The ACC/AHA hyperlipidemia guidelines of 2013 identify four groups shown to benefit from high-intensity and moderate-intensity statin therapy for use in secondary and primary prevention of CVD. High-risk individuals who would be a candidate for high-intensity statin therapy for LDL-C lowering would include all except:
Primary elevations of LDL-C ≥160 mg/dL. In these recommendations, LDL-C would need to be above 190 mg/dL to be considered for highintensity statin therapy (Table below).
American College of Cardiology/American Heart Association 2013 Guidelines: Four Treatment Groups and Intensity of Statin Therapy:
Clinical ASCVD is defined as acute coronary syndromes, a history of MI, stable or unstable angina, coronary or other arterial revascularization, stroke, TIA, or peripheral arterial disease of atherosclerotic origin. It is recommended that the absolute 10-year ASCVD risk (defined as nonfatal MI, CHD death, and including nonfatal and fatal stroke) should be used to guide the initiation and intensity of statin therapy and should be estimated using the Pooled Cohort Equations for the primary prevention of ASCVD in individuals without clinical ASCVD and LDL-C 70 to 189 mg/dL and to determine intensity of therapy in diabetics (DM types 1 and 2). For those with clinical ASCVD or with LDL-C ≥190 mg/dL who are already in a statin benefit group, it is not appropriate to estimate 10- year ASCVD risk. In individuals over 75 years of age falling into these groups or diabetics with 10-year risk <7.5%, consider moderate-intensity therapy to reduce possible side effects.
The American Academy of Pediatrics (AAP) 2008 lipid management recommendations for children and teenagers include all of the following except:
Bile acid sequestrants as initial therapy in younger patients under 16 years of age. The AAP recommends screening beginning as early as 2 years of age and before age 10 in children with family history of hyperlipidemia or premature CVD in parents and grandparents or if family history is not known and other risk factors (overweight, obese, hypertension, smoking, and DM) are present. They now recommend considering pharmacologic treatment with statins as the first choice drug rather than resins and consider beginning pharmacologic therapy as early as 8 years of age if after lifestyle intervention LDL-C remains >190 mg/dL, >160 mg/dL with one or more other cardiovascular risk factors (including obesity), or >130 mg/dL if diabetes is present.
In decisions regarding screening for and treating hyperlipidemia in children and adolescents, it is important to remember that all of the following are true except that:
1. cholesterol is lowest intrauterine and at birth.
2. concentrations are similar to young adult levels by 2 years of age with strongest relation to adult levels at 5 to 10 years and 17 to 19 years.
3. cholesterol levels decrease from 10% to 20% during pre-pubertal and pubertal development.
4. low-fat diets should not be implemented until after age 5 years.
5. statins have not been shown to have an adverse effect on sexual or physical maturation. 6. impact on the atherosclerotic process and clinical outcomes has been demonstrated with statin treatment in children and adolescents.
4 and 6. Child and Adolescent Trial for CV Health reported that 13.3% of fourth graders had TC >200. NHANES 2010 notes that approximately 8% of adolescents have TC >200. A population approach including weight maintenance, healthy diet, and exercise is recommended for all children. An individual approach to therapy is reserved for those at higher risk for CVD and with elevated LDL-C levels as summarized in the previous question. Other high-risk children and adolescents for whom earlier pharmacologic therapy may be considered include post transplantation, human immunodeficiency virus (HIV), chronic inflammatory disease such as lupus and rheumatoid arthritis, renal disease (nephrotic syndrome), Kawasaki disease, overweight/obese with metabolic syndrome, and childhood cancer survivors. Statins have not been shown to delay or adversely affect physical and sexual development. Cholesterol levels may drop significantly during pubertal development. Therefore, screening before or after is most representative. Studies in ages 7 months to adolescents have shown safety of low total fat, saturated fat, and cholesterol diets and initiation of low-fat diet is recommended after age 2 years. Benefits of statin treatment on the atherosclerotic process have been demonstrated in children using surrogate markers such as flow-mediated dilatation and CIMT. However, the impact on clinical outcomes has not been studied in large prospective trials. Since there are little outcome data to show that treatment in childhood decreases adult CVD, treatment recommendations are based on extrapolations from adult studies.
