Cholesterol Drugs - Statins

Prescribed Statins

What are statins?

Statins are among the most powerful cholesterol-lowering medications prescribed; they include atorvastatin (Lipitor) and simvastatin (Zocor). Statins reduce the production of cholesterol in the liver by inhibiting an enzyme called HMG CoA reductase; they are sometimes called HMG CoA reductase inhibitors. They are very effective at lowering total cholesterol and LDL (bad) cholesterol, making them the drug of choice for most women with high cholesterol. Statins also reduce the risk of dying or having a heart attack in women with heart disease, and they are increasingly prescribed to women at risk for heart problems even if their cholesterol levels are not very high. In 2003, 65.5 million prescriptions were written for atorvastatin (Lipitor) alone, and an additional 45.6 million for the next 3 most popular statins then available.⁷ Rosuvastatin (Crestor) was approved by the Food and Drug Administration (FDA) in August 2003.

How do statins affect cholesterol and triglyceride levels?

Combined results from 19 trials involving more than 50,000 people (23% were women) show that statins lower LDL (bad) cholesterol by 20% to 40%.⁸ This benefit was seen in women and the elderly, and across a wide range of LDL cholesterol levels. Some statins are better than others for lowering LDL cholesterol (See Which statin is best for lowering cholesterol? below) and the same statin is generally more effective at higher doses. Statins also lower total cholesterol by about 25% and triglycerides (another type of lipid that is associated with heart disease) by 15%.⁹

Do statins prevent heart attacks or dying from heart disease in women with heart disease?

Yes. Studies show that statins lower the risk of dying from heart disease by 26%, and the risk of having a heart attack by 29% in women with heart disease even if their LDL cholesterol levels are not that high.¹⁰ In addition, women with heart disease treated with statins are 20% less likely to experience heart problems (including the need for a for angioplasty or bypass surgery) than women who do not take statins.¹¹

Do statins prevent heart attacks and death in women who do not have heart disease?

Studies have shown that statins prevent heart attacks and reduce the risk of dying from heart disease in men with high cholesterol who do not have heart disease. However, when the results of 6 large studies including more than 11,000 women were analyzed by gender, this benefit was not proven in women.¹⁰ This didn't seem to make sense because statins lower cholesterol just as effectively in men and women, and there is no evidence that they work differently in men and women.^{12, 13} The researchers believe that there were simply too few women and the studies were too short to show the full benefits of statins in women. Women have a lower risk of heart disease than men at any age and they live longer, so you have to study a lot more women for a much longer time to see whether statins have a statistically significant effect on heart attack and death rates. It is estimated that almost twice as many women than men without heart disease have to be treated with statins to prevent a single heart problem including heart attack (140 women compared with 77 men).

Some experts believe that one of the six studies, the ALLHAT study, was not as thorough as the other five. When the ALLHAT study was left out of the pooled analysis, statins were shown to lower the risk of dying or having a heart attack in women who did not have heart disease.

Do statins prevent stroke?

Yes. The Heart Protection Study found that simvastatin reduced the risk of any stroke by 25% in more than 20,000 people (25% were women) with diabetes, or blockages in their arteries including heart disease and cerebrovascular disease (blockages in the arteries in the head and neck).¹⁴ This benefit is mainly due to a reduction in the most common type of stroke (ischemic stroke) caused by a blood clot in the arteries of the brain. Statins do not seem to reduce the risk of bleeding in the brain (hemorrhagic stroke).¹⁵ Overall, a 39 mg/dL reduction in LDL (bad) cholesterol lowers the risk of any type of stroke by 21%.¹⁴ The benefits are even greater in men and women who have already suffered a stroke or mini stroke (transient ischemic attack or TIA). If you have a stroke, you will probably be prescribed a statin even if your cholesterol levels are not very high.¹⁶

Do women with diabetes benefit from statins?

Men and women with diabetes who are considered at high risk for heart disease benefit from statins even if they do not already have heart disease, stroke, or high cholesterol. In one study of nearly 3,000 people with diabetes (32% were women) atorvastatin (10 mg) reduced the risk of stroke and heart problems including heart attack by 37%.¹⁷ Gender analysis showed that women with diabetes benefited as much as men. There were nearly 6,000 people with diabetes in the Heart Protection Study (30% were women); those treated with simvastatin were 25% less likely to die from heart disease or suffer a heart attack or stroke compared with those who got dummy pills.¹⁸ Again, women benefited just as much as men, as did people with relatively low LDL cholesterol levels (under 116 milligrams per deciliter [mg/dL]). Some of the men and women in these studies had heart disease or a history of stroke; others were considered high risk. The National Cholesterol Education Program Adult Treatment Panel III (ATP III for short) guidelines set a target LDL cholesterol of under 70 mg/dL for patients with diabetes and heart disease.¹⁹ However, it is not clear whether men and women with diabetes who are not otherwise high-risk for heart disease (usually young people without other risk factors such as high blood pressure or obesity) would benefit from taking statins.

Do statins help prevent osteoporosis?

Statins are not used to treat or prevent osteoporosis. Test tube and animal studies suggest that statins promote bone development,²⁰ but it is not clear whether they help prevent bone fracture in people.^{21, 22}

When researchers looked at more than 23,000 women enrolled in various studies (not necessarily statin studies), there was suggestive but not definitive evidence that women who took statins had a lower risk of hip and vertebrae fractures.23 However, in two large trials investigating the effects of statins on heart disease in more than 13,000 people (over 2,300 women), statins did not protect against hip fracture or other types of fracture in either men or women.^{24, 25}

Which statin is best for lowering cholesterol?

Dose for dose, some statins are more powerful at lowering bad cholesterol than others. A standard dose generally refers to the amount that will lower LDL cholesterol by 30% to 40% (see table above). Which statin is best for you will depend on your cholesterol levels and your overall risk of having a heart attack or dying from heart disease. Cholesterol-lowering drugs are not a substitute for a healthy lifestyle; you must continue to eat a heart-healthy diet, exercise, and stop smoking (if you smoke) while taking your medication.
One study that directly compared four statins found that rosuvastatin (Crestor) reduced LDL cholesterol and total cholesterol more than atorvastatin, simvastatin, or pravastatin.²⁶ There are safety concerns with the more powerful statins. Dose for dose, rosuvastatin is two to four times more potent than atorvastatin (the next most potent statin).²⁷

Are very high doses of statins better than regular doses?

Some experts believe “the lower, the better” for LDL (bad) cholesterol. With this in mind, studies have compared high doses of statins (80 mg atorvastatin or simvastatin) with regular doses (40 mg pravastatin or simvastatin) in men and women who suffered a heart attack or who have been diagnosed with heart disease. In women who had a heart attack, taking a high dose statin within 10 days reduced the risk of future heart problems such as heart attack or stroke compared with regular doses, but did not reduce the risk of dying.^{28, 29} Women taking high dose statins suffered more side effects, including liver and muscle problems, than the women who took lower doses. Similar results were seen for men and women with stable heart disease who took either regular dose (10 mg) or high dose (80 mg) atorvastatin.³⁰
Because of the risk of side effects, women should only take high dose statins if regular doses (and lifestyle changes) do not lower their LDL cholesterol enough. If you are hospitalized for a heart attack, you may be given high dose therapy right away.

Why do I have to take another cholesterol-lowering medication in addition to a statin?

Your doctor may prescribe another cholesterol medication ( fibrates, bile acid resins, ezetimibe) or a diet that includes plant sterols and stanols in addition to a lower dose statin. This combination can lower LDL cholesterol by as much as 30% to 40%.¹⁹ Doubling the statin dose reduces LDL cholesterol by an extra 6% to 9%,³¹ and the risk of side effects increases with higher doses of statins.³² Some combinations of cholesterol-lowering medications, particularly statin-fibrate therapy (notably gemfibrozil [Lopid]) have a higher risk of muscle problems compared with a statin alone. Statins increase HDL (good) cholesterol levels by a small amount. If your HDL cholesterol is low, your doctor may prescribe an additional medication, usually niacin, as well as a statin.

Statins & CRP

In addition to lowering cholesterol, statins slow down the buildup of fatty plaque in the arteries of the heart ( atherosclerosis) and they lower levels of C-reactive protein (CRP).^{33, 34} High CRP is a sign of inflammation, the body's response to injury, and it is linked to a higher risk of heart disease. The aptly titled REVERSAL study found that heart disease patients who lowered their CRP levels the most with statins showed signs of reversing the fatty plaque buildup in the arteries of their hearts.³⁵ The results were not analyzed separately for women but other studies have shown that statins lower CRP in women.

For people who have had a heart attack, lowering CRP reduces the risk of dying from heart disease or having another heart attack. In one study of nearly 4,000 heart attack patients (22% were women), those who lowered their CRP below 2 milligrams per liter (mg/L) were less likely to die or have another heart attack than those with higher CRP levels even if their LDL (bad) cholesterol did not fall below the target 70 mg/dL.³⁶ The patients who lowered both LDL and CRP to target levels fared best. The results were not confirmed separately in women. Overall, intensive statin therapy (80 mg atorvastatin) lowered CRP and LDL cholesterol more than regular dose statin (40 mg pravastatin); however, there was a wide variation in how individual patients responded to these drugs. Previous research shows that statins do not lower CRP levels in some people.^{37, 38}

It is not clear whether lowering CRP with statins has similar benefits in men and women who have not had a heart attack, but ongoing studies may provide an answer.³⁹ Meanwhile, you are unlikely to be prescribed a statin for high CRP alone.

Muscle-related Side Effects

Overall statins are safe medications. The main side effects are muscle pain or weakness. This can be serious if there are signs that the muscle is breaking down—your doctor will do tests to see if this is the case. In rare cases, this can develop into rhabdomyolysis, a potentially fatal condition in which muscle cells break down and release their contents into the bloodstream. Signs of rhabdomyolysis include muscle pain, swelling, or weakness, usually affecting the back or lower calves. Fever, nausea, dark urine, and a general feeling of discomfort may also occur. If you are taking statins and experience any of these symptoms, you should contact your healthcare provider immediately. The risk of muscle problems is higher if you are taking fibrates (another type of cholesterol-lowering drug) along with statins, and women have a higher risk than men when using both fibrates and statins.⁴⁰ Medications for other conditions can also increase your risk for muscle-related side effects including cyclosporine, and certain antibiotics (such as erythromycin) or antifungals (such as itraconazole [Diflucan]). It is important that you always tell your doctor what other medications you are taking.
Rhabdomyolysis occurs in approximately 1 patient out of every 100,000 treated with statins, and accounts for less than 1 death per million statin prescriptions.⁴¹ However, some of the newer, more potent statins have a higher risk of this potentially fatal side effect. Cerivastatin (Baycol) was banned in the US in August 2001 after being linked to 31 such deaths. According to FDA figures, the incidence of rhabdomyolysis was 10 to 50 times higher for cerivastatin compared with other statins.⁴¹ The risks were higher at higher doses, and when cerivastatin was combined with the fibrate gemfibrozil (Lopid). Below are some factors that increase the risