Journal of Clinical Lipidology - Articles in Press

From the Editor March/April 2012 Issue - Accepted Manuscript

W. Virgil Brown — 2012-01-30

Novel missense variants in LCAT and APOB genes in an Italian kindred with familial LCAT deficiency and hypobetalipoproteinemia - Accepted Manuscript

2012-01-30

Abstract: Background: Lecithin:cholesterol acyltransferase (LCAT) is responsible for cholesterol esterification in plasma. Mutations of LCAT gene cause familial LCAT deficiency, a metabolic disorder characterized by hypoalphalipoproteinemia. Apolipoprotein B (apoB) is the main protein component of VLDL and LDL. Mutations of APOB gene cause familial hypobetalipoproteinemia, a co-dominant disorder characterized by low plasma levels of LDL cholesterol and apoB.Objective: The genetic and biochemical analysis of an Italian kindred with hypobetalipoproteinemia, whose proband presented with hypoalphalipoproteinemia and severe chronic kidney disease.Methods: Plasma lipids and apolipoproteins, cholesterol esterification and HDL subclass distribution were analyzed. LCAT and APOB genes were sequenced.Results: The proband had severe impairment of plasma cholesterol esterification and high preβ-HDL content. He was heterozygote for the novel LCAT P406L variant, as two other family members. Proband's wife and children presented with familial hypobetalipoproteinemia and were heterozygotes for the novel apoB H1401R variant. Cholesterol esterification rate of apoB H1401R carriers was reduced, likely due to the low amount of circulating LDL. After renal transplant, proband's lipid profile, HDL subclass distribution and plasma cholesterol esterification were almost normalized, suggesting a mild contribution of the LCAT P406L variant to his pre-transplant severe hypoalphalipoproteinemia and impairment of plasma cholesterol esterification.Conclusion: LCAT P406L variant had a mild effect on lipid profile, HDL subclass distribution and plasma cholesterol esterification. ApoB H1401R variant was identified as possible cause of familial hypobetalipoproteinemia and resulted in a reduction of cholesterol esterification rate.

Significant reduction of elevated serum lipoprotein(a) concentrations during levo-thyroxine replacement therapy in a hypothyroid patient - Accepted Manuscript

Toshio Murase, Sadao Arimoto, Minoru Okubo, Shinichi Morinaga — 2012-01-30

Abstract: A number of previous studies have reported the effect of the thyroid status on the changes of the serum lipids, whereas on serum Lp(a) concentrations have been limited and the results are controversial. Recently, we encountered a hypothyroid patient with elevated serum Lp(a) concentrations in whom serial measurements of serum Lp(a) concentration were performed during the hormone replacement therapy. Our observation on this patient is of particular interest: the serum Lp(a) concentrations tended to continue to decrease even after 1 year 5 months, suggesting that the effects of thyroid hormone on the serum Lp(a) levels may continue for much longer than those on the serum LDL-C. Our findings may suggest a possible role of this hormone in the regulation of Lp(a) metabolism. Together with the recent reports indicating a thyroid hormone analogue lowered serum Lp(a) levels, our observation may also pave the way for the development of Lp(a)-lowering agents.

Compared with traditional lipid parameters, non-high density lipoprotein cholesterol was associated with albuminuria more closely in Chinese type 2 diabetic patients with normal renal function - Accepted Manuscript

Jiemin Pan, Fei Gao, Yuqian Bao, Lei Zhang, Yinfang Tu, Weiping Jia — 2012-01-30

Abstract: Background: Urinary albumin excretion rate (UAER) is a remarkable index reflecting the progression of kidney disease in diabetic subjects. The linkage between UAER and lipid metabolism is still unclear. Apolipoprotein B (ApoB) has been investigated correlating to albuminuria. It has been recommended by NCEP-ATPIII (National Cholesterol Education Program-Adult Treatment Panel III) to consider non-high density lipoprotein cholesterol (non-HDL-c) as a surrogate marker for Apolipoprotein B (ApoB).Objective: The aim is to evaluate the relationship of UAER with lipid profile, especially with non-HDL-c in type 2 diabetic patients without renal dysfunction.Methods: A total of 507 type 2 diabetic patients with normal renal function participated in this study. Demographic and anthropometric data were collected. 24 hour urine samples were collected for UAER measurement. Blood samples were collected for lipid parameters, HbA1c measurement.Results: The albuminuric patients had higher levels of non-HDL-c and ApoB. The frequencies of albuminuria among the four quartiles of lipid parameters, triglycerides, total cholesterol, non-HDL-c and ApoB showed significant linear test for trend (P<0.01). After adjustment, UAER was significantly correlated with total cholesterol, triglycerides, ApoB and non-HDL-c, but not with low density lipoprotein cholesterol (LDL-c) or lipoprotein(a) [Lp(a)]. Stepwise regression analysis showed that age (β=0.255, P=0.000), systolic blood pressure (β=0.261, P=0.000), non-HDL-c (β=0.164, P=0.000) and diabetes duration (β=0.105, P=0.024) were independently correlated with UAER in diabetic patients without renal dysfunction.Conclusion: Compared with the lipid parameters of total cholesterol, triglycerides, high density lipoprotein cholesterol (HDL-c), LDL-c, ApoB, Apolipoprotein A-I (ApoA-I) and Lp(a), non-HDL-c was more closely associated with albuminuria in Chinese type 2 diabetic patients without impaired renal function.

