Current Medical Diagnosis & Treatment 2015

28

Lipid Disorders

Robert B. Baron, MD, MS

For patients with known cardiovascular disease (secondary prevention), cholesterol lowering leads to a consistent reduction in total mortality and recurrent cardiovascular events in men and women and in middle-aged and older patients. Among patients without cardiovascular disease (primary prevention), the data are less conclusive, with rates of cardiovascular events, heart disease mortality, and all-cause mortality differing among studies. Nonetheless, treatment algorithms have been designed to assist clinicians in selecting patients for cholesterol-lowering therapy based on their overall risk of developing cardiovascular disease.

LIPID FRACTIONS & THE RISK OF CORONARY HEART DISEASE

In fasting serum, cholesterol is carried primarily on three different lipoproteins—the VLDL, LDL, and HDL molecules. Total cholesterol equals the sum of these three components:

Most triglyceride is found in VLDL particles, which contain five times as much triglyceride by weight as cholesterol. The amount of cholesterol found in the VLDL fraction can be estimated by dividing the triglyceride by 5:

Because the triglyceride level is used as a proxy for the amount of VLDL, this formula works only in fasting samples and when the triglyceride level is < 400 mg/dL or < 4.52 mmol/L. At higher triglyceride levels, LDL and VLDL cholesterol levels can be determined after ultracentrifugation or by direct chemical measurement.

The total cholesterol is reasonably stable over time; however, measurements of HDL and especially triglycerides may vary considerably because of analytic error in the laboratory and biologic variation in a patient’s lipid level. Thus, the LDL should always be estimated as the mean of at least two determinations; if those two estimates differ by more than 10%, a third lipid profile is obtained. The LDL is estimated as follows:

When using SI units, the formula becomes

Some authorities use the ratio of the total to HDL cholesterol as an indicator of lipid-related coronary risk: the lower this ratio is, the better. Although ratios are useful predictors within populations of patients, they may obscure important information in individual patients. (A total cholesterol of 300 mg/dL [7.76 mmol/L] and an HDL of 60 mg/dL [1.56 mmol/L] result in the same ratio as a total cholesterol of 150 mg/dL [3.88 mmol/L] with an HDL of 30 mg/dL [0.78 mmol/L].) Moreover, the total cholesterol-to-HDL cholesterol ratio will magnify the importance of variations in HDL measurement.

THERAPEUTIC EFFECTS OF LOWERING CHOLESTEROL

Reducing cholesterol levels in healthy middle-aged men without CHD (primary prevention) reduces their risk in proportion to the reduction in LDL cholesterol. Treated adults have statistically significant and clinically important reductions in the rates of myocardial infarctions, new cases of angina, and need for coronary artery bypass procedures. The West of Scotland Study showed a 31% decrease in myocardial infarctions in middle-aged men treated with pravastatin compared with placebo. The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) study showed similar results with lovastatin. As with any primary prevention interventions, large numbers of healthy patients need to be treated to prevent a single event. The numbers of patients needed to treat (NNT) to prevent a nonfatal myocardial infarction or a coronary artery disease death in these two studies were 46 and 50, respectively. The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) study of atorvastatin in subjects with hypertension and other risk factors but without CHD also demonstrated a convincing 36% reduction in CHD events. The Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) showed a 44% reduction in a combined end point of myocardial infarction, stroke, revascularization, hospitalization for unstable angina, or death from cardiovascular causes in both men and women. The NNT for 1 year to prevent one event was 169.

Primary prevention studies have found a less consistent effect on total mortality. The West of Scotland study found a 20% decrease in total mortality, tending toward statistical significance. The AFCAPS/TexCAPS study with lovastatin showed no difference in total mortality. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT) also showed no reduction either in all-cause mortality or in CHD events when pravastatin was compared with usual care. Subjects treated with atorvastatin in the ASCOT study had a 13% reduction in mortality, but the result was not statistically significant. This study, however, was stopped early due to the marked reduction in CHD events. The JUPITER trial demonstrated a statistically significant 20% reduction in death from any cause. The NNT for 1 year was 400.

