You’ve seen the magazine ad — a man and woman sit next to each other at a lunch counter. His haunches spread way beyond the edges of the stool, and his shirt back ripples with rolls of fat. On the other hand, she looks great; her blouse is tucked into a skirt that spans a waist of enviable proportions. Slim legs, crossed at the ankles — not an extra ounce of fat anywhere. The kicker — both have sky-high cholesterol. Both need the medication advertised. Make no assumptions, the ad implies. You can’t tell from the outside whose cholesterol is high and who boasts a normal level. Get tested, and get treated now, it seems to say. In fact, under the criteria of current National Institutes of Health guidelines, an estimated 36 million Americans fit the description of those who require medication therapy to manage hyperlipidemia.¹ Moreover, treatment can vary from person to person regardless of each one’s lipid profile. Some people respond well to changes in diet and exercise. Others need to add medication therapy to the lifestyle changes they’ve made, and still others require more than one drug to meet LDL goal levels and decrease their risk of cardiovascular disease (CVD).

Part one of this self-study module on cholesterol management (available online at http://nsweb.nursingspectrum.com/ce/ce337.htm) presented information on assessing patients at risk for CVD related to various types and degrees of hyperlipidemia; it explained how concurrent medical conditions affect risk. Therapeutic lifestyle changes that may help reduce hyperlipidemia were also discussed. Part two presents information about five groups of medications available to treat patients with hyperlipidemia who require more than a healthier lifestyle to reach LDL goal levels and decrease their risk of CVD; a summary of major alternative therapies is also included.

The medication route

To guide health care practitioners, the National Institutes of Health published the third report of the National Cholesterol Education Program (NCEP) in May 2001. An expert panel reviewed major studies on lipid control and developed the evidence-based Adult Treatment Panel III (ATP III) guidelines, which were updated in 2004 based on further clinical trials.^2,3

Treatment recommendations target elevated LDL as the primary lipid to lower, although elevated triglycerides and/or a low HDL may also be treated. The ATP III guidelines present criteria for the use of medication to control lipids when patients have not been able to reach their goal after a trial of therapeutic lifestyle changes, also outlined by ATP III. Nurses who educate patients on the risks associated with continued hyperlipidemia and the importance of diet and exercise in lipid management and overall health also teach them about the medications they need to manage their lipid disorder. They teach patients about the importance of ongoing follow-up to monitor their cardiovascular health and their response to lifestyle changes and medications.

Most patients need follow-up that includes a fasting lipid profile and liver function tests (LFTs) four to six weeks after starting a medication regimen, after a dosage change, and then periodically, usually every six to 12 months. Clinicians should also check creatinine kinase (CK or CPK) levels to assess for potential muscle damage if the patient complains of muscle pain or weakness while taking medication.⁴

Currently, five classes of prescription medications are available to treat dyslipidemia. When medication is prescribed, nurses must reinforce the fact that dietary recommendations and exercise can’t take a back seat. Medication is just one more tool to help lower the risk of CVD.

Statins

The most commonly used medications to lower total and LDL cholesterol are HMG-coenzyme A reductase inhibitors, referred to as statins. Lovastatin (Mevacor) was the first approved in this class and became available in 1987. Today, six statins are available in the U.S. Statins interrupt liver cholesterol synthesis at the HMG-CoA reductase step and also cause the liver to clear LDL from circulation. The liver forms more cholesterol at night, so the statin medications with a shorter half-life (simvastatin [Zocor], fluvastatin [Lescol], and lovastatin) are somewhat more effective if taken in the evening. The other statins (pravastatin [Pravachol], atorvastatin [Lipitor], and rosuvastatin [Crestor]) may be taken at any time during the day.⁵ It is also thought that statins stabilize unstable plaque and improve endothelial dysfunction.^6,7 In addition to lowering total and LDL cholesterol, statins lower triglycerides and raise HDL by varying degrees.

