Michael B. Rocco
1.a. It occurs in 1 in 5,000 persons. Homozygous FH occurs in 1 in 1 million individuals while heterozygous FH in 1 in 500 individuals. The other statements are true.
2.d. LDLRAP1 mediates internalization of LDL-C via clathrin-coated pits, and loss-of-function mutations would decrease LDL-C clearance. Defects in apolipoprotein B (apoB). The LDL-R on the hepatocyte binds to apoB (acts as ligand, binding LDL particle to receptor) on the LDL particle inducing internalization via clathrin-coated pits (mediated by LDLRAP1) and endocytosis of the complex. Defects in the receptor itself or the apoB molecule may reduce LDL-C clearance. The protein PCSK9 can bind to the LDL/LDL-R complex and when internalized prevents recycling of the LDL-R to the hepatocyte surface. A gain in function mutation of PCSK9 (by further reducing recycling of LDL-Rs) has been shown to be associated with increase in LDL-C and CVD.
3.c. Familial combined hyperlipidemia. Familial combined hyperlipidemia is a common dyslipidemia (1 in 33 to 1 in 100 individuals) characterized by complex inheritance. Xanthomas are rarely present (unlike in heterozygous FH), but xanthelasmas and arcus cornea can be seen. They are generally overweight, are hypertensive, and have insulin resistance or diabetes. Affected individuals generally exhibit a TC of 250 to 350 mg/dL, LDL-C of 200 to 300 mg/dL, and TG of >140 mg/dL (two-thirds of patients have TG of 200 to 500 mg/dL). Patients with polygenic hypercholesterolemia (1 in 20 to 1 in 100 individuals) have alterations in the function or expression of several key proteins involved in LDL metabolism including defective LDL-R and apoB100, and the presence of the apoE4 allele (which has a higher affinity for the LDL-R than the other apoE isoforms leading to downregulation of LDL-R). They have similar elevations in LDL-C as familial combined hyperlipidemia except they do not generally have elevated TG. Hyperapobetalipoproteinemia is associated with increased apoB synthesis. TG may be normal or elevated and arcus cornea and xanthelasmas may be present. However, LDL-C is typical below 160 mg/dL. Familial endogenous hypertriglyceridemia is associated with increased hepatic VLDL formation and TG of 200 to 500 mg/dL but without significant elevations in LDL-C and is not consistently linked with increased CVD risk.
4.d. Lomitapide has been approved to treat homozygous and heterozygous FH. Homozygous FH occurs in 1 in 1 million individuals. TC levels are generally >600 mg/dL, with LDL-C levels six- to eightfold higher than average. Without treatment, death from MI occurs in the first or second decades of life. In addition to the xanthomas observed in heterozygotes, FH homozygotes are commonly affected by interdigital xanthomas; tuberous xanthomas on the hands, elbows, buttocks, and feet; and planar xanthomas on the posterior thighs, buttocks, and knees. The mainstay of therapy for FH homozygotes is LDL apheresis and has been associated with stabilization or regression of atherosclerotic lesions and improvement in symptoms. Since immediate reductions in LDL-C of 50% to 80% rebound quickly, the process is performed every 2 to 4 weeks to keep intrapheresis LDL-C ≤120 mg/dL.
Both mipomersen and lomitapide were FDA approved in 2013 as orphan drugs for management of patients with homozygous FH only. Mipomersen is a subcutaneously injectable RNA antisense oligonucleotide. Lomitapide blocks microsomal TG transport protein (a key protein in assembly and secretion of apoB-containing lipoproteins in the liver and intestines) reducing hepatic secretion of VLDL. These therapies have a small target population, require risk evaluation and mitigation strategy limiting use to specialized centers, and have concerns with liver toxicity and hepatic steatosis due to accumulation of TGs not secreted into VLDL.
Several clinical diagnostic criteria for FH exist, with the 15-year Simon Broome Register Group being the most commonly used. Definite FH is as defined above. Possible FH by this criteria is defined as (a) above PLUS and (b) MI before age 50 in second-degree relative, or before 60 in first-degree relative or elevated cholesterol in first-degree relative, or >290 mg/dL in second-degree relative.