In patients with CHD, the benefits of cholesterol lowering are clearer. Major studies with statins have shown significant reductions in cardiovascular events, cardiovascular deaths, and all-cause mortality in men and women with coronary artery disease. The NNT to prevent a non-fatal myocardial infarction or a coronary artery disease death in these three studies were between 12 and 34. Aggressive cholesterol lowering with these agents causes regression of atherosclerotic plaques in some patients, reduces the progression of atherosclerosis in saphenous vein grafts, and can slow or reverse carotid artery atherosclerosis. Meta-analysis suggests that this latter effect results in a significant decrease in strokes. Results with other classes of medications have been less consistent. For example, gemfibrozil treatment subjects had fewer cardiovascular events, but there was no benefit in all-cause mortality when compared with placebo.

The disparities in results between primary and secondary prevention studies highlight several important points. The benefits and adverse effects of cholesterol lowering may be specific to each type of drug; the clinician cannot assume that the effects will generalize to other classes of medication. Second, the net benefits from cholesterol lowering depend on the underlying risk of CHD and of other disease. In patients with atherosclerosis, morbidity and mortality rates associated with CHD are high, and measures that reduce it are more likely to be beneficial even if they have no effect—or even slightly harmful effects—on other diseases.

Cholesterol Treatment Trialists’ (CTT) Collaboration; Collings R et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010 Nov 13;376(9753): 1670–81. [PMID: 21067804]

Kini AS et al. Changes in plaque lipid content after short-term intensive versus standard statin therapy: the YELLOW trial (reduction in yellow plaque by aggressive lipid-lowering therapy). J Am Coll Cardiol. 2013 Jul 2;62(1):21–9. [PMID: 23644090]

Ridker PM et al. A trial-based approach to statin guidelines. JAMA. 2013 Sep 18:310(11):1123–4. [PMID: 23942579]

Sbrana F et al. High density lipoprotein cholesterol in coronary artery disease: when higher means later. J Atheroscler Thromb. 2013 Jan 25;20(1):23–31. [PMID: 22878704]

Savarese G et al. Benefits of statins in elderly subjects without established cardiovascular disease: a meta-analysis. J Am Coll Cardiol. 2013 Dec 3;62(22):2090–9. [PMID: 23954343]

Wang X et al. Cholesterol levels and risk of hemorrhagic stroke: a systematic review and meta-analysis. Stroke. 2013 Jul; 44(7): 1833–9. [PMID: 23704101]

SECONDARY CONDITIONS THAT AFFECT LIPID METABOLISM

Several factors, including drugs, can influence serum lipids. These are important for two reasons: abnormal lipid levels (or changes in lipid levels) may be the presenting sign of some of these conditions, and correction of the underlying condition may obviate the need to treat an apparent lipid disorder. Diabetes and alcohol use, in particular, are commonly associated with high triglyceride levels that decline with improvements in glycemic control or reduction in alcohol use, respectively. Thus, secondary causes of high blood lipids should be considered in each patient with a lipid disorder before lipid-lowering therapy is started. In most instances, special testing is not needed: a history and physical examination are sufficient. However, screening for hypothyroidism in patients with hyperlipidemia is cost effective.

CLINICAL PRESENTATIONS

Most patients with high cholesterol levels have no specific symptoms or signs. The vast majority of patients with lipid abnormalities are detected by the laboratory, either as part of the workup of a patient with cardiovascular disease or as part of a preventive screening strategy. Extremely high levels of chylomicrons or VLDL particles (triglyceride level above 1000 mg/dL or 10 mmol/L) result in the formation of eruptive xanthomas (Figure 28–1) (red-yellow papules, especially on the buttocks). High LDL concentrations result in tendinous xanthomas on certain tendons (Achilles, patella, back of the hand). Such xanthomas usually indicate one of the underlying genetic hyperlipidemias. Lipemia retinalis (cream-colored blood vessels in the fundus) is seen with extremely high triglyceride levels (above 2000 mg/dL or 20 mmol/L).

 Figure 28–1. Eruptive xanthoma on the arm of a man with untreated hyperlipidemia and diabetes mellitus. (Reproduced with permission from Richard P. Usatine, MD)

SCREENING & TREATMENT OF HIGH BLOOD CHOLESTEROL

All patients with cardiovascular disease and diabetes should have their lipids measured. The only exceptions are patients in whom lipid lowering is not indicated or desirable for other reasons. Patients who already have evidence of atherosclerosis are the group at highest risk for suffering additional manifestations in the near term and thus have the most to gain from lipid lowering. Additional risk reduction measures for atherosclerosis are discussed in Chapter 10; lipid lowering should be just one aspect of a program to reduce the progression and effects of the disease.