Pravastatin, fluvastatin, and rosuvastatin have fewer interactions and may be more appropriate for patients taking several medications. Table 1 (in the online version of this CE) gives a summary of the statin medications available in the U.S. Key points for clinicians to include in managing therapy are to —

• Draw a baseline fasting lipid profile and LFTs before statin therapy starts.
• Assess the patient’s baseline muscle status, including complaints of muscle aches and weakness.
• As an option, a baseline CK level may be checked before starting a statin. Myalgia, myopathy, and muscle weakness can occur as the result of statin therapy, particularly if the statin is used in a high dose or in combination with niacin or a fibrate.
• Assess for any significant change from baseline muscle status after the drug therapy starts, and instruct patients to report changes to their health care provider.
• Observe for other adverse effects, e.g., gastrointestinal (GI) disturbances, rash, and liver toxicity (rare, although dose-dependent elevations in LFTs occur in 0.5 to 2% of patients talking statins).⁶
• Watch for signs of muscle breakdown, known as rhabdomyolysis, accompanied by acute renal failure, an even rarer adverse effect that usually occurs with concomitant use of fibrates, antifungals, cyclosporines, or macrolides, which includes erythromycin, telithromycin (Ketek) and azithromycin (Zithromax).
• Caution patients on statins to avoid grapefruit since it is also metabolized through the same liver pathway as several of the statins; taking one of these statins with grapefruit may increase the effects and risk of adverse effects of the statin.
• Take into account that most statins should be used at lower dosages in patients with renal impairment.
• The hepatic enzyme CYP 3A4 (a pathway to metabolize certain substances, including many medications) metabolizes simvastatin, lovastatin, and atorvastatin and may interact with many other drugs, including erythromycin, ketoconazole (Nizoral), clarithromycin (Biaxin), verapamil (Calan), and diltiazem (Cardizem).
• Check on the need to withhold statins during hospitalization for major surgery, except cardiovascular surgery, to reduce the risk of serious myopathy.⁶

Nicotinic Acid/Niacin

Niacin, which is vitamin B3, has been used in high doses to treat dyslipidemia for 40 years. Niacin is most effective in treating a low HDL and elevated triglycerides. Its mechanism of action is to decrease the production and release of very low density lipoproteins (VLDL) and decrease the release of free fatty acids from adipose tissue into the circulation.⁶ A dose of 1-2 g extended release/day will decrease LDL by 5% to 25 %, increase HDL by 15% to 35%, and lower triglycerides by 20% to 50%. Niacin also decreases Lp(a), an emerging risk factor for coronary heart disease.^3,6 Niacin is available in an immediate-release, generic, over-the-counter form, but is often not well-tolerated, causing flushing and itching in more than 90% of users, and it has been associated with hepatotoxicity.^6,8 Prescription, extended-release niacin (Niaspan) has improved tolerability, particularly if the patient takes aspirin 325 mg 30 minutes before taking the niacin with a low-fat snack. Extended-release niacin is started at a dose of 500 mg daily, and titrated up to improve tolerability. Extended-release niacin is associated with improved safety, having a reduced incidence of hepatic toxicity compared with immediate release.⁸

Key points to remember include —

• Draw baseline fasting lipids, glucose, and liver function studies before starting niacin; draw uric acid levels for those with a history of gout. Recheck these levels six to 12 weeks after reaching the target dose.
• Monitor LFTs every three months for a year, then every six to 12 months.^2,8
• Advise patients to take niacin with food at bedtime to lessen gastrointestinal (GI) disturbance. Avoid hot beverages, spicy foods, and alcohol to improve tolerance.
• Avoid niacin in those with liver disease.
• Start with a low dose, and gradually increase to the therapeutic dose.
• Use cautiously in those with gout, diabetes, and peptic ulcer. Niacin can increase uric acid levels and cause glucose intolerance.
• Monitor blood glucose periodically. Niacin has the potential to elevate glucose.
• Monitor patients taking niacin and statins together. The combination can increase the risk of myopathy.^6,8

