The Effect of Proprotein Convertase Subtilisin/Kexin Type 9 Inhibition on Sterol Absorption Markers in a Cohort of Real-World Patients.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is expressed in multiple tissues, including the small intestine. The effect of PCSK9 inhibition on cholesterol absorption is not known. OBJECTIVES: Measure serum cholesterol absorption markers before and after initiation of PCSK9 inhibitors. METHODS: Single-center retrospective cohort of patients administered evolocumab and alirocumab between July 2015 and January 2017. Paired t tests were used to compare mean serum cholesterol marker concentrations, and ratios to total cholesterol, before and after PCSK9 inhibitor initiation. Analyses were repeated for those taking and not taking statins and taking or not taking ezetimibe at both initiation and follow-up, for each PCSK9 inhibitor, and based on follow-up time (<60, 60-120, and >120 days). RESULTS: There were 62 possible participants, 34 were excluded for lack of data or unknown PCSK9 inhibitor initiation date. Average follow-up was 92.5 days. Mean campesterol (before 3.14 µg/mL, 95% CI: 2.79-4.38 µg/mL; after 2.09 µg/mL, 95% CI: 1.87-2.31 µg/mL; P < .0001), sitosterol (before 2.46 µg/mL, 95% CI: 2.23-2.70 µg/mL; after 1.62 µg/mL, 95% CI: 1.48-1.75 µg/mL; P < .0001), and cholestanol (before 3.25 µg/mL, 95% CI: 3.04-3.47 µg/mL; after 2.08 µg/mL, 95% CI: 1.96-2.21 µg/mL; P < .0001) all significantly decreased at follow-up. There was no significant change in absorption marker to total cholesterol ratios. Findings were not influenced by statin or ezetimibe use or nonuse, which PCSK9 inhibitor was prescribed, or time to follow-up. CONCLUSION: Proprotein convertase subtilisin/kexin type 9 inhibition was associated with decreased cholesterol absorption markers.

Comparison of cardiometabolic risk biomarkers from a national clinical laboratory with the US adult population.

BACKGROUND: Clinical laboratory patient databases are an untapped source of valuable diagnostic and prognostic information. However, the lack of associated clinical and/or demographic information and questionable generalizability to nonpatient populations often limit utility of these data. OBJECTIVES: This study compared levels of cardiometabolic biomarkers between a national clinical laboratory patient cohort (Health Diagnostic Laboratory [HD Lab]) and the US population as inferred from the National Health and Nutrition Examination Survey (NHANES, 2011-2012). METHODS: Sample sizes for HD Lab ranged from 199,000 to 739,000 and for NHANES from 2200 to 5300. The latter were weighted to represent the adult US population (∼220 million). Descriptive statistics were compared for body mass index, 5 lipid biomarkers, and 3 glycemic biomarkers. RESULTS: Using age- and sex-matched data, mean biomarker values (mg/dL unless noted) and percent differences (%) for HD Lab vs NHANES were body mass index (kg/m(2)), 29.1 vs 28.6 (1.7%); total cholesterol, 185 vs 193 (-4.1%); apolipoprotein B, 92 vs 90 (2.2%); low-density lipoprotein cholesterol, 107 vs 115 (-7%); high-density lipoprotein cholesterol, 53 vs 53 (0%); triglycerides, 128 vs 127 (0.8%); glucose, 99 vs 108 (-8.3%); insulin (uU/mL), 13.7 vs 13.4 (2.2%); and hemoglobin A1c (%), 5.6 vs 5.8 (-3.4%). Although all differences were statistically significant, only low-density lipoprotein cholesterol and glucose differed by more than 5%. These may reflect a greater use of medications among HD Lab patients and/or preanalytical factors. CONCLUSIONS: Cardiometabolic risk markers from a national clinical laboratory were broadly similar to those of the US population; thus, with certain caveats, data from the former may be generalizable to the latter.

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

BACKGROUND: Circulating 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. OBJECTIVES: To 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. METHODS: A 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. RESULTS: Mean 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. CONCLUSIONS: We 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.

Hypertriglyceridaemia unresponsive to multiple treatments.

A 52-year-old man with a longstanding history of hypertriglyceridaemia (approximately 7 mmol/L (600 mg/dL)), unresponsive to treatment, presented to a lipid-specialty clinic. Additional triglyceride-lowering therapies were added with no effect. It was then noted that despite the apparent hypertriglyceridaemia, his serum sample was clear. A 'glycerol blank' was then requested from an advanced lipid laboratory, which reported a triglyceride value of 0.7 mmol/L (62 mg/dL). These findings suggest isolated asymptomatic glycerol kinase deficiency (GKD) or 'pseudohypertriglyceridaemia'. The falsely elevated triglyceride values in such individuals are a result of excess serum glycerol and clinical laboratories measuring glycerol to report triglyceride concentrations. After discontinuation or modification of the patient's primary triglyceride-lowering agents, the lipid panels and triglyceride values remained comparable to previous readings. Recognition of asymptomatic GKD is important to prevent unnecessary treatment and overestimated cardiovascular risk.