In patients with cardiovascular disease, a complete lipid profile (total cholesterol, HDL cholesterol, and triglyceride levels) after an overnight fast should be obtained. According to the 2013 American College of Cardiology/American Heart Association (ACC/AHA) guidelines, however, such patients are treated with statins independent of their lipid levels. Similarly, patients aged 40–75 with diabetes should also have a complete lipid profile. Those with diabetes and LDL ≥ 70 mg/dL (≥ 1.81 mmol/L) should be treated with statins.

The best screening and treatment strategy for adults who do not have atherosclerotic cardiovascular disease is less clear. Several algorithms have been developed to guide the clinician in treatment decisions, but management decisions are individualized based on the patient’s risk.

Although the 2013 ACC/AHA guidelines recommend screening of all adults aged 21 years or older for high blood cholesterol, the United States Preventive Services Task Force (USPSTF) suggests beginning at age 20 years only if there are other cardiovascular risk factors such as tobacco use, diabetes, hypertension, obesity, or a family history of premature cardiovascular disease. For men without other risk factors, screening is recommended beginning at age 35 years. For women and for men aged 20 to 35 without increased risk, the USPSTF makes no recommendation for or against routine screening for lipid disorders. Although there is no established interval for screening, screening can be repeated every 5 years for those with average or low risk and more often for those whose levels are close to therapeutic thresholds.

Individuals without cardiovascular disease should have their 10-year risk of CHD calculated. Although those with LDL cholesterol > 190 mg/dL (> 4.91 mmol/L) are recommended for treatment independent of their 10-year risk of cardiovascular disease, all other patients are recommended for treatment based on their overall cardiovascular risk. The best method for estimating 10-year risk is controversial. The 2013 ACC/AHA guidelines include a risk calculator that measures cardiovascular risk. It can be downloaded athttp://my.americanheart.org/professional/StatementsGuidelines/Prevention-Guidelines/Prevention-Guidelines_UCM_457698_SubHomePage.jsp. It has been criticized by some authors as overestimating risk. The older Framingham 10-year calculator (Table 28–1) includes CHD but not stroke risk. One approach is to use both risk calculators until better data are available.

Table 28–1. Framingham 10-year coronary heart disease risk projections. Calculate the number of points for each risk factor. Sum the total risk score and estimate the 10-year risk. (continued)

Numerous other risk factors have been studied in an attempt to better predict future CHD events. These include high-sensitivity C-reactive protein (hs-CRP), electron beam computed tomography (EBCT), homocysteine, fibrinogen, lipoprotein a, LDL subfractions, ankle-brachial index, and others. Several of these, particularly hs-CRP and EBCT, may add additional prognostic ability after accounting for traditional risk factors, but no clinical trials have yet examined the effect of these on health outcomes. Clinical guidelines suggest limiting the use of additional risk factors such as hs-CRP to selected patients if additional data are likely to change a therapeutic decision.

Several strategies for obtaining the initial cholesterol measurement have been proposed, including: (1) measuring total cholesterol alone, (2) measuring total cholesterol and HDL cholesterol, or (3) measuring LDL cholesterol. Initial measurement of the LDL cholesterol is least likely to lead to patient misinformation and misclassification and is the strategy recommended by the 2013 ACC/AHA guidelines.

Treatment decisions are based on the presence of clinical cardiovascular disease or diabetes, patient age, LDL cholesterol > 190 mg/dL (> 4.91 mmol/L), and the estimated 10-year risk of developing cardiovascular disease. The 2013 ACC/AHA guidelines define four groups of patients who benefit from statin medications: (1) individuals with clinical atherosclerotic cardiovascular disease; (2) individuals with primary elevation of LDL cholesterol >190 mg/dL (> 4.91 mmol/L); (3) individuals aged 40–75 with diabetes and LDL ≥ 70 mg/dL (≥ 1.81 mmol/L); and (4) individuals aged 40–75 without clinical atherosclerotic cardiovascular disease or diabetes, with LDL 70–189 mg/dL (1.81–4.91 mmol/L), and estimated 10-year CVD risk ≥ 7.5% or higher.