A meta-analysis of randomized controlled trials comparing lipid effects of beef with poultry and/or fish consumption - Accepted Manuscript

2012-01-24

Abstract: Background: : Limited consumption of red meat, including beef, is one of many often suggested strategies to reduce risk for coronary heart disease. However, the role beef consumption, specifically, in promoting adverse changes in the cardiovascular risk factor profile is unclear.Objective: : A meta-analysis of randomized, controlled, clinical trials (RCTs) was conducted to evaluate the effects of beef, independent of other red and processed meats, compared with poultry and/or fish consumption, on lipoprotein lipids.Methods: : RCTs published from 1950-2010 were considered for inclusion. Studies were included if they reported fasting lipoprotein lipid changes following beef and poultry/fish consumption by subjects free of chronic disease. A total of 124 RCTs were identified and 8 studies involving 406 subjects met the pre-specified entry criteria and were included in the analysis.Results: : Relative to the baseline diet, mean ± standard error changes (in mg/dL) following beef versus poultry/fish consumption, respectively, were -8.1 ± 2.8 vs. -6.2 ± 3.1 for total cholesterol (p = 0.630), -8.2 ± 4.2 vs. -8.9 ± 4.4 for low-density lipoprotein cholesterol (p = 0.905), -2.3 ± 1.0 vs. -1.9 ± 0.8 for high-density lipoprotein cholesterol (p = 0.762), and -8.1 ± 3.6 vs. -12.9 ± 4.0 mg/dL for triacylglycerols (p = 0.367).Conclusion: : Changes in the fasting lipid profile were not significantly different with beef consumption compared to those with poultry and/or fish consumption. Inclusion of lean beef in the diet increases the variety of available food choices, which may improve long-term adherence with dietary recommendations for lipid management.

A novel omega-3 free fatty acid formulation has dramatically improved bioavailability during a low-fat diet compared with omega-3-acid ethyl esters: the ECLIPSE (Evaluation of COPD Longitudinally to Identify Surrogate Endpoints) study - Uncorrected Proof

Michael H. Davidson, Judith Johnson, Michael W. Rooney, Douglas F. Kling — 2012-01-24

Background: Omega-3 (OM-3) fatty acid products are indicated for the treatment of severe hypertriglyceridemia; however, the omega-3-acid ethyl ester (OM-3 EE) formulations require significant pancreatic lipase stimulation with high-fat meals for adequate intestinal absorption of the metabolites eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). A novel omega-3 free fatty acid (OM-3 FFA) formulation (Epanova®, Omthera Pharmaceuticals Inc., Princeton, NJ) was developed to maximize EPA and DHA bioavailability during a low-fat diet.Objective: To compare the relative bioavailability of EPA and DHA from single 4-gram doses of OM-3 FFA and a prescription OM-3 EE (Lovaza®, GlaxoSmithKline, Research Triangle Park, NC).Methods: This was a randomized, open-label, single dose, 4-way crossover, bioavailability study of OM-3 FFA and OM-3 EE administered during periods of low-fat and high-fat consumption to 54 overweight adults. Bioavailability was determined by the ln-transformed area under the plasma concentration versus time curve (AUC0-t) during a 24-hour interval for EPA and DHA (baseline-adjusted).Results: The baseline-adjusted AUC0-t for total EPA + DHA during the low-fat period was 4.0-fold greater with OM-3 FFA compared with OM-3 EE (2650.2 vs 662.0 nmol·h/mL, respectively; P < .0001). During the high-fat period, AUC0-t for OM-3 FFA was approximately 1.3-fold greater than OM-3 EE (P < .0001). During the low-fat period, 30 of 51 (58.8%) subjects dosed with OM-3 FFA maintained an AUC0-t that was ≥50% of the respective high-fat AUC0-t in contrast to only 3 of 50 (6.0%) subjects dosed with OM-3 EE.Conclusions: During a low-fat consumption period, the OM-3 FFA formulation provided dramatically improved bioavailability over the OM-3 EE formulation in overweight subjects. These findings offer a potential therapeutic advantage of the OM-3 FFA formulation for the treatment of severe hypertriglyceridemia as these patients are expected to adhere to a low-fat diet.