5.d. National Health and Nutrition Examination Survey (NHANES) data through 2006 reported that 10.3% of adolescents (12 to 19 years) have abnormal lipid levels. In adolescents between the ages of 12 and 19, the number of individuals with one or more abnormal lipid level is higher at 20.3% and increases further to 42.9% in association with obesity. All the other facts noted are true. The AHA has established TC <170 mg/dL in children and <200 mg/dL in adults as one of seven goals for ideal cardiovascular health. In one survey in 2010, 38.1% of children and 52.7% of adults did not meet these criteria. Although average adult TC levels have been dropping over the past two decades from 208 to 197 mg/dL, obesity and lack of physical activity (two factors associated with dyslipidemia and diabetes risk) have been on the rise. From 2011 to 2012 only 20.7% of adults and 49.5% of adolescents, respectively, achieved recommended activity levels. These facts and more can be found in the most recent Heart Disease and Stroke Statistics-2014 Update from the AHA published in Circulation.
6.b. The JUPITER trial demonstrated that in individuals without documented cardiovascular disease (CVD) and median LDL-C of 108 mg/dL, aggressive statin therapy with rosuvastatin offered greater benefit in individuals with ultrasensitive C-reactive protein (usCRP) >2 versus <2 mg/L. JUPITER demonstrated that primary prevention patients with only modest elevations in LDL-C but elevated usCRP above 2 mg/L benefited from treatment with statins. However, the trial only enrolled individuals with usCRP >2 mg/L. There was no comparison arm to individuals with low LDL-C and low usCRP. While ASCOT-LLA showed reductions in nonfatal MI and CHD death, coronary events or procedures, stroke, and chronic stable angina, but did not show a reduction in total mortality. However, this trial did demonstrate that initiation of moderate intensity statin therapy in higher-risk individuals without clinical CVD and without significant elevations in LDL-C significantly reduced CVD events. The study with average LDL-C at entry of 130 mg/dL was stopped early by the safety monitoring board. Primary prevention trials WOSCOPS and AFCAPS/TexCAPS and secondary prevention trials including 4S, CARE, PIPID, and Heart Protection Study (HPS) across a wide range of pretreatment LDL-C and using various statins demonstrated approximately 1% reduction in CVD events for every 1% reduction in LDL-C.
7.b. 1, 3, and 5. In making treatment decisions regarding initiation and intensity of treatment for dyslipidemia in patients without documented CVD or diabetes, assessment of future risk of CVD development is important. In individuals with two or more standard cardiovascular risk factors (hypertension, family history, low HDL-C, and smoking), the FRS can be used to calculate 10-year risk of MI or coronary disease mortality. The calculator is based on assessment of TC (or LDL-C), HDL-C, hypertension history, age, and smoking stratified by gender. It does not incorporate family history, assessment of metabolic syndrome, or other nontraditional risk markers such as usCRP, lipoprotein(a), and CACS. Risk may be underestimated in younger individuals and data may not be transferable to ethnic groups not well represented in the cohort. Other risk assessment tools include some of these additional risk markers such as the Reynolds Risk Score (usCRP and family history), PROCAM (prospective cardiovascular Münster heart study) Score (TG and family history), and SHAPE (Screening for heart attack prevention and education) guidelines (carotid intimal medial thickness [CIMT] and CACS). The recent 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults has promoted a new Pooled Cohort Equations risk calculator that incorporates race into the calculation and stroke as an outcome event.