 Screening & Treatment in Women

The foregoing screening and treatment guidelines are designed for both men and women. Yet several observational studies suggest that a low HDL cholesterol is a more important risk factor for CHD in women than a high LDL cholesterol. Meta-analysis of studies including women with known heart disease, however, has found that statins prevent recurrent myocardial infarctions in women. There is insufficient evidence to be certain of a similar effect from statins in women without evidence of CHD. Although most experts recommend application of the same primary prevention guidelines for women as for men, clinicians should be aware of the uncertainty in this area. Estimating the 10-year cardiovascular risk is particularly important in women since a larger percentage of women than men will have estimated 10-year cardiovascular risks below 7.5% per year and be advised not to take statins unless their LDL is very high (> 190 mg/dL or > 4.91 mmol/L).

 Screening & Treatment in Older Patients

Meta-analysis of evidence relating cholesterol to CHD in the elderly suggests that cholesterol is not a risk factor for CHD for persons over age 75 years. Clinical trials have rarely included such individuals. One exception is the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). In this study, elderly patients with cardiovascular disease (secondary prevention) benefited from statin therapy, whereas those without cardiovascular disease (primary prevention) did not. The 2013 ACC/AHA guidelines suggest continuing statin treatment in patients over age 75 who have cardiovascular disease. The guidelines, however, suggest not screening or treating patients over the age of 75 who do not have evidence of cardiovascular disease. Individual patient decisions to discontinue statin therapy should be based on overall functional status and life expectancy, comorbidities, and patient preference and should be made in context with overall therapeutic goals and end-of-life decisions.

Centers for Disease Control and Prevention (CDC). Prevalence of cholesterol screening and high blood cholesterol among adults—United States, 2005, 2007, and 2009. MMWR Morb Mortal Wkly Rep. 2012 Sep 7;61:697–702. [PMID: 22951451]

Goff DC Jr et al. 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013 Nov 12. [Epub ahead of print] [PMID: 24239921]

Keaney JF Jr et al. A pragmatic view of the new cholesterol treatment guidelines. N Engl J Med. 2014 Jan 16;370(3):275–8. [PMID: 24283199]

Krumholz HM. Target cardiovascular risk rather than cholesterol concentration. BMJ. 2013 Nov 27;347:f7110. [PMID: 24284344]

Ridker PM et al. Statins: new American guidelines for prevention of cardiovascular disease. Lancet. 2013 Nov 30; 382(9907):1762–5. [PMID: 24268611]

Stone NJ et al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013 Nov 7. [Epub ahead of print] [PMID: 24239923]

TREATMENT OF HIGH LDL CHOLESTEROL

Reduction of LDL cholesterol with statins is just one part of a program to reduce the risk of cardiovascular disease. Other measures—including smoking cessation, hypertension control, and aspirin—are also of central importance. Less well studied but of potential value is raising the HDL cholesterol level. Quitting smoking reduces the effect of other cardiovascular risk factors (such as a high cholesterol level); it may also increase the HDL cholesterol level. Exercise (and weight loss) may reduce the LDL cholesterol and increase the HDL. Modest alcohol use (1–2 ounces a day) also raises HDL levels and appears to have a salutary effect on CHD rates.

The use of medications to raise the HDL cholesterol has not been demonstrated to provide additional benefit. For example, cholesteryl ester transfer protein inhibitors is a class of medicines being investigated to raise HDL levels. Agents in this class, however, have not been shown to be effective. The use of niacin in addition to statins has also been carefully studied in the AIM-HIGH study and also shown not to be effective.

 Diet Therapy

Studies of nonhospitalized adults have reported only modest cholesterol-lowering benefits of dietary therapy, typically in the range of a 5–10% decrease in LDL cholesterol, with even less in the long term. The effect of diet therapy, however, varies considerably among individuals, as some patients will have striking reductions in LDL cholesterol—up to a 25–30% decrease—whereas others will have clinically important increases. Thus, the results of diet therapy should be assessed about 4 weeks after initiation.

Cholesterol-lowering diets may also have a variable effect on lipid fractions. Diets very low in total fat or in saturated fat may lower HDL cholesterol as much as LDL cholesterol. It is not known how these diet-induced changes affect coronary risk.