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

BACKGROUND: Discordance 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. OBJECTIVES: To 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. METHODS: Two 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. RESULTS: ApoB and LDL-PNMR values were highly correlated (R(2) = 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). CONCLUSION: Discordance between apoB and LDL-PNMR in routine clinical practice is more widespread than currently recognized and may be associated with insulin resistance.

Validation of a lipoprotein(a) particle concentration assay by quantitative lipoprotein immunofixation electrophoresis.

BACKGROUND: Low-density lipoprotein (LDL) particle (P, or molar) concentration has been shown to be a more sensitive marker of cardiovascular disease (CVD) risk than LDL cholesterol. Although elevated circulating lipoprotein(a) [Lp(a)] cholesterol and mass have been associated with CV risk, no practicable method exists to measure Lp(a)-P. We have developed a method of determining Lp(a)-P suitable for routine clinical use. METHODS: Lipoprotein immunofixation electrophoresis (Lipo-IFE) involves rigidly controlled electrophoretic separation of serum lipoproteins, probing with polyclonal apolipoprotein B antibodies, then visualization after staining with a nonspecific protein stain (Acid Violet). Lipo-IFE was compared to the Lp(a) mass assay for 1086 randomly selected patient samples, and for 254 samples stratified by apo(a) isoform size. RESULTS: The Lipo-IFE method was shown to be precise (CV <10% above the 50 nmol/l limit of quantitation) and linear across a 16-fold range. Lipo-IFE compared well with the mass-based Lp(a) assay (r=0.95), but was not affected by variations in apo(a) isoform size. With a throughput of 100 samples in 90 min, the assay is suitable for use in the clinical laboratory. CONCLUSIONS: The Lipo-IFE method will allow Lp(a)-P to be readily tested as a CVD risk factor in large-scale clinical trials.

Lipoprotein(a) mass: a massively misunderstood metric.

The importance of lipoprotein (a)-Lp(a)-as a cardiovascular (CV) risk marker has been underscored by recent findings that CV risk is directly related to baseline Lp(a) levels, even in well-treated patients. Although there is currently little that can be done pharmacologically to lower Lp(a) levels, knowledge of its serum concentration is important in overall risk assessment. This review focuses on 1 aspect of Lp(a) that is rarely discussed directly: how to express its levels in serum. There is considerable confusion on this point, and a fuller understanding of what the concentration units mean will help improve study-to-study comparisons and thereby advance our understanding of the pathobiology of this lipoprotein particle. As discussed here, the term Lp(a) mass refers to the entire mass of the particle: lipids, proteins, and carbohydrates combined. At present, there are no commercially available assays that are completely insensitive to the variability in particle mass, which arises not only from differences in apo(a) isoform mass but also from variations in lipid mass. Because lipoprotein "particle number" (molar concentration) has been found to be superior to component-based metrics (ie, low-density lipoprotein particle vs cholesterol concentrations) for CV disease risk prediction, the development of a mass-insensitive Lp(a) assay should be a high priority.

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.

Omega-3 fatty acids and cardiovascular disease: new developments and applications.

The omega-3 fatty acids (FA) found in fish oils, eicosapentaenoic and docosahexaenoic acids (EPA and DHA, respectively), have been extensively studied therapeutically in a wide variety of disease conditions, but in none more than cardiovascular disease (CVD). Our review summarizes mechanisms of action, recent meta-analyses of CVD outcome trials, sources (fish and supplements), and recommendations for use of omega-3 FA in clinical practice. With the ability to now measure the omega-3 FA biostatus through blood tests, patients can achieve cardioprotective levels by either taking fish oil supplements or simply eating more oily fish. Two omega-3 FA formulations (both in the ethyl ester form) have been approved by the US Food and Drug Administration (FDA) for the treatment of patients with very high triglyceride levels (> 500 mg/dL); one contains both EPA and DHA, whereas the other contains only EPA. The agents have been extensively tested in 2 patient populations, those with very high triglycerides and those with triglycerides between 200 and 500 mg/dL while on background statin therapy. In general, treatment with EPA+DHA appears to lower patient triglycerides more effectively, but in those patients with very high triglyceride levels, use of EPA+DHA also raised low-density lipoprotein cholesterol levels, whereas EPA alone did not. Both formulations, at doses that do not lower triglycerides, have been shown to reduce CVD events in some, but not all, studies. Given the favorable risk-to-benefit ratio for these essentially nutritional agents, use is expected to continue to expand.

