Peter P. Toth

Familial Hypercholesterolemia: Screening, diagnosis and management of pediatric and adult patients: Clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia

The familial hypercholesterolemias (FH) are a group of genetic defects resulting in severe elevations of blood cholesterol levels and increased risk of premature coronary heart disease. FH is among the most commonly occurring congenital metabolic disorders. FH is a treatable disease. Aggressive lipid lowering is necessary to achieve the target LDL cholesterol reduction of at least 50% or more. Even greater target LDL cholesterol reductions may be necessary for FH patients who have other CHD risk factors. Despite the prevalence of this disease and the availability of effective treatment options, FH is both underdiagnosed and undertreated, particularly among children. Deficiencies in the diagnosis and treatment of FH indicate the need for greatly increased awareness and understanding of this disease, both on the part of the public and of healthcare practitioners. This document provides recommendations for the screening, diagnosis and treatment of FH in pediatric and adult patients developed by the National Lipid Association Expert Panel on Familial Hypercholesterolemia. This report goes beyond previously published guidelines by providing specific clinical guidance for the primary care clinician and lipid specialist with the goal of improving care of patients with FH and reducing their elevated risk for CHD.

Clinical utility of inflammatory markers and advanced lipoprotein testing: Advice from an expert panel of lipid specialists

The National Cholesterol Education Program Adult Treatment Panel guidelines have established low-density lipoprotein cholesterol (LDL-C) treatment goals, and secondary non-high-density lipoprotein (HDL)-C treatment goals for persons with hypertriglyceridemia. The use of lipid-lowering therapies, particularly statins, to achieve these goals has reduced cardiovascular disease (CVD) morbidity and mortality; however, significant residual risk for events remains. This, combined with the rising prevalence of obesity, which has shifted the risk profile of the population toward patients in whom LDL-C is less predictive of CVD events (metabolic syndrome, low HDL-C, elevated triglycerides), has increased interest in the clinical use of inflammatory and lipid biomarker assessments. Furthermore, the cost effectiveness of pharmacological intervention for both the initiation of therapy and the intensification of therapy has been enhanced by the availability of a variety of generic statins. This report describes the consensus view of an expert panel convened by the National Lipid Association to evaluate the use of selected biomarkers [C-reactive protein, lipoprotein-associated phospholipase A(2), apolipoprotein B, LDL particle concentration, lipoprotein(a), and LDL and HDL subfractions] to improve risk assessment, or to adjust therapy. These panel recommendations are intended to provide practical advice to clinicians who wrestle with the challenges of identifying the patients who are most likely to benefit from therapy, or intensification of therapy, to provide the optimum protection from CV risk.

Integrated guidance on the care of familial hypercholesterolaemia from the International FH Foundation

Familial hypercholesterolaemia (FH) is a dominantly inherited disorder present from birth that markedly elevates plasma low-density lipoprotein (LDL) cholesterol and causes premature coronary heart disease. There are at least 20 million people with FH worldwide, but the majority remain undetected and current treatment is often suboptimal. To address this major gap in coronary prevention we present, from an international perspective, consensus-based guidance on the care of FH. The guidance was generated from seminars and workshops held at an international symposium. The recommendations focus on the detection, diagnosis, assessment and management of FH in adults and children, and set guidelines for clinical purposes. They also refer to best practice for cascade screening and risk notifying and testing families for FH, including use of genetic testing. Guidance on treatment is based on risk stratification, management of non-cholesterol risk factors, and safe and effective use of LDL lowering therapies. Recommendations are given on lipoprotein apheresis. The use of emerging therapies for FH is also foreshadowed. This international guidance acknowledges evidence gaps, but aims to make the best use of contemporary practice and technology to achieve the best outcomes for the care of FH. It should accordingly be employed to inform clinical judgement and be adjusted for country-specific and local health care needs and resources.

Familial Hypercholesterolemias: Prevalence, genetics, diagnosis and screening recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia

Familial hypercholesterolemia (FH) may be the most common serious genetic condition and is a well-known and frequent cause of premature coronary heart disease (CHD). About 5% of heart attacks under age 60 and as many as 20% under age 45 are due to FH. Too often, FH is diagnosed after the occurrence of a major coronary event; hence a population-based approach to identify affected individuals prior to the discovery of atherosclerosis is clearly

Friedewald-estimated versus directly measured low-density lipoprotein cholesterol and treatment implications.

