7 billion (95% CI, $6.8 B - $14.6 B). Conclusion In US adults on statins and at high risk for CVD, the health care costs associated with HTG are substantial.

  • The association of plasma lipids with white blood cell counts: Results from the Multi-Ethnic Study of Atherosclerosis
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2019-07-15
    Yong Chang Lai, Kevin J. Woollard, Robyn L. McClelland, Matthew A. Allison, Kerry-Anne Rye, Kwok Leung Ong, Blake J. Cochran

    Background Previous studies have demonstrated that elevated cholesterol results in increased white blood cell counts in mouse models. However, there is insufficient evidence to support this in humans. Objective The objective of the study was to investigate the relationship of plasma lipids with white blood cell counts (basophils, eosinophils, monocytes, neutrophils and lymphocytes) in the Multi-Ethnic Study of Atherosclerosis. Methods The analysis included 2873 Multi-Ethnic Study of Atherosclerosis participants with a complete white blood count and differential analysis. The cross-sectional association of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglyceride levels with different white blood cell counts was analyzed by multivariable linear regression. Results After adjusting for sociodemographic and confounding factors including red blood cell counts, platelet counts, use of lipid-lowering medication, cardiovascular disease risk factors and other lipid measures, and multiple testing correction, a one–standard deviation increment in total cholesterol and low-density lipoprotein cholesterol was associated with 2.8% and 2.3% lower total white blood cell counts, 3.7% and 3.0% lower monocyte counts, and 3.4% and 2.7% lower neutrophil counts (all P < .01). The same increment in logarithm-transformed triglyceride levels was associated with 2.3% higher total white blood cell counts and 4.5% higher lymphocyte counts (both P < .001). Similar results were obtained after excluding participants taking lipid-lowering medication. A one–standard deviation increase in high-density lipoprotein cholesterol was associated with a 1.5% lower white blood cell count (P = .018) but was not significantly associated with changes in any individual cell type. Conclusion While significant associations were observed between plasma lipid levels and white blood cell populations, the heterogeneous and modest nature of these relationships makes it hard to support the hypothesis that lipids are in the causal pathway for leukogenesis in humans.

  • Translating plasma eicosapentaenoic acid concentrations into erythrocyte percentages of eicosapentaenoic acid plus docosahexaenoic acid during treatment with icosapent ethyl
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2019-07-12
    William S. Harris, Kristina H. Jackson

    Background The Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT) study demonstrated that 4 g/d of eicosapentaenoic acid (EPA) ethyl esters (icosapent ethyl [IPE]) reduced risk for major cardiovascular events by 25% in statin-treated patients with residual hypertriglyceridemia. How this treatment affected red blood cell (RBC) EPA and docosahexaenoic acid (DHA) levels (ie, the Omega-3 Index [O3I]) was not reported, but effects on plasma EPA concentrations were reported. Objective The aim of the study was to estimate baseline and final O3I levels in REDUCE-IT. Methods First, deidentified data from our laboratory on RBC and plasma EPA and DHA from 2311 patients with similar lipid profiles as those in REDUCE-IT were used to generate a regression equation, which was then used to estimate the O3I from plasma FA concentrations. Second, previously published data on the effects of IPE on RBC FA concentrations were also converted to the O3I. Results Both approaches (from calculations and prior publications) suggested that baseline and follow-up O3I levels were about 5% and 7%, respectively. In addition, plasma EPA levels (but not the O3I) were noted to be influenced by triglyceride levels. Conclusion For patients using 4 g of IPE, an estimated O3I value of about 7% reflects a cardioprotective state. Plasma EPA concentrations may be ill-suited as treatment targets because they are confounded by triglyceride levels.

  • Impact of improved low-density lipoprotein cholesterol assessment on guideline classification in the modern treatment era—Results from a racially diverse Brazilian cross-sectional study
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2019-07-09
    Vincent A. Pallazola, Vasanth Sathiyakumar, Oluseye Ogunmoroti, Oluwaseun Fashanu, Steven R. Jones, Raul D. Santos, Peter P. Toth, Marcio S. Bittencourt, Bruce B. Duncan, Paulo A. Lotufo, Isabela M. Bensenor, Michael J. Blaha, Seth S. Martin

