Ezetimibe therapy: mechanism of action and clinical update.

The lowering of low-density lipoprotein cholesterol (LDL-C) is the primary target of therapy in the primary and secondary prevention of cardiovascular events. Although statin therapy is the mainstay for LDL-C lowering, a significant percentage of patients prescribed these agents either do not achieve targets with statin therapy alone or have partial or complete intolerance to them. For such patients, the use of adjuvant therapy capable of providing incremental LDL-C reduction is advised. One such agent is ezetimibe, a cholesterol absorption inhibitor that targets uptake at the jejunal enterocyte brush border. Its primary target of action is the cholesterol transport protein Nieman Pick C1 like 1 protein. Ezetimibe is an effective LDL-C lowering agent and is safe and well tolerated. In response to significant controversy surrounding the use and therapeutic effectiveness of this drug, we provide an update on the biochemical mechanism of action for ezetimibe, its safety and efficacy, as well as the results of recent randomized studies that support its use in a variety of clinical scenarios

Understanding hypertriglyceridemia in women: clinical impact and management with prescription omega-3-acid ethyl esters

Thomas D DayspringNorth Jersey Institute of Menopausal Lipidology, Wayne, NJ, USABackground: Elevated triglycerides (TGs) are a common lipid disorder in the US and are associated with comorbidities such as pancreatitis, obesity, type 2 diabetes, and metabolic syndrome. TGs are generally elevated in postmenopausal women compared with premenopausal women. Meta-analysis has shown that elevated TGs are associated with an increased risk of coronary heart disease (CHD).Objective: This article provides a general overview of TG metabolism and reviews data on the epidemiology and risk of elevated TGs in women, as pregnancy and menopause, in particular, have been associated with unfavorable changes in the lipoprotein profile, including elevations in TGs. In addition, this review seeks to explain the recommended TG goals and treatment options for hypertriglyceridemia with an emphasis on severe hypertriglyceridemia (TGs ≥ 500 mg/dL) and its respective treatment with prescription omega-3-acid ethyl esters (P-OM3).Methods: MedLine was searched for articles published through August 2009 using the terms “hypertriglyceridemia” and “dyslipidemia”, with subheadings for “prevalence”, “women”, “treatment”, “guidelines”, “risk”, and “omega-3 fatty acids”. Publications discussing the epidemiology of hypertriglyceridemia, CHD risk, treatment guidelines for lipid management, or clinical trials involving P-OM3 were selected for review. The reference lists of relevant articles were also examined for additional citations.Results: Hypertriglyceridemia is associated with increased CHD risk. Women, especially those with polycystic ovarian syndrome, type 2 diabetes, or who are postmenopausal, should be monitored regularly for the impact of hypertriglyceridemia on their lipid profile. Cardiovascular risk of TGs can be indirectly assessed by monitoring non-high-density lipoprotein cholesterol (non-HDL-C) levels. There are multiple sets of guidelines providing recommendations for desirable low-density lipoprotein cholesterol, TG, and non-HDL-C levels. Treatment of hypertriglyceridemia includes lifestyle interventions and, if needed, pharmacologic therapy. In patients with severe hypertriglyceridemia, P-OM3 can reduce TGs by up to 45%.Conclusion: Physicians should regularly monitor the lipid profile of their female patients. Any lipid abnormality should be managed promptly according to established guidelines. P-OM3 provide a well-tolerated option for the treatment of severe hypertriglyceridemia.Keywords: triglycerides, Lovaza, P-OM3, women, lipids, omega-

Does APOE Genotype Modify the Relations Between Serum Lipid and Erythrocyte Omega-3 Fatty Acid Levels?