Plasma exchange for severe hypertriglyceridemia-induced pancreatitis in an orthotopic heart transplantation recipient - Uncorrected Proof

Danesh K. Kella, Sana Shoukat, Laurence Sperling — 2012-01-24

Hypertriglyceridemia (HTG) is a well-known cause of pancreatitis. The most popular theory explaining HTG-induced pancreatitis involves the release of free fatty acids from triglycerides (TGs) by pancreatic enzymes creating an acidic environment and resulting in capillary destruction, ischemia, necrosis, and inflammation. Successful lowering of the TG levels has been shown to improve outcomes in pancreatitis associated with HTG. Since the advent of plasma exchange for managing HTG, this modality has been successfully used in treating HTG-induced pancreatitis. It has also been used for prevention of pancreatitis in patients with refractory HTG.

Lipoprotein(a) particle concentration and lipoprotein(a) cholesterol assays yield discordant classification of patients defining four physiologically discrete groups - Uncorrected Proof

Matthew Konerman, Krishnaji Kulkarni, Peter P. Toth, Steven R. Jones — 2012-01-24

Abstract: There is little known about the relative predictive value of different lipoprotein(a) [Lp(a)] assays in clinical use, although each has been shown to predict similar incremental risk over conventional clinical and lipid risk factors. Thus, we examined the classification behavior of two commonly used Lp(a) assays and their associations with other lipid parameters. Serum lipid and Lp(a) concentrations were measured in 144 primary and secondary prevention patients. Lp(a) cholesterol [Lp(a)-C] was measured with the Vertical Auto Profile (upper limit of normal, 10 mg/dL). Lp(a) particle concentrations [Lp(a)-P] were measured with an isoform-independent molar assay (upper limit of normal, 70 nmol/L). The subjects were divided into the following four groups on the basis of their Lp(a)-C and Lp(a)-P levels: normal Lp(a)-P and Lp(a)-C; high Lp(a)-P and normal Lp(a)-C; normal Lp(a)-P and high Lp(a)-C; and high Lp(a)-P and Lp(a)-C. The proportion of subjects with values above the upper limit of normal was similar with both assays (P = .15). However, the Lp(a)-C and Lp(a)-P assays discordantly classified 23% of the study’s subjects. In addition, the four Lp(a)-defined groups displayed differences in their relationships with other lipoproteins. The two groups with elevated Lp(a)-C showed significant associations with higher high-density lipoprotein cholesterol, apolipoprotein AI, and high-density lipoprotein cholesterol/apolipoprotein AI ratios. Triglycerides were also noted to be above normal in discordant and normal within concordant Lp(a) groups. Finally, the amount of cholesterol per Lp(a) particle [Lp(a)-C/Lp(a)-P] varied widely across the four groups. These findings suggest that the four Lp(a)-defined groups are physiologically discrete. Further investigation is warranted to assess which parameters among Lp(a)-P, Lp(a)-C, and Lp(a)-C/Lp(a)-P can be used to more accurately characterize Lp(a)-associated cardiovascular risk.

Genotype–phenotype correlation related to lipid profile in beta-thalassemia major and intermedia in southern Iran - Corrected Proof

2011-12-28

Background: Beta-thalassemia is commonly associated with lipid abnormalities. The aim of this study was to search for links between these lipid alterations and different types of β-thalassemia mutations.Methods: The study, conducted from 2009 to 2010, included 100 patients with thalassemia major (TM) and 100 with thalassemia intermedia (TI). The control group was selected from 100 age- and sex-matched healthy individuals with normal hematologic indices. Serum lipid profiles, including total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG), were determined and their relationship with different covariates, including different β-globin gene mutations, was analyzed.Results: Patients with TI had significantly lower values for TC, LDL-C, HDL-C, and LDL-C/HDL-C ratio compared with TM patients and controls (P < .001). TG was greater in TM compared with TI patients (P = .001) and healthy individuals (P = .007). Hemoglobin was positively associated with TC (P < .001), LDL-C (P = .004), and HDL-C (P = .01) in TM patients. Splenectomy correlated with greater TC (P = .006) and LDL-C (P = .01) in TI patients, but only with greater LDL-C in TM patients (P = .02). The average amounts of TC and LDL-C were lower in persons with the β0/β0 mutation compared with the β+/β+ group.Conclusion: Lower amounts of TG, TC, LDL-C, and HDL-C were seen in TI patients compared with TM patients and healthy individuals. The severity of the genotype (ie, β0 type mutations compared with β+ type mutations) affected the degree of reduction in serum lipids.