    Background The Martin/Hopkins low-density lipoprotein cholesterol equation (LDL-CN) was previously demonstrated as more accurate than Friedewald LDL-C estimation (LDL-CF) in a North American database not able to take race into account. Objectives We hypothesized that LDL-CN would be more accurate than LDL-CF and correlate better with LDL particle number (LDL-P) in a racially diverse Brazilian cohort. Methods We performed a cross-sectional analysis of 4897 participants in the Brazilian Longitudinal Study of Adult Health, assessing LDL-CF and LDL-CN accuracy via overlap with ultracentrifugation-based measurement among clinical guideline LDL-C categories as well as mg/dL and percent error differences. We analyzed by triglyceride categories and correlated LDL-C estimation with LDL-P. Results LDL-CN demonstrated improved accuracy at 70 to <100 and <70 mg/dL (P < .001), with large errors ≥20 mg/dL about 9 times more frequent in LDL-CF at LDL-C <70 mg/dL, mainly due to underestimation. Among individuals with LDL-C <70 mg/dL and triglycerides ≥150 mg/dL, 65% vs 100% of ultracentrifugation-based low-density lipoprotein cholesterol calculation fell within appropriate categories of estimated LDL-CF and LDL-CN, respectively (P < .001). Similar results were observed when analyzed for age, sex, and race. Participants at LDL-C <70 and 70 to <100 mg/dL with discordantly elevated LDL-CN vs LDL-CF had a 58.5% and 41.5% higher LDL-P than those with concordance (P < .0001), respectively. Conclusions In a diverse Brazilian cohort, LDL-CN was more accurate than LDL-CF at low LDL-C and high triglycerides. LDL-CN may avoid underestimation of LDL-C and better reflect atherogenic lipid burden in low particle size, high particle count states.

  • Individuals with familial hypercholesterolemia and cardiovascular events have higher circulating Lp(a) levels
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2019-07-04
    Chiara Pavanello, Carlo Pirazzi, Kristina Bjorkman, Joakim Sandstedt, Claudia Tarlarini, Lorena Mosca, Stefano Romeo, Laura Calabresi, Rosellina Margherita Mancina

    Background Cardiovascular disease (CVD) is a major cause of mortality and morbidity. Increased low-density lipoprotein cholesterol (LDL-C) level is its major risk factor. Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated LDL-C since birth and subsequent premature CVD. There is a heterogeneity in the CVD onset in patients with FH. This is potentially due to the presence of other independent risk factors. Lipoprotein(a) [Lp(a)] is an LDL-like particle and represents a strong risk factor for CVD. Objective Our objective was to understand the contribution of Lp(a) in the susceptibility to CVD in individuals with genetic diagnosis of FH. Methods We measured Lp(a) levels in 2 independent and well-characterized genetic-FH cohorts: the FH-Gothenburg cohort (n = 190) and the FH-CEGP Milan cohort (n = 160). The genetic diagnosis was performed by targeted next-generation sequencing (FH-Gothenburg and part of the FH-CEGP Milan cohort), or by Sanger sequencing. Results We show that among individuals with genetic diagnosis of FH, those with previous CVD had higher Lp(a) levels. In addition, analyzing the response to the lipid-lowering therapies, we have also shown that statins had the same LDL-C–lowering effect irrespective of the type of FH-causative mutation. However, when we examined the lipid-lowering effect of proprotein convertase subtilisin/kexin type 9 inhibition by antibodies, we observed a trend in a better reduction of the LDL-C level in carriers of nonsense mutations. Conclusion In conclusion, our results suggest that Lp(a) contributes to CVD onset in individuals with genetic diagnosis of FH. Our finding supports the importance to identify an efficacious therapy to lower Lp(a) in patients with FH to prevent CVD onset or recurrence.

  • PCSK9 inhibition in patients with heart transplantation: A case series
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2019-07-03
    Pratik B. Sandesara, Devinder Dhindsa, Benjamin Hirsh, Maan Jokhadar, Robert T. Cole, Laurence S. Sperling

    PCSK9 inhibitors are potent low-density lipoprotein cholesterol–lowering medications. There is a lack of data regarding safety and efficacy of PCSK9 inhibitors in cardiac transplant patients. In this case series, we provide data supporting the low-density lipoprotein–lowering efficacy and short-term safety of PCSK9 inhibitors in three cardiac transplant patients.

  • The patient journey with proprotein convertase subtilisin/kexin type 9 inhibitors in community practice
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2019-07-02
    Corey K. Bradley, Peter Shrader, Robert J. Sanchez, Eric D. Peterson, Ann Marie Navar

    Background Trials have demonstrated that proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are effective as an adjunct to statin therapy, but access and cost issues have limited their use in community practice. Objective The aim of the study was to better understand patients’ experiences when trying to obtain, fill, and use PCSK9 inhibitor therapy in community practice. Methods We conducted a patient survey to evaluate patient experiences with PCSK9 inhibitors including medication initiation, indication for treatment, insurance approval status, medication persistence, and reason for discontinuation. The survey was emailed to 4740 adults who used a patient access support program. Results Overall, 1327 of 4740 adults completed the survey (28.0% response rate). Of those, 75.0% were aged >60 years, 52.8% were male, and 92.4% were White. At the time of PCSK9 inhibitor prescription, 70.2% were not on a statin (with 84.4% of those not on a statin reporting statin intolerance). Overall, 74.6% of patients found the drug approval process to be “somewhat” or “very” burdensome. Among n = 1216 patients who initiated treatment, 33.7% discontinued by the time of the survey, with 50.0% taking the drug for 1 to 6 months. Patient out-of-pocket costs were the leading reported reason for discontinuation. Conclusions Most PCSK9 inhibitor users in community practice were not on a statin, presumably because of statin intolerance. The drug approval process and costs continue to be strong reasons for lower initiation of PCSK9 agents, as well as higher discontinuation rates.

