Cholesterol Treatment

Statins are generally administered once a day, typically in the evening because most cholesterol synthesis occurs between midnight and 3 A.M. Statins are often prescribed along with other cholesterol-lowering drugs such as bile acid-binding resins, nicotinic acid (niacin), and fibrates.

Beneficial Effects on the Heart and Circulation.

Statins are particularly effective for lowering LDL levels. They also reduce triglycerides, apparently in direct proportion to their LDL-lowering effects. Statins also raise HDL levels, but to a lesser extent than other anti-cholesterol drugs. (The newer "superstatins" appear to produce more significant increases in HDL.) Evidence now strongly suggests that statins may offer other health benefits beyond lowering cholesterol:

• Statins may improve the function of the endothelium (the lining of blood vessels), thereby improving blood flow. (This benefit apparently does not extend to people with diabetes.)
• Statins appear to reduce inflammation in the arteries, which is now believed to be a major factor in blood vessel injury.
• Some evidence suggests that statins may help prevent blood clotting, a major factor in heart attacks.

Beneficial Effects Outside the Heart. Studies also suggest that the benefits of statins go beyond the heart. At this time, nearly all studies on the following conditions have used natural statins:

• Stroke. Statins may reduce the risk for ischemic stroke in high-risk patients with a wide range of cholesterol and lipid levels. (Ischemic strokes occur from blockage in the blood vessels that lead to the brain.) In 2003, statin therapy was shown to reduce both fatal and non-fatal stroke in patients with hypertension and at least three additional cardiovascular risk factors. A 2004 study of stroke patients found that those who were receiving statin therapy at the time of their stroke had more favorable long-term outcomes than patients who were not on statin therapy, suggesting that statin therapy may provide additional benefits to patients who develop stroke.
• Diabetes. Statins may have a number of effects that are helpful for patients with diabetes, and may even prevent diabetes in some people with high cholesterol. Statins, however, do not appear to have any effect on blood vessel inflexibility in diabetes, which is an important risk factor for heart disease in these patients. A major 2003 study found that statin therapy helped prevent cardiovascular events including coronary death, heart attack, stroke, and the need for revascularization therapy in patients with diabetes, even in those who did not have high cholesterol levels or established coronary disease.
• High Blood Pressure. In an important 2002 study, patients with high blood pressure but norhMG-CoA reductasemal or slightly high cholesterol levels had fewer heart attacks and strokes when they took the statin atorvastatin. The study was stopped so all subjects could take statins. An earlier study showed similar benefits with the statin simvastatin.
• Alzheimer's Disease. A number of studies have reported a significantly lower risk for Alzheimer's disease in people who take specific statins. Some evidence suggests they may even improve mental function in people without unhealthy cholesterol levels. Statis showing the greatest promise include lovastatin (Mevacor), pravastatin (Pravachol), and atorvastatin (Lipitor.) These statins appear to reduce levels of beta-amyloid. Other statins have not been associated with a lower risk for Alzheimer's. In fact, some researchers are concerned that certain statins that cross the blood-brain barrier may actually worsen Alzheimer's in people who already have it.
• Osteoporosis. Some preliminary reports have suggested that statins may protect against bone loss in older women. It is not clear, however, if the statins themselves have properties that prevent osteoporosis or if any cholesterol-lowering drug would work equally well.
• Kidney Disease. Statins may prove to protect against heart disease development in patients with mild kidney disorders. According to a 2004 study, statins may also help slow the progression of existing kidney disease.
• Eye Disease. Studies are investigating whether statins can help prevent macular degeneration, an age-related eye disease that can lead to blindness. Research is still preliminary, and results have been mixed.

Adverse Effects. The statins tend to be better tolerated than other cholesterol-lowering drugs. In many studies the side effects reported were nearly the same as those taking placebo. Side effects may include gastrointestinal discomfort, headaches, skin rashes, muscle aches, sexual dysfunction, drowsiness, dizziness, nausea, constipation, and peripheral neuropathy (numbness or tingling in the hands and feet).

The primary safety concern with statins has involved an uncommon condition called myopathy, which can cause muscle damage and in some cases, muscle and joint pain. A specific myopathy, called rhabdomyolysis, can lead to kidney failure. Reports of rhabdomyolysis prompted the recall of cerivastatin (Baycol) in 2001. The risk for myopathy/rhabdomyolysis is highest at higher doses and in older people (over 65 years), those with hyperthyroidism, and those with renal insufficiency (kidney disease). Both statins and fibrates carry a risk for myopathy. The combination of the two drugs increases this side effect. Some people who use a statin-fibrate combination withdraw from the regimen because of muscle discomfort.

In 2005, the FDA issued a public health advisory for rosuvastatin (Crestor), noting that this drug, like other statins, increased the risk for myopathy and rhabdomyolysis. The risks were greatest at the highest dose level (40 mg). The FDA advises that patients should not start therapy at this dose. In addition, the FDA reported the results of a post-marketing study that found that people of Asian heritage had twice the blood levels of the drug as Caucasians who had taken the same dose. Because of this difference in drug metabolism, the FDA advises that Asian Americans should start treatment at the lowest rosuvastatin dose (5 mg). In general, all statin therapy should start at a lower dose and be raised incrementally until healthy cholesterol levels are maintained. Patients should immediately tell their doctor about any unusual muscle discomfort or weakness, fever, nausea or vomiting, or darkening of urine color.