8.c. HDL-C of <40 mg/dL in men and women. Metabolic syndrome is characterized by abdominal obesity, an atherogenic dyslipidemia with elevated TG, increased number of small LDL particles, low HDL-C, elevated BP, insulin resistance (glucose intolerance), a prothrombotic state, and a proinflammatory state. There is an increased risk of CVD development of two- to fourfold in individuals with metabolic syndrome. Focus of treatment should be on intensive lifestyle intervention. In the NCEP ATP III recommendations for diagnosis of metabolic syndrome, cutoffs for HDL-C are <40 mg/dL in men but <50 mg/dL in women. The other criteria listed are correct. Modifications since initial publication include lowering the fasting glucose cutoff to 100 mg/dL and population-specific waist circumferences such as ≥90 cm in men and ≥80 cm in women of South Asian ancestry. Metabolic syndrome is present if three or more of these criteria are identified.
9.e. Both higher-dose statins and addition of fibrates and niacin to achieve non-HDL-C goals should be considered to achieve secondary targets and to further reduce cardiovascular event rate. Between NCEP ATP III in 2001 and the update in 2004, multiple randomized controlled clinical trials offered new information supporting more aggressive treatment of hyperlipidemia and led to lowering the treatment goals and pretreatment LDL-C cutoffs for treatment in high- and intermediate-risk individuals (Table 12.1). The HPS demonstrated statin benefit in high-risk patients even with low pretreatment LDL-C. The ASCOTT LLA and Collaborative Atorvastatin Diabetes Study (CARDS) trials showed benefit when treating high-risk primary prevention patients with hypertension or DM even if LDL-C was not significantly elevated. Studies such as Treat to New Targets (TNT) and PROVE-IT TIMI-22 demonstrated that increasing the intensity of LDL-C lowering using higher doses or more potent statins in secondary prevention populations was associated with incremental cardiovascular risk reduction. The guidelines recommend that in treating individuals with hyperlipidemia the first priority of treatment is to lower LDL-C; the first line of drug therapy to manage LDL-C is statin therapy and intensity of therapy should be selected to achieve at least a 30% to 40% LDL reduction. Intensity of therapy and LDL-C goals should be based on level of CVD risk. Although NCEP ATP III recommended non-HDL-C (TC minus HDL-C) as a secondary therapeutic goal after achieving LDL-C goals and considering addition of niacin and fibrates to achieve this goal, this has not yet been definitively shown in clinical trials to reduce adverse cardiovascular events when added to adequate statin therapy.
10.e. Non–HDL-C goal equals the LDL-C goal +30 mg/dL. Although the ADA, the American Association of Clinical Endocrinologists (AACE), and the AHA/ACC women’s preventive guidelines set specific goals for TG below 150 mg/dL and HDL-C >50/40 mg/dL in women/men, NCEP ATP III guidelines do not and instead focus on non–HDL-C targets. The primary target for therapy is LDL-C reduction and statins remain the primary therapy for reducing LDL-C. However, in individuals with TGs >500 mg/dL initial therapy with aggressive diet and lifestyle intervention and medications should be first addressed. Non–HDL-C is recommended as a secondary target after achieving LDL-C goals if TG are greater than 200 mg/dL with therapeutic options to lower non–HDL-C including more intense LDL-C lowering or addition of niacin, fibrates, or high-dose omega-3 fish oils. Bile acid sequestrants should be avoided in individuals with TG over 300 mg/dL. NCEP ATP III recognizes a role for HDL-C as an important determinant of risk and if low a reason to achieve LDL-C and non–HDL-C goals as well as cause to emphasize diet and exercise. Although specific treatment to raise HDL-C may be considered in very high-risk individuals, the best therapies to accomplish this are not known and clinical trials documenting CVD risk reduction with HDL-C–directed therapies are lacking. An appropriate approach to HDL-C management is lifestyle. Dietary changes are associated with a 3% to 15% increase in HDL-C with an average 0.35 mg/dL increase in HDL for each 1 kg of weight loss. About 120 to 180 minutes of aerobic exercise a week and discontinuation of smoking can each raise HDL-C by 5% to 10%.