  • Impact of lipoprotein apheresis on thrombotic parameters in patients with refractory angina and raised lipoprotein(a): Findings from a randomized controlled cross-over trial
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2019-07-02
    Tina Z. Khan, Diana A. Gorog, Deepa J. Arachchillage, Josefin Ahnström, Samantha Rhodes, Jacqueline Donovan, Winston Banya, Alison Pottle, Mahmoud Barbir, Dudley J. Pennell

    Background Raised lipoprotein(a) [Lp(a)] is a cardiovascular risk factor common in patients with refractory angina. The apolipoprotein(a) component of Lp(a) exhibits structural homology with plasminogen and can enhance thrombosis and impair fibrinolysis. Objectives The objective of the study was to assess the effect of lipoprotein apheresis on markers of thrombosis and fibrinolysis in patients with high Lp(a). Methods In a prospective, single-blind, crossover trial, 20 patients with refractory angina and raised Lp(a) > 50 mg/dL were randomized to three months of weekly lipoprotein apheresis or sham. Blood taken before and after apheresis/sham was assessed using the Global Thrombosis Test, to assess time taken for in vitro thrombus formation (occlusion time) and endogenous fibrinolysis (lysis time), as well as von Willebrand Factor, fibrinogen, D-dimer, thrombin/anti-thrombin III complex, prothrombin fragments 1 + 2, and thrombin generation assays. Results Lp(a) was significantly reduced by apheresis (100.2 [interquartile range {IQR}, 69.6143.0] vs 24.8 [17.2,34.0] mg/dL, P = .0001) but not by sham (P = .0001 between treatment arms). Apheresis prolonged occlusion time (576 ± 116 s vs 723 ± 142 s, P < .0001) reflecting reduced platelet reactivity and reduced lysis time (1340 [1128, 1682] s vs 847 [685,1302] s, P = .0006) reflecting enhanced fibrinolysis, without corresponding changes with sham. Apheresis, but not sham, reduced von Willebrand Factor (149 [89.0, 164] vs 64.2 [48.5, 89.8] IU/dL, P = .0001), and fibrinogen (3.12 ± 0.68 vs 2.20 ± 0.53 g/L, P < .0001), and increased prothrombin fragments 1 + 2 (158.16 [128.77, 232.09] vs 795.12 [272.55, 1201.00] pmol/L, P = .0006). There was no change in D-dimer, thrombin/anti-thrombin III complex, or thrombin generation assay with apheresis or sham. Conclusion Lipoprotein apheresis reduces Lp(a) and improves some thrombotic and fibrinolytic parameters in patients with refractory angina.

  • Race–ethnic differences in the associations of maternal lipid trait genetic risk scores with longitudinal fetal growth
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2019-06-29
    Marion Ouidir, Pauline Mendola, Tsegaselassie Workalemahu, Jagteshwar Grewal, Katherine L. Grantz, Cuilin Zhang, Jing Wu, Fasil Tekola-Ayele

    Background Fetal growth, an important predictor of cardiometabolic diseases in adults, is influenced by maternal and fetal genetic and environmental factors. Objective We investigated the association between maternal lipid genetic risk score (GRS) and fetal growth among 4 US racial–ethnic populations (Whites, Blacks, Hispanics, and Asians). Methods We extracted genotype data for 2008 pregnant women recruited in the National Institute of Child Health and Human Development Fetal Growth Studies—Singleton cohort with up to 6 standardized ultrasound examinations. GRS was calculated using 240 single-nucleotide polymorphisms previously associated with higher total cholesterol (GRSTChol), low-density lipoprotein cholesterol (GRSLDLc), and triglycerides (GRSTG) and lower high-density lipoprotein cholesterol (GRSHDLc). Results At 40 weeks’ gestation, a unit increase in GRSTG was associated with 11.4 g higher fetal weight (95% confidence interval [CI] 2.8–20.0 g) among normal-weight Whites, 26.3 g (95% CI 6.0–46.6 g) among obese Blacks, and 30.8 g (95% CI 6.3–55.3 g) among obese Hispanics. Higher GRSHDLc was associated with increased fetal weight across 36 to 40 weeks among normal-weight Whites and across 13 to 20 weeks among normal-weight Asians, but with decreased fetal weight across 26 to 40 weeks among normal-weight Hispanics. Higher GRSTChol was suggestively associated with increased fetal weight in males and decreased in females. Associations remained consistent after adjustment for serum lipids. Conclusion Associations between fetal weight and maternal lipid GRS appear to vary by maternal race–ethnic group, obesity status, and offspring sex. Genetic susceptibility to unfavorable lipid profiles contributes to fetal growth differences even among normal-weight women suggesting a potential future application in predicting aberrant fetal growth.