Pregnancy during adolescence has lasting adverse effects on blood lipids: A 10-year longitudinal study of black and white females - Corrected Proof

2011-12-26

Background: Primiparity has been associated with 3 to 4 mg/dL lower high-density lipoprotein cholesterol concentrations in black and white adult women that persist several years after delivery.Objective: To examine the lasting effects of adolescent pregnancy on blood lipids, an early risk factor for future cardiometabolic diseases.Design: The National Heart Lung and Blood Institute’s Growth and Health Study is a multicenter prospective cohort that measured fasting blood lipids for 1013 (513 black, 500 white) participants at baseline (1987–1988) ages 9–10, and again at follow-up (1996–1997) ages 18–19.Methods: Change in fasting plasma total cholesterol, triglycerides, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol, defined as the difference between baseline and follow-up measurements, was compared among 186 (145 black, 41 white) primi- or multiparas, 106 (55 black, 51 white) nulliparous, gravidas versus 721 (313 black, 408 white) nulligravidas. Fully adjusted multiple linear regression models estimated blood lipid changes among these pregnancy groups adjusted for race, age at menarche, baseline lipids, physical inactivity, body mass index, and family sociodemographics.Results: In the 10-year study period, adolescent paras compared with nulligravidas had greater decrements in high-density lipoprotein cholesterol (mg/dL; fully adjusted mean [95% confidence interval] group differences in black −4.3 [−6.7, −2.0]; P < .001 and white: −4.5 [−8.2, −0.7]; P = .016) and greater increments in fasting triglycerides (mg/dL; adjusted mean [95% confidence interval] group differences in black: 10.4 [3.9, 16.8]; P < .001, and white: 11.6 [−3.6, 26.8]; P = .167).Conclusion: Adolescent pregnancy contributes to pro-atherogenic lipid profiles that persist after delivery. Further research is needed to assess whether adolescent pregnancy has implications for future cardiovascular disease risk in young women.

Difference between calculated and direct-measured low-density lipoprotein cholesterol in subjects with diabetes mellitus or taking lipid-lowering medications - Corrected Proof

2011-12-26

Objective: We evaluated factors that caused differences between calculated low-density lipoprotein cholesterol (C-LDL-C) and direct-measured LDL-C (D-LDL-C) and compared them in subjects with diabetes mellitus (DM) or taking lipid-lowering medications.Methods: 21,452 subjects (9,177 women, 12,275 men; 8.1% with DM and 8.5% on lipid-lowering medications) were included in the analysis. Participants were classified into 3 groups, i.e., group 1: the subjects without DM and not on lipid-modifying drugs (n = 18,287), group 2: without DM and on lipid-modifying drugs (n = 1,423), and group 3: with DM (n = 1,742). LDL-C concentrations were either directly measured by a homogenous method or calculated by Friedewald formula.Results: There was a significant correlation between C-LDL-C and D-LDL-C (r = 0.966, P < .001). The absolute values of the differences between two LDL-C values were 7.0 ± 6.2 mg/dl and 6.6 ± 7.3% (6.6 ± 5.9 mg/dl and 6.0 ± 6.5%, 8.8 ± 6.7 mg/dl and 9.1 ± 9.7%, and 10.1 ± 7.3 mg/dl and 10.7 ± 10.1% in group 1, 2, and 3 respectively, P < .001). The subjects with the absolute value of the differences of LDL-C ≥10% was 20.2% (17.3%, 31.3%, and 41.1% in group 1, 2, and 3 respectively, P < .001). In the multiple logistic regression analysis, high triglyceride (≥150 mg/dl), low high-density lipoprotein cholesterol (HDL-C) (<40 mg/dl), male gender, obesity (body mass index ≥25 kg/m2), DM and taking lipid-lowering drugs were significant associated with high LDL-differences (the absolute value of the differences ≥10% or ≥10 mg/dl).Conclusion: D-LDL-C was generally higher by 5 mg/dl or 5% than C-LDL-C. The differences C-LDL-C and D-LDL-C were higher in subjects with DM and on lipid-lowering medications. Male gender, high triglyceride, low HDL-C, and obesity were also associated with the greater differences between C-LDL-C and D-LDL-C.

Elevation of fasting morning glucose relative to hemoglobin A1c in normoglycemic patients treated with niacin and with statins - Corrected Proof

