Chapter 22: Dyslipidemias

The Framingham Heart Study firmly established an epidemiologic link between elevated serum cholesterol and an increased risk of morbidity and mortality from ASCVD. Although the benefits of lowering cholesterol were assumed for many years, not until 2001 had enough evidence accumulated to show unequivocal benefits from using lifestyle and pharmacologic therapy to lower serum cholesterol. Evidence in support of using statin agents is particularly strong and has revolutionized the treatment of dyslipidemias.

The efficacy of lipid reduction for the secondary prevention of ASCVD (reducing further disease-related morbidity in those with manifest disease) is supported by multiple trials and is appropriate in all patients with ASCVD. The efficacy of primary prevention (reducing the risk of disease occurrence in those without overt cardiovascular disease) is now supported even in patients at a low risk of ASCVD by the 10-year Framingham risk assessment (available at http://hp2010.nhlbihin.net/atpiii/calculator.asp).

The National Cholesterol Education Program (NCEP), Adult Treatment Panel (ATP) III released guidelines in 2001. New integrated guidelines for cardiovascular disease reduction were released at the end of 2013. These guidelines emphasize aggressive treatment of dyslipidemias and other cardiovascular risk factors with the intensity of treatment titrated to the patients risk status.

Serum cholesterol is carried by three major lipoproteins: high-density lipoprotein (HDL), low-density lipoprotein (LDL), and very-low-density lipoprotein (VLDL). Most clinical laboratories measure the total cholesterol, total triglycerides (TG), and the HDL fraction.

The triglyceride fraction, and to a lesser extent the HDL level, vary considerably depending on the fasting status of the patient. The NCEP/ATP III guidelines recommend that only fasting measurements including total cholesterol, triglycerides, HDL cholesterol, and a LDL cholesterol be used to guide management decisions.

Different populations have different median cholesterol values. For example, Asian populations tend to have total cholesterol values 20–30% lower than those of populations living in Europe or the United States. It is important to recognize that unlike a serum sodium electrolyte value, there is no normal cholesterol value. Instead, there are cholesterol values that predict higher morbidity and mortality from ASCVD if left untreated, and lower cholesterol values that correlate with less likelihood of cardiovascular disease.

Atherosclerosis is an inflammatory disease in which cells and mediators participate at every stage of atherogenesis from the earliest fatty streak to the most advanced fibrous lesion. Elevated glucose, increased blood pressure, and inhaled cigarette byproducts can trigger inflammation. However, one of the key factors triggering this inflammation is oxidized LDL. When LDL is taken up by macrophages, it triggers the release of inflammatory mediators, which can lead to thickening and/or rupture of plaque lining the arterial walls. Ruptured or unstable plaques are responsible for clinical events such as myocardial infarction and stroke. Lipid lowering, whether by diet or medication, can therefore be regarded as an anti-inflammatory and plaque stabilizing therapy.

A. Symptoms and Signs

Most dyslipidemia patients have no signs or symptoms, of the disease, which is usually detected by routine laboratory screening in an asymptomatic individual. Rarely, patients with familial forms of hyperlipidemia may present with yellow xanthomas on the skin or in tendon bodies, especially the patellar tendon, Achilles tendon, and the extensor tendons of the hands.

A few associated conditions can cause a secondary hyperlipidemia (Table 22-1). These conditions should be considered before lipid-lowering therapy is begun or when the response to therapy is much less than predicted. In particular, poorly controlled diabetes and untreated hypothyroidism can lead to an elevation of serum lipids resistant to pharmacologic treatment.

B. Screening

The US Preventive Services Task Force (USPSTF) bases its screening recommendations on the age of the patient. It strongly recommends (rating A) routinely screening men aged ≥35 years and women aged ≥45 years for lipid disorders.

The USPSTF recommends (rating B) screening younger adults (men aged 20–35 years and women aged 20–45 years), if they have other risk factors for coronary disease. They make no recommendation for or against screening in younger adults in the absence of known risk factors.

In contrast, the NCEP guidelines advise that screening should occur in adults aged ≥20 years with a fasting, lipid profile once every 5 years.

