Journal of Clinical Lipidology - Articles in Press

From the Editor - Accepted Manuscript

W. Virgil Brown — 2010-07-26

Response from Dr. W. Virgil Brown - Uncorrected Proof

W. Virgil Brown — 2010-07-23

Dr. John Brown’s points regarding the potential benefits of blocking cholesterol and phytosterol absorption as a means of reducing sterol content of lipoproteins are of great interest. It is quite true that ezetimibe does reduce the cholesterol content of atherogenic lipoproteins, including chylomicrons remnants, very low-density lipoprotein remnants, and LDL. The additive effects on LDL cholesterol reduction achieved with statin treatment offers a very powerful combination, allowing treatment to goals not achievable in the past. The 15% to 25 % reduction of LDL cholesterol in patients who are not able to take other lipid-lowering drugs has provided a useful drug in monotherapy for certain individuals. However, as he has recognized, a more definitive trial demonstrating reduction of vascular events with this therapy has not been completed and reported. The overwhelming evidence that statins alone reduce virtually all clinical manifestations of arteriosclerosis makes them first-line therapy. Furthermore, the use of highly potent statins at high doses has shown greater benefit than therapy with the same statin at lower dose or therapy with a less efficacious statin. The adverse rates measured in thousands of patients have been extremely low with 80 mg of atorvastatin (TNT trial) or with 20 mg of rosuvastatin (Jupiter). Myalgias were not different with these high doses than with low dose or placebo therapy in these trials.

Management of Lp(a)† - Uncorrected Proof

W. Virgil Brown, Christie M. Ballantyne, Peter H. Jones, Santica Marcovina — 2010-07-15

This Roundtable discussion was held to provide a broad discussion of one of the less-well-known lipoprotein risk factors, “lipoprotein little a,” or as it is more commonly written, Lp(a). This lipoprotein was identified in 1963 by Kare Berg, MD, PhD, as a lipoprotein antigen that induced antibodies in patients receiving blood transfusions. Initially thought to be an unusual protein found only in some blood donors that induce antibodies in recipients of transfusions, we later learned that all humans have this lipoprotein in the blood. However, the concentration and the structure are highly variable. These differences in structure determined the antigenicity in patients who had different alleles and therefore differing gene products. The later finding that high plasma concentrations of Lp(a) appear to be markers of vascular disease risk has made the assessment of Lp(a) of relevance to all clinicians concerned with risk assessment and treatment. I asked three experts who have extensive experience in assessing and managing lipoprotein-related risk to join me to discuss the issues presented by Lp(a). Dr. Santica Marcovina from the University of Washington in Seattle is an international expert on the structure and laboratory assessment of Lp(a). Drs. Christie Balantyne and Peter H. Jones are well-known experts in lipid management from Baylor College of Medicine in Houston, Texas.

News from the NLA - Uncorrected Proof

2010-07-15

Highlights from the outstanding Annual Scientific Sessions, held May 13–16 in Chicago, are available on the NLA’s website, http://www.lipid.org. Topics covered include the “Atherosclerosis Imaging Debate: CAC vs. CIMT,” “Diet Debate: The Mediterranean Diet vs. Low Carbohydrate Diets,” and “Controversy: Rationale for Prescribing Ezetimibe.” In addition, highlights from the keynote presentation on “Mechanisms of Atherogenesis and Plaque Regression” by Dr. Ira Tabas are available online and in the Summer 2010 issue of the Lipid Spin.