Statins can also affect the liver, particularly at higher doses, so patients should have periodic liver function tests. Statins should not be taken by anyone with liver problems or by women during pregnancy or breast-feeding. Similarly, high statin doses increase the risk for kidney failure, particularly for patients with other existing risk factors (diabetes, hypertension, atherosclerosis, history of heart failure).

Interactions with Drugs and Food. Statins may have some adverse interactions with other drugs, including other cholesterol-lowering medications. Among the drugs that increase the risk for adverse effects are cyclosporine, macrolide antibiotics, and certain antifungals. Patients should tell their doctors about any other medications they are taking. Grapefruit juice and Seville oranges may increase statin potency.

Nicotinic Acid (Niacin)

Brands. Nicotinic acid is the active compound found in niacin, or vitamin B3. It is the first choice for patients with low HDL levels. Brands include Niacor, Nicolar, and Slo-Niacin. An extended-release form (Niaspan), administered at bedtime, may have fewer side effects, including headaches and flushing, than rapidly-acting niacin drugs. Although niacin is available over the counter, the active form used for cholesterol is given in much higher doses and is available only by prescription. It is important to take this medication under a doctor's direction in order to ensure its safety and effectiveness.

Benefits. When used in high doses, it has the following benefits:

• Raises HDL levels higher than other anti-cholesterol drugs
• Reducing triglyceride levels very effectively
• Lowers LDL-cholesterol and lipoprotein(a).
• Costs less than other anti-cholesterol drugs

Combinations with other drugs, particularly statins, may add significant benefits.

Side Effects. Many patients find nicotinic acid's side effects intolerable. About a quarter of patients who use rapid-acting forms of nicotinic acid stop taking them. The most common side effects are flushing of the face and neck, itching, headache, blurred vision, and dizziness. They usually occur between 5 minutes to hours after taking the drug and can last for minutes to, uncommonly, hours. The body does eventually become tolerant to these effects, and they generally subside.

The following may reduce flushing and itching:

• Starting with low doses taken at mealtime and gradually working up to the prescribed dose.
• Taking low-dose aspirin about 30 minutes before taking nicotinic acid. This may help prevent flushing.
• Avoiding hot drinks.
• Choosing an extended release form. (Even with this form, it is wise to gradually increase the bedtime dose over time and take a low-dose aspirin a half-hour beforehand.)

Stomach problems are common. Other side effects include dry skin and mucous membranes and darkening of the skin.

About 30% of patients who take niacin experience elevated levels in blood glucose, which can be a problem for people with diabetes. Niacin's effects on HDL and triglycerides, however, are especially suited for the lipid imbalances that are common in diabetes. And, some studies report that people with diabetes who use niacin have little trouble with blood sugar control.

Potentially Serious Complications. About 3 - 5% of people taking nicotinic acid develop liver problems, which disappear after the medication is discontinued. The extended form (Niaspan) appears to be safe for the liver, but people with chronic liver disease should not use any form of nicotinic acid. People with gout should also avoid nicotinic acid because it elevates uric acid.

Bile-Acid Binding Resins

Bile-acid binding resins work, as their name suggests, by binding to bile in the digestive tract. This reduces cholesterol in the following way:

• Bile is made in the liver and is used as one of the body's primary manufacturing components.

Click the icon to see an image of the gallbladder.

• Once the resins bind to bile in the digestive tract, the bile is excreted in feces.
• As the resins eliminate bile from the body, the liver takes more cholesterol from the bloodstream in order to produce more bile.
• As cholesterol is taken out of the bloodstream, LDL levels drop.

When used in combination with dietary control, LDL levels are reduced by 15 - 20%. Combinations with nicotinic acid are even more effective, with reductions of 40 - 60% observed.

Brands. The bile-acid binding resins and similar drugs include cholestyramine (Questran, Questran Light) and colestipol (Colestid). They are commonly used either in a powder that is dissolved in liquid or as a chewable bar (Cholybar). Colesevelam (Cholestagelm, Welchol) is available in tablet form.

Side Effects. None of these drugs poses major risks. Most, however, cause constipation, heartburn, gas, and other gastrointestinal problems, side effects that many people cannot tolerate. One study found that only half the standard dose of colestipol was needed when psyllium, (a soluble fiber supplement found in Metamucil, Fiberall, and Perdiem), was added to the drink. In addition, bloating and constipation were reduced. Colesevelam, a newer resin, appears to have significantly fewer of these side effects.

Bile-acting drugs may contribute to calcium loss and therefore increase the risk for osteoporosis. Over time, deficiencies of vitamins A, D, E, and K may occur, and vitamin supplements may be necessary.

Rarely, toxic effects on the liver have been reported. Patients with liver disorders should be monitored.