  • Treatment effect of alirocumab according to age group, smoking status, and hypertension: Pooled analysis from 10 randomized ODYSSEY studies
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2019-06-29
    Frederick J. Raal, Jaakko Tuomilehto, Andrei C. Sposito, Francisco A. Fonseca, Maurizio Averna, Michel Farnier, Raul D. Santos, Keith C. Ferdinand, R. Scott Wright, Eliano Pio Navarese, Danielle M. Lerch, Michael J. Louie, L. Veronica Lee, Alexia Letierce, Jennifer G. Robinson
  • Inclisiran - new hope in the management of lipid disorders?
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2019-11-12
    Dyrbuś Krzysztof, Gąsior Mariusz, Penson Peter, Ray Kausik K, Banach Maciej

    Drugs reducing plasma concentrations of apolipoprotein-B (ApoB) containing lipoproteins have been demonstrated to reduce the risk of cardiovascular disease (CVD) in both primary and secondary prevention. Despite the demonstrated efficacy of statins and ezetimibe on low-density lipoprotein (LDL) concentration and long-term CVD risk, a large number of patients do not achieve their therapeutic goals. The introduction of monoclonal antibodies against proprotein convertase subtilisin/kexin type 9 (PCSK9) protein was a milestone in the treatment of lipid disorders, as their administration leads to unprecedentedly low LDL-C concentrations. Inclisiran represents an entirely new mechanism of PSCK9 protein inhibition in hepatocytes, targeting the messenger RNA (mRNA) for PCSK9. Its administration is necessary only every 3-6 months, which is an essential advantage over statin and monoclonal antibody therapy. The infrequent administration regimen can increase the number of patients who maintain their therapeutic goals, especially in patients struggling to comply with daily or biweekly pharmacotherapy. Preclinical studies and Phase I and Phase II clinical trials of inclisiran have demonstrated its tolerability and efficacy in promoting long-term reduction of both PCSK9 protein and LDL-C. The efficacy and safety of inclisiran will continue to be assessed in ongoing and forthcoming trials on larger patient groups. If the results of these trials reflect previously published data, they will add further evidence that inclisiran might be a revolutionary new tool in the pharmacological management of plasma lipids. This review summarizes the currently available literature data on inclisiran with respect to its mechanism of action, effectiveness and safety as a lipid-lowering drug for CVD prevention.

  • National Lipid Association Scientific Statement on the Use of Icosapent Ethyl in Statin-treated Patients with Elevated Triglycerides and High- or Very-high ASCVD Risk
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2019-11-02
    Carl E. Orringer, Terry A. Jacobson, Kevin C. Maki

    Representatives from the National Lipid Association (NLA) participated in the development of the 2018 American Heart Association/American College of Cardiology/Multisociety Guideline on the Management of Blood Cholesterol, which reaffirmed that lifestyle changes and statin treatment are therapeutic cornerstones for atherosclerotic cardiovascular disease (ASCVD) risk reduction. It also updated prior recommendations to incorporate newer data demonstrating ASCVD risk reduction with ezetimibe and proprotein convertase subtilisin kexin type 9 inhibitors as adjuncts to statin therapy for patients at high and very high ASCVD risk. The 2018 Guideline was finalized shortly before full results were available from a randomized, placebo-controlled cardiovascular outcomes trial (Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial; REDUCE-IT) that examined the effects of icosapent ethyl (IPE) on major adverse cardiovascular events in selected high- or very high-risk, statin-treated patients with elevated triglycerides. The primary outcome variable of first major adverse cardiovascular event (cardiovascular death, myocardial infarction, stroke, coronary revascularization and hospitalization for unstable angina) was reduced by 25% (95% confidence interval 17-32%, p < 0.001). REDUCE-IT served as the primary basis for the NLA’s review of evidence for the use of IPE for ASCVD risk reduction. Based on this review, the NLA position is that for patients ≥45 years of age with clinical ASCVD, or ≥50 years of age with diabetes mellitus requiring medication plus ≥1 additional risk factor, with fasting triglycerides 135-499 mg/dL on high-intensity or maximally tolerated statin therapy (±ezetimibe), treatment with IPE is recommended for ASCVD risk reduction (evidence rating: Class I; evidence level: B-R).