11.d. Omega-3 polyunsaturated fatty acid supplements of 800 to 1,000 mg a day. Diets high in omega-3 saturated fat are recommended but universal use of supplements is not. The AHA recommends 800 to 1,000 mg/day in dietary consumption and to consider supplements in secondary prevention patients without an adequate dietary source. Omega-3 fatty acids have a role in managing high TGs (>500 mg/day) by using high doses of prescription or supplement forms at 2,000 to 4,000 mg/day. Long-term outcome data supporting definitive reduction in CVD events with omega-3 supplementation in primary prevention populations are lacking. All of the other recommendations listed are supported by the guidelines.
12.a. Hyperthyroidism. Identifying and treatment of or modifying secondary causes of dyslipidemia is an important component in the management of dyslipidemia. Treating hypothyroidism and better control of diabetes may have significant impact on correcting lipid abnormalities. If possible, identification of medications associated with dyslipidemia and substitution of alternate medications when possible may help. Cholesterol and TGs rise progressively throughout pregnancy. Drugs such as statins, niacin, and ezetimibe are contraindicated during pregnancy and lactation.
13.b. FRS indicating a 10-year risk of MI or coronary death of >10%. Any clinically significant non-coronary vascular diseases such as peripheral artery disease, carotid artery disease, and aortic disease would qualify. Diabetics also fall into this category, particularly those >40 years of age and with at least one additional CVD risk factor. CHD risk equivalent status is present in individuals without clinically evident CHD, other CVD, or diabetes but with two or more CVD risk factors and FRS associated with a 10-year risk of a fatal or nonfatal MI of >20% not >10%. All of these individuals would be candidates for aggressive lipid management. The NCEP ATP III guidelines recommend LDL-C goals <100 mg/dL and optional LDL-C goals <70 mg/dL in this group. The ACC/AHA 2013 hyperlipidemia guidelines have eliminated LDL-C goals for therapy and recommend high-intensity statin therapy to achieve LDL-C lowering of >50% in high-risk groups <75 years old. This includes individuals with coronary and non- coronary disease, diabetics with new Pooled Cohort Equation calculator risk of >7.5% 10-year risk.
14.a. LDL <70 mg/dL and non-HDL <100.
15.f. Answers a and d.
16.a. Atorvastatin 40 mg/day. Patients with diabetes are CHD risk equivalent patients and therefore at high cardiovascular risk and candidates for aggressive lipid-lowering therapy. The NCEP ATP III update in 2004, ACC/ADA consensus statement in 2008, and the ADA and AAACE (American Association of Clinical Endocrinologists) guidelines in 2013 all support a primary LDL-C goal of <70 mg/dL and secondary non–HDL-C goal of <100 mg/dL. In addition, the consensus statement and recent ADA/AACE guidelines recommend considering apoB of <80 mg/dL and LDL-P of <1,000 as secondary targets for therapy. usCRP is a marker for CVD risk and reduced by many therapies including statins and lifestyle interventions but is not a recognized specific target or therapeutic goal (Tables 12.2 and 12.3).
The first-line therapy is statins, at a dose needed to achieve LDL-C reductions of at least 30% to 40%. Only atorvastatin 40 mg/day would achieve recommended treatment goals. Simvastatin at this dose is unlikely to result in sufficient LDL-C reduction to achieve goals and since the FDA alert in 2011, doses higher than 20 mg are not recommended in combination with amlodipine. Monotherapy with ezetimibe generally lowers LDL-C <20% and outcome benefit has not been demonstrated. Although LDL-C is not significantly elevated and the TG and HDL-C abnormalities may be improved by the other listed therapies, statins remain the primary treatment choice, supported by beneficial outcome data in trials such as CARDS and diabetic subsets in other large prospective trials and meta-analyses. Outcome data regarding cardiovascular risk reduction with these other listed therapies are lacking or less robust. New lipid treatment guidelines from the ACC/AHA published in November 2013 recommend a different approach to the management of lipids. These new guidelines support therapy initiation and intensity dependent on the level of risk and they recognize that most patients with diabetes are candidates for high-intensity statin therapy (defined as a statin able to achieve >50% reduction in LDL-C, e.g., 40 to 80 mg of atorvastatin or 20 to 40 mg of rosuvastatin).