OBJECTIVES The aim of this study was to compare Friedewald-estimated and directly measured low-density lipoprotein cholesterol (LDL-C) values. BACKGROUND LDL-C is routinely estimated by the Friedewald equation to guide treatment; however, compatibility with direct measurement has received relatively little scrutiny, especially at levels <70 mg/dl now targeted in high-risk patients. METHODS We examined 1,340,614 U.S. adults who underwent lipid profiling by vertical spin density gradient ultracentrifugation (Atherotech, Birmingham, Alabama) from 2009 to 2011. Following standard practice, Friedewald LDL-C was not estimated if triglyceride levels were ≥ 400 mg/dl (n = 30,174), yielding 1,310,440 total patients and 191,333 patients with Friedewald LDL-C <70 mg/dl. RESULTS Patients were 59 ± 15 years of age and 52% were women. Lipid distributions closely matched those in the National Health and Nutrition Examination Survey. A greater difference in the Friedewald-estimated versus directly measured LDL-C occurred at lower LDL-C and higher triglyceride levels. If the Friedewald-estimated LDL-C was <70 mg/dl, the median directly measured LDL-C was 9.0 mg/dl higher (5th to 95th percentiles, 1.8 to 15.4 mg/dl) when triglyceride levels were 150 to 199 mg/dl and 18.4 mg/dl higher (5th to 95th percentiles, 6.6 to 36.0 mg/dl) when triglyceride levels were 200 to 399 mg/dl. Of patients with a Friedewald-estimated LDL-C <70 mg/dl, 23% had a directly measured LDL-C ≥ 70 mg/dl (39% if triglyceride levels were concurrently 150 to 199 mg/dl; 59% if triglyceride levels were concurrently 200 to 399 mg/dl). CONCLUSIONS The Friedewald equation tends to underestimate LDL-C most when accuracy is most crucial. Especially if triglyceride levels are ≥ 150 mg/dl, Friedewald estimation commonly classifies LDL-C as <70 mg/dl despite directly measured levels ≥ 70 mg/dl, and therefore additional evaluation is warranted in high-risk patients.

Comparison of a Novel Method vs the Friedewald Equation for Estimating Low-Density Lipoprotein Cholesterol Levels From the Standard Lipid Profile

IMPORTANCE In clinical and research settings worldwide, low-density lipoprotein cholesterol (LDL-C) is typically estimated using the Friedewald equation. This equation assumes a fixed factor of 5 for the ratio of triglycerides to very low-density lipoprotein cholesterol (TG:VLDL-C); however, the actual TG:VLDL-C ratio varies significantly across the range of triglyceride and cholesterol levels. OBJECTIVE To derive and validate a more accurate method for LDL-C estimation from the standard lipid profile using an adjustable factor for the TG:VLDL-C ratio. DESIGN, SETTING, AND PARTICIPANTS We used a convenience sample of consecutive clinical lipid profiles obtained from 2009 through 2011 from 1,350,908 children, adolescents, and adults in the United States. Cholesterol concentrations were directly measured after vertical spin density-gradient ultracentrifugation, and triglycerides were directly measured. Lipid distributions closely matched the population-based National Health and Nutrition Examination Survey (NHANES). Samples were randomly assigned to derivation (n = 900,605) and validation (n = 450,303) data sets. MAIN OUTCOMES AND MEASURES Individual patient-level concordance in clinical practice guideline LDL-C risk classification using estimated vs directly measured LDL-C (LDL-CD). RESULTS In the derivation data set, the median TG:VLDL-C was 5.2 (IQR, 4.5-6.0). The triglyceride and non-high-density lipoprotein cholesterol (HDL-C) levels explained 65% of the variance in the TG:VLDL-C ratio. Based on strata of triglyceride and non-HDL-C values, a 180-cell table of median TG:VLDL-C values was derived and applied in the validation data set to estimate the novel LDL-C (LDL-CN). For patients with triglycerides lower than 400 mg/dL, overall concordance in guideline risk classification with LDL-CD was 91.7% (95% CI, 91.6%-91.8%) for LDL-CN vs 85.4% (95% CI, 85.3%-85.5%) for Friedewald LDL-C (LDL-CF) (P < .001). The greatest improvement in concordance occurred in classifying LDL-C lower than 70 mg/dL, especially in patients with high triglyceride levels. In patients with an estimated LDL-C lower than 70 mg/dL, LDL-CD was also lower than 70 mg/dL in 94.3% (95% CI, 93.9%-94.7%) for LDL-CN vs 79.9% (95% CI, 79.3%-80.4%) for LDL-CF in samples with triglyceride levels of 100 to 149 mg/dL; 92.4% (95% CI, 91.7%-93.1%) for LDL-CN vs 61.3% (95% CI, 60.3%-62.3%) for LDL-CF in samples with triglyceride levels of 150 to 199 mg/dL; and 84.0% (95% CI, 82.9%-85.1%) for LDL-CN vs 40.3% (95% CI, 39.4%-41.3%) for LDL-CF in samples with triglyceride levels of 200 to 399 mg/dL (P < .001 for each comparison). CONCLUSIONS AND RELEVANCE A novel method to estimate LDL-C using an adjustable factor for the TG:VLDL-C ratio provided more accurate guideline risk classification than the Friedewald equation. These findings require external validation, as well as assessment of their clinical importance. The implementation of these findings into clinical practice would be straightforward and at virtually no cost. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01698489.