Drug Interactions. Bile-acid binding resins may also interfere with other medications, including digoxin (Lanoxin), warfarin, beta-blocker drugs, and a number of medications used to treat low blood sugar. In order to prevent drug interactions, other drugs should be taken 1 hour before or 4 to 6 hours after taking the bile acid-binding resins.

Fibrates

Brands. Fibrates (sometimes called fibric acid derivatives) break down the particles that make triglycerides. Gemfibrozil (Lopid) is the standard fibrate. It is usually taken twice a day, 30 minutes before breakfast and before the evening meal. Newer fibrates, including fenofibrate (Tricor) and bezafibrate (Bezalip), may be more effective in lowering cholesterol than gemfibrozil. Clofibrate (Atromid-S) was the first fibrate used but is now rarely prescribed because of its serious side effects.

Benefits. Most fibrates have been shown to lower the risk of heart attack. In a 2001 study, men with both low HDL and LDL levels had a slightly lower risk of stroke after taking gemfibrozil. Fibric acid derivatives, or fibrates, have the following effects on cholesterol, lipids, and other factors:

• They are good choices for many patients who need to lower triglyceride levels and increase HDL but who cannot take drugs ordinarily used for these purposes, such as nicotinic acid. In one study gemfibrozil, the standard fibrate, reduced the risk for adverse heart events by 22%.
• Fibrates can produce modest reductions in LDL levels, although not as effectively as statins or other drugs. LDL may actually increase in patients with very high triglycerides who take these drugs. (The newer fibrates are much more effective in lowering LDL than gemfibrozil.)
• A study on bezafibrate suggested it might have anti-inflammatory effects in patients with high triglyceride levels. Inflammation in the blood vessels is now recognized as a major contributor to the disease process leading to heart disease. However, according to a 2004 study, patients with diabetes or impaired fasting glucose levels were less likely to benefit from bezafibrate.
• A study on fenofibrate further suggested that it reduced certain clotting factors (another risk factor for heart disease) and also uric acid (a risk factor for gout). Another study, published in 2004, demonstrated that like bezafibrate, fenofibrate has significant anti-inflammatory properties in patients with high triglyceride levels.

Concerns. Fibrates do not appear to reduce mortality rates. In one study, people who took gemfibrozil had higher rates of death from other causes, including cancer. Some evidence suggests that fibrates may affect receptors involved in cancer development. However, a number of studies have found no higher incidence of cancer.

Side Effects. Side effects may include gastrointestinal discomfort, aching muscles, sensitivity to sunlight, and skin rashes. Fibrates have been known to cause gallstones, so people with gallbladder problems should not use these drugs.

Click the icon to see an image of gallstones in the gallbladder.

The drugs may cause abnormal heart rhythms and can affect the liver and kidney.

Drug Interactions. Fibrates interact with a number of drugs and substances including warfarin, some oral drugs used for diabetes, certain antibiotics, and grapefruit juice.

Plasmapheresis and Familial Hypercholesterolemia

Plasmapheresis is a blood-filtering procedure that is used to dramatically reduce triglycerides and may also be used to remove LDL. The procedure may be beneficial for patients with severe hereditary forms of high cholesterol that do not respond to other therapies. Studies suggest, for example, that plasmapheresis is particularly useful for patients with familial hypercholesterolemia. The process takes about 3 hours. If not performed regularly, its benefits last only about 2 weeks. People using this procedure are still advised to maintain a healthy diet and continue to take any prescribed medications to control cholesterol.

Ezetimibe

Ezetimibe (Zetia) inhibits the absorption of cholesterol in the intestines and is proving to be very effective when used in combination with statins. In one study, a combination of ezetimibe and simvastatin (Zocor) reduced LDL cholesterol levels by 57% compared to 18% with ezetimibe alone and 44% with simvastatin alone. A 2004 study demonstrated that ezetimibe might be particularly useful for patients who cannot achieve their cholesterol goals with statins alone.

Investigative Therapies

CETP Inhibitors. Cholesteryl ester transfer protein (CETP) inhibitors, such as the experimental drug torcetrapib, are being investigated for their effect on raising HDL ("good" cholesterol) levels while lowering LDL ("bad" cholesterol) levels. Torcetrapib, both alone and in combination with statin therapy, is being studied in several clinical trials. A small trial published in 2004 in the New England Journal of Medicine indicated promising results, particularly when torcetrapib was administered along with a statin.

Selective Estrogen-Receptor Modulators(SERMs). Selective estrogen-receptor modulators (SERMs) have been designed to produce the benefits of estrogen without its risks. They are thought to act like estrogen in some tissues but behave like estrogen blockers (antiestrogens) in others. They include tamoxifen (Nolvadex), raloxifene (Evista), and droloxifene. Any beneficial effects of the SERMs on cholesterol and the heart are still unclear. SERMs pose a risk for deep vein blood clots, which may have implications for people with heart problems. Longer studies are needed on possible risks and benefits.

Recombinant ApoA-I Milano. ApoA-I Milano is a type of HDL protein that is found in people with very low levels of HDL. A 2003 study showed that treating patients with a synthetic form of HDL, derived from ApoA-I Milano, caused a significant regression of atherosclerosis. Ongoing trials will evaluate whether this drug can prevent cardiovascular events such as heart attack or death.