An assessment of cholesterol goal attainment in patients with chronic kidney disease - Uncorrected Proof

2010-07-09

Background: Patients with chronic kidney disease (CKD) are at significant risk for cardiovascular disease (CVD). The National Kidney Foundation developed clinical practice guidelines (Kidney Disease Outcomes Quality Initiative) for targeting low-density lipoprotein cholesterol (LDL-C) goals.Objective: This study evaluated the extent to which these guidelines were adhered to among patients with CKD and to examine factors associated with the attainment of LDL-C goals.Methods: In this cross-sectional study we evaluated patients with a glomerular filtration rate of 15 to 59 mL/min per 1.73 m2. Patients with previous CVD, who were receiving dialysis, or were post kidney transplant were excluded. Administrative databases were used to determine the percentage of patients with a fasting lipid profile performed within the previous year, the percentage who attained a LDL-C goal less than 100 mg/dL, and to determine lipid-lowering medications prescribed. Logistic regression analysis was used to identify factors associated with LDL-C goal attainment.Results: Of the 4541 patients evaluated, 3157 (69.5%) had a fasting lipid profile performed within the previous year. Overall, 60.8% attained a LDL-C less than 100 mg/dL. Among patients at goal, 72.2% were taking lipid-lowering therapy compared with 37.9% of those not at goal (P < .01). Characteristics independently associated with LDL-C goal attainment were increasing age, male gender, increasing chronic disease score, history of diabetes, and statin use.Conclusion: Although most patients were screened and attained LDL-C goal, there was room for improvement. Statin use was independently associated with LDL-C goal attainment. Future prospective studies should focus on evaluating clinical outcomes of lipid-lowering interventions within the CKD population.

Role of dietary supplements in lowering low-density lipoprotein cholesterol: A review - Uncorrected Proof

Prabhjot S. Nijjar, Frances M. Burke, Annette Bloesch, Daniel J. Rader — 2010-07-09

Coronary heart disease (CHD) remains a major source of morbidity and mortality. As the epidemic of obesity, diabetes, and hypertension continues to grow among young adults, the population at risk for atherosclerotic CHD is ever increasing. More than a century of laboratory and human findings link cholesterol levels with a propensity to develop atherosclerosis. Low-density lipoprotein (LDL) is the major atherogenic lipoprotein, and numerous clinical trials have shown the efficacy of lowering LDL-cholesterol (LDL-C) for reducing CHD risk. New trial data have resulted in LDL-C goals being lowered over time and expansion of the population of patients that are candidates for LDL-lowering therapy to decrease their lifetime risk of CHD. Although statins are relatively safe and well tolerated, there are still significant numbers of patients who cannot tolerate them and many others who only require mild LDL-C reduction and prefer nonprescription alternatives to statin therapy. A number of dietary supplements and functional foods have been suggested to reduce LDL-C levels, but only a few have withstood the rigors of randomized controlled trials. Here we review the evidence in support of dietary supplements and their LDL-C−lowering effects. We also review supplements that, after initial excitement about their purported effect, were not found to lower LDL-C significantly.

Letter to the Editor - Uncorrected Proof

James D. Mickle — 2010-07-09

Dr. Sniderman’s reminders of the superiority of apolipoprotein B (apoB) over low-density lipoprotein cholesterol (LDL-C) in treatment of hyperlipidemia alert us that clinicians continue to expect too much from statin therapy. In contributions to the literature in the past, researchers have bemoaned the failure of statins to eradicate disease, leaving a significant reservoir of patients with residual risk despite a reduction in LDL-C. Sniderman and others have warned us that our target is a bit misdirected, with many patients attaining their LDL-C goal but with a discordantly high apoB, making these patients susceptible to continued risk. However, we can’t expect statins to correct disease if we’re attacking the wrong target!

Uncorrected Proof

John R. Brown — 2010-07-08

Ezetimibe (Zetia) has recently been the basis of much discussion. This is mostly in part because of the ARBITER 6- HALTS (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6: HDL and LDL Treatment Strategies in Atherosclerosis) study as well as the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial. We are all well aware of study design flaws, early termination of HALTS, and lack of harm in terms of Zetia use. However, there are still many unanswered questions that need further evaluation. And we are all in agreement that further hard outcome studies are needed to better formulate expert opinion for add-on therapy to statin.