2011-12-26

Background: Niacin increases fasting glucose levels, and statins modestly increase the rate of new-onset diabetes. The clinical importance and mechanisms of these effects are not fully explored.Objective: On the basis of anecdotal observations, we hypothesized that elevated morning fasting glucose may be accompanied by relatively normal hemoglobin A1c (HbA1c) in patients treated with niacin and other lipid-modifying drugs. We conducted a retrospective cohort analysis to test this hypothesis.Methods: The Duke Lipid Clinic database (1994–2007) was screened for simultaneous determinations of fasting morning glucose and HbA1c, yielding 1483 data pairs among 554 subjects. Subjects with diabetes, by clinical diagnosis, medication, or any HbA1c ≥6.5%, or nondiabetes were analyzed separately. Repeated-measures linear regression featured glucose as dependent variable and included terms for HbA1c, drug(s), and their interaction.Results: Regression lines for glucose on HbA1c had altered slopes in the presence of niacin and/or statin use in normoglycemic subjects. The corresponding interaction terms (drug and HbA1c) were significant (niacin P = .026, statin P = .013). Fibrate use had no effect (interaction P = .49). When modeled together, niacin and statin effects were independent. Regression curves in diabetic patients were not affected by lipid medications.Conclusion: Elevated fasting glucose may be accompanied by relatively normal HbA1c in niacin- and statin-treated patients. HbA1c reflects average daily glucose levels and is likely a better measure of the glycemic effect of lipid medications. Because our data were retrospective, confirmation from randomized trials is needed.

The use of lipopheresis in the practice of clinical lipidology† - Uncorrected Proof

W. Virgil Brown, Robert Brook, Linda C. Hemphill, Patrick M. Moriarty — 2011-12-23

W. Virgil Brown, MD: In this issue of the Journal, I have invited three clinical lipidologists who are treating patients with very high LDL concentrations using devices that physically remove apolipoprotein B (apoB)-containing lipoproteins from the blood. We have discussed the clinical use of these methods that trap lipoproteins in physical systems while directly connected to the vasculature. Although extremely efficacious in the short term, they require repeated use to achieve the longer-term effects necessary to successfully reduce vascular disease risk. The several methods in this arena have become known as lipopheresis or lipoprotein apheresis. Dr. Robert Brook, from the University of Michigan, Dr. Linda Hemphill, from Harvard, and Dr. Patrick Moriarty, from the University of Kansas, have agreed to answer my questions regarding the appropriate applications of these procedures.

Polish Lipid Association – A strong response to the problem of lipid disorders in Poland and Central and Eastern Europe - Corrected Proof

Maciej Banach, Michael Davidson, Peter P. Toth — 2011-12-12

As a group, lipid disorders constitute one of the most important and common risk factors for atherosclerotic disease. According to the cardiovascular continuum theory, lipid disorders promote the development of atherosclerosis and its clinical sequelae, including acute coronary syndromes (ACS), ischemic stroke, peripheral arterial disease, heart failure, and sudden cardiac death. Despite the introduction of very effective lipid-modifying drugs, hyperlipidemia is still poorly controlled and treated worldwide.

Changes in prescription patterns before and after reporting of the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression trial (ENHANCE) results and expected effects on low-density lipoprotein-cholesterol reduction - Corrected Proof

2011-12-08

Background: Recent trends suggest a decreased use of ezetimibe/simvastatin combination and coadministered ezetimibe plus statin therapies.Objective: This analysis evaluated changes in prescription patterns for ezetimibe/simvastatin, ezetimibe plus statins, and statin therapies and expected effects on low-density lipoprotein cholesterol (LDL-C) lowering during 2007 to 2008.Methods: Prescription pattern changes were assessed by the use of patient-level data from the IMS Health Longitudinal Rx database during two time periods, July 14, 2007 to January 13, 2008 (n = 8,813,674) and January 14, 2008 to July 13, 2008 (n = 9,131,030), 6 months before and after reporting of the results of The Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression trial (ENHANCE) trial on January 14, 2008. Expected LDL-C reductions were estimated using data from previous controlled clinical trials.Results: During 6 months post-ENHANCE, greater proportions of patients were switched from ezetimibe/simvastatin and ezetimibe plus statins to other lipid-lowering therapies by health care providers than 6 months pre-ENHANCE (21.1% vs 6.0% and 46.9% vs 38.5%, differences: −15.06% [95% confidence interval −15.14%, −14.97%] and −8.43% [95% confidence interval −8.70%, −8.17%], respectively). Greater proportions of these patients switched to statin monotherapy in the later than earlier period. Prescription patterns were similar for statins during both time periods, although fewer patients switched to ezetimibe/simvastatin and ezetimibe plus statin therapies post-ENHANCE. In both time periods, greater proportions of patients on ezetimibe/simvastatin and ezetimibe plus statins switched to less-than-equivalent LDL-C lowering efficacy doses of statins than those on statin therapy. On the basis of previous clinical data for these therapies, smaller LDL-C reductions would be expected in patients who switched from ezetimibe/simvastatin and ezetimibe plus statins to statins, despite a trend toward switching to greater statin doses in the later time period.Conclusions: More patients switched from ezetimibe/simvastatin and ezetimibe plus statin to statin monotherapy 6 months after the reporting of the ENHANCE trial, the majority of which were prescribed less potent, LDL-C–lowering therapies. On the basis of the known LDL-C lowering efficacies for these therapies, such changes would be expected to increase LDL-C levels in these patients and may reduce the proportion of patients who achieve guideline-recommended LDL-C goals.

