General Overview and Goals of Treatment
The primary goal of dyslipidemia management is to reduce cardiovascular morbidity and mortality. ATP III last issued evidence-based guidelines in 2001, with a 2004 update suggesting more aggressive LDL-C goals for high-risk patients.4 LDL-C is considered the primary target for cholesterol-lowering therapy, and statins are first-line therapy.2,4,10 There is currently no hard evidence that lowering LDL-C levels too far has intrinsic danger.11 Multiple well-designed trials and meta-analyses have confirmed the beneficial effects of statins on cardiovascular endpoints, including a 12% to 13% reduction in all-cause mortality.12-15 Recommended LDL-C goals and clinical strategies based on CHD risk are summarized in Tables 4-1 and 4-2. Framingham risk scoring is required in patients with two or more risk factors to triage them into three levels of 10-year risk for hard CHD events (CHD death, myocardial infarction).
TABLE 4-1 Updated 2004 ATP III LDL-C Goals and Cutpoints for TLC and Drug Therapy ||Download (.pdf)
TABLE 4-1 Updated 2004 ATP III LDL-C Goals and Cutpoints for TLC and Drug Therapy
|Risk Category||LDL-C Goal||Initiative TLC||Consider Drug Therapy|
|High risk: CHD or CHD risk equivalents (10-y risk >20%)a||<100 mg/dL (optional goal: <70 mg/dL if very high riskb)||≥100 mg/dL||≥100 mg/dL (<100 mg/dL: consider drug options)|
|Moderately high risk: 2+ risk factors (10-y risk 10%-20%)||<130 mg/dL (optional goal: <100 mg/dL)||≥130 mg/dL||≥130 mg/dL (100-129 mg/dL: consider drug options)|
|Moderate risk: 2+ risk factors (10-y risk <10%)||<130 mg/dL||≥130 mg/dL||≥160 mg/dL|
|Lower risk: 0-1 risk factor||<160 mg/dL||≥160 mg/dL||≥190 mg/dL (160-189 mg/dL: LDL-lowering drug optional)|
TABLE 4-2 ATP III Definitions ||Download (.pdf)
TABLE 4-2 ATP III Definitions
|Major Risk Factors That Modify LDL Goalsa|
Cigarette smoking (within the past month)
Hypertension (BP ≥140/90 mm Hg or on antihypertensive medication)
Low HDL cholesterol (<40 mg/dL)
Family history of premature CHD (CHD in male first-degree relative <55 y of age or in female first-degree relative <65 y of age)
Age (men ≥45; women ≥55 years)
|CHD Risk Equivalents|
Peripheral arterial disease
Abdominal aortic aneurysm
Carotid artery disease (transient ischemic attacks or stroke of carotid origin or >50% obstruction of a carotid artery)
2+ risk factors with 10-y risk for hard CHD >20%
History of coronary artery procedures (angioplasty or bypass surgery)
Evidence of clinically significant myocardial ischemia
The only exception to targeting LDL-C first is when TG ≥500 mg/dL, requiring immediate TG lowering to prevent pancreatitis. Fibrates, fish oil, or nicotinic acid may be used as initial drug therapy for these patients.4,8-9,16 As benefits of lowering TG on CHD are unclear, non-HDL-C is the recommended secondary goal if the TG remain ≥200 mg/dL once LDL-C is at goal.3 The non-HDL-C (total − HDL-C; sum of LDL-C + VLDL-C) goal is 30 mg/dL higher than the LDL-C goal. The non-HDL-C includes the atherogenic VLDL-C and LDL-C. Metabolic syndrome is also considered a potential secondary target.5 If TG are <200 mg/dL but HDL-C is low, clinicians may consider a tertiary target of increasing HDL-C for patients with CHD and CHD risk equivalents.4-5 However, controlled clinical trials do not provide evidence to warrant setting a specific goal for raising HDL-C.3-5,8
A 2008 American Diabetes Association (ADA) and American College of Cardiology consensus panel recommends a greater focus on apo B and non-HDL-C, both clinical markers of small, dense LDL-C and better predictors of CVD risk than LDL-C.3,7 They suggest an apo B goal of <80 mg/dL if the LDL-C goal is <70 mg/dL and apo B goal of <90 mg/dL if the LDL-C goal is <100 mg/dL.3,9 The safety and benefit of combining statins with other agents to achieve lipid targets is inadequately studied, although pending trials should provide clarification.3-5,9 The panel currently recommends niacin as the preferred agent to add to statins. Niacin has been shown to increase regression of atherosclerosis when combined with statins or bile acid sequestrants (BAS).10,17-18 In one study, niacin resulted in a 26% decrease in myocardial infarction risk in men with hypercholesterolemia and CHD and also decreased mortality up to 11% after 15 years of follow up.7,17