Low-density lipoprotein cholesterol target achievement in patients at high risk for coronary heart disease - Uncorrected Proof

Danai Kitkungvan, Nicole M. Lynn Fillipon, Sourbha S. Dani, Brian C. Downey — 2010-07-08

Objectives: Although improvement in target lipid achievement has been observed in recent studies, a significant proportion of patients still do not reach their recommended low-density lipoprotein (LDL-C) targets. We conducted a study in high-risk patients to evaluate the success rate in attaining LDL-C goals.Methods: Medical records of patients referred for cardiac stress testing were reviewed. Demographic data, coronary heart disease (CHD) risk factors, and the most recent lipid profile were recorded. The patients who did not achieve LDL-C target on initial evaluation were reassessed in 12 months.Results: A total of 765 patients were classified as high-risk CHD. The average age was 66 ± 12 years; 62% were men, and 29% had a previous history of CHD. The mean LDL-C was 96 ± 35 mg/dL and the LDL-C goal of less than 100 mg/dL was achieved in 62%. In 217 patients with very high CHD risk, 83% had LDL-C less than 100 mg/dL and 37% had LDL-C less than 70 mg/dL. At month 12, data from 267 patients were reviewed, and 161 patients (60%) reached LDL-C less than 100 mg/dL. The mean LDL-C was 131 ± 27 mg/dL and 100 ± 29 mg/dL (P < .001) at month 0 and 12, respectively. Antihyperlipidemics were initially prescribed in 49% of these patients and 71% at month 12 (P < .001).Conclusion: Our study confirms an improving trend in lipid goal attainment in high and very high CHD-risk patients, but despite this, certain high- and very high-risk patients may require more aggressive intervention.

Proteinuria and severe mixed dyslipidemia associated with a novel APOAV gene mutation - Uncorrected Proof

2010-07-08

Lipoprotein glomerulopathy (LPG) is a rare disease characterized by lipid thrombi in dilated glomerular capillaries and type III hyperlipoproteinemia (familial dysbetalipoproteinemia). Since it was first described in 1989, some 50 cases have been reported, mostly from Japan and East Asian countries. Typically type III hyperlipoproteinemia is associated with apolipoprotein (apo) E2 homozygosity and more rarely with APOE mutations. In LPG, APOE mutations predominate as the cause of the dyslipidemia. Another glomerulopathy presenting as proteinuria associated with type III hyperlipoproteinemia has been described in which the lipid thrombi are absent but there is a marked accumulation of foam cells in the renal glomeruli. This has been called lipoprotein glomerulopathy-like glomerulopathy (LPG-LG) and occurs in association with the APOE2 homozygosity more typical of type III hyperlipoproteinemia. APOAV gene variants have recently been reported in association with hypertriglyceridemia. We report a novel APOAV mutation in a white patient with LPG-LG who was not homozygous for APOE2, had no APOE mutation, and whose proteinuria improved when his hyperlipidemia was treated.

Is directly measured low-density lipoprotein clinically equivalent to calculated low-density lipoprotein? - Corrected Proof

2010-06-28

Background: Low-density lipoprotein cholesterol (LDL-C) can either be calculated or measured directly. Clinical guidelines recommend the use of calculated LDL-C (C-LDL-C) to guide therapy because the evidence base for cholesterol management is derived almost exclusively from trials that use C-LDL-C, with direct measurement of LDL-C (D-LDL-C) being reserved for those patients who are nonfasting or with significant hypertriglyceridemia.Objective: Our aim was to determine the clinical equivalence of directly measured-LDL-C, using a Siemens Advia Chemistry System, and fasting C-LDL-C.Methods: Eighty-one subjects recruited for two cholesterol treatment studies had at least one C-LDL-C and D-LDL-C performed simultaneously; 64 had a repeat lipid assessment after 4 to 6 weeks of therapy, resulting in 145 pairs of C-LDL-C and D-LDL-C.Results: There was significant correlation between D-LDL-C and C-LDL-C (r2 = 0.86). Correlation was significantly better in those with lower total cholesterol, triglycerides, and high-density lipoprotein. In 60% of subjects, the difference between D-LDL-C and C-LDL-C was more than 5 mg/dL and greater than 6%. Clinical concordance between D-LDL-C and C-LDL-C was present in 40% of patients, whereas clinical discordance was noted in 25%. One-third had greater than a 15 mg/dL difference between D-LDL-C and C-LDL-C, whereas 25% had a greater than 20 mg/dL difference. In 47% of subjects, the difference between D-LDL-C and C-LDL-C at baseline and follow-up changed by a minimum of 10% or 10 mg/dL.Conclusions: Our findings suggest that D-LDL-C is not clinically equivalent to C-LDL-C. This puts into question the current recommendation of using D-LDL-C in situations in which C-LDL-C would be inaccurate.

