Journal of Clinical Lipidology - Articles in Press

Response to letter from Douglas Trenkle D.O - Accepted Manuscript

David T. Nash — 2010-03-08

Letter to the Editor Re: Journal of Clinical Lipidology (2009) 3, 368-71 - Accepted Manuscript

Douglas Trenkle — 2010-03-04

New mutations in APOB100 involved in Familial Hypobetalipoproteinemia - Accepted Manuscript

K. Brusgaard, L. Kjaersgaard, A.-B. Hansen, S. Husby — 2010-03-03

Abstract: Familial hypolipoproteinemia (FHBL) is characterised by an inherited low plasma level of apolipoprotein B containing lipoproteins. FHBL can be caused by mutations of APOB. Individuals with FHBL is characterised by intestinal malabsorption and they frequently suffers from deficiency of fatsoluble vitamins. Most mutations causing FHBL are APOB truncating mutations. We here describe a patient with FHBL caused by a novel truncating mutation together with a novel missense mutation.

In Memoriam: William E. Connor, MD (1921−2009) - Uncorrected Proof

Carlos A. Dujovne — 2010-02-22

Bill Connor passed away peacefully at his home on October 25, 2009. He was born September 14, 1921, in Pittsburgh, Pennsylvania. He grew up in Dubuque, Iowa, and attended the University of Iowa, where he received a BA degree and then a MD degree after serving in the Army Signal Corp in Hawaii during World War II. He was a faculty member in the Department of Internal Medicine, University of Iowa, College of Medicine from 1961 to 1975 and Director of the Clinical Research Center from 1968 to1975. He moved to Portland in 1975. Bill was a faculty member in the Department of Medicine at Oregon Health & Science University (OHSU) from 1975 to 2009. Bill, a physician scientist with a boundless curiosity, was a pioneer in diet and heart disease, a field that took him (and many who were caught up in his wake) on a remarkable tour of the breadth and depth of research about dietary cholesterol, omega-3 fats, changing eating habits (The Family Heart Study), and diseases of sterol metabolism. His fascination with other cultures led to studies with the Tarahumara Indians in the Copper Canyon area of Mexico. He was devoted to his patients at OHSU as well as those he administered to once a month first at the Neighborhood Health Clinic and, more recently, at the Wallace Medical Clinic along with his son Rodney, also a physician.

From the Editor - Uncorrected Proof

W.Virgil Brown — 2010-02-22

The number of parameters that provide information about risk of vascular disease development and recurrence of known disease seems to grow with every month. It is tempting to combine these individual measures by developing equations with the goal of fewer numbers with greater predictive value. There is no question that this practice works in certain settings, but it comes with a price. The simple subtraction of the cholesterol content of high-density lipoprotein (HDL) from total plasma cholesterol concentrations gives “non-HDL cholesterol,” a value that can be shown to have a much stronger relationship to cardiovascular events than total cholesterol alone. However, it is still useful to consider the HDL cholesterol (HDL-C) because the inverse relationship with this value and risk remains a powerful predictor as well. A much greater hazard comes from taking ratios of values. The division of total cholesterol (TC) or of triglyceride (TG) concentrations by HDL-C also provides a number that is among the most predictive to date in large community studies and clinical trial cohorts. There is no question that these are powerful tools for epidemiologists and clinical trialists in judging the event rates in groups of individuals. However, data from such studies may be applied to individual patients with considerable uncertainty. The division of a relatively stable value, such as fasting TC, by a value that has considerable laboratory error, such as HDL-C, causes big swings in the ratio −TC/HDL-C. In this case biological variation (the patient's visit to visit true values) is a relatively minor problem until one intervenes, as with diet or weight loss. A low cholesterol/low saturated fat diet causes both values to decrease and may produce no improvement in the ratio although risk appears to decrease. This problem is even more dramatic with the TG/HDL-C ratio, where TG values are very variable from visit to visit. As a result, the guideline writing committees have usually avoided recommending such calculations, and most laboratories do not report them.