Lipid-altering efficacy of ezetimibe plus statin and statin monotherapy and identification of factors associated with treatment response: A pooled analysis of over 21,000 subjects from 27 clinical trials

OBJECTIVE Patients with dyslipoproteinemia constitute the largest risk group for development of atherosclerosis and cardiovascular disease (CVD). Despite extensive statin use, many patients with CVD risk do not achieve guideline-recommended low-density lipoprotein cholesterol (LDL-C) targets. This pooled analysis of 27 previously published clinical trials conducted between 1999 and 2008 evaluated the lipid-altering efficacy and factors related to treatment response of ezetimibe combined with statin and statin monotherapy. METHODS Patient-level data were combined from double-blind, placebo-controlled or active comparator studies randomizing adult subjects to ezetimibe 10mg plus statin (n=11,714) versus statin alone (n=10,517) for 6-24 weeks (mean=9 weeks). Association of factors with treatment response, percent change from baseline LDL-C and other lipids, and attainment of guideline-recommended lipid and lipoprotein targets were evaluated. RESULTS Higher baseline LDL-C, diabetes mellitus, Black race, greater age, and male gender were associated with small but significantly greater percent reductions in LDL-C regardless of treatment. Treatment influenced efficacy, with ezetimibe plus statin producing significantly greater reductions in LDL-C, total-cholesterol, non-HDL-C, ApoB, triglycerides, lipid ratios, hs-CRP; significantly larger increases in HDL-C and ApoA1; and significantly higher achievement of LDL-C (<70mg/dl, <100mg/dl), non-HDL-C (<100mg/dl, <130mg/dl), and ApoB (<80mg/dl, <90mg/dl) targets than statin monotherapy at statin potencies compared (p<0.0001 for all). Differential treatment effects were seen with first-/second-line therapy and statin potency. CONCLUSION These results suggest that patient characteristics have a limited influence on response to lipid-lowering therapy and demonstrate the consistent treatment effect of ezetimibe combined with statin and statin monotherapy across a diverse patient population.

High-Density Lipoprotein and Cardiovascular Risk

Low serum levels of high-density lipoprotein (HDL) are commonly encountered in patients with coronary artery disease (CAD). An example of this type of patient is a 42-year-old white man with a history of sudden-onset angina secondary to a 90% obstructive lesion along the proximal left anterior descending coronary artery. The family history was significant for his father, who died of a myocardial infarction (MI) at age 44 years. The patient underwent percutaneous transluminal angioplasty with stenting but developed in-stent restenosis. He underwent cutting balloon angioplasty and brachytherapy and was asymptomatic for approximately 6 months. The stent then developed a high-grade occlusion with recurrence of angina, and the patient required single-vessel bypass surgery. The patient’s baseline serum lipid profile revealed low-density lipoprotein (LDL) 128 mg/dL, HDL 27 mg/dL, and triglycerides 92 mg/dL. His lipoprotein(a), C-reactive protein, and homocysteine levels were normal. He was not hypertensive, had no impairment of glycemic control, and did not smoke. With a combination of simvastatin 40 mg and niacin (Niaspan; Kos Pharmaceuticals) 1000 mg daily, the patient’s lipid profile improved, with LDL 78 mg/dL, HDL 43 mg/dL, and triglycerides 60 mg/dL. Follow-up stress testing demonstrated normal myocardial perfusion, and the patient has been asymptomatic for 2 years. With few exceptions, low HDL is an independent risk factor for CAD in case-control and prospective observational studies. In contrast, high HDL levels are associated with longevity and are protective against the development of atherosclerotic disease. In the Framingham Study, risk for CAD increases sharply as HDL levels fall progressively below 40 mg/dL.1 In the Quebec Cardiovascular Study, for every 10% reduction in HDL, risk for CAD increased 13%.2 Many clinicians believe that low HDL is associated with increased CAD risk because it is a marker for hypertriglyceridemia and elevated remnant particle concentrations. The Prospective Cardiovascular Munster …