  • Supplementation with saury oil, a fish oil high in omega-11 monounsaturated fatty acids, improves plasma lipids in healthy subjects
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2019-10-31
    Zhi-Hong Yang, Marcelo Amar, Alexander V. Sorokin, James Troendle, Amber B. Courville, Maureen Sampson, Martin P. Playford, Shanna Yang, Michael Stagliano, Clarence Ling, Kwame Donkor, Robert D. Shamburek, Nehal N. Mehta, Alan T. Remaley

    Background Fish oil enriched in omega-11 long-chain monounsaturated fatty acids (LCMUFA; C20:1 and C22:1 isomers combined) have shown lipid-lowering and atheroprotective effects in animal models. Objective To perform a first-in-human trial of LCMUFA-rich saury fish oil supplementation to test its safety and possible effect on plasma lipids. Methods A double-blind, randomized cross-over clinical trial was carried out in 30 healthy normolipidemic adults (BMI <25 kg/m2; mean TG, 84 mg/dL). Treatment periods of 8 weeks were separated by an 8-week washout period. Subjects were randomized to receive either 12 g of saury oil (3.5 g of LCMUFA and 3.4 g of omega-3 FAs) or identical capsules with control oil (a mixture of sardine and olive oil; 4.9 g of shorter-chain MUFA oleate and 3 g of omega-3 FAs). Results Saury oil supplementation was safe and resulted in LDL particle counts 12% lower than control oil (P <0.001). Saury oil also had a minor effect on increasing HDL particle size (9.8 nm vs 9.7 nm; P <0.05) based on a linear mixed effect model. In contrast, control oil, but not saury oil, increased LDL-C by 7.5% compared to baseline (P <0.05). Saury oil had similar effects compared to control oil on lowering plasma TG levels, VLDL and TG-rich lipoprotein particle counts (by ∼16%, 25% and 35%, respectively; P <0.05), and increasing HDL-C and cholesterol efflux capacity (by ∼6% and 8%, respectively; P <0.05) compared to baseline. Conclusion Saury oil supplementation is well tolerated and has beneficial effects on several cardiovascular parameters, such as LDL particle counts, HDL particle size, and plasma TG levels.

  • High-density Lipoprotein Cholesterol Efflux Capacity is not associated with Atherosclerosis and Prevalence of Cardiovascular Outcome: The CODAM Study
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2019-10-31
    Tatjana Josefs, Kristiaan Wouters, Uwe J.F. Tietge, Wijtske Annema, Robin P.F. Dullaart, Tomas Vaisar, Ilja C.W. Arts, Carla J.H. van der Kallen, Coen D.A. Stehouwer, Casper G. Schalkwijk, Ira J. Goldberg, Edward A. Fisher, Marleen M.J. van Greevenbroek

    Background Cholesterol Efflux Capacity (CEC) is considered to be a key atheroprotective property of high-density lipoproteins (HDL). However, the role of HDL-CEC in atherosclerosis and cardiovascular (CV) risk is still controversial and data in individuals with diabetes are limited. Objective In this study, we have investigated the relationship of CEC and other HDL characteristics with clinical and subclinical atherosclerosis in subjects with elevated CVD risk and Type 2 Diabetes Mellitus (T2DM). Methods Using multiple linear regression analyses, we determined the relationship of HDL-CEC with carotid intima media thickness (cIMT, Z-Score), an endothelial dysfunction (EnD) Score (Z-Score), prevalent CV disease (CVD, n=150 cases) and history of CV events (CVE, n=85 cases) in an observational cohort (CODAM, n= 574, 59.6±0.3 yr, 61.3% men, 24.4% T2DM). Stratified analyses were performed to determine if the associations differed between individuals with normal glucose metabolism (NGM) and those with a disturbed glucose metabolism. Results HDL-CEC was not associated with either marker of atherosclerosis (cIMT, EnD Score) nor with CVD or CVE. In contrast, other HDL characteristics i.e. HDL-Cholesterol (HDL-C, Z-Score), apolipoprotein A-I (apoA-I, Z-Score), HDL size (Z-Score) and HDL particle number (HDL-P, Z-Score) were inversely and significantly associated with the EnD Score (ßs -0.226 to -0.097, p<0.05) and CVE (ORs 0.61 to 0.68, p<0.05). In stratified analyses, HDL size and HDL-P were significantly associated with the EnD Score in individuals with NGM (pinteraction 0.039 and 0.005, respectively), but not in those with (pre)diabetes. HDL-C and apoA-I were inversely associated with prevalent CVD in individuals with (pre)diabetes (pinteraction=0.074 and 0.034, respectively), but not in those with NGM. Conclusion HDL-CEC is not associated with clinical or subclinical atherosclerosis, neither in the whole population nor in individuals with (pre)diabetes, while other HDL characteristics show atheroprotective associations. The atheroprotective associations of HDL-size and HDL-P are lost in (pre)diabetes, while higher concentrations of HDL-C and apoA-I are associated with lower prevalence of CVD in (pre)diabetes.