Regarding outcomes with other classes of medications, a meta-analysis found a 32% reduction in cardiac mortality and a 23% reduction in overall mortality with use of omega-3 fatty acids.12 BAS monotherapy reduced cardiac mortality by 30% with no apparent effect on overall mortality.12 Fibrates increased risk of noncardiac mortality by 13% with no significant difference in overall and cardiac mortality, although there was a slight trend toward improvement in cardiac mortality.12 Ezetimibe currently has no hard outcomes data.7,18-20
Response to therapy should be evaluated after 4 to 6 weeks of therapy. If the LDL-C goal is not achieved, therapy can be intensified with reassessment at 6-week intervals.5-6 Once LDL-C is at target, clinicians can focus on other lipid and nonlipid risk factors.5 Maintenance response is monitored every 6 to 12 months unless clinical changes require more frequent testing.6
HMG-CoA Reductase Inhibitors (Statins)
Statins competitively inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, therefore reducing biosynthesis of mevalonate, a cholesterol precursor. LDL-C clearance is also increased by an increased expression of LDL receptors. Statins are the most effective class of drugs at reducing LDL-C (Table 4-3), and they also raise HDL-C 5% to 15% and lower TG 7% to 30%, with varying effects based on the statin and dose used.4 In general, approximately a 6% decrease in LDL-C can be expected for every doubling of the statin dose.4
TABLE 4-3 Percentage Reduction in Serum LDL-C Based on Statin and Daily Dose ||Download (.pdf)
Statins also have pleiotropic effects beyond cholesterol lowering, including reduced inflammation, coronary plaque stabilization, improved endothelial cell function, reduced viscosity and fibrinogen levels, reduced uptake of aggregated LDL-C by vascular smooth muscle cells, suppressed release of tissue factor, and activation of endothelial nitric oxide synthase.
Statins are well tolerated, with side effects such as dyspepsia, headaches, insomnia, constipation, and diarrhea occurring in <5% of patients. Patients rarely report rash, arthralgia, peripheral neuropathy, tendon pain, and memory problems. Observational studies suggest myalgias, usually mild and tolerable, in up to 5% to 10% of patients.21 Myalgia is usually symmetrical, impacting large proximal muscle groups. Myopathy, as defined by the National Lipid Association (NLA), describes all potential statin effects on muscle, including symptomatic myopathy (myalgias, weakness, and cramps), creatine kinase (CK) elevations with or without symptoms, and clinically important rhabdomyolysis, referring to any muscle cell destruction (regardless of CK level) thought to have caused changes in renal function.22 Mild CK elevation is <10 times the upper limit of normal (ULN), moderate ≥10 but <50 times ULN, and marked ≥50 times ULN.22 Moderate to marked CK elevations occurred in only 0.17% of statin-treated and 0.13% of placebo-treated patients in clinical trials, although higher risk populations were generally excluded.23
Although older guidelines recommended CK levels at baseline for all patients prior to starting statins, experts more recently recommend this practice only in high-risk individuals.21-22 The CK should be checked in the event of unexplained muscle pain but not monitored on a routine basis.22 Fatal rhabdomyolysis occurrence was not higher than placebo in trials of currently available statins.18 Fatal rhabdomyolysis is estimated to occur in one per million person-years of statin use, with most cases involving a potential drug interaction with a fibrate or known CYP-3A4 inhibitor.22-24
Contraindications to statins include pregnancy and active liver disease.18 Manufacturer recommendations vary, but liver function tests (LFTs) are generally checked before and 12 weeks after starting therapy, 12 weeks after any dose increase, and periodically thereafter. However, the NLA Statin Safety Assessment Task Force found no data to support routine monitoring of LFTs. Liver failure was not reported in clinical trials and is estimated to occur in only one per million person-years of statin use.23 Although elevated LFTs occur in 0.5% to 2% of patients, they are generally transient and mild to moderate.18,23,25
