Cholesterol, Other Lipids, and Lipoproteins

Description

An in-depth report on the diagnosis, treatment, and prevention of high cholesterol.

Treatment

In 2002, the National Cholesterol Education Program's Adult Treatment Panel issued its latest recommendations. The results of these guidelines would increase the number of Americans who should LDL-lowering agents from 15 million to 36 million, with significant increases occurring in people younger than 45, those older than 65, and among men in all age groups. An interim update to the NCEP guidelines is expected in 2004.

Starting Medications. According to a 2003 report, only 5.4% of patients with hypercholesterolemia are adequately treated, meaning that they have reached their target cholesterol levels with lipid-lowering therapy. Even modest lowering of cholesterol in those whose levels are high, whether through drug therapy or lifestyle changes, reduces the risk of disability and death from heart disease. Most experts now focus on lowering LDL cholesterol, the bad kind. Expert guidelines now recommend starting cholesterol-lowering drugs along with a diet and exercise regimen for the following groups:

• People with LDL levels of 130 mg/dL or greater if they have existing heart disease or risk factors that pose a 10% to 20% risk for a heart attack within 10 years. Such factors include diabetes or other diseases that suggest atherosclerosis (such as peripheral artery disease or blockage in the carotid artery). Their goal is to achieve LDL of 100 mg/dL. (Some of these individuals may actually want to start medication at LDL levels as low as 100 mg/dL.)

• People with LDL cholesterol levels of 160 mg/dL or greater who have no existing heart disease but have two or more risk factors for heart disease. Their goal is an LDL of 130 mg/dL or less.
• People whose LDL is 190 mg/dL or over and have one or no risk factors. They should strive for LDL levels of 160 mg/dL or less. (Some of these individuals might consider medications if they have LDL over 160 mg/dL.)

In 2004, two major studies found that aggressive lipid lowering with high-dose statin therapy is more beneficial than standard statin therapy in patients with existing cardiovascular disease. In one study of patients who had recently been hospitalized for high-risk unstable angina or myocardial infarction, those who achieved a mean LDL-C level of 62 mg/dL on high-dose statin therapy had a significantly lower risk of death, MI, recurrent unstable angina, stroke, and the need for revascularization therapy than did patients on standard therapy. The second study found treatment with high-dose statin therapy halted the progression of atherosclerosis, whereas standard-dose statin therapy allowed atherosclerosis to progress.

Three additional studies evaluating the benefits of high-dose versus moderate- or low-dose stating therapy are expected to report their results in late 2004 or early 2005. As clear benefits of aggressive lipid lowering with high-dose statin therapy start to emerge, experts predict that future cholesterol guidelines will recommend target LDL-C well below the current target of 100 mg/dL in patients with diagnosed cardiovascular disease.

Evidence now strongly suggests that cholesterol-lowering drugs are improving survival in heart attack patients. Nevertheless, a 2001 study of Massachusetts residents reported that only 24% of patients were tested for high cholesterol levels after a heart attack and only about 30% who showed unhealthy cholesterol were actually given cholesterol-lowering drugs.

It is always important to emphasize that cholesterol-lowering medications are used along with healthy lifestyle habits , not in place of them. In spite of these guidelines, fewer than half of people who would presumably benefit from cholesterol-lowering drugs are taking them.

Choosing the Correct Lipid-Lowering Medication. Experts now recommend that drug treatments be tailored for raising or lowering specific lipids, depending on the patient's blood lipid picture:

• Statins are now the standard agents for most people who require LDL-lowering therapy. Bile-acid binding resins or niacin may be considered. (Another LDL-lowering agent, probucol, is usually limited to people with genetic disorders that cause severely high cholesterol levels.) If LDL goals are not achieved, combinations of a statin with a bile-acid resin or niacin should be considered.
• Fibrates or niacin are beneficial for people who need to lower triglycerides and increase HDL.

Considerations for Children and Adolescents. Children and adolescents with high cholesterol levels should first change any lifestyle risk factors (obesity, high-fat diet, sedentary habits) that might responsible. Young people over seven or eight years old with evidence of inherited unhealthy cholesterol levels (LDL over 190 mg/dL) may benefit from the following medications:

• Statins are proving to be effective for children with genetic conditions that cause early elevations in cholesterol and is proving to be helpful in reducing long-term dangers.
• Bile-acid binding resins may be an alternative option choice, assuming the child has normal triglyceride levels. A multiple vitamin with folic acid and iron supplements may be needed in such cases.
• Nicotinic acid (niacin) may be an option for young people with high triglycerides.