17.f. All of the above. On statin therapy, the LDL-C goal of <70 mg/dL has been achieved but non–HDL-C remains above an ideal goal of <100 mg/dL. Any of these therapies would help to achieve the secondary non–HDL-C goals. NCEP ATP III recommends intensification of statins, further LDL-C lowering with non-statin therapies, niacin, or fibrates to achieve secondary non–HDL-C goal. There are clinical trial data to support further risk reduction with intensification of statin therapy although outcome data are absent when niacin, fibrates, fish oil, or ezetimibe is added to adequate statin therapy. Intensification of lifestyle interventions should be a part of any pharmacologic intervention in this patient. The patient is on a high-intensity statin with <50% reduction in LDL-C. Based on new ACC/AHA 2013 guidelines for management of hyperlipidemia, there is insufficient RTC evidence that adding additional therapies will further reduce cardiovascular events. Intensification of statin therapy does appear to offer benefit. In individuals receiving maximum tolerated intensity of statin with less than anticipated therapeutic response and in high-risk groups, the addition of non-statin therapy may be considered if the CVD risk reduction benefits outweigh the adverse effects.
18.c. NHANES data from 2010 indicate that although goals of HbA1c <7 mg/dL, systolic BP <130 mmHg, and LDL-C <100 mg/dL are recommended for diabetics, only 32% of diabetics in the survey currently achieve all three of these goals. The NHANES survey in 2010 demonstrated that although greater than 50% of diabetic patients achieved LDL <100 mg/dL, systolic BP <130 mmHg, or HbA1c <7 mg/dL, only <20% achieved all three goals. Studies such as the East-West study in 1998 demonstrated that a diabetic without CHD history had a similar approximate 20% incidence of MI over 7 years compared with a nondiabetic with known previous MI. Diabetics have a two- to fourfold increased risk of CVD events and the majority of deaths in patients with diabetes are due to CVD, accounting for up to 75% of deaths. These observations emphasize the concept of diabetes as a CHD equivalent and a rationale for intensive therapy of hyperlipidemia.
19.d. HDL particle size and number. usCRP has been shown in studies such as the Women’s Health Study (WHS) to reclassify risk when added to the FRS and in the JUPITER trial to be a factor in determining benefit of early statin therapy for primary prevention of CVD. Similar reclassification of risk has been demonstrated with anatomic measurements for preclinical atherosclerosis such as CACS and CIMT. Post hoc analyses of studies such as the WHS and MESA (multi-ethnic study of atherosclerosis) have demonstrated LDL-P to be a better predictor of future cardiovascular risk, and the National Lipid Association has recommended it as a tool for further risk assessment. However, data supporting the benefit and use of HDL particle size and number in assessing risk and guiding treatment are absent. NCEP ATP III recommends that intermediate-risk patients (FRS 10% to 20% estimated 10-year risk) with these additional risk markers should be considered for more intensive therapies. The ACC/AHA hyperlipidemia guidelines in 2013 suggest that in selected individuals, particularly those with a 10-year CVD risk of 5% to 7.5% not falling into defined treatment groups for high- or moderate-intensity statin therapy, factors including LDL-C >160 mg/dL, family history of premature CVD, usCRP >2 mg/dL, CACS >300 Agatston units or >75th percentile for age/sex/ethnicity, and ankle brachial index <0.9 may be used to consider initiation or intensification of pharmacologic therapy.