Niacin is a B-complex vitamin that inhibits hepatic production of VLDL-C by reducing mobilization of free fatty acids from adipose tissues. It also increases the rate of TG removal from plasma, resulting in a 20% to 50% decrease in TG.4,10 Niacin reduces LDL-C 5% to 25% by reducing hepatic synthesis and causes a shift to larger, buoyant particles. Niacin is the most potent medication at increasing HDL-C (15%-35%) and the only lipid-lowering therapy that also reduces Lp(a).4,6,26
Prostaglandin-mediated flushing is a common side effect that usually mitigates over time. Patients may also experience paresthesias, headaches, pruritus, and syncope. Niacin can cause mild gastrointestinal (GI) effects such as dyspepsia, nausea, and diarrhea but may also more seriously activate peptic ulcers. Niacin can also cause hyperpigmentation, rash, maculopathy, and small decreases in phosphorus and platelet count. Niacin commonly increases LFTs and (unlike statins) is clearly linked to severe hepatic toxicity, especially with doses >2000 mg/d.18
LFTs should be checked at baseline, every 6 to 12 weeks for the first year, and then approximately every 6 months. Absolute contraindications include active liver disease or unexplained LFT elevations, active peptic ulcer disease, arterial bleeding, and known hypersensitivity. Precautious include unstable angina or acute phase of myocardial infarction, use of concomitant anticoagulants, concomitant vasodilators, renal disease, substantial alcohol consumption, and history of liver disease. Niacin should also be used with caution in patients with gout due to possible uric acid increases.18 Although niacin can worsen glucose in patients with diabetes (a usually transient effect with an average 5% increase in fasting glucose and 0.3% increase in A1c), it can be particularly beneficial for dyslipidemia in this patient population.18
BAS bind to negatively charged, cholesterol-containing bile acids in the intestinal lumen, preventing their reabsorption. The liver then uses cholesterol to make more bile, which further lowers cholesterol.10
These agents lower LDL-C by 10% to 30%. They increase HDL-C by 3% to 5% and either have no effect or can increase TG.4 Studies show a TG increase as much as 18% to 22% in patients taking insulin and sulfonylureas.27 BAS can lower apo B, C-reactive protein, and in combination with a statin or niacin, reduce small, dense LDL-C particles.3 Although all BAS can also lower fasting glucose and A1c modestly, colesevelam is the only one approved for type 2 diabetes treatment.
BAS are nonsystemic drugs with primarily GI side effects such as constipation, nausea, vomiting, dyspepsia, bloating, flatulence, and aggravation of hemorrhoids. Side effects are less likely with colesevelam. BAS may interfere with absorption of fat and fat-soluble vitamins (A, D, E, K), and there are rare reports of increased bleeding tendency caused by vitamin K deficiency. Contraindications to BAS therapy include history of hypersensitivity, elevated TG >500 mg/dL (colesevelam) or hyperlipidemia types III, IV, or V (cholestyramine), history of bowel or biliary obstruction, and history of hypertriglyceridemia-induced pancreatitis. BAS are not generally recommended for patients at risk for bowel obstruction secondary to gastroparesis, GI motility disorders, and history of major GI surgery. Caution should be used for patients with TG >300 mg/dL, susceptibility to fat-soluble vitamin deficiencies, preexisting constipation, and dysphagia (colesevelam).
Omega-3-Acid Ethyl Esters
The active lipid-lowering components of fish oil are eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which both increase lipoprotein lipase activity, lower TG biosynthesis, and reduce hepatic lipogenesis.18,28-29 EPA and DHA may also have direct cardioprotective effects, including reduced platelet aggregation, decreased inflammation, mildly decreased blood pressure, reduced arrhythmias, improved endothelial function, and enhanced nitric oxide production.10,17,30 The American Heart Association (AHA) recommends all patients with CHD consume 1 g of EPA and DHA per day from fish and/or supplements. Higher doses of 3 to 4 g/d of EPA and DHA are usually needed for significant TG lowering.30 These doses can lower TG by 25% to 52%, with an increase in LDL-C by 5% to 10% and HDL-C by 1% to 3%.28-30 HDL-C and LDL-C can increase more impressively in patients with very high TG, as much as 5% to 14% and 49%, respectively.28-29 However, increased LDL-C is caused primarily by a shift to larger, buoyant particles and does not appear to be atherogenic.