Cholesterol-lowering agents are also being for some children with high cholesterol levels without evidence of genetic causes. It should be noted that there is no evidence on the long-term safety of statins or any cholesterol-lowering agents in children. Parents should discuss medications very carefully with their physicians and, in any case, should always focus on lifestyle factors.

Considerations for People with Diabetes. At this time the best agents for improving cholesterol and lipid levels in people with diabetes are the statins. Studies suggest that they can reduce the risk for adverse heart events in people with diabetes, even if their cholesterol levels are normal or if their diabetes is mild. Further, in one study, a statin was shown to reduce the risk of developing diabetes by 30% in people with high cholesterol. Fibrates may also be useful for people with type 2 diabetes. Niacin (nicotinic acid) has the best effect on the cholesterol profile of people with diabetes but it also increases blood sugar levels. One well-controlled study, however, found that diabetics who used niacin had little trouble with glucose control, and some experts believe it now may be used as an alternative to or in combination with statins.

Statins

Statins are the most effective drugs for the treatment of high cholesterol, and may even become important agents for many people at risk for heart disease who have normal cholesterol levels or below. Statins inhibit the liver enzyme hMG-CoA reductase, which is used in the manufacturing of cholesterol. These agents effectively reduce the risk of major coronary events, including first and second heart attacks, in both women and men and in adults at any age (including the elderly) with unhealthy cholesterol levels. Experts estimate a 25% to 30% reduction in mortality rates when patients take statins after a heart attack. (Some believe the decrease may even be greater.) These drugs may also help improve the outcome in patients with heart disease who have had angioplasty.

Furthermore, important 2002 studies reported lower rates of heart attack, stroke, and mortality rates from all causes in statin users who were at high risk for heart disease, even if they had normal or low cholesterol levels. Benefits were proportionately similar in these people regardless of gender, age, or the presence of specific heart risk factors, such as diabetes or peripheral artery disease. One major 2002 study, however, muddied these findings by reporting no reduction in mortality rates or heart disease in high-risk patients with moderately high LDL levels. Some experts believe that statin treatment was not aggressive enough in this study.

Brands. The statins may currently be categorized into three groups:

• So-called natural statins, including lovastatin (Mevacor), pravastatin (Pravachol), and simvastatin (Zocor). These are the most studied statins and have proven effectiveness and good safety record.
• Synthetic statins include fluvastatin (Lescol) and atorvastatin (Lipitor). Studies using atorvastatin suggest they reduce LDL more effectively at equal doses to the natural statins. Lipitor has also now been approved for children. One 2002 study further reported an association between atorvastatin and a reversal in coronary artery disease. Disease only stabilized with the use of less potent statins.
• The newer statins, called "superstatins" by their manufacturers, include rosuvastatin (Crestor) and itavastatin, which has not yet been FDA approved. Crestor is more effective in lowering LDL and increasing HDL levels than most other statins, and enables more patients to achieve target LDL-C goals. Itavastatin, a Japanese agent, may be even more potent. Longer and more objective research is needed, however, to confirm any of these findings as well as any long-term adverse effects.

Statins are generally administered once a day, typically in the evening because most cholesterol synthesis occurs between midnight and 3 A.M. (One interesting 2002 study suggested that Lipitor could be taken every other day, which reduces its cost, and still remain effective.)

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.) Furthermore, evidence now strongly suggests that statins have mechanisms beyond lowering cholesterol levels that offer health benefits -- not only to the heart but to other organs. Some studies suggest the following:

• Statins improves the function of the endothelium (the lining of blood vessels), thereby improving blood flow. (Oddly, 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 curtail blood clotting, a major factor in heart attacks.