News from the NLA - Uncorrected Proof

2010-02-19

This year, the annual NLA Scientific Sessions will be held in Chicago, May 13–16, 2010. The Chairs of the 2010 meeting, Drs. Peter Toth, Vera Bittner, Michael Davidson, and Carl Orringer, have planned an outstanding program. On Thursday afternoon, the Sessions will open with Keynote speaker, Ira Tabas, MD, PhD, whose address will explore “The Macrophage and Atherosclerosis.” Dr. Tabas is Professor of Medicine and Anatomy and Cell Biology (in Physiology and Cellular Biophysics) at Columbia University College of Physicians and Surgeons. The recipient of multiple awards from Columbia University and the American Heart Association, Dr. Tabas has lectured worldwide on the role of macrophages in atherosclerosis, and he has published numerous articles on cholesterol metabolism.

Safety of extended-release niacin/laropiprant in patients with dyslipidemia - Uncorrected Proof

2010-02-15

Objective: To evaluate the safety profile of extended-release niacin/laropiprant (ERN/LRPT) and pooling data from studies in the clinical development program.Methods: Data were pooled from three active- or placebo-controlled phase 3 studies and three 1-year extensions of phase 2 studies that ranged from 12 to 52 weeks (N = 4747): ERN/LRPT = 2548; ERN or Niaspan® (ERN-NSP = 1268); or simvastatin or placebo (SIMVA-PBO = 931).Results: The safety and tolerability profile for ERN/LRPT was similar to that of ERN-NSP, except for fewer flushing-related adverse experiences and discontinuations with ERN/LRPT than ERN-NSP. The incidence of consecutive ≥3× the upper limit of normal increases in alanine aminotransferase and/or aspartate aminotransferase was numerically (but not statistically) greater with ERN/LRPT (1.0%) than ERN-NSP (0.5%) and similar to SIMVA-PBO (0.9%). Elevations were reversible with therapy discontinuation and not associated with clinical hepatotoxicity. There was no evidence that ERN/LRPT administered alone or concurrently with a statin had adverse effects on muscle. ERN/LRPT and ERN-NSP produced small median increases in fasting blood glucose levels (∼4 mg/dL) after 24 weeks of treatment, consistent with known effects of niacin.Conclusion: The favorable safety and tolerability profile of ERN/LRPT for up to 1 year supports the use of LRPT to achieve improved therapeutic dosing of niacin, an agent with comprehensive lipid-modifying efficacy and shown to reduce cardiovascular risk.

Point: Low-density lipoprotein goals in patients with diabetes are not adequately based on evidence - Uncorrected Proof

W.E. Feeman — 2010-02-15

The article by Davidson et al in a recent issue of the Journal deserves comment. Since 1974 I have directed an aggressive clinic for the primary and secondary prevention of atherothrombotic disease (ATD) and have published my results. In brief, my treated patients have sustained only two fatal myocardial infarctions since January 1, 2000: One was a cigarette-smoking hypertensive patient with a low-density lipoprotein (LDL) level of 89 and HDL of 95 mg/dL; I controlled her blood pressure but had no reason to treat her lipids. She did not stop smoking as I requested and sustained a cardiac arrest at age 60 years. The other patients was a nonsmoking insulin-dependent diabetic (for 40 years) who had his first myocardial infarction at age 49; I controlled his lipids and blood pressure, but he controlled his insulin therapy and did not do a great job of controlling his blood sugar. He sustained his terminal infarction at age 72 years.

Reply - Uncorrected Proof

Michael H. Davidson — 2010-02-15

I fully agree with Dr. Feeman's main point that atherosclerosis is a multifunctional disease and, therefore, focusing on only one risk factor (i.e., low-density lipoprotein), is inappropriate. Comprehensive risk factor modification is the cornerstone to prevent cardiovascular events. I also believe that, too often, risk factors are looked at in “silos” and frequently, global risk factor reduction is not emphasized sufficiently. I appreciate you pointing these issues out and applaud efforts to look beyond a single factor in improving patient outcomes in the prevention of cardiovascular disease.