Relationship between serum uric acid and metabolic syndrome: An analysis by structural equation modeling - Corrected Proof

2011-12-06

Objective: To investigate the nature of the relationships between uric acid and metabolic syndrome (MetS) components.Methods: Body mass index, waist circumference, serum uric acid, fasting glucose, lipid profiles, and blood pressure were measured in 13,811subjects aged between 18 and 85 years of age. Two structural equation models (SEMs) were used to test a hypothesis regarding the linking roles of uric acid in the occurrence of MetS components in male and female separately.Results: The findings of the SEM demonstrated that increased uric acid level was associated with fasting glucose (beta = 0.221, P < .001), blood pressure (beta = 0.158, P < .001), and lipid profiles (beta = 0.391, P < .001) in women. Increased uric acid level was associated with decreased fasting glucose (beta = −0.071, P < .001) and increased lipid profiles (beta = 0.352, P < .001) in men. The association was stronger between uric acid and lipid profiles than those between uric acid and other MetS components.Conclusion: By using SEM, we were able to confirm the intimate relationships between uric acid and MetS components, particularly in women. The associations between uric acid and MetS components were gender specific, and the nature of such association requires further exploration.

Low-density lipoprotein apheresis is effective in reducing lipoprotein (a) levels and in improving symptoms in a patient with refractory angina secondary to accelerated coronary artery disease - Corrected Proof

Michael Ibrahim, Bassey Ussen, Alison Pottle, Mahmoud Barbir — 2011-12-05

Abstract: Coronary artery disease remains a significant cause of morbidity and mortality in the Western world. High plasma Lp(a) concentrations are related to the risk of cardiovascular disease, but Lp(a) is rarely assayed and treated. We present the case of a 50-year-old gentleman with refractory angina, whose coronary disease continued to progress despite optimal medical and surgical therapy. We show that the aggressive reduction of Lp(a) successfully ameliorated the progression of coronary stenosis and provides effective and durable relief of symptoms.

Effects of coadministered extended-release niacin/laropiprant and simvastatin on lipoprotein subclasses in patients with dyslipidemia - Corrected Proof

2011-12-05

Background: The use of extended-release niacin and the prostaglandin D2 receptor antagonist laropiprant (ERN/LRPT) reduces niacin-induced flushing in patients while preserving its lipid-modifying effects.Objective: This predefined exploratory analysis examined the individual and combined effects of ERN/LRPT and simvastatin (SIM) on lipoprotein subclasses.Methods: This double-blind study randomized 1398 dyslipidemic patients equally to ERN/LRPT 1 g/20 mg, SIM (10, 20, or 40 mg), or ERN/LRPT 1 g/20 mg + SIM (10, 20, or 40 mg) once daily for 4 weeks. At week 5, doses were doubled, except SIM 40 mg (unchanged) and ERN/LRPT 1 g/20 mg + SIM 40 mg (switched to ERN/LRPT 2g/40 mg + SIM 40 mg). Cholesterol associated with lipoprotein subclasses was quantified by vertical auto profile II (VAP II).Results: ERN/LRPT + SIM and SIM alone lowered LDL-C 1 and 3, whereas the effects were variable for ERN/LRPT; all three treatments increased LDL-C 4. ERN/LRPT + SIM and ERN/LRPT raised HDL-C 2 and 3, with greater relative percent changes in HDL 2 than HDL 3. ERN/LRPT + SIM for 12 weeks produced substantial reductions in IDL-C, which was additive compared with each monotherapy.Conclusion: Coadministered ERN/LRPT + SIM produced marked reductions in atherogenic lipoproteins, with the greatest effect on IDL-C, and increases in protective HDL subclasses.

The relationship between subclinical atherosclerosis, non–high-density lipoprotein cholesterol, exercise, and diet among male participants of the PACC Project - Corrected Proof