20.a. None, all are true. The ACC/AHA 2013 guidelines have attempted to offer recommendations based on a balance of benefit and therapeutic risk of treatment strategies as supported whenever possible by RTCs. The guidelines are based on observations including the absolute benefit in CVD risk reduction is proportional to baseline risk; cholesterol-lowering medications used in clinical trials (particularly statins) reduce risk of cardiovascular events proportional to the intensity of stain therapy rather than LDL-C achieved and therefore more intensive statin therapy could reduce risk more than moderate- or lower-intensity statin therapy; and statins are associated with similar relative risk reductions for CVD events across the majority of patient groups studied, and little clinical trial evidence to support use of other non-statin therapies particularly when added to treatment with statins. Therefore, in these guidelines a greater degree of emphasis is placed on level of treatment with statins and less on other lipid-lowering therapies either alone or in combination with statins. Patients or groups at higher baseline absolute risk will derive greater absolute benefit from initiation of statin therapy over a period of 5 to 10 years as studied in clinical trials. Like the NCEP ATP III recommendations, intensity of therapy is based on a measure of level of CVD risk but defined as dose or potency of statin therapy to be used rather than titration to specific LDL-C and non–HDL-C goals. Both sets of guidelines recommend statin therapy as primary and most beneficial therapy for CVD risk reduction although the ACC/AHA recommendations deemphasize the use of add-on non-statin therapies in the absence of RCT data and balance the risk of pharmacologic therapies in lower-risk populations. The ACC/AHA guidelines position treatment of TGs and use of non–HDL-C in treatment decision making as future clinical questions to be addressed and updated after future clinical trials. It should be mentioned that since these guidelines have appeared many have offered criticism of the document, including the elimination of LDL-C targets and concern with use of a new risk assessment tool that has not been prospectively validated, may overexpand treatment of lower-risk populations, and delay treatment in other high-risk populations. It should be remembered that these are guidelines and not doctrine and individual treatment plans should be tailored to the individual patient’s risk and needs after carefully assessing side effects and risk of treatment and discussion with the patient.
21.b. 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 high-intensity statin therapy (Table 12.4). 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.
22.c. 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.
23.c. 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.
24.d. 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 HPS-THRIVE (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 non-HDL 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.
25.b. 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 cytokine-induced 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 (SR-B1) 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.
26.c. Renal insufficiency. Statins have not been shown to worsen renal function. There was concern raised when proteinuria was noted in clinical trials with rosuvastatin. However, in analyses of RCTs, creatinine has not been shown to worsen and may improve. The other adverse effects listed above have all been noted with statins. In a meta-analysis by Naci et al. in 2013 comparing statins to placebo, the odds ratio for elevation in LFTs was 1.51, diabetes development 1.09, myalgia 1.07, CPK abnormality 1.13, and cancer 0.96, statistically significant only for liver test abnormalities and diabetes. Concerns have been raised about memory loss but there is a lack of large prospective trials designed to address this question and limited. A recent report in fact suggests a reduction in dementia with statin therapy.
27.d. Myalgia symptoms reported in prescribing information range from 5% to 10%. Definitions specified by the ACC/AHA NHLBI (National Heart, Lung, and Blood Institute) 2002 Clinical Advisory offer the following terminology to describe muscle injury: myalgias (muscle ache/weakness without CPK elevation), myopathy (muscle symptoms with CPK levels more than 10 times ULN), rhabdomyolysis (muscle symptoms with marked CPK elevation typically more than 10 times ULN with creatinine elevation and often with urinary myoglobin). Myalgia is reported in prescribing information at 1.2% to 3.2% but up to 11% in registries. Myopathy occurs in 0.1% to 0.5% of patients in a dose-dependent fashion. Fortunately, the risk of rhabdomyolysis is quite rare and reported <0.1%. Meta-analysis has reported rates of 0.03% to 0.05%. Muscle symptoms are more likely to occur at higher doses and doses should not exceed those recommended to achieve treatment goals. Attention should be paid to factors that may increase risk for myopathy. Concomitant medications such as fibrates, nicotinic acid (rarely), cyclosporine, azole antifungals, itraconazole, ketoconazole, macrolide antibiotics, erythromycin, clarithromycin, HIV protease inhibitors, nefazodone (antidepressant), verapamil, amiodarone, large quantities of grapefruit juice (>1 qt/day), and alcohol abuse may increase drug exposure and increase myopathy risk. This may be particularly true for simvastatin (metabolized via CYP3A) prompting an FDA advisory not to exceed 40 mg dose in general and reduce dose to 10 to 20 mg with concomitant use of drugs such as high-dose niacin, verapamil, ranolazine, and amiodarone. Other factors contributing to a higher likelihood of muscle symptoms include advanced age (especially >80 years; women more than men), small body frame, frailty, multisystem disease (e.g., chronic renal insufficiency, especially due to diabetes), and perioperative periods.