Prevalence of lipid abnormalities in the United States: The National Health and Nutrition Examination Survey 2003–2006

BACKGROUND The association between increased low-density lipoprotein cholesterol (LDL-C) and increased risk for cardiovascular events is well established, with treatment focusing on LDL-C lowering. Other lipid abnormalities are also associated with increased cardiovascular risk (eg, low high-density lipoprotein cholesterol [HDL-C], high triglycerides [TG], and high non-HDL-C). Despite national lipid guidelines, the prevalence of these abnormal lipid parameters alone or in combination (mixed dyslipidemia) is not well recognized. OBJECTIVE We assessed the prevalence of high LDL-C, low HDL-C, high TG, high non-HDL-C, and mixed dyslipidemia by using National Health and Nutrition Examination Survey (NHANES) data to estimate the proportions of U.S. adults not at guideline-recommended lipid goals. METHODS NHANES 2003-2006 fasting blood serum data were used to categorize adults aged ≥20 years by LDL-C (risk stratum-specific), HDL-C (men, <40 mg/dL; women, <50 mg/dL), non-HDL-C (in subjects with TG ≥200 mg/dL), and TG (≥150 mg/dL) target levels with use of the NCEP ATP III definitions based on coronary heart disease (CHD) risk. RESULTS An estimated 53% (105.3M) of U.S. adults have lipid abnormalities: 27% (53.5M) have high LDL-C, 23% (46.4M) have low HDL-C, and 30% (58.9M) have high TG. Among patients with serum TG levels ≥200 mg/dL, approximately 13% (25.7M) of adults have non-HDL-C levels ≥130 mg/dL. Also, 21% (42.0M) of U.S. adults have mixed dyslipidemia (high LDL-C with either low HDL-C and/or high TG), with nearly 6% (11.6M) having all three lipid abnormalities. For LDL-C, an estimated 23M adults with CHD or a CHD risk equivalent and 17M with ≥2 risk factors but a Framingham risk ≤20% are not at goals of <100 and <130 mg/dL, respectively. CONCLUSION Prevalence of dyslipidemia in the United States continues to be high, with the majority of U.S. adults now affected by some form of lipid abnormality. Efforts to promote screening, risk stratification, and initiating appropriate treatment should be intensified.

Residual macrovascular risk in 2013: what have we learned?

Cardiovascular disease poses a major challenge for the 21st century, exacerbated by the pandemics of obesity, metabolic syndrome and type 2 diabetes. While best standards of care, including high-dose statins, can ameliorate the risk of vascular complications, patients remain at high risk of cardiovascular events. The Residual Risk Reduction Initiative (R3i) has previously highlighted atherogenic dyslipidaemia, defined as the imbalance between proatherogenic triglyceride-rich apolipoprotein B-containing-lipoproteins and antiatherogenic apolipoprotein A-I-lipoproteins (as in high-density lipoprotein, HDL), as an important modifiable contributor to lipid-related residual cardiovascular risk, especially in insulin-resistant conditions. As part of its mission to improve awareness and clinical management of atherogenic dyslipidaemia, the R3i has identified three key priorities for action: i) to improve recognition of atherogenic dyslipidaemia in patients at high cardiometabolic risk with or without diabetes; ii) to improve implementation and adherence to guideline-based therapies; and iii) to improve therapeutic strategies for managing atherogenic dyslipidaemia. The R3i believes that monitoring of non-HDL cholesterol provides a simple, practical tool for treatment decisions regarding the management of lipid-related residual cardiovascular risk. Addition of a fibrate, niacin (North and South America), omega-3 fatty acids or ezetimibe are all options for combination with a statin to further reduce non-HDL cholesterol, although lacking in hard evidence for cardiovascular outcome benefits. Several emerging treatments may offer promise. These include the next generation peroxisome proliferator-activated receptorα agonists, cholesteryl ester transfer protein inhibitors and monoclonal antibody therapy targeting proprotein convertase subtilisin/kexin type 9. However, long-term outcomes and safety data are clearly needed. In conclusion, the R3i believes that ongoing trials with these novel treatments may help to define the optimal management of atherogenic dyslipidaemia to reduce the clinical and socioeconomic burden of residual cardiovascular risk.