Several nutritional approaches to diet therapy are available. Most Americans currently eat over 35% of calories as fat, of which 15% is saturated fat. Dietary cholesterol intake averages 400 mg/d. A cholesterol-lowering diet recommends reducing total fat to 25–30% and saturated fat to < 7% of calories. Dietary cholesterol should be limited to < 200 mg/d. These diets replace fat, particularly saturated fat, with carbohydrate. In most instances, this approach will also result in fewer total calories consumed and will facilitate weight loss in overweight patients. Other diet plans, including the Dean Ornish Diet, the Pritikin Diet, and most vegetarian diets, restrict fat even further. Low-fat, high-carbohydrate diets may, however, result in reductions in HDL cholesterol.

An alternative strategy is the Mediterranean diet, which maintains total fat at approximately 35–40% of total calories but replaces saturated fat with monounsaturated fat such as that found in canola oil and in olives, peanuts, avocados, and their oils. This diet is equally effective at lowering LDL cholesterol but is less likely to lead to reductions in HDL cholesterol. Several studies have suggested that this approach may also be associated with reductions in endothelial dysfunction, insulin resistance, and markers of vascular inflammation and may result in better resolution of the metabolic syndrome than traditional cholesterol-lowering diets. A clinical trial demonstrated reduced cardiovascular events in persons on a Mediterranean diet supplemented with additional nuts or extra-virgin olive oil compared to persons on a less intensive Mediterranean diet.

Other dietary changes may also result in beneficial changes in blood lipids. Soluble fiber, such as that found in oat bran or psyllium, may reduce LDL cholesterol by 5–10%. Garlic, soy protein, vitamin C, pecans, and plant sterols may also result in reduction of LDL cholesterol. Because oxidation of LDL cholesterol is a potential initiating event in atherogenesis, diets rich in antioxidants, found primarily in fruits and vegetables, may be helpful (see Chapter 29). Studies have suggested that when all of these elements are combined into a single dietary prescription, the impact of diet on LDL cholesterol may approach that of statin medications, lowering LDL cholesterol by close to 30%.

AIM-HIGH Investigators; Boden WE et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011 Dec 15;365(24):2255–67. [PMID: 22085343]

Eckel RH et al. 2013 AHA/ACC Guideline on Lifestyle Management to Reduce Cardiovascular Risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013 Nov 7. [Epub ahead of print] [PMID: 24239922]

Estruch R et al; PREDIMED Study Investigators. Primary prevention of cardiovascular disease with a Mediterannean Diet. N Engl J Med. 2103 Apr 4;368(14):1279–90. [PMID: 23432189]

Kelley GA et al. Comparison of aerobic exercise, diet or both on lipids and lipoproteins in adults: a meta-analysis of randomized controlled trials. Clin Nutr. 2012 Apr;31(2):156–67. [PMID: 22154987]

Nordmann AJ et al. Meta-analysis comparing Mediterranean to low-fat diets for modification of cardiovascular risk factors. Am J Med. 2011 Sep;124(9):841–51. [PMID: 21854893]

Rubenfire M et al. HDL cholesterol and cardiovascular outcomes: what is the evidence? Curr Cardiol Rep. 2013 Apr;15(4):349. [PMID: 23420445]

 Pharmacologic Therapy

Most patients whose risk from CHD is considered high enough to warrant pharmacologic therapy of an elevated LDL cholesterol should be given aspirin prophylaxis at a dose of 81 mg/d unless there are contraindications such as aspirin sensitivity, bleeding diatheses, or active peptic ulcer disease. The benefit of aspirin in reducing the risk of CHD in men is equivalent to that of cholesterol lowering. Other CHD risk factors, such as hypertension and smoking, should also be controlled.

The 2013 ACC/AHA guidelines suggest treatment with statins for all patients who require drug treatment. As discussed above, the guidelines define four groups of patients who benefit from statin medications.

  1. Hydroxymethylglutaryl-Coenzyme A (HMG-CoA) Reductase Inhibitors (Statins)

The HMG-CoA reductase inhibitors (statins) work by inhibiting the rate-limiting enzyme in the formation of cholesterol. They reduce myocardial infarctions and total mortality in secondary prevention, as well as in older middle-aged men free of CHD. A meta-analysis has demonstrated significant reduction in risk of stroke. Cholesterol synthesis in the liver is reduced, with a compensatory increase in hepatic LDL receptors (presumably so that the liver can take more of the cholesterol that it needs from the blood) and a reduction in the circulating LDL cholesterol level by up to 35%. There are also modest increases in HDL levels and decreases in triglyceride levels.