28.b. No. Routine measurement of CPK on statin therapy is not recommended but it is reasonable to obtain at baseline prior to therapy in individuals at higher risk for myopathy and if new symptoms develop on treatment. When a patient presents with complaints of pain, tenderness, stiffness, cramping, weakness, or fatigue the first approach should be to document the severity of the symptoms, obtain CPK, creatinine, and urinalysis to exclude rhabdomyolysis, and search for other causes (such as hypothyroidism, rheumatologic disorders, vitamin D deficiency, and steroid use). If there are clinical signs of severe pain, new muscle weakness, CPK greater than 10 times ULN, or myoglobinuria the statin should be stopped. If symptoms are mild to moderate and CPK is less than three times ULN it is reasonable to hold the statin until symptoms can be evaluated. If symptoms resolve rechallenge with the same or lower dose of the statin to establish whether a causal relationship exists. If so starting a low dose of a different statin is reasonable followed by slow titration. If an asymptomatic individual on statin therapy has an elevated CPK, complete a thorough muscular examination and if unremarkable check for other causes. If greater than 10 times ULN, hold statin and evaluate for other primary or secondary myopathies. If a baseline CPK is known to be elevated prior to therapy, it is not an absolute contraindication to initiate statin therapy if less than three times ULN and asymptomatic. If higher, a search for other causes such as hypothyroidism, recent injury, and other myopathies would be prudent before initiating therapy with a statin and consideration of referral to a rheumatologist for further evaluation.
29.c. Statins have been shown to worsen the outcome in persons with chronic transaminase elevations due to hepatitis B or C. Dose-related elevation in AST or ALT has been reported between 0.1% and 2%. Statins have not been shown to worsen the outcome in persons with chronic transaminase elevations due to hepatitis B or C. A search for other causes of LFT elevations is essential including review of prescription and over-the-counter drugs and supplements, recent infections, and alcohol use. In this patient with LFT less than three times ULN, it is reasonable to repeat in 6 to 12 weeks on the same or a lower dose. If LFTs greater than three times ULN repeat in 2 weeks and if continued elevation stop statin, recheck in 2 to 4 weeks and if improving consider rechallenge with a lower-dose or different statin. Reversal of transaminase elevation is frequently noted with a reduction in statin dose, and elevations do not often recur with either readministration or selection of another statins.
30.d. Statin therapy may lower LFTs in patients with fatty liver infiltration. Prior to initiation of statin therapy it is reasonable to exclude other causes for LFT elevation. However, there are small studies supporting the safety of use in appropriate patients. Kiyici et al. examined 44 patients with biopsy-proven NASH (nonacoholic steatosis) and found that on atorvastatin 10 mg for 6 months there was a decrease in cholesterol, AST, ALT, AP (alkaline phosphatase), and GGT (gammaglutaryl transferase). Chalasani et al. examined the effect of statins over 6 months in patients with baseline moderate elevations in LFTs. In patients with normal LFTs placed on statin, the incidence of mild/moderate or severe elevation in LFTs was 1.9% and 0.2%, respectively, in those with baseline elevations placed on statin (4.7% and 0.6%) compared with those not placed on statin (6.4% and 0.4%). Progression to liver failure due to statins is not zero but exceedingly rare reported at 0.02 to 0.07 per million treated. In this patient, an ultrasound of the liver confirmed fatty infiltration. Manufacturer’s prescribing information lists unexplained ALT greater than three times ULN as a contraindication to statin therapy. The best approach is to counsel on a diet program low in sugar and carbohydrates, weight loss, and exercise, and start statin therapy following the LFTs more closely.