Lauren A. Simprini, Todd C. Villines, Michael Rich, Allen J. Taylor — 2011-12-05

Background: Non-high-density lipoprotein (HDL) cholesterol is recommended as a secondary lipid goal treated initially with lifestyle modification. However, the relationship between non-HDL and subclinical atherosclerosis is unknown. We examined the independent relationships between coronary artery calcium (CAC), lipids including non-HDL, exercise, and diet among healthy male participants of the Prospective Army Coronary Calcium (PACC) Project.Methods: Male participants from the PACC Project (n = 1637, mean age 42.8 years; no history of coronary heart disease) were studied. We used validated surveys to measure dietary quality and habitual physical exercise. Fasting lipid concentrations and other cardiovascular risk variables were measured. Subclinical atherosclerosis was detected with the use of electron beam computed tomography for CAC. Factors independently associated with the presence of any detectable CAC (CAC score > 0), including standard CV risk variables, non-HDL, exercise, and diet, were evaluated with the use of logistic regression.Results: The mean Framingham risk score was 4.6 ± 2.6%; CAC was present in 22.4%. Fasting lipid concentrations showed mean LDL-C 128 ± 32 mg/dL, HDL-C 50 ± 13 mg/dL, TG-C 130 ± 86 mg/dL, and non-HDL-C 154 ± 37 mg/dL. Men with CAC had significantly greater levels of LDL-C (135 vs 127 mg/dL), TG (148 vs 124 mg/dL), and non-HDL-C (164 vs 151 mg/dL) and less habitual physical activity (P = 0.006). There were nonsignificant trends between prevalent CAC, greater amounts of dietary fat intake, and lower HDL-C. In successive multivariable logistic regression models for the dependent variable CAC, only non-HDL-C (odds ratio [OR] 1.012 per mg/dL; 95% CI 1.002–1.023; P = .019) and age (OR 1.119 per year; 95% CI 1.063–1.178; P < .001) were independently associated with the presence of CAC, and exercise (OR 0.808; 95% CI 0.703–0.928; P = 0.003) was associated with the absence of CAC.Conclusions: Non-HDL-C and exercise are independently predictive of the presence of subclinical CAC among healthy lower-risk middle-aged men.

The high-dose rosuvastatin once weekly study (The HD-ROWS) - Corrected Proof

James M. Backes, Cheryl A. Gibson, Janelle F. Ruisinger, Patrick M. Moriarty — 2011-11-21

Background: Alternative dosing is often used clinically to address common barriers with statin therapy, such as intolerance and cost. Previous findings have demonstrated significant and clinically similar reductions in low-density lipoprotein (LDL) cholesterol to daily dosing, when comparing similar total weekly doses.Objective: To determine whether rosuvastatin 80 mg once weekly produced comparable lipid and high-sensitivity C-reactive protein (hsCRP) changes to atorvastatin 10 mg daily, when measured at key points after last dose.Methods: This was a randomized, double-blind, parallel group, 8-week pilot study. Eligible subjects, 18 to 65 years of age, had documented dyslipidemia with LDL cholesterol >100 mg/dL and triglycerides <200 mg/dL. Participants were randomized to receive either rosuvastatin 80 mg once weekly (n = 10) or atorvastatin 10 mg daily (n = 10), for 8 weeks. Lipid panels and hsCRP were measured at baseline and 1–4 and 5–8 days after the last dose.Results: Participants in each arm experienced significant and comparable reductions from baseline in total cholesterol, total cholesterol/high-density lipoprotein cholesterol ratio, non-high-density lipoprotein cholesterol, and overall LDL cholesterol (−29%). Changes in high-density lipoprotein cholesterol, triglycerides, and hsCRP were nonsignificant and similar between groups. Each regimen was well tolerated, with no major adverse events reported.Conclusion: Rosuvastatin 80 mg once weekly produced comparable lipid changes to atorvastatin 10 mg daily when measured at specific points after the last dose. Our findings support previous data demonstrating a significant reduction in LDL-C with once weekly statin dosing.

Search and rescue for hypotheses surviving AIM-HIGH, the niacin therapy earthquake - Uncorrected Proof

Eliot A. Brinton — 2011-11-11

Approximately 57 years ago, niacin became one of the first medications reported to lower cholesterol levels when Rudolf Altschul and coworkers first published results in rabbits. During the next 10 years, these and other scientists linked those observations to humans and extended them beyond total cholesterol-lowering to low-density lipoprotein (LDL)-lowering, high-density lipoprotein (HDL)-increasing, reduction of cutaneous atheromata, and even regression of lower-extremity atherosclerosis. Research on niacin has continued forward from this promising early beginning to show many additional benefits, including reduction in plasma levels of apolipoprotein B (apo B), triglycerides and lipoprotein (a), increased plasma apo A-I, as well as regression and/or reduced progression of atherosclerosis in the coronary, femoral, and carotid arteries. Most importantly, niacin has been shown consistently to reduce cardiovascular disease (CVD) clinical events, including coronary and cerebrovascular, and was the first lipid agent shown to reduce total mortality.