Although statin therapy and LDL-C reduction is the main thrust of pharmacologic therapies, there has been an interest in treating beyond LDLC with other therapies directed toward HDL-C and TG to further reduce CVD events.
This concept is supported by the following observations except that:
The ACCORD trial demonstrated a benefit of fenofibrate when added to baseline simvastatin therapy in diabetic patients. Observational studies support that for every 1 mg/dL increase in HDL-C, there is a 2% to 3% decrease in CVD risk. The Framingham Heart Study recognized that the lower the level of HDL-C, the greater the risk of a coronary event, regardless of LDL-C level. In fact, a person with a “desirable” LDL-C of 100 mg/dL but a low HDL-C of 25 mg/dL had the same risk of a cardiac event as a person with an LDL-C of 220 mg/dL and an HDL-C of 45 mg/dL. Further strengthening the link between HDL-C and TG and poor CVD outcomes is the observation that patients presenting with a new diagnosis of CHD have higher TGs and lower HDL-C than those without CHD. In the TNT trial, this relationship continued to exist even following aggressive statin therapy. When a subgroup of individuals all achieving LDL-C below 70 mg/dL was examined, CVD events increased significantly when HDL-C was below 42 mg/dL even in this group with very low LDL-C levels. A meta-analysis in 2010 of multiple statin trials reported that the inverse relationship of HDL-C to CVD events was not altered by statin therapy. Meta-analyses have shown a relationship between elevations of TG and CVD risk even when controlling for confounding factors and HDL-C. In the treatment arms of statin placebo-controlled studies and even when including those in which very low LDL-C levels are achieved, a significant residual CVD risk persists. NHANES reports that of the 48% of U.S. adults with dyslipidemia approximately a third have elevations in TGs and/or HDL-C. With the growing prevalence of obesity, diabetes, inactivity, and metabolic syndrome more individuals are presenting with a combined dyslipidemia characterized by only moderate elevation of LDL-C but increased numbers of small dense LDL and other atherogenic apoB particles, elevated TGs, and low high density HDL-C. Particularly in these groups it is reasonable to hypothesize that therapies beyond LDL-C lowering may be beneficial. Evidence supports titration of statin to higher doses or use of more potent statins to achieve greater risk reduction. However, data from long-term outcome studies demonstrating incremental benefit when therapy directed toward low HDL-C and TG is added to statins have been disappointing. The AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health) trial and HPSTHRIVE (Treatment of HDL to Reduce the Incidence of Vascular Events) did not demonstrate improved outcomes when niacin preparations were added to individuals with well-controlled LDL-C on statin ± ezetimibe (LDL-C prerandomization of 74 and 63, respectively). The ACCORD trial did not demonstrate benefit when fenofibrate was added to baseline statin therapy in the total population of diabetics studied. A prospectively defined but subanalysis noted a borderline statistically significant 31% CVD event reduction in a subgroup with TG above 204 mg/dL and HDL-C below 34 mg/dL. However, until further studies are available there still may remain a role for niacin, fibrates, or ezetimibe in the management of elevated nonHDL after maximally tolerated statin therapy, those not at LDL-C goal after maximally tolerated statin therapy, or those intolerant to statins. The NCEP ATP III, ADA, and ACCE guidelines do recommend considering therapies including niacin and fibrates to achieve non–HDL-C goals after treating LDL-C. The AHA/ACC 2013 guidelines are less enthusiastic regarding the addition of non-statin therapies. Also note that other recommendations still recommend treatment targets and utilization of non-statin therapies in certain populations.
In the setting of strong observational and epidemiologic data supporting HDL-C’s relationship to CVD risk, the limitations of current therapies, and the increase in incidence of diabetes/metabolic syndrome, there remains a strong interest in focusing on other therapeutic interventions in addition to LDL-C lowering, particularly HDL modulation. HDL is more than a simple carrier of cholesterol.