The 2013 ACC/AHA guidelines divide statins into high-intensity and moderate-intensity statin therapy (Table 28–2). High intensity statins lower LDL cholesterol by approximately 50%. Examples include atorvastatin 40–80 mg and rosuvastatin 20–40 mg/d (Table 28–3). Moderate intensity statins lower LDL cholesterol by approximately 30–50%. Examples include atorvastatin 10–20 mg, rosuvastatin 5–10 mg, simvastatin 20–40 mg, pravastatin 40–80 mg, and lovastatin 40 mg. All statins are given once daily in the morning or evening. The most common side effects are muscle aches, occurring in up to 10% of patients, and mild gastrointestinal effects. Statins are associated with a 10% increase in the risk of diabetes. Other serious, but extremely uncommon, side effects include liver failure and muscle disease including myositis and rhabdomyolysis. Some patients experience muscle pain even when the serum creatine kinase levels are normal. Liver disease is more common in patients who are also taking fibrates or niacin. Manufacturers of HMG-CoA reductase inhibitors recommend monitoring liver enzymes before initiating therapy and as clinically indicated thereafter. Muscle disease is more common with statins and fibrates and niacin as well as with erythromycin, antifungal medications, nefazadone, and cyclosporine. Simvastatin at the highest approved dose—80 mg—is associated with a higher risk of muscle injury or myopathy. This dose should only be used in those who have been taking the medication for longer than 1 year without muscle toxicity.

Table 28–2. Indications for high intensity and moderate intensity statins: Recommendations of the 2013 ACC/AHA Guidelines.

Table 28–3. Effects of selected lipid-modifying drugs.

  1. Niacin (Nicotinic Acid)

Niacin was the first lipid-lowering agent that was associated with a reduction in total mortality. Long-term follow-up of a secondary prevention trial of middle-aged men with previous myocardial infarction disclosed that about half of those who had been previously treated with niacin had died, compared with nearly 60% of the placebo group. This favorable effect on mortality was not seen during the trial itself, though there was a reduction in the incidence of recurrent coronary events. A meta-analysis of 10 randomized trials using niacin has also shown a 27% reduction in cardiovascular events.

Niacin reduces the production of VLDL particles, with secondary reduction in LDL and increases in HDL cholesterol levels. The average effect of full-dose niacin therapy, 3–4.5 g/d, is a 15–25% reduction in LDL cholesterol and a 25–35% increase in HDL cholesterol. Full doses are required to obtain the LDL effect, but the HDL effect is observed at lower doses, eg, 1 g/d. Niacin will also reduce triglycerides by half and will lower lipoprotein(a) (Lp[a]) levels and will increase plasma homocysteine levels. Intolerance to niacin is common; only 50–60% of patients can take full doses. Niacin causes a prostaglandin-mediated flushing that patients may describe as “hot flashes” or pruritus and that can be decreased with aspirin (81–325 mg/d) or other nonsteroidal anti-inflammatory agents taken during the same day. Flushing may also be decreased by initiating niacin therapy with a very small dose, eg, 100 mg with the evening meal. The dose can be doubled each week until 1.5 g/d is tolerated. After rechecking blood lipids, the dose is increased and divided over three meals until the goal of 3–4.5 g/d is reached (eg, 1 g with each meal). Extended-release niacin is better tolerated by most patients. It is not known whether routine monitoring of liver enzymes results in early detection and thus reduced severity of this side effect. Niacin can also exacerbate gout and peptic ulcer disease. Although niacin may increase blood sugar in some patients, clinical trials have shown that niacin can be safely used in diabetic patients.