  • From the editor: Considering less carbohydrate.
    J. Clin. Lipidol. (IF 3.581) Pub Date : null
    John R Guyton

  • Pseudohypertriglyceridemia-Raising clinical awareness.
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2019-10-19
    James M Backes,Thomas Dayspring,Patrick M Moriarty

  • Screening for hyperglycerolemia by triglyceride assay in urine.
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2019-10-13
    Jacinto Fernández-Pardo,José L Quílez-Fernández,Juan Pedro-Botet

  • Mortality reduction with PCSK9 inhibition: A case of cautious optimism.
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2019-08-03
    Dave L Dixon,Salim S Virani

  • Autosomal recessive hypercholesterolemia: Case report.
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2019-11-18
    Zaneta Petrulioniene,Urte Gargalskaite,Violeta Mikstiene,Rimvydas Norvilas,Egle Skiauteryte,Algirdas Utkus

    INTRODUCTION Autosomal recessive hypercholesterolemia (ARH; OMIM #603813) is a very rare monogenic disorder affecting less than 1 in 1000,000 people and is characterized by very high levels of low-density lipoprotein cholesterol (LDL-C), leading to aggressive and premature atherosclerotic cardiovascular disease if left untreated. Lowering of LDL-C is the main target of the treatment. We report on a 29-year-old male patient born in nonconsanguineous Lithuanian family homo(hemi-)zygous for LDLRAP1 gene variant causing ARH. This variant is not present in population databases and, to our knowledge, has not been reported in scientific literature before. METHODS AND RESULTS The earliest clinical sign, noticed at the age of 5 years, was painful and enlarging nodules on Achilles tendons. At the age of 10 years, xanthomas of the metacarpal joint area on both hands emerged. The first lipid panel was performed at the age of 12 years. In accordance with Dutch Lipid Clinic Network diagnostic criteria for familial hypercholesterolemia (FH), definite FH (type IIA hyperlipoproteinemia) was diagnosed and the treatment with cholestyramine 4 grams per day was initiated. As the patient was 15 years old, direct adsorption of low-density lipoprotein apheresis was started and repeated monthly. At the age of 20 years, along with lipoprotein apheresis, 10 mg of rosuvastatin daily intake was prescribed. At the age of 28 years, the dose of rosuvastatin was increased to 40 mg per day, and 10 mg of ezetimibe daily intake was added. At the age of 28 years, homozygous LDLRAP1 gene variant NM_015627.2:c.488A>C, NP_056442.2:p.(Gln163Pro) causing autosomal recessive hypercholesterolemia was determined by genetic testing. CONCLUSIONS This case report implies that ARH, being an extremely rare disorder, is a severe disease. As there is limited routine testing, including genetic testing, patients suffering from both this disease and FH may remain undiagnosed. Cascade screening and genetic counseling differ for ARH as compared with FH, as the carrier of a pathogenic variant in the LDLRAP1 gene does not have marked total cholesterol and LDL-C elevations. However, genetic testing of the proband and their relatives is essential to evaluate the risk of development of FH and to provide prognosis as well as adequate, timely treatment. To improve the quality of life of patients with FH and prolong their life expectancy, national registries of FH and wider laboratory and genetic testing are undoubtedly necessary. A national FH screening program was set up in Lithuania, which helps to identify, monitor, and treat subjects with FH.

  • 更新日期:2019-11-01
  • Type 1 diabetes is associated with an increase in cholesterol absorption markers but a decrease in cholesterol synthesis markers in a young adult population.
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2019-11-11
    Ivana Semova,Amy E Levenson,Joanna Krawczyk,Kevin Bullock,Kathryn A Williams,R Paul Wadwa,Amy S Shah,Philip R Khoury,Thomas R Kimball,Elaine M Urbina,Sarah D de Ferranti,Franziska K Bishop,David M Maahs,Lawrence M Dolan,Clary B Clish,Sudha B Biddinger