Erratum - Corrected Proof

2010-06-28

In the June 2010 issue (4/3) of Journal of Clinical Lipidology, in the section titled “Scientific Poster Abstracts Selected for the National Lipid Association 2010 Annual Scientific Sessions” (2010;4:198-231), changes were made post-submission as noted below.

No evidence of impaired endothelial function or altered inflammatory state in patients with familial hypercholesterolemia treated with statins - Corrected Proof

2010-05-31

Background: Familial hypercholesterolemia (FH) is associated with an increased risk of premature atherosclerosis. Central in this aspect is enhanced inflammation and endothelial dysfunction.Objective: We sought to examine inflammatory cytokines and endothelial dysfunction in patients with FH treated with statins (n = 14) compared with healthy control patients (n = 11).Methods: Endothelial function was evaluated by the use of the Endo-PAT® system which measured mean reactive hyperemia index. Fasting blood samples were drawn, and 27 biomarkers in addition to standard laboratory tests were analyzed.Results: There were no statistically significant differences between the FH group and the control group regarding age, weight, blood pressure, or body mass index. Endothelial function given as RHI was 1.58 and 1.93 (P = NS) in the control and FH groups, respectively. There were no differences between the groups in tumor necrosis factor-alpha, interleukin (IL-1) beta, IL-1 receptor antagonist, IL-6, IL-10, monocyte chemoattractant protein 1, high-sensitivity C-reactive protein, or any of the other inflammatory markers tested. Furthermore, no significant differences between the groups in high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, apolipoprotein A, apolipoprotein B, lipoprotein (a), homocysteine, HbA1c, platelets, and fibrinogen were found.Conclusion: Endothelial function assessed by reactive hyperemia index-peripheral arterial tonometry or inflammatory state assessed by soluble inflammatory biomarkers were not different in FH patients on statins compared with healthy control patients.

Complete Apo AI Deficiency in an Iraqi Mandaean Family: Case studies and review of the literature - Corrected Proof

2010-05-31

Complete apo A1 deficiency is a rare genetic disorder that has been associated with premature atherosclerosis. We describe a family of Iraqi Mandaean background with complete apo A1 deficiency caused by a new nonsense mutation in the APOA1 gene. Interestingly, there were marked differences in the clinical presentation of the two homozygotes in this family. A 35-year-old woman presented with xanthelasmas and xanthomas but showed only minimal changes on cardiovascular examinations and no clinical symptoms. However, her 37-year-old brother was diagnosed with myocardial infarction at age 35. In addition, both the homozygotes had elevated C-reactive protein levels. The C-reactive protein levels increased three-fold during pregnancy, then decreased postpartum and further decreased with statin treatment. Cholesterol ester transfer protein mass was close to the upper reference range, whereas the activity was low, likely because of the lack of the substrate. Here, we characterize the phenotype and genotype of the first Middle Eastern family with apo A1 deficiency and compare and contrast the findings in the two homozygous siblings and review the previously reported cases of apo A1 deficiency.