  1. Bile Acid–Binding Resins

The bile acid–binding resins include cholestyramine, colesevelam, and colestipol. Treatment with these agents reduces the incidence of coronary events in middle-aged men by about 20%, with no significant effect on total mortality. The resins work by binding bile acids in the intestine. The resultant reduction in the enterohepatic circulation causes the liver to increase its production of bile acids, using hepatic cholesterol to do so. Thus, hepatic LDL receptor activity increases, with a decline in plasma LDL levels. The triglyceride level tends to increase slightly in some patients treated with bile acid–binding resins; they should be used with caution in those with elevated triglycerides and probably not at all in patients who have triglyceride levels above 500 mg/dL. The clinician can anticipate a reduction of 15–25% in the LDL cholesterol level, with insignificant effects on the HDL level.

The usual dose of cholestyramine is 12–36 g of resin per day in divided doses with meals, mixed in water or, more palatably, juice. Doses of colestipol are 20% higher (each packet contains 5 g of resin). The dose of colesevelam is 625 mg, 6–7 tablets per day.

These agents often cause gastrointestinal symptoms, such as constipation and gas. They may interfere with the absorption of fat-soluble vitamins (thereby complicating the management of patients receiving warfarin) and may bind other drugs in the intestine. Concurrent use of psyllium may ameliorate the gastrointestinal side effects.

  1. Fibric Acid Derivatives

The fibrates are peroxisome proliferative-activated receptor-alpha (PPAR-alpha) agonists that result in potent reductions of plasma triglycerides and increases in HDL cholesterol. They reduce LDL levels by about 10–15%, although the result is quite variable, and triglyceride levels by about 40% and raise HDL levels by about 15–20%. The fibric acid derivatives or fibrates approved for use in the United States are gemfibrozil and fenofibrate. Ciprofibrate and bezafibrate are also available for use internationally.

Gemfibrozil reduced CHD rates in hypercholesterolemic middle-aged men free of coronary disease in the Helsinki Heart Study. The effect was observed only among those who also had lower HDL cholesterol levels and high triglyceride levels. In a VA study, gemfibrozil was also shown to reduce cardiovascular events in men with existing CHD whose primary lipid abnormality was a low HDL cholesterol. There was no effect on all-cause mortality.

The usual dose of gemfibrozil is 600 mg once or twice a day. Side effects include cholelithiasis, hepatitis, and myositis. The incidence of the latter two conditions may be higher among patients also taking other lipid-lowering agents. In the largest clinical trial that used clofibrate, there were significantly more deaths—especially due to cancer—in the treatment group; it should not be used.

  1. Ezetimibe

Ezetimibe is a lipid-lowering drug that inhibits the intestinal absorption of dietary and biliary cholesterol by blocking passage across the intestinal wall by inhibiting a cholesterol transporter. The usual dose of ezetimibe is 10 mg/d orally. Ezetimibe reduces LDL cholesterol between 15% and 20% when used as monotherapy and can further reduce LDL in patients taking statins who are not yet at therapeutic goal.

However, the effects of ezetimide on CHD and its long-term safety are not yet known. Results from one small clinical trial, ENHANCE (a study of 720 persons with heterozygous familial hypercholesterolemia), showed no significant difference of intimal media thickness with ezetimibe plus an HMG-CoA reductase inhibitor compared with an HMG-CoA reductase inhibitor alone. A second study compared a statin plus ezetimibe with a statin plus extended-release niacin. The statin plus niacin caused a significant regression of carotid intima-media thickness and was superior to the statin plus ezetimibe combination.

 Initial Selection of Medication

For patients who require a lipid-modifying medication, an HMG-CoA reductase inhibitor is recommended. Although niacin will also have beneficial effects on lipids in both men and women with CHD, there is less evidence demonstrating the desired effects on CHD and all-cause mortality. Resins are the only lipid-modifying medication considered safe in pregnancy.

Combination therapy is rarely indicated. Despite improvements in the lipid profile, there are few data demonstrating improved clinical outcomes of combination therapy when compared with HMG-CoA reductase inhibitors alone. The AIM-High Study of niacin added to simvastatin, for example, was stopped early due to a lack of efficacy. Combinations may also increase the risk of complications of drug therapy. The combination of gemfibrozil and HMG-CoA reductase inhibitors increases the risk of muscle and liver disease more than either drug alone.