Fibric acid derivatives

In the U.S., two fibric acid derivatives (fibrates) are available — gemfibrozil (Lopid) and fenofibrate (TriCor). These medications are used primarily in patients with elevated triglycerides or low HDL and may lower triglycerides by 20% to 50%, while raising HDL by 10% to 35%.⁹ Fenofibrate is more likely to lower LDL than gemfibrozil, with reductions of 5% to 20%. Fibrates also alter the composition of small dense LDL.⁶

The fibrates act as peroxisome proliferative-activated receptor (PPAR) agonists, which are important in lipoprotein metabolism. The result is an increase in HDL, a lowering of triglycerides, and an increase in LDL particle size.¹⁰ In addition, fibrates reduce hepatic cholesterol synthesis and increase cholesterol excretion in bile. Recent studies have shown they may lower coronary heart disease mortality in patients with obesity, type-2 diabetes mellitus, or metabolic syndrome.¹¹

Gemfibrozil is usually given as 600 mg twice a day, ideally 30 minutes before breakfast and dinner. Fenofibrate is given as 145 mg once daily, with or without food. Lower doses may be used in patients with renal disease or in those already taking a statin.

Fibrates are generally well tolerated when used alone, with mild adverse effects, such as GI upset and rash. The risk of myopathy and rhabdomyolysis increases when fibrates are used with statins. Key points to keep in mind —

• Start fibrates, particularly gemfibrozil, at a low dose if used in combination with statins.
• Check baseline hepatic function, renal function, and CK levels and closely monitor the patient for muscle complaints if used in combination with statins, i.e., watch for tenderness, weakness, and brown urine (myoglobinurea).¹²
• Give fibrates with great caution or not at all to people with severe hepatic or renal insufficiency. Fibrates are metabolized in the liver and excreted in the urine.
• Watch for cholilithiasis and cholecystitis. The risk increases with fibrates.
• Monitor LFTs and CBC periodically. Fibrates occasionally decrease Hgb, Hct, and WBCs.
• Be prepared to reduce the dose of warfarin up to 30% in those receiving this drug. Fibrates can potentiate its action.⁶

Bile acid sequestrants (resins)

Bile acid sequestrants include cholestyramine (Questran), colestipol (Colestid), and colesevelam (WelChol). Colesevelam is the newest and best tolerated of this class. The most common adverse effects are GI, because bile acid sequestrants work by decreasing the reabsorption of bile acids in the intestine. With increased excretion of bile acid in the stool, the liver responds by increasing the rate of clearance of LDL from the plasma to form new bile acids.^2,6 Resins can lower LDL by 15% to 30%, with a possible increase in HDL of 3% to 5% and no effect, or a slight increase, for triglycerides. Colesevelam is dosed at 3,750 mg once a day or in two divided doses with meals, which consists of three capsules of 625 mg twice a day. It is the best tolerated of the resins, causing less constipation, but possibly abdominal discomfort and flatulence. Unlike cholestyramine and colestipol, colesevelam does not impair absorption of other medications. Because this medication works in the gut rather than systemically, it is viewed as safe. One key point is to monitor LFTs in patients receiving a statin and a resin; mild elevations in LFTs may occur.⁶

Cholesterol absorption inhibitor

Ezetimibe (Zetia) is the first medication of a new class called cholesterol absorption inhibitors. Released in 2002, ezetimibe inhibits absorption of cholesterol at the brush border of the intestine and is used primarily as an add-on medication to statin therapy. The usual dose is 10 mg daily. The drug lowers LDL by 18% and triglycerides by 8%; it raises HDL by 10% when used alone. When used in conjunction with a statin to help a patient reach goal, ezetimibe reduces total cholesterol an additional 17%, LDL an additional 25%, and triglycerides by 14%. HDL increases an additional 3% above the benefit shown by statins. The hs-CRP (high sensitivity C-reactive protein) is also reduced an additional 10%. Maximum effect of ezetimibe is seen within two weeks. Key points —

• Do not adjust the dose for patients with renal or liver disease if ezetimibe is used alone.
• Monitor LFTs when the patient takes ezetimibe with a statin.^2,6,13