Lipid levels in obese and nonobese subjects as predictors of fasting and postload glucose metabolism - Corrected Proof

2011-10-03

Background: Dyslipidemia in the overweight/obese patient often is associated with impaired glucose metabolism. The authors of large clinical trials in different ethnic groups highlighted the correlation between glycemia and lipid profile, although the effect of abdominal adiposity was not explored.Objective: To evaluate the relationship of visceral adiposity and lipid profile with fasting (FPG) and postload glucose (2hPG) in subjects without known diabetes (DM2).Methods: A total of 3030 subjects were divided in three groups: obese subjects (OB; n = 490), nonobese subjects with an increased waist circumference (NOB/W+; n = 500), and nonobese subjects without an increased waist circumference (NOB/W−; n = 2040). We performed a linear regression analysis among lipid fractions and fasting and 2hPG in the three groups, with or without diagnosis of DM2 after 2hPG.Results: Our data confirmed the significant association (P < .01) of high triglycerides and low high-density lipoprotein cholesterol (HDL-C) with fasting and 2hPG in all three groups such as for non-HDL cholesterol, whereas total cholesterol (TC) showed a significant correlation only with fasting glucose in OB and NOB/W+ subjects (P < .01). The analysis with or without DM2 demonstrated no difference in the statistical significance, although a better correlation in subjects without DM2 was observed. In addition, for each quartile of TC a significant trend (P < .01) in prevalence of fasting hyperglycemia in obese and in NOB/W+ patients was observed.Conclusion: This study suggests that triglycerides and HDL-C, together with non-HDL cholesterol, are associated with impaired fasting and 2hPG and that high total cholesterol levels are associated with abnormalities of fasting glucose metabolism only in patients with elevated waist circumference.

A multicenter study of nutraceutical drinks for cholesterol (evaluating effectiveness and tolerability) - Corrected Proof

Mitchell Karl, Mark Rubenstein, Chad Rudnick, John Brejda — 2011-09-22

Background: We hypothesized that a nutraceutical formulation containing small amounts of bioactive constituents that exert cholesterol-lowering effects by different mechanisms may exhibit synergistic efficacy with a clean tolerability profile. The purpose of this study was to evaluate nutraceutical fruit-flavored drinks with and without red yeast rice (RYR) for effects on low-density lipoprotein (LDL) and total cholesterol.Methods: In double-blinded fashion, 79 subjects were randomized to one of three fruit-flavored drinks, ie, a placebo, and two active drinks containing niacin, phytosterol esters, L-carnitine, vitamin C, and Co-Q-10, one with and without RYR, twice daily. Primary end points were LDL and total cholesterol percent reductions from baseline. Secondary end points were high-density lipoprotein and C-reactive protein percent change from baseline. Physician contact and laboratory work were obtained at baseline, 4 weeks, and 8 weeks of subject participation.Results: A total of 59 subjects completed the study. The placebo group and the group receiving the nutraceuticals without RYR showed no change in primary or secondary end points. The nutraceutical drink with RYR reduced total cholesterol at week 4 by 13% (−35 mg/dL) and week 8 by 14% (−46 mg/dL). LDL cholesterol decreased 17.1% at 4 weeks (−28 mg/dL) and 17.8% at week 8 (−30 mg/dL). In the effective drink arm containing nutraceuticals and RYR there were no biochemical or subjective intolerance, with the exception of one subject who experienced headache.Conclusions: A nutraceutical drink with RYR can be a safe and effective natural alternative to pharmacologic therapies for people intolerant to or refusing statins but still in need of achieving and maintaining a healthy and low cholesterol level.

A systematic review on evidence of the effectiveness and safety of a wax-matrix niacin formulation - Corrected Proof

Andrew P. Dunatchik, Matthew K. Ito, Carlos A. Dujovne — 2011-07-26

Abstract: Niacin is a uniquely efficacious therapy in the treatment of dyslipidemia because of its broad spectrum of beneficial effects on every aspect of the lipid profile and because it has been shown to reduce both total mortality and coronary death. However, niacin therapy is hindered by its side-effect profile, which appears to be dependent on its formulation with immediate-release niacin, associated with a greater incidence of flushing, and sustained-release niacin, associated with greater liver function test (LFT) abnormalities and hepatotoxicity. One such sustained-release niacin nutritional supplement formulation, Endur-acin (Endurance Products Company, Tigard, OR), claims to have clinical evidence to support its use in the treatment of dyslipidemias, which prompted us to systematically review the literature. We identified four published papers in which the authors reported the results of two separate clinical trials and one pharmacokinetic study that fulfilled the inclusion criteria and were included in this review. Endur-acin significantly reduced total cholesterol, low-density lipoprotein cholesterol, and total cholesterol/high-density lipoprotein cholesterol ratio with mean reductions up to 19%, 26%, and 20%, respectively, at a dose of 2000 mg/day. Less-impressive benefits were also seen with high-density lipoprotein cholesterol (+10%) and serum triglycerides (−23%). Mean LFT elevations of up to 1.6-fold were seen at the 2000 mg per day dose, however, not exceeding three times the upper limit of normal, with abnormal results occurring at similar frequency in placebo and one patient experiencing marked gastrointestinal symptoms and a hepatitis-like syndrome with reversible elevated LFT. Short-term randomized controlled trials suggest Endur-acin is effective in modifying serum lipids, although study limitations prevent a comprehensive evaluation of safety.

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

W. Virgil Brown — 2008-07-14