Beneficial Effects Outside the Heart. Studies are also suggesting that the benefits of statins go beyond the heart. At this time, nearly all these studies on the following conditions have been conducted with the 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 did patients who were not on statin therapy, suggesting that statin therapy may provide additional benefits to patients who develop stroke.
• Diabetes. Studies have suggested that statins may have a number of effects that can be very helpful for patients with diabetes, and may even prevent it 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 helps prevent cardiovascular events including coronary death, MI, stroke, and the need for revascularization therapy in patients with diabetes, even in those who do not have high cholesterol levels or established coronary disease.
• High Blood Pressure. An important 2002 study, patients with high blood pressure but normal 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 had shown similar benefits with the statin simvastatin.
• Alzheimer's Disease. Of considerable interest are a number of studies now reporting a significantly lower risk for Alzheimer's disease in people who were taking specific statins. Some evidence suggests they may even improve mental function in people without unhealthy cholesterol levels. Those showing promise include lovastatin (Mevacor), pravastatin (Pravachol), and atorvastatin (Lipitor.) Such statins appear to reduce levels of beta-amyloid. Other statins have not been associated with an 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. There have been some reports and animal studies suggesting 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 agent can be helpful. Few clinical trials have been published, to date, and more work is needed to confirm any effect on bones.
• Kidney Disease. Statins may prove to safely protect against heart disease in patients with mild kidney disorders. According to a 2004 study, statins may also help slow the progression of existing kidney disease.
• Eye Disease. In one small 2002 study, statins appeared to help prevent macular degeneration, an age-related eye disease that can lead to blindness.

Macular degeneration is a disease of the retina that affects the macula in the back of the eye. The macula is important for clear cental vision, allowing an individual to see fine details. There are two types of macular degeneration, dry and wet. Dry macular degeneration is more common and is characterized by the thinning of the retina and drusen, small white deposits that form within the retina. The dry form of macular degeneration is usually mild. Wet macular degeneration can happen more quickly and be more serious. It occurs when vessels under the retinal layer hemorrhage and cause the retinal cells to die creating blind spots or distorted vision in the central vision. The disease becomes increasingly common amongst people in each succeeding decade over 50.

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 (inactive agents). Those reported 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. The risk for myopathy is highest at higher doses and in older people, those who are small or frail, people who abuse alcohol, and those who are hypothyroid. There is also a higher risk if statins are used before surgery, and if people are taking multiple medications.

Severe cases of myopathy warrant discontinuation. In the past, there have been a few reports of a specific myopathy called rhabdomyolysis that can lead to kidney failure. Of note, fatal events from rhabdomyolysis occurred in less than 1 out of a million prescriptions and nearly always with the statin cerivastatin (Baycol), particularly at high doses and in combination with fibrates. Baycol has been withdrawn from the market.) There have been no reports of rhabdomyolysis with current statin and fibrate combinations. Patients should tell their physicians about any unusual muscle discomfort or weakness and if their urine becomes brown-colored.

Statins also can effect the liver, particularly at higher doses, so periodic liver function tests should be administered. Statins should not be taken by anyone with liver problems or by women during pregnancy or breast-feeding. It should be noted that no studies have reported liver failure from statins, even in people with liver disease.

There have also been a few reports of peripheral neuropathy in patients taking statins. This condition causes sensation changes in the limbs, fingers and toes that can include numbness, tingling, or pain.

Interactions with Drugs and Food. Statins may have some adverse interactions with other drugs, including other cholesterol-lowering agents. Among the agents that increase the risk for adverse effects are cyclosporine, macrolide antibiotics, and certain antifungal agents. Patients should tell they physicians about any other medications they are taking. Grapefruit juice and Seville oranges (found in some marmalade and other condiments) may also increase their potency. One study suggested that antioxidant supplements, such as vitamin E and C, may blunt the effects of a statin-niacin combination.

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 agents. 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 physician's direction in order to ensure its safety and effectiveness.

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

• It raises HDL levels higher than any other anti-cholesterol drug.
• It is extremely effective in reducing triglyceride levels.
• It lowers LDL-cholesterol and lipoprotein(a).
• It is also the least expensive.

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

Side Effects. Many patients find its side effects intolerable, however. About a quarter of patients taking 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 five minutes to hours after taking the drug and can last for minutes to, uncommonly, hours. The body does become tolerant to these effects eventually, and they generally subside.

Flushing and itching may be reduced with the following measures:

• Start with low doses taken at mealtime and gradually work up to the prescribed dose.
• Consider taking low-dose aspirin about 30 minutes before taking nicotinic acid, which appears to help prevent flushing.
• Avoid hot drinks.
• Choose 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.)

Gastrointestinal 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 could 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 have reported that diabetics who use niacin had little trouble with glucose control.

Potentially Serious Complications. About 3% to 5% of people taking nicotinic acid develop liver abnormalities, 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 avoid nicotinic acid because it elevates uric acid. The role of nicotinic acid in people with diabetes is less clear.

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% to 20%. Combinations with nicotinic acid are even more effective, with reductions of 40% to 60% observed.