Ezetimibe/simvastatin 10/20 mg versus simvastatin 40 mg in coronary heart disease patients - Uncorrected Proof

Maurizio Averna, Augusto Zaninelli, Cristina Le Grazie, Gian Franco Gensini — 2010-05-31

Background: Reducing low-density lipoprotein cholesterol (LDL-C) is the primary goal of therapy in patients with hypercholesterolemia and coronary heart disease (CHD).Methods: This double blind placebo-controlled study enrolled patients 18 to 75 years of age with primary hypercholesterolemia and established CHD who were taking a stable daily dose of simvastatin 20 mg. Patients were randomized to ezetimibe/simvastatin 10/20 mg (eze/simva; n = 56) or simvastatin 40 mg (simva; n = 56) for 6 weeks. Percent change from baseline in LDL-C, total cholesterol, high-density lipoprotein cholesterol (HDL-C), and triglycerides were assessed by use of the Student t test. The percent of patients achieving LDL-C less than 100 mg/dL (<2.6 mmol/L) or less than 80 mg/dL (<2.0 mmol/L) was analyzed via logistic regression with terms for treatment, baseline LDL-C, age, and gender.Results: Baseline characteristics were similar between groups. Treatment with eze/simva combination resulted in significantly greater reductions in LDL-C, total cholesterol, and triglycerides versus doubling the dose of simva to 40 mg (all P < 0.01). Significantly more patients achieved LDL-C less than 2.6 mmol/L and less than 2.0 mmol/L with ezetimibe/simvastatin versus doubling the dose of simva to 40 mg (73.2% vs 25.0%; P < .001) for simvastatin. Changes in HDL-C were similar between treatments. Both treatments were generally well tolerated.Conclusion: In high-risk CHD patients with hypercholesterolemia, treatment with eze/simva combination resulted in significantly greater reductions in LDL-C, total cholesterol and triglycerides, as well as greater achievement of recommended LDL-C targets, compared with doubling the simvastatin dose to 40 mg over the 6-week period.(Clinical trial registration number: NCT00423579)

Treatment with pravastatin and fenofibrate improves atherogenic lipid profiles but not inflammatory markers in ACTG 5087 - Corrected Proof

Carl J. Fichtenbaum, Tzu-Min Yeh, Scott R. Evans, Judith A. Aberg — 2010-05-07

Objectives: Statins and fibrates alter lipids, apolipoproteins, and inflammatory markers in persons without HIV. The objective of this study was to evaluate changes in lipoproteins, apolipoproteins, and other markers of inflammation with the use of pravastatin and fenofibrate.Design: Evaluation of participants in ACTG A5087, a randomized trial of pravastatin 40 mg/day or fenofibrate 200 mg/day for the treatment of dyslipidemia. Participants that failed single-agent therapy at week 12 were given the combination.Methods: Participants with available specimens were tested for apolipoproteins A1 and B, adiponectin, plasminogen-activator inhibitor type 1 (PAI-1), P-selectin, and high-sensitivity C-reactive protein (hs-CRP).Results: A total of 74 participants (37 per randomized arm) received either pravastatin or fenofibrate for 12 weeks with 60 receiving combination treatment from weeks 12 to 48. There were no significant changes in hs-CRP, PAI-1, and P-selectin. From baseline to week 12, the median Apo B levels (−8 mg/dL, P = .01 for fenofibrate and −27 mg/dL, P < .01 for pravastatin) and ApoB/A1 ratios (−0.16, P < .01 for both arms) significantly decreased. From baseline to week 48, median adiponectin (−1 ng/dL, P < .01), Apo B (−22 mg/dL, P < .01) and Apo B/A1 ratios (−0.2, P < .01) all decreased in those who went on combination therapy, whereas Apo A1 (9.5 mg/dL, P = .01) levels increased.Conclusion: Treatment with pravastatin or fenofibrate improves the atherogenic lipid profile within the first 12 weeks and is sustained through 48 weeks with combination therapy. Adiponectin levels decrease with lipid-lowering therapy. However, markers of inflammation and platelet activation were not appreciably changed suggesting that the biologic properties of these agents differ in persons with HIV infection.