“Atherogenic index of plasma” (log10 triglyceride/high-density lipoprotein−cholesterol) predicts high blood pressure, diabetes, and vascular events - Uncorrected Proof

Altan Onat, Günay Can, Hasan Kaya, Gülay Hergenç — 2010-02-15

Objectives: To determine the association of atherogenic index of plasma (AIP), the logarithm of molar ratio of triglyceridemia to high-density lipoprotein cholesterol (TG/HDL-cholesterol) with cardiometabolic disorders was investigated in a sample of the Turkish population.Methods: A total of 2676 middle-aged adults were prospectively evaluated with a clinical examination and laboratory tests during 7.8 years' follow-up.Results: AIP was significantly associated in multiple linear regression analyses with greater apolipoprotein B and lower low-density lipoprotein (LDL)-cholesterol levels, reflecting the presence of smaller LDL particle size. Whereas in men insulin levels, obesity, and nonHDL-cholesterol were major determinants, C-reactive protein (CRP) was the strongest determinant of AIP among women, independent of body mass index. Top quartiles of AIP predicted significantly age-adjusted incident coronary heart disease (CHD) in both sexes, more strongly in women, in whom quartile 3 also was a predictor with a greater than 2-fold relative risk. Associations remained significant after adjustment for CRP and traditional risk factors. AIP significantly predicted diabetes and high blood pressure in both sexes after adjustment for age and CRP. With regard to incident high blood pressure, the risk ratio in men was attenuated when body mass index also was adjusted.Conclusions: High AIP, a surrogate of small LDL particle size, reflects obesity and hyperinsulinemia in men and high CRP status in women. It predicts CHD independently, type 2 diabetes mediated by obesity in men and in women, high blood pressure, metabolic syndrome, and CHD potentially mediated by involvement in a proinflammatory status reflected by CRP.

Vitamin D is associated with atheroprotective high-density lipoprotein profile in postmenopausal women - Uncorrected Proof

2010-02-08

Background: Low vitamin D has been associated with low levels of high-density lipoprotein (HDL) cholesterol, a marker of coronary risk. Whether atheroprotective HDL particle composition accounts for this association and whether fat affects this association is not known.OBJECTIVE: To explore the association between HDL particle composition and 25-hydroxy vitamin D (25[OH]D) in post-menopausal women.METHODS: Vitamin D levels and lipoprotein composition were assessed in fasting blood samples of apparently healthy women from a diverse Chicago community. Visceral (VAT) and subcutaneous (SAT) abdominal fat area were assessed using computed tomography. Total body fat mass was measured by dual-energy X-ray absorptiometry.RESULTS: We enrolled 78 women (50% black; 50% white), age 48 to 64 years, all of whom were participants in a longitudinal study of fat patterning. They had a mean 25[OH]D of 31 ± 15 μg/L, HDL cholesterol 57±11 mg/dL, and large HDL particle subclass 8.6±3.4 μmol/L. In a multivariable-adjusted regression model, each 5 μg/L higher 25[OH]D predicted 0.57 μmol/L (95%CI 0.20–0.95) higher large HDL particles, independent of race, season, and total HDL particle concentration. This association was only partially confounded by total body fat mass (0.49, 95%CI 0.10–0.89), SAT (0.50, 95%CI 0.11–0.90), or VAT (0.37, 95%CI 0.01–0.74). Age did not significantly influence the strength of associations.CONCLUSIONS: Higher 25[OH]D levels are associated with large HDL particles. This association is stronger than that of HDL cholesterol and only partially confounded by body fat. Theoretically, vitamin D may protect against cardiovascular risk by promoting formation of large HDL particles, affecting reverse cholesterol transport.