Screening children and adolescents is controversial. New Integrated guidelines released by the National Heart Lung and Blood Institute (NHLBI) in 2011 recommend universal screening of all 9–11-year-olds and gave this a grade B recommendation. Expert opinion recommends screening children from 2 to 8 years of age with significant family histories of hypercholesterolemia, premature ASCVD.

The current NCEP/ATP treatment guidelines are as rooted in evidence as possible. They are available online at www.nhlbi.nih.gov.

The 2001/2004 NCEP/ATP III guidelines follow a nine-step process (Table 22-2).

Step 1 begins after obtaining fasting lipoprotein levels. The profile is categorized according to the LDL, HDL, and total cholesterol values:

Step 2 focuses on determining the presence of clinical atherosclerotic disease such as coronary heart disease, peripheral arterial disease, or diabetes mellitus.

In Step 3 the clinician should determine the presence of other major CAD risk factors, including smoking, age >45 years in men (>55 years in women), hypertension, HDL cholesterol <40 mg/dL, a family history of premature CHD in a male first-degree relative aged <55 years or a female first-degree relative aged <65 years of age. An HDL cholesterol of >60 mg/dL negates one risk factor.

Step 4 uses the Framingham coronary risk calculator to classify the patient into one of four risk categories: high-risk, having coronary artery disease or a 10-year risk of >20%; moderately high risk, having a 10-year risk of 10–20%; moderate-risk, having two or more risk factors but a 10-year risk of <10%; or low-risk, having zero to one risk factors. The Framingham risk calculator can be found at http://hp2010.nhlbihin.net/atpiii/calculator.asp.

Step 5 is the key step that determines the patient’s suggested LDL cholesterol treatment goals. Table 22-3 summarizes risk category determination and treatment goals.

A. Behavior Modification

Step 6 reviews the contents of therapeutic lifestyle changes (TLC). Saturated fat is limited to <7% of total calories; cholesterol intake to <200 mg/d. In addition, weight management and increased physical activity are encouraged. TLC also includes advice to increase the consumption of soluble fiber (10–25 gm/d) and the intake of plant sterols (sitostanol approximately 2 g/d). Several margarines (Benecol™, Take Control™) contain these plant sterols, and evidently they work in conjunction with cholesterol-lowering drugs. Excellent information sources of soluble fiber can be found at www.nhlbi.nih.gov/chd/tipsheets/solfiber.htm.

The cultural background of the patient will impact the choice of dietary recommendations. A skilled nutritional medicine consultant can easily adapt the fat/cholesterol intake recommendations to various culturally normative diets. Indeed, components of some cultures’ diets that encourage the consumption of soluble fiber, plant sterols, soy protein, or fish oils have cholesterol-lowering effects. Dietary advice given without regard to a patient’s culturally accepted diet is counterproductive.

B. Pharmacotherapy

Step 7 reviews the options for drug therapy if required (Table 22-4). Of note, NCEP/ATPIII now recommends the simultaneous use of TLC and drugs in patients at the highest risk. Medications should be added to TLC after 3 months if goal LDL levels are not reached in lower-risk patients. Given their proven efficacy, and enhanced patient compliance over other classes of medications, statin agents are the drugs of first choice. In particular, patients with diabetes or those in the highest-risk category derive special benefits from their use, due to their innate anti-inflammatory effects. Myopathy and increased liver enzymes are the main potential side effects from statin agents. A reversible increase of serum aminotransferase levels to >3 times normal (ULN) occurs in 1% of patients taking high doses of statins. Discontinuation of the agent is required only if liver enzymes increase to >3 times ULN. Routine monitoring of liver function tests is no longer recommended by the FDA since hepatic side effects trigger symptoms that facilitate prompt discontinuation. Rhabdomyolysis occurs in <0.1% of cases. It can be prevented by the prompt discontinuation of the agent when muscle pain and elevated muscle enzymes occur. Unexplained pain in large muscle groups should prompt investigation for myopathy; however, routine monitoring of muscle enzymes is not supported by any evidence. Side effects from statins may not be class-specific. Therefore, a side effect with one agent should not prevent a trial with another statin agent. Prior concerns about statins causing cataracts or cancer have been alleviated by the release of several meta-analyses.