Prescription Omega-3 fatty acid

A prescription strength (1 Gm) Omega-3 fatty acid capsule (Omacor) was released in 2005. The target dose to lower very high triglycerides of >500mg/dL is 4 Gm/day. Omega-3 fatty acids at high doses may potentiate anticoagulants, so caution is advised.¹⁰

Combination therapy

Lowering LDL cholesterol is the primary treatment goal as defined in ATP III. Not infrequently, a statin medication used alone may lower the LDL, but not to the goal level recommended by ATP III. In other cases, the LDL may be at goal, but high triglycerides (>200 mg/dL) or low HDL (<40 mg/dL) remain. This continues to leave the patient at risk for CVD. Statin medications are estimated to prevent 20% to 30% of cardiac events. Combinations of medication can further lower risk and help patients attain their LDL goals.

A standard dose of a statin medication will lower LDL by 30% to 40%. When further reduction in LDL is needed, doubling the standard dose of the statin leads to only about a 6% further reduction, but can greatly increase the risk of adverse effects.¹² Combination therapy can give better LDL reduction and lessen the risk of adverse effects.

Combining medications that have different modes of action can produce an additive or synergistic effect. Lower doses of each medication can be used, causing fewer adverse effects. A disadvantage is that more medications are taken, which may increase patient cost and decrease compliance.⁹

Some patients are unable to tolerate a statin, usually due to myalgia or myopathy. In these cases, a reduced dose or another statin may be tried, which may be better tolerated. If the patient is unable to take any statin, ezetimibe may be used alone or with other medications to lower LDL. If the patient’s LDL is near goal, but the triglycerides remain high or HDL is too low, niacin or a fibrate are the most effective in correcting these lipid problems.¹²

What’s the alternative?

While a large amount of data supports medication therapy to reduce risk, patients often ask about alternative methods. Some are hesitant to take medication to control high cholesterol. Some may deny the health risk involved or balk at the cost of medication. Others may want to try a “natural” approach. Often, the caring professional is the one to provide the key information that helps patients make the healthy choice. Despite thorough education, patients may still feel reluctant to take the well-studied statins, or they may not be able to tolerate these medications. A few other options are available, with the best-researched summarized below:

• Therapeutic lifestyle changes, such as weight loss if overweight, exercise of at least 30 minutes each day, no tobacco use, and a diet as outlined by ATP III can lower total and LDL cholesterol, reduce triglycerides, and raise HDL. The addition of oat bran, fiber, nuts, and soy may have benefit. Plant stanols, available in margarine-like spreads called Benecol® and Take Control®, can lower LDL by 10% to 15% if taken daily in sufficient quantities. Alcohol in modest amounts (one to two drinks per day) may increase HDL, but higher alcohol consumption causes elevated triglycerides.
• Fish oil/omega-3 fatty acids at 2 Gms/day to 4 Gms/day may lower triglycerides 25% to 30% and have antiplatelet and antiarrhythmic properties, as well as modestly increasing HDL.^6,14
• Red yeast rice can reduce total cholesterol by 16% to 31%, decrease LDL, and raise HDL. Adverse effects include stomach upset, gastroesophageal reflux, and dizziness.¹⁵
• Policosanol, derived from sugar cane, may reduce LDL and raise HDL by inhibiting hepatic cholesterol synthesis. Doses of 5 mg to 10 mg twice a day are usual. Adverse effects include headache and insomnia.¹⁶

If patients decide to try alternative therapy, nurses must help them understand that the products used are not well researched. Long-term safety is not established, and often the active ingredients in products cannot be identified or guaranteed. In addition, no outcome data exists that clearly demonstrates the effectiveness of alternative products in decreasing the rate of actual cardiovascular events or death.

Well-informed nurses are often the ones who best understand the communication strengths, learning style, and cultural beliefs of patients. Nurses are in a key position to explain the risks associated with lipid disorders and the effective treatment options available and then help patients make conscious, informed choices. They are also there to coach patients through necessary lifestyle changes and guide them through follow-up of a medication regimen.