31.c. 2 and 3. Sattar in a meta-analysis of 13 statin trials in 91,140 patients noted that 4,278 developed DM (4.89% on statins versus 4.5% on placebo; 0.39% absolute increased difference and 9% relative risk of incident diabetes). This represented 1 additional case of DM per 1,000 patient-years. Preiss published a meta-analysis of 5 trials in 32,772 patients comparing high- versus moderate-dose statins and reported 2,749 developed DM (8.8% versus 8.4% or an absolute increase of 0.4%). There were two additional cases of DM (18.9 versus 16.9) per 1,000 patient-years of follow-up. The development of diabetes did not appear to reduce the benefits of treatment. Sattar found 5.4 less cardiac events for 255 patients treated over 4 years for each 1 mmol/L reduction in LDL-C compared with 1 extra case of diabetes for the same time period. Preiss noted 1 additional case of diabetes for every 498 patients over 1 year compared with 1 fewer CVD event for every 155 patients over 1 year. In a separate analysis of three high-dose atorvastatin trials, Waters et al. reported no difference in CVD events occurring in 11.3% with new DM and 10.8% without new DM. This compared with those with diabetes at baseline (10.1% versus 17.5%). The FDA reported this association in February 2012 but added that it does not appear to reduce the benefits of statin therapy in appropriately selected patients. Therefore, statin therapy should not be denied or appropriate doses reduced to avoid diabetes. However, since the individuals that developed diabetes are those at risk for diabetes it is prudent to measure for glycemic control more frequently and emphasize lifestyle interventions to reduce diabetes risk. This approach has been supported in the ACC/AHA 2013 guidelines.
32.b. 1, 2, 3, and 5. This patient is at very high risk for recurrent events. Since the greatest reduction in CVD events has been demonstrated with statins, further attempts to rechallenge with statins are appropriate. Small clinical trials and observational studies have shown that tolerance may be improved by trying multiple alternate statins, often using a potent statin beginning at low and intermittent rather than daily dosing with slow titration. Small investigations of coenzyme Q10 appear to lower the incidence of muscle complaints when added to statins. An analysis of patients referred to the Cleveland Clinic for intolerance to statins (the majority due to muscle complaints) revealed that over two-thirds of patients were able to tolerate some statin regimen with average LDL-C reduction of ~28% in those able to tolerate daily dosing. Niacin in high doses has been shown in the Coronary Drug Project to reduce recurrent MI and mortality after MI and is a reasonable component of a combination therapy program in patients resistant to all statins. Both LDL-C apheresis and mipomersen can lower LDL-C but with LDL-C levels in this range he would not meet the FDA recommendation for apheresis and although trials with mipomersen have been shown to be effective in both homozygous and heterozygous FH patients it is only currently approved for homozygotes.
33.c. Although difficult to demonstrate in individual studies, meta-analysis of fibrate trials has demonstrated reduction in cardiovascular mortality on therapy. An increase in myopathy has been reported with both gemfibrozil and fenofibrate as monotherapy but to a greater extent when added to statins (5.5-fold increased risk of myopathy when combined with statins) and more so with gemfibrozil compared with fenofibrate. A meta-analysis of monotherapy fibrate trials published in 2007 in the American Heart Journal reported a reduction in nonfatal MI but no reduction in fatal MI or total/cardiovascular mortality. Subanalyses of individuals with a metabolic dyslipidemia in fibrate trials such as BIP (bezafibrate infarction prevention), FIELD (fenofibrate intervention and event lowering in diabetes), and ACCORD trials demonstrated significant reduction in the primary endpoint of combined cardiovascular events, although not in the overall populations studied. Renal status should be evaluated within 3 months of initiation of therapy and every 6 months thereafter. Plasma half-life of fenofibric acid is prolonged in renal insufficiency and requires lower dose with glomerular filtration rate (GFR) 30 to 59 and avoidance if GFR <30. An increase in creatinine of 12% was reported in the FIELD study using fenofibrate, usually reversible with discontinuation of therapy.
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