Brands. The bile-acid binding resins and similar agents include cholestyramine (Questran, Questran Light) and colestipol (Colestid). They are commonly used in powder form, which is dissolved in liquid, or as a chewable bar (Cholybar). Colesevelam (Cholestagelm, Welchol) is available in tablet form. It is therefore easier to administered and is proving to lower LDL without as many side effects, such as constipation.

Side Effects. None of these drugs poses major risks, but most 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 agents 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 hypoglycemia. In order to prevent drug interactions, other drugs should be taken one hour before or four to six 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 lower cholesterol than the Lopid. Clofibrate (Atromid-S) was the first fibrate used but is now rarely prescribed because of perceived 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. In fact, LDL may increase in patients with very high triglycerides who take these drugs. (The newer fibrates, are much more effective in lowering LDL than Lopid).
• A study on the new agent 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 general. In one study, people who took gemfibrozil had higher rates of death from other causes, including cancer. Laboratory evidence further suggests that fibrates may affect receptors involved in cancer development. However, a number of studies have found no higher incidence of cancer, and a 1999 study found, in fact, a lower cancer rate.

Side Effects. Side effects may include gastrointestinal discomfort, aching muscles, sensitivity to sunlight, and skin rashes. Impotence has been associated with fibrates in less than 1% of patients. 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. They interact with a number of drugs and substances including warfarin, some oral drugs used for diabetes, certain antibiotics, and grapefruit juice.

Probucol

Probucol (Lorelco) lowers LDL-cholesterol levels by 10% to 15% and is also an antioxidant. Unfortunately, it also lowers the beneficial HDL levels by 20% to 30%. Probucol is generally used for certain genetic disorders that cause high cholesterol levels, or when other cholesterol-lowering drugs are ineffective or cannot be used. Common side effects include gastrointestinal discomforts such as diarrhea, bloating, nausea, and dizziness.

Hormone Replacement Therapy

In spite of estrogen's benefits on cholesterol levels and other factors that effect the heart, recent evidence suggests that hormone replacement therapy (HRT) may be harmful for women with existing heart disease, at least in the first few years. In July 2001, the American Heart Association sent out an advisory regarding the use of HRT in postmenopausal women. These guidelines state that women with heart disease, or women who have a heart attack while on HRT, should strongly consider stopping the therapy. In addition, they recommend that doctors stop telling women that hormone replacement therapy has any cardiovascular benefits.

HRT is also more likely to produce harm than benefit in women without diagnosed heart disease. In the 2003 Womens Health Initiative (WHI), a trial of 16,608 healthy post-menopausal women treated with estrogen plus progestin or placebo to prevent heart disease. Compared to women taking placebo, women taking estrogen plus progestin were more likely to have heart attacks, strokes, blood clots, and breast cancer. Therefore, the HRT regimen provides no protection against heart disease among healthy postmenopausal women, and may even increase the risk of heart disease. The scientists concluded that HRT should not be used to prevent CHD in healthy postmenopausal women.

If a woman's sole goal is to improve her cholesterol profile, statins are now the recommended first choice for most.

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. In such patients, plasmapheresis produced a significantly lower number of adverse heart events than other treatments. The process takes about three hours. If not performed regularly, its benefits last only about two 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 a very useful adjunct to 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. (The percentages used were with the highest dose of simvastatin.) A 2004 study demonstrated that ezetimibe might be particularly useful for patients who cannot achieve their cholesterol goals with statins alone.

Investigative Therapies

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 the heart are still unclear. Raloxifene may have some benefits on cholesterol levels. A 2002 study reported possible heart protection in women with existing heart disease, although the findings could have been due to chance. SERMs still pose a risk for deep vein blood clots, which may have long-term implications on heart problems. Longer studies are needed on possible risks and benefits.

Cholestin. Cholestin is a red yeast used in traditional Chinese medicine that may have some ability to reduce cholesterol levels. One of the primary actions of the yeast is to produce lovastatin, one of the major statin agents. Side effects are said to include mild digestive problems. It appears to be safe, but more studies are needed. One report suggests it may also cause myopathy (muscle disease) and possibly the severe form rhabdomyolysis, which has observed with statins and other cholesterol-lowering agent.

Avasimibe. This unique agent inhibits cholesterol storage and so may reduce atherosclerosis. Small early studies report reductions in triglycerides and very low density (VLDL) cholesterol but no changes in LDL or HDL. Trials using the drug alone and in combination with a statin are under way.

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 agent can prevent cardiovascular events such as MI or death.