Statin agents can be combined with fibrates and nicotinic acid, but the potential for side effects is increased. When a statin is combined with a fibrate, the use of fenofibrate is preferred over gemfibrozil because the rate of rhabdomyolysis is much lower. Fibrate agents and nicotinic acid have special efficacy in patients with low HDL and elevated triglycerides, but to date there is limited evidence of improved cardiovascular outcomes despite favorable changes in lipid subfractions. Additionally, nicotinic acid can cause an increase in blood glucose, which can limit its use in diabetic patients.

The bile acid sequestrants cause gastrointestinal side effects and can lead to decreased absorption of other medications. Given their relatively low potency, they are useful mainly as adjuncts. Ezetimibe is a cholesterol absorption inhibitor that lowers LDL and is ideally used in combination with a statin agent. However, trials have not demonstrated benefits in improving cardiovascular outcomes.

C. Complementary and Alternative Therapies

Several complementary or alternative therapies are employed for cholesterol reduction, but the evidence supporting their use is variable. Several are harmless and some could lead to significant side effects. Oat bran (½ cup/d) is a soluble fiber that can reduce TC by 5 mg/dL and TG by 5%. Fish oil (1 g daily of unsaturated omega-3 fatty acids) can reduce triglycerides by ≤30% and raise HDL slightly with long-term use.

Garlic has few side effects, but several trials have shown that it changes lipids minimally. Soy can reduce LDL by ≤15%, with an intake of 25 g/d. This amount is unlikely to be achieved in a Western-style diet. Went yeast (Monascus purpureus) is the natural source for statin agents. As such, it is effective at lowering lipid values, but carries the same side effect profile as statins. Red wine can raise HDL’ however, in amounts of >2 glasses per day, red wine will raise TG and potentially cause hepatic damage and other deleterious health effects. Several other supplements such as ginseng, chromium, and myrrh all have putative cholesterol-lowering effects but little patient-oriented clinical outcome evidence.

Step 8 of the NCEP/ATP III guidelines encourages clinicians to look for the “metabolic syndrome.” The components of this syndrome are abdominal obesity, hypertriglyceridemia, low HDL, hypertension, and glucose intolerance. Aggressive treatment of inactivity, obesity, hypertension, and the use of low-dose aspirin are encouraged in these patients.

Step 9 is the final step of the algorithm. This step focuses on treating elevated triglycerides and low HDL as secondary endpoints of cholesterol therapy. Triglycerides are administered as follows:

The initial steps consist in employing TLC, (weight reduction, increased physical activity, dietary change) and then adding a fibrate or nicotinic acid to reach goal levels.

D. Treatment of Special Groups

The treatment of dyslipidemias in special groups presents problems because fewer trial data are available.

1. Women

Several statin trials included women, although they accounted for only 15–20% of the total enrolled patient population. Subset analysis and meta-analysis reveal that statins reduced coronary events by a similar proportion in women as in men.

2. Elderly

Given that ASCVD is more common in the elderly, it is expected that the benefits of cholesterol lowering would extend to this subgroup. Because of the increased frequency of ASCVD events in this population, the number needed to treat (NNT) is reduced from approximately 35:1, in patients aged 40–55 years, to just 4:1 in patients aged 65–75 years. The 2002 Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) study and several others have confirmed the benefits of lipid lowering with statins for the primary and secondary prevention of ASCVD in patients aged 65–84 years.

3. Children

There are accumulating studies showing the safety of statins in adolescents. However, given concerns of interrupting cholesterol synthesis in the growing body, therapy is usually confined to the very high risk. Therapeutic lifestyle interventions are safe, and can have a profound impact on the long-term health of the child. Cholesterol levels should not be checked in children aged <2 years.

4. Patients aged <35 years

The Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study has demonstrated the ability to correlate degrees of arterial intimal narrowing with the risk factors present in a patient across all age groups. The NCEP/ATP III guidelines specifically address this issue for patients aged 20–35 years. They state that although clinical CHD is rare in young adults, coronary atherosclerosis may progress rapidly, and young men who smoke and have an LDL 160–189 mg/dL may be candidates for drug therapy. In addition, drug therapy should be considered in young men and women with an LDL of >190 mg/d.

E. Indications for Referral

Patients who do not respond to combination therapy or have untoward side effects following therapy should be considered for specialty consultation. Combinations of multiple agents or lipid plasmapheresis may sometimes be required.