Earlier reports indicated that patients with the apolipoprotein APOE ε4 allele responded to fish oil supplementation with a rise in serum low-density lipoprotein cholesterol (LDL-C) compared to ε3 homozygotes. In this study, we used clinical laboratory data to test the hypothesis that the cross-sectional relation between RBC omega-3 fatty acid status (the Omega-3 Index) and LDL-C was modified by APOE genotype. Data from 136,701 patients were available to compare lipid biomarker levels across Omega-3 Index categories associated with heart disease risk in all APOE genotypes. We found no adverse interactions between APOE genotype and the Omega-3 Index for LDL-C, LDL particle number, apoB, HDL-C, or triglycerides. However, we did find evidence that ε2 homozygotes lack an association between omega-3 status and LDL-C, apoB, and LDL particle number. In summary, we found no evidence for a deleterious relationship between lipid biomarkers and the Omega-3 Index by APOE genotype. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12265-014-9554-8) contains supplementary material, which is available to authorized users

Biomarkers of cholesterol homeostasis in a clinical laboratory database sample comprising 667,718 patients

BackgroundCirculating noncholesterol sterols/stanols (NCS) are used in clinical lipidology as surrogate measures of cholesterol synthesis and absorption, where they can be valuable tools in assessing cholesterol metabolism and personalizing therapies in patients with dyslipidemia.ObjectivesTo describe the distributions of plasma NCS concentrations and inter-NCS correlations in a large cohort of American patients constituting a clinical laboratory database, and to investigate the relationship between circulating NCS, age, sex, and apolipoprotein E (APOE) genotype.MethodsA total of 667,718 patient blood samples submitted for testing to Health Diagnostic Laboratory, Inc. (Richmond, VA) were analyzed for cholesterol absorption markers (sitosterol, campesterol, and cholestanol) and one cholesterol synthesis marker (desmosterol). NCS percentiles were determined, along with intermarker correlations (Pearson's R). Analysis of variance was used to assess the effect of age and sex on NCS level, and to evaluate the relationship between cholesterol synthesis/absorption status and APOE genotype in a subset of 336,866 patients.ResultsMean NCS concentrations were: sitosterol, 2.45 μg/mL; campesterol, 3.3 μg/mL; cholestanol, 2.92 μg/mL; and desmosterol 0.99 μg/mL. The correlations between each NCS and its ratio to total cholesterol ranged from 0.72 (cholestanol) to 0.94 (desmosterol). NCS levels were significantly affected by age and sex (P < .0001), and prevalence of cholesterol hyperabsorption was higher in APOE ε4 allele carriers compared with the other APOE genotypes.ConclusionsWe have described sample distributions of NCS biomarkers and characterized their relationship to age, sex, and APOE genotype. These data may facilitate research into altered cholesterol homeostasis and human disease, and help physicians optimize lipid-lowering therapies

Discordance between apolipoprotein B and low-density lipoprotein particle number is associated with insulin resistance in clinical practice

BackgroundDiscordance between measures of atherogenic lipoprotein particle number (apolipoprotein B [ApoB] and low-density lipoprotein [LDL] particle number by nuclear magnetic resonance spectroscopy [LDL-PNMR]) is not well understood. Appropriate treatment considerations in such cases are unclear.ObjectivesTo assess discordance between apoB determined by immunoassay and LDL-PNMR in routine clinical practice, and to characterize biomarker profiles and other clinical characteristics of patients identified as discordant.MethodsTwo retrospective cohorts were evaluated. First, 412,013 patients with laboratory testing performed by Health Diagnostic Laboratory, Inc., as part of routine care; and second, 1411 consecutive patients presenting for risk assessment/reduction at 6 US outpatient clinics. Discordance was quantified as a percentile difference (LDL-PNMR percentile − apoB percentile) and attainment of percentile cutpoints (LDL-PNMR ≥ 1073 nmol/L or apoB ≥ 69 mg/dL). A wide range of cardiovascular risk factors were compared.ResultsApoB and LDL-PNMR values were highly correlated (R2 = 0.79), although substantial discordance was observed. Similar numbers of patients were identified as at-risk by LDL-PNMR when apoB levels were < 69 mg/dL (5%-6%) and by apoB values when LDL-PNMR was < 1073 nmol/L (6%-7%). Discordance (LDL-PNMR > apoB) was associated with insulin resistance, smaller LDL particle size, increased systemic inflammation, and low circulating levels of “traditional” lipids, whereas discordance (apoB > LDL-PNMR) was associated with larger LDL particle size, and elevated levels of lipoprotein(a) and lipoprotein-associated phospholipase A2 (Lp-PLA2).ConclusionDiscordance between apoB and LDL-PNMR in routine clinical practice is more widespread than currently recognized and may be associated with insulin resistance