Cost-effectiveness of lower targets for blood pressure and low-density lipoprotein cholesterol in diabetes: The Stop Atherosclerosis in Native Diabetics Study (SANDS) - Uncorrected Proof

2010-02-08

Background: The Stop Atherosclerosis in Native Diabetics Study (SANDS) reported cardiovascular benefit of aggressive versus standard treatment targets for both low-density lipoprotein cholesterol (LDL-C) and blood pressure (BP) in diabetic individuals.Objective: In this analysis, we examined within trial cost-effectiveness of aggressive targets of LDL-C ≤70 mg/dL and systolic BP ≤115 mmHg versus standard targets of LDL-C ≤100 mg/dL and systolic BP ≤130 mmHg.Design: Randomized, open label blinded-to-endpoint 3-year trial.Data Sources: SANDS clinical trial database, Quality of Wellbeing survey, Centers for Medicare and Medicaid Services, Wholesale Drug Prices.Target Population: American Indians ≥age 40 years with type 2 diabetes and no previous cardiovascular events.Time Horizon: April 2003 to July 2007.Perspective: Health payer.Interventions: Participants were randomized to aggressive versus standard groups with treatment algorithms defined for both.Outcome Measures: Incremental cost-effectiveness.Results of Base-Case Analysis: : Compared with the standard group, the aggressive group had slightly lower costs of medical services (−$116) but a 54% greater cost for BP medication ($1,242) and a 116% greater cost for lipid-lowering medication ($2,863), resulting in an increased cost of $3,988 over 3 years. Those in the aggressively treated group gained 0.0480 quality-adjusted life-years (QALY) over the standard group. When a 3% discount rate for costs and outcomes was used, the resulting cost per QALY was $82,589.Results of Sensitivity Analysis: The use of a 25%, 50%, and 75% reduction in drug costs resulted in a cost per QALY of $61,329, $40,070, and $18,810, respectively.Limitations: This study was limited by use of a single ethnic group and by its 3-year duration.Conclusions: Within this 3-year study, treatment to lower BP and LDL-C below standard targets was not cost-effective because of the cost of the additional medications required to meet the lower targets. With the anticipated availability of generic versions of the BP and lipid-lowering drugs used in SANDS, the cost-effectiveness of this intervention should improve.

Evaluation of a pharmacist-managed lipid clinic that uses point-of-care lipid testing - Uncorrected Proof

Katherine R. Gerrald, Dave L. Dixon, Debra J. Barnette, Virginia G. Williams — 2010-02-08

Background: Hyperlipidemia is a significant, modifiable risk factor for developing coronary heart disease. Low-density lipoprotein cholesterol (LDL-C) goal achievement has improved overall, but many high-risk patients remain above the desired LDL-C goals. Published data have demonstrated the ability of pharmacist-managed lipid clinics to improve lipid management in a variety of clinical settings.Objective: This observational analysis aimed to report the impact of a newly developed hospital-based, outpatient lipid clinic by the use of point-of-care testing on LDL-C goal attainment.Methods: A retrospective, observational analysis was conducted from February 2007 to December 2008. The primary outcome measure was the change in the proportion of patients who achieved their LDL-C goal at the end of the observation period compared with baseline.Results: A total of 81 patients met study inclusion criteria. Mean duration of follow-up was 9.0 ± 4.9 (SD) months. At the end of the observation period, 82.9% of patients achieved their LDL-C goal compared with 55.3% at baseline (P < .0001). The mean LDL-C decreased from 103 ± 45 mg/dL at baseline to 82 ± 28 mg/dL at the end of the observation period (P < .0001).Conclusion: An outpatient hospital-based, pharmacist-managed lipid clinic improved LDL-C goal attainment. Our results are unique in that pharmacists used point-of-care testing to obtain lipid results for making therapy adjustments during the face-to-face visit.