Adjustment of direct high-density lipoprotein cholesterol measurements according to intercurrent triglyceride corrects for interference by triglyceride-rich lipoproteins - Corrected Proof

2010-04-26

Background: Low plasma levels of high-density-lipoprotein cholesterol (HDL-C) and high triglyceride (TG) are strongly associated with cardiovascular disease (CVD). Clinical recognition of this high-risk population demands accurate measurement of HDL-C, whereas cost and clinical demand dictate that optimal HDL-C measurement requires fully automated methods that avoid manual precipitation. Commercial techniques use specific reagents to selectively expose and “directly” measure cholesterol in HDL. However, these “direct” methods may experience interference from the cholesterol content of triglyceride-rich-lipoproteins (TRL), leading to analytical overestimation of HDL-C, with subsequent underestimation of low-density-lipoprotein cholesterol (LDL-C) and of CVD risk.Objective: : The aim of this study was to develop a method to overcome this interference.Methods: Serum/Li+-heparin plasma samples from consecutive patients were analyzed for HDL-C by the comparison of three generations of the Roche Diagnostics, HDL-C assay on a Hitachi-917 or Modular-PPE analyzer. HDL-C measurement was performed before and after removal of TRL by ultracentrifugation (“direct” HDL-C and HDL-UC, respectively). We examined the effect of TG on the relationship between HDL-UC and “direct” HDL-C. Analysis of variance multiregression analysis was performed for each generation of the commercial assay.Results: We observed progressive TG interference that increased “direct” HDL-C by 10% to 15% or more in moderately hypertriglyceridemic samples (<600 mg/dL). Predictive equations were derived for each generation of the assay to estimate HDL-C in the absence of TRL.Conclusions: This study casts doubt on the specificity of “direct” HDL-C assays in the presence of hypertriglyceridemia. The use of assay-specific correction formulae to adjust for interference from TRL reduces the overestimation of HDL-C that influences CVD risk calculation, treatment, and follow-up of patients.

Nonoptimal high-density lipoprotein cholesterol levels are highly prevalent in patients presenting with acute coronary syndromes and well-controlled low-density lipoprotein cholesterol levels - Corrected Proof

Erika M. Felix-Getzik, Jeffrey T. Kuvin, Richard H. Karas — 2010-04-20

Background: Low levels of high-density lipoprotein cholesterol (HDL-C) are an independent risk factor for coronary artery disease. For this study, nonoptimal HDL-C is defined as less than 40 mg/dL for male patients and less than 50 mg/dL for female patients. Even when low-density lipoprotein cholesterol (LDL-C) and non-HDL-C goals are met, significant risk for subsequent cardiovascular events remains in patients with acute coronary syndrome (ACS).Objective: This study is a prospective, observational study to determine the prevalence of low HDL-C levels in 250 consecutive patients presenting with ACS who have well-controlled LDL-C levels.Methods: This was an institutional review board-approved, prospective, observational study in which we evaluated consecutive patients admitted to the adult general cardiology service with a diagnosis of ACS.Results: One hundred nine (44%) patients had LDL-C levels less than 100 mg/dL on admission. Of those patients, 90 (83%) had a nonoptimal HDL-C. Interestingly, a majority of patients, 94 (86%), had non-HDL-C levels at target. At discharge, approximately one half of eligible patients were started on therapy to increase their HDL-C levels.Conclusion: In conclusion, nonoptimal HDL-C levels are highly prevalent in patients presenting with ACS and reasonably controlled LDL-C and non-HDL-C levels.

Letter to the Editor - Corrected Proof

Ryan C. Van Woerkom, Douglas G. Adler — 2010-04-02

A 53-year-old man with a history of hypercholesterolemia treated to target values was noted to have an elevated fasting serum cholesterol level on routine follow-up examination. At that time, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were normal. The patient had maintained adequate control of his lipoprotein concentrations during the previous 3 years by taking 5 mg of rosuvastatin. Rosuvastatin was then changed to ezetimibe/simvastatin 10/20 mg per day without a washout period. Within 12 hours after the first and only dose of ezetimibe/simvastatin, the patient developed intense mid-epigastric abdominal pain, malaise, and nausea. He sought relief for the pain and presented to his primary care physician. A series of routine plasma chemical analyses were ordered as part of this evaluation.

Responses of Authors to the Arguments made in the Point and Counterpoint. - Accepted Manuscript

W. Virgil Brown — 2008-07-14