Fish oil supplements are well tolerated even at higher doses. Eructation, dyspepsia, taste perversion, flu-like syndrome, and infection are the most common adverse effects occurring in <5% of patients.28 Patients may also report nausea, flatulence, bloating, and/or diarrhea. Fish oil has been shown to slightly prolong bleeding time and may theoretically increase bleeding risk at higher doses.28-30 Fish oil may also increase risk of ventricular arrhythmias in patients with implantable defibrillators, although evidence is contradictory.30 Alanine aminotransferase and LDL-C should be monitored periodically due to occasional increases.28 Clinically significant drug interactions are unlikely, with the exception of orlistat which reduces absorption. A prescription omega-3-acid ethyl esters product, approved for treatment of very high (≥500 mg/dL) TG in adults, is contraindicated only in patients with past hypersensitivity (eg, anaphylaxis) to any product ingredient.29
Fibric Acid Derivatives (Fibrates)
Fibrates activate peroxisome proliferator–activated receptors to stimulate lipoprotein lipase, accelerating lipoprotein degradation. Fibrates also reduce hepatic apoprotein synthesis, resulting in lower TG and higher HDL-C.10 Fibrates lower LDL-C by 5% to 20% (more with fenofibrate) and cause a beneficial shift in particle size. Generally, TGs are decreased by 20% to 50% and HDL-C increased by 10% to 20%.4
GI effects such as abdominal discomfort are generally transient but occur in approximately 10% of patients receiving gemfibrozil and clofibrate. Fenofibrate appears better tolerated. Fibrates can cause elevated creatinine, increased LFTs, gallstones, and myopathy.18,22 Anemia and white blood cell decreases have been observed and usually stabilize with long-term use. Other adverse effects include urticaria, increased homocysteine, acute hypersensitivity reactions, and rarely, venous thromboembolism.17-18 Patients on warfarin should be closely monitored since fibrates can increase prothrombin time.
Contraindications to fibrates include gallbladder disease, history of hypersensitivity reactions, hepatic dysfunction, and severe renal impairment (defined by manufacturer as CrCl <30 mL/min for fenofibrate and <10 mL/min for gemfibrozil). Fibrates require renal adjustment in patients with mild to moderate renal impairment. Fenofibrate is also contraindicated in nursing mothers, and gemfibrozil is contraindicated in patients taking repaglinide (due to increased risk of severe hypoglycemia). Monitor CBC periodically during the first year of therapy, CK in patients with muscle pain or on other myopathy-associated medications, LFTs every 3 months during first year of gemfibrozil and then periodically thereafter, and LFTs periodically throughout therapy with fenofibrate.
Cholesterol Absorption Inhibitors
Ezetimibe inhibits dietary cholesterol absorption at the brush border of the small intestine. Ezetimibe also increases cholesterol clearance from the plasma, reduces formation of LDL-C, lowers apo B, and decreases hepatic cholesterol stores.10 LDL-C is reduced by 16% to 21%, TG reduced by 8% to 12% and HDL-C increased by 1% to 5% with therapy.18 Ezetimibe is approved as monotherapy and in combination with a statin or fenofibrate, but it should not be combined with gemfibrozil because of increased risk of cholelithiasis. No dose adjustments are necessary in renal or hepatic impairment, although it should be avoided in patients with moderate to severe hepatic disease.
Ezetimibe is generally well tolerated. Adverse reactions occurring in <4% of patients include diarrhea, fatigue, upper respiratory infection, arthralgia, fatigue, and myagias.6 There are rare case reports of myopathy and rhabdomyolysis, usually when combined with a statin or fibrate, but also with monotherapy.25,31 There are rare reports of angioedema and allergic reactions, and ezetimibe is contraindicated in patients with past hypersensitivity reactions. Patients on ezetimibe with statins are more likely to have elevated LFTs compared to statin monotherapy, and LFTs should be monitored per statin recommendations. Increase in cancer observed in the SEAS trial was not replicated in larger studies but requires follow-up of longer duration.7,20,32
Most new CHD events and coronary deaths occur in the elderly, and there are no clear age restrictions for drug therapy. Trials have demonstrated risk reduction with statin therapy in older persons with and without established CVD up to 82 years of age.4 Older patients are at greater risk for adverse effects and may require lower doses. However, the safety and efficacy of statins, fish oil, ezetimibe, niacin (Niaspan), colesevelam, and fenofibrate did not appear different for elderly subjects in clinical trials. Although the PROSPER trial found a 25% increase in new cancer in elderly subjects randomized to pravastatin, subsequent meta-analyses have found no increase in cancer incidence.4,12-13,33
Coronary atherosclerosis begins in childhood, and high cholesterol in children and young adults is associated with greater risk of premature CHD in middle age.5-6,34 Therefore, cholesterol screening is recommended in children over 2 years of age and no later than 10 years of age if there is a positive family history of dyslipidemia or premature CVD.34 Children should also be screened if the family history is unknown or if they have other CVD risk factors (overweight or obese, hypertension, smoking, or diabetes). High-risk children with values within the reference range are retested every 3 to 5 years.34
The 2008 American Academy of Pediatrics recommends consideration of drug therapy following ineffective diet changes in children 8 years of age with very high LDL-C (≥190 mg/dL), those with family history of early CHD or with two or more additional risk factors with LDL-C ≥160 mg/dL, and those with diabetes when LDL-C is ≥130 mg/dL.5,34
Pharmacologic intervention should be considered in children younger than 8 years old only for dramatic LDL-C elevations (>500 mg/dL).34