Non-HDL-cholesterol/apolipoprotein B ratio: a useful distinguishing feature in the screening for type III hyperlipoproteinemia - Uncorrected Proof

Toshio Murase, Minoru Okubo, Ichiro Takeuchi — 2010-02-01

Background: Dysbetalipoproteinemia, also known as type III hyperlipoproteinemia (type III HL), is characterized by the accumulation of β-very low density lipoprotein (β-VLDL). However, demonstration of the presence of β-VLDL is not easy because it requires preparative ultracentrifugation of lipoproteins. The primary genetic defect in type III HL is the presence of apolipoprotein (apo) E2, a mutant form of apoE. However, another metabolic defect, such as overproduction of VLDL, is also required for the full phenotype. Patients with only E2 homozygosity usually do not have HL. Because apoE genotyping is expensive, the selection of patients for this analysis by effective use of common clinical measures would be very helpful.Objective: We examined the non-HDL-C/apoB ratio as an index for type III HL screening.Methods: We studied nine patients with type III HL. Most patients with type III HL show mixed hyperlipidemia. We compared the plasma of patients with combined hyperlipidemia and the dyslipidemia of hypothyroidism with those with type III HL. The serum levels of total cholesterol, triglyceride, and high-density lipoprotein cholesterol (HDL-C), as well as the serum apoB and apoE levels, were measured by routine laboratory methods.Results: Individual values of serum lipids and apolipoproteins did not distinguish type III HL from the two other types of HL. The non-HDL-C/apoB ratio in type III HL was significantly greater than that in the two comparison groups, with no overlap.Conclusion: The non-HDL-C/apoB ratio is a novel index that appears to be reliable for screening of patients for type III HL, and the index can be determined at regular clinical laboratories without the need for any complicated lipoprotein analysis. Thus, we propose the clinical usefulness of this index.

When is equal not equal? - Uncorrected Proof

Allan D. Sniderman, Ken Williams, Matthew J. McQueen, Curt D. Furberg — 2010-02-01

Abstract: The meta-analysis of the Emerging Risk Factor Collaboration demonstrated that the hazard ratios (HR) of the major cholesterol markers and the major apolipoproteins for vascular disease did not differ significantly in the studies they examined. Their conclusion was that they were functionally interchangeable. We believe there are important limitations in the execution of this study. Nevertheless, even if their findings are correct for groups, their conclusions do not follow for individuals. Conventionally, the HR expresses the increase in risk per standard deviation change for that parameter in a group. However, the predicted risk of vascular disease from an atherogenic parameter depends on its concentration within the individual. Depending on the composition of the apoB lipoproteins, individuals may have either concordant or discordant levels of cholesterol and apoB. For those who are concordant, the two markers predict equal risk. For those who are discordant, the predicted risks for the individual are different. We demonstrate that substantial discordance in the individual HR of non-high-density lipoprotein cholesterol and apoB is common. The result is that even with identical overall HR, apoB points to higher risk in a substantial number of individuals whereas the converse is the case for non- high-density lipoprotein cholesterol. Because we are concerned with risks in individuals, not groups, this discordance is important to appreciate and analyze. Our objective should be to learn how to combine the information from parameters rather than eliminate them and we need to focus on evaluation of risk in individuals and not just groups.

A case report of a diabetic woman with very low HDL cholesterol - Uncorrected Proof

Leila Chaychi, William B. Kinlaw, Bela F. Asztalos, Ernest J. Schaefer — 2010-01-29

Lipid patterns of low high-density lipoprotein cholesterol (HDLc) and high triglycerides (TGs), particularly in patients with diabetes mellitus, are of concern to the physician. This is particularly true when plasma low-density lipoprotein (LDL) cholesterol is within the normal range or elevated. This is a report of a diabetic patient with low HDLc and high TGs but a very low total plasma cholesterol. The abnormal HDL particle composition and the response to treatment was thought to be of interest to lipidologists.

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

W. Virgil Brown — 2008-07-14