Which of the following statements regarding HDL-C metabolism and function is not true?
ATP-binding cassette transporter 1 (ABCA1) and ABCG1 both facilitate free cholesterol efflux to lipid-poor pre-β1-HDL. There are many proposed mechanisms offered to explain the beneficial anti-atherosclerotic activity of HDL-C including increase in nitric oxide production and enhanced endothelial function, inhibition of LDL-C oxidation, reduction of cytokineinduced endothelial vascular cell adhesion molecule induction and macrophage infiltration, as well as anti-inflammatory, antithrombotic (including reduction of platelet activation/ aggregation, activation of protein C–mediated anticoagulant effects, and stimulation of fibrinolysis), and antioxidant effects. However, reverse cholesterol transport, the transfer of cholesterol from the peripheral tissues to the liver for excretion in the feces or bile, appears to offer the greatest cardioprotective role. The mature α-HDL particles are generated from lipid-free apolipoprotein A1 (apoA1) or lipid-poor pre–β1-HDL as the precursors are produced by the liver or intestine, released from lipolyzed VLDL and chylomicrons or released by interconversion of mature HDL particles. ABCA1 facilitates efflux of cholesterol from cells and initial lipidation of these precursors. Lipid efflux to more mature HDL particles also occur via ABCG1-mediated transfer. Enzymatic modification with lecithin cholesterol acyltransferase (LCAT) enables esterification of cholesterol and generates spherical particles that continue to grow with ongoing cholesterol esterification. The larger mature HDL particles are converted into smaller HDL particles via CETP-enabled exchange of cholesterol esters for TGs between HDL and apoB-containing lipoproteins (LDL and VLDL) and scavenger receptor class-B type 1 (SRB1) selective uptake of cholesteryl esters into liver and steroidogenic organs. HDL can deliver cholesterol to the liver via the SR-B1 receptor or by holoparticle uptake (direct reverse cholesterol transport). It may also dispose of cholesterol via CETP-mediated transfer of cholesterol esters to LDL and VLDL and removal through normal clearance by hepatic LDL-Rs (indirect reverse cholesterol transport).
Studies in atherogenic animals show that raising HDL-C via genetic modification, infusion of HDL has favorable effects on experimental plague size and structure and reports of the ability of apoA1 Milano infusion therapy to reduce IVUS measured atherosclerotic plaque volume over a short period of 6 weeks in individuals following MI rekindled the interest in newer HDL-directed therapies. This raised hopes that synthetic forms of HDL, HDL mimetics, reconstituted HDL, reinfusion of delipidated HDL, and other therapies designed to increase HDL-C would be potential therapeutic approaches to reduce CVD. Upregulation of liver X receptor (LXR), the nuclear receptor that protects cells from cholesterol toxicity, may be of benefit by resulting in the cellular transduction of the ATP-binding cassette sterol transporters that efflux free cholesterol into either nascent HDL or mature HDL. Enhancing LCAT activity increases the esterification of cholesterol in HDL, resulting in HDL maturation. Modifying the holoparticle uptake of HDL (a possible mechanism of niacin) may delay catabolism by allowing the HDL particle to continue circulating and potentially increase reverse cholesterol transport. Genetic and pharmacologic studies in mice suggest that overexpression of apoA1 and SR-B1 or LXR agonists may be beneficial. Unfortunately methodology, delivery concerns, and off-target adverse effects have so far limited the use of these therapeutic approaches in humans. Despite many new possible therapeutic strategies only inhibiting CETP which increases HDL particle size and delays catabolism of HDL is currently under active clinical phase 3 trial investigations. Two previous studies with CETP inhibitors (which raise HDL-C anywhere from 30% to 140%) were stopped early for adverse events with torcetrapib or lack of benefit/futility with dalcetrapib, but ongoing outcome trials with the more potent anacetrapib and evacetrapib continue.
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