    BACKGROUND To optimize treatment and prevent cardiovascular disease in subjects with type 1 diabetes, it is important to determine how cholesterol metabolism changes with type 1 diabetes. OBJECTIVE The objective of the study was to compare plasma levels of campesterol and β-sitosterol, markers of cholesterol absorption, as well as lathosterol, a marker of cholesterol synthesis, in youth with and without type 1 diabetes. METHODS Serum samples were obtained from adolescent subjects with type 1 diabetes (n = 175, mean age 15.2 years, mean duration of diabetes 8.2 years) and without diabetes (n = 74, mean age 15.4 years). Campesterol, β-sitosterol, and lathosterol, were measured using targeted liquid chromatography tandem mass spectrometry, compared between groups, and correlated with the available cardiometabolic variables. RESULTS Campesterol and β-sitosterol levels were 30% higher in subjects with type 1 diabetes and positively correlated with hemoglobin A1c levels. In contrast, lathosterol levels were 20% lower in subjects with type 1 diabetes and positively correlated with triglycerides, body mass index, and systolic blood pressure. CONCLUSION Plasma markers suggest that cholesterol absorption is increased, whereas cholesterol synthesis is decreased in adolescent subjects with type 1 diabetes. Further studies to address the impact of these changes on the relative efficacy of cholesterol absorption and synthesis inhibitors in subjects with type 1 diabetes are urgently needed.

  • Coronary artery disease in a child with homozygous familial hypercholesterolemia: Regression after liver transplantation.
    J. Clin. Lipidol. (IF 3.581) Pub Date : null
    Constance E Cephus,Athar M Qureshi,S Kristen Sexson Tejtel,Mahboob Alam,Douglas S Moodie

    Children with homozygous familial hypercholesterolemia are at risk for early cardiovascular events secondary to coronary artery disease. Current medical therapy does not ameliorate this risk. Liver transplantation offers the most effective option to reduce circulating levels of low-density lipoprotein cholesterol and thereby reduce risk of cardiovascular events. Angiographic evidence of regression of coronary artery disease is presented.

  • Low LDL cholesterol-Friend or foe?
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2019-05-28
    Jacob Hartz,Robert A Hegele,Don P Wilson

  • JCL roundtable-Lipoprotein(a): The emerging risk factor.
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2018-12-12
    Santica M Marcovina,Patrick M Moriarty,Marlys L Koschinsky,John R Guyton

    Lipoprotein(a), or Lp(a), is a major risk factor for atherothrombotic events along with low-density lipoprotein cholesterol and, inversely, high-density lipoprotein cholesterol. Lp(a) also contributes to the progression of calcific aortic stenosis and to the rare occurrence of arterial thrombotic strokes without atherosclerosis in children and younger women. Much has been learned about the inheritance of Lp(a) levels and the relationship between apolipoprotein(a) structure and function. Recent work suggests an intriguing interaction between oxidized phospholipids on Lp(a) and inflammatory interleukin-1 genotypes. New pharmaceutical approaches with antisense and RNA interference technology may achieve up to 90% lowering of Lp(a). This Roundtable includes practical considerations for clinically measuring and responding to Lp(a) levels.

  • From the editor: Lessons from the East.
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2018-12-12
    John R Guyton

  • Metreleptin therapy lowers plasma angiopoietin-like protein 3 in patients with generalized lipodystrophy.
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2017-05-16
    Ranganath Muniyappa,Brent S Abel,Asha Asthana,Mary F Walter,Elaine K Cochran,Alan T Remaley,Monica C Skarulis,Phillip Gorden,Rebecca J Brown

    BACKGROUND Reduced triglyceride clearance due to impaired lipoprotein lipase-mediated lipolysis contributes to severe hypertriglyceridemia in lipodystrophy. Angiopoietin-like protein 3 (ANGPTL3) and 4 (ANGPTL4) impair clearance of triglycerides by inhibiting lipoprotein lipase. Whether circulating ANGPTL3/4 levels are altered in lipodystrophy and the effects of leptin replacement on these ANGPTLs are unknown. OBJECTIVE To examine if ANGPTL3/4 levels are elevated in patients with generalized lipodystrophy and assess the effects of leptin replacement on these ANGPTLs. METHODS Preleptin treatment plasma levels of ANGPTLs in patients with generalized lipodystrophy (n = 22) were compared with healthy controls (n = 39) using a post hoc case-control study design. In a prospective open-label study, we studied the effects of metreleptin therapy (16-32 weeks) on plasma ANGPTL3/4 in patients with generalized lipodystrophy. RESULTS Plasma ANGPTL3 (geometric mean [95% confidence interval]; 223 [182-275] vs 174 ng/mL [160-189], P = .02) but not ANGPTL4 levels (55 [37-81] vs 44 ng/mL [37-52], P = .26) were higher in patients with lipodystrophy compared with healthy controls. There was a significant decrease in total cholesterol, triglycerides, and glycosylated hemoglobin (A1C) levels following metreleptin therapy. After metreleptin, ANGPTL3 concentrations decreased significantly (223 [182-275] vs 175 ng/mL [144-214], P = .01) with no change in ANGPTL4 (55 [37-81] vs 48 ng/mL [32-73], P = .11). CONCLUSIONS These findings suggest that elevated plasma levels of ANGPTL3 in leptin-deficient states is attenuated with leptin therapy.