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.

Drug safety evaluation of rosuvastatin.

INTRODUCTION: Rosuvastatin is a highly efficacious statin approved for use throughout the world. Rosuvastatin has been exhaustively evaluated in the setting of a broad variety of dyslipidemias and cardiovascular disease states in clinical trials encompassed within the GALAXY program. AREAS COVERED: The efficacy and adverse event profile of rosuvastatin are evaluated based on the results of randomized, controlled clinical trials and observational studies available in the Medline database. EXPERT OPINION: Rosuvastatin is a safe and efficacious lipid modifying drug in a broad variety of patient populations (men and women, irrespective of race) for treating multiple forms of dyslipidemia. Rosuvastatin reduces atherogenic lipoproteins and triglycerides and increases high-density lipoprotein cholesterol better than other statins. Compared to other statins, it has no excess signal for liver, skeletal muscle or renal toxicity. This is supported by evidence from both an extensive clinical trial program as well as post-marketing surveillance. The incidence of myalgia with this drug is comparable to that observed with other statins. Rosuvastatin does not depend on cytochrome P450 3A4-dependent metabolism and has a favorable drug interaction profile. Care must be taken to reduce the dose of rosuvastatin in patients of Asian ancestry or with stage IV chronic kidney disease (severe renal insufficiency), as well as patients being treated with protease inhibitors or cyclosporine.

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

BACKGROUND: 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.

Impact of triglycerides on lipid and lipoprotein biology in women.

BACKGROUND: Because atherosclerosis, a leading cause of morbidity and mortality in women, is thought of as a sterol (cholesterol and noncholesterol sterol)-mediated disease, plasma triglyceride (TG) levels (the concentration of all TG trafficked within all of the lipoproteins per dL of plasma), TG biology, and TG pathobiology historically have been ignored or frequently misunderstood in both risk assessment and treatment decisions. OBJECTIVES: This review presents information on the importance of TG (chemical name, triacylglycerol) in atherogenesis and the relationship of TG to gender, adiposopathy (the pathophysiological transformation of functional adipose tissue into an organ with pathogenic endocrine and immune responses), insulin resistance, sterol-trafficking lipoproteins, and overall vascular health. In addition, this review seeks to explain the complexities of lipid homeostasis and how it is influenced by lipid-modulating medications, reproductive hormones, and selective estrogen receptor modulators (SERMs). METHODS: Using peer-reviewed materials published in English from the extensive libraries of the authors, this narrative review references key epidemiologic, basic science lipid/lipoprotein publications as well as efficacy trials of lipid-modulating, hormonal, and SERM therapies. RESULTS: TG are associated with insulin resistance; the metabolic syndrome; increased atherogenic lipo-proteins; and rheologic, inflammatory, and coagulation abnormalities. TG can be influenced by lifestyle and multiple medications used by women, including hormonal therapies. Several studies, but not all, support sex differences in TG. CONCLUSIONS: Through effects on sterol-trafficking lipoproteins, TG have a significant influence on atherosclerotic cardiovascular disease risk in menopausal women. TG-rich lipoproteins are affected by lipid-modulating drugs, estrogen therapy, estrogen-progestogen therapy, and SERMs.

Drug therapy for hypertriglyceridemia: fibrates and omega-3 fatty acids.

The reduction of low-density lipoprotein cholesterol in patients at risk for acute cardiovascular events is the cornerstone of lipid management in both the primary and secondary prevention settings. Serum triglyceride levels exceeding 150 mg/dL are abnormal and confer increased risk for developing coronary artery disease in both men and women. Serum triglycerides are derived from both dietary and endogenous biosynthetic pathways. Triglyceride metabolism has a complex regulatory circuitry and intimately impacts the production and disposal of multiple lipoprotein species. Hypertriglyceridemia is highly prevalent and is associated with multiple forms of dyslipidemia but tends to be undertreated. Therapeutic intervention with fibric acid derivatives and omega-3 fish oils is associated with significant reductions in both fasting and postprandial serum triglyceride concentrations. A variety of prospective, placebo-controlled clinical trials have also shown that these agents significantly impact risk for multiple cardiovascular end points.

Coronary heart disease in women: triglycerides and lipoprotein biology.

An examination of coronary heart disease in women over the past two decades in the United States reveals a disturbing gender difference that points to more treatment success in men than in women, which raises the question as to whether women have been as aggressively evaluated and treated. It is only over the last several years that evidence from randomized clinical trials on coronary heart disease etiology and treatment in women has become available. In addition, the previous widely held viewpoint that estrogen is cardioprotective and should be an integral part of pharmacologic therapy has been abandoned. Triglycerides and their very important influence on lipoproteins have emerged as a critical part of the pathobiological forces related to atherothrombosis in women.