ACCORD Study Group et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010 Apr 29; 362(17):1563–74. [PMID: 20228404]

Adams SP et al. Lipid-lowering efficacy of atorvastatin. Cochrane Database Syst Rev. 2012 Dec 12;12:CD008226. [PMID: 23235655]

AIM-HIGH Investigators; Boden WE et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011 Dec 15;365(24):2255–67. [PMID: 22085343]

Choi HD et al. Safety and efficacy of statin treatment alone and in combination with fibrates in patients with dyslipidemia: a meta-analysis. Curr Med Res Opin. 2014 Jan;30(1):1–10. [PMID: 24063624]

Hayek S et al. Effect of ezetimibe on major atherosclerotic disease events and all-cause mortality. Am J Cardiol. 2013 Feb 15;111(4):532–9. [PMID: 23219178]

Julius U et al. Nicotinic acid as a lipid-modifying drug—a review. Atheroscler Suppl. 2013 Jan;14(1):7–13. [PMID: 23357134]

Jun M et al. Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis. Lancet. 2010 May 29; 375(9729):1875–84. [PMID: 20462635]

Lavigne PM et al. The current state of niacin in cardiovascular disease prevention: a systematic review and meta-regression. J Am Coll Cardiol. 2013 Jan 29;61(4):440–6. [PMID: 23265337]

Maron DJ et al. Impact of adding ezetimibe to statin to achieve low-density lipoprotein cholesterol goal (from the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation [COURAGE] trial). Am J Cardiol. 2013 Jun 1;111(11):1557–62. [PMID: 23538020]

Naci H et al. Comparative tolerability and harms of individual statins: a study level network meta-analysys of 246,955 participants from 135 randomized, controlled trials. Circ Cardiovasc Qual Outcomes. 2013 Jul;6(4):390–9. [PMID: 23838105]

Nicholls SJ et al. Effect of two intensive statin regimens on progression of coronary disease. N Engl J Med. 2011 Dec 1;365(22): 2078–87. [PMID: 22085316]

Sniderman A et al. Is lower and lower better and better? A re-evaluation of the evidence from the Cholesterol Treatment Trialists’ Collaboration meta-analysis for low-density lipoprotein lowering. J Clin Lipidol. 2012 Jul;6(4):303–9. [PMID: 22836065]

HIGH BLOOD TRIGLYCERIDES

Patients with very high levels of serum triglycerides (> 1000 mg/dL) are at risk for pancreatitis. The pathophysiology is not certain, since pancreatitis never develops in some patients with very high triglyceride levels. Most patients with congenital abnormalities in triglyceride metabolism present in childhood; hypertriglyceridemia-induced pancreatitis first presenting in adults is more commonly due to an acquired problem in lipid metabolism.

Although there are no clear triglyceride levels that predict pancreatitis, most clinicians treat fasting levels above 500 mg/dL (5 mmol/L). The risk of pancreatitis may be more related to the triglyceride level following consumption of a fatty meal. Because postprandial increases in triglyceride are inevitable if fat-containing foods are eaten, fasting triglyceride levels in persons prone to pancreatitis should be kept well below that level.

The primary therapy for high triglyceride levels is dietary, avoiding alcohol, simple sugars, refined starches, saturated and trans fatty acids, and restricting total calories. Control of secondary causes of high triglyceride levels may also be helpful. In patients with fasting triglycerides ≥ 500 mg/dL (≥ 5 mmol/L) despite adequate dietary compliance—and certainly in those with a previous episode of pancreatitis—therapy with a triglyceride-lowering drug (eg, niacin, a fibric acid derivative, omega-3-acid ethyl esters, or an HMG-CoA reductase inhibitor) is indicated. Combinations of these medications may also be used.

Whether patients with elevated triglycerides (> 150 mg/dL or 1.5 mmol/L) should be treated to prevent CHD is not known. Meta-analysis of 17 observational studies suggests that after adjustment for other risk factors, elevated triglycerides increased CHD risk in men by 14% and in women by 37%. Elevated triglycerides are also an important feature of the metabolic syndrome, found in an estimated 25% of Americans—defined by three or more of the following five abnormalities: waist circumference > 102 cm in men or > 88 cm in women, serum triglyceride level of at least 150 mg/dL, HDL level of < 40 mg/dL in men or < 50 mg/dL in women, blood pressure of at least 130/85 mm Hg, and serum glucose level of at least 110 mg/dL. Other data, however, suggest that triglyceride measurements do not improve discrimination between those with and without CHD events, and clinical trial data are not available to support the routine treatment of high triglycerides in all patients.

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