  • Characterizing familial chylomicronemia syndrome: Baseline data of the APPROACH study.
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2018-10-16
    Dirk J Blom,Louis O'Dea,Andres Digenio,Veronica J Alexander,Ewa Karwatowska-Prokopczuk,Karren R Williams,Linda Hemphill,Ovidio Muñiz-Grijalvo,Raul D Santos,Seth Baum,Joseph L Witztum

    BACKGROUND Familial chylomicronemia syndrome (FCS) is a rare metabolic disorder caused by mutations in lipoprotein lipase (LPL) or genes required for LPL functionality and is characterized by hyperchylomicronemia that results in recurrent episodes of acute pancreatitis. Owing to the rarity of FCS, there are few case series describing the phenotypic variability in FCS patients in detail. OBJECTIVE To provide baseline characteristics in the largest study population to date of patients with FCS. METHODS We analyzed baseline demographic and clinical characteristics of adult FCS patients in the phase 3 APPROACH study of volanesorsen sodium (antisense inhibitor of apolipoprotein C-III). RESULTS Sixty-six patients were included in the analysis. Mean (SD) age was 46 (13) years; and mean body mass index was 24.9 (5.7) kg/m2. We identified causal mutations in 79% (52) of patients, with LPL mutations accounting for 62% (41) of cases. Median age at diagnosis was 24 years, 54% were females, and 81% were Caucasian. All patients followed a low-fat diet, 43% received fibrates, 27% fish oils, and 21% statins. Median fasting triglyceride levels (P25, P75) were 1985 (1179, 3047 mg/dL). Overall, 76% of patients reported ≥1 lifetime episode of acute pancreatitis; 23 patients reported a total of 53 pancreatitis events in the 5 years before enrollment. CONCLUSIONS Our data emphasize the severe hypertriglyceridemia characteristic of FCS patients despite restrictive low-fat diets and frequent use of existing hypolipemic therapies. Acute pancreatitis and recurrent acute pancreatitis are frequent complications of FCS. Diagnosis at an older age suggests likely underdiagnosis and underappreciation of this rare disorder.

  • Case reports of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition nonresponse.
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2018-10-16
    Anum Saeed,Salim S Virani,Peter H Jones,Christie M Ballantyne,Vijay Nambi

    Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, a novel class of monoclonal antibodies, reduces low-density lipoprotein cholesterol levels and improves cardiovascular outcomes. Given the short time frame, these agents have been available for use; reports of nonresponse to the PCSK9 inhibitor therapy are scarce in literature. We describe 2 cases with substantially lesser than expected low-density lipoprotein cholesterol lowering on PCSK9 therapy. Nonresponse to PCSK9 inhibition was attributed to autosomal recessive hypercholesterolemia (secondary to low-density lipoprotein receptor adaptor protein 1 mutation) and plasmapheresis after PCSK9 inhibitor drug injections. Additional PCSK9 inhibitor nonresponders are likely to emerge as the use of these agents increases overtime.

  • JCL roundtable: High-density lipoprotein function and reverse cholesterol transport.
    J. Clin. Lipidol. (IF 3.581) Pub Date : 2018-10-14
    Marina Cuchel,Anand Rohatgi,Frank M Sacks,John R Guyton

    High-density lipoproteins (HDL) have been known since the 1960s to be associated with protection from atherosclerotic cardiovascular disease. However, the mechanisms of this protection are unclear. The extent to which HDL per se vs other correlated metabolic factors may mitigate atherosclerosis has been seriously questioned. In fact, new epidemiologic studies have found that in some clinical settings, very high HDL cholesterol levels correlate with increased atherosclerotic risk. Most importantly, over the past 2 decades, randomized clinical trials targeting HDL have failed to reproduce the usual epidemiologic inverse relation of HDL cholesterol to atherosclerotic events. In this roundtable discussion, we bring together 3 expert investigators working in the HDL field to elucidate questions of HDL function. One area of agreement is that reverse cholesterol transport remains a primary hypothesis for an anti-atherogenic role of HDL. Bioassays that measure cholesterol efflux capacity of HDL (or of apolipoprotein [apo] B-depleted plasma) have emerged as potentially accurate surrogates for reverse cholesterol transport. ApoA-I is the major functional apoprotein of HDL, but apoE- and apoC-III-containing subpopulations of HDL may have significant roles. Anti- and pro-inflammatory functions of various HDL particles, as well as the role of oxidative and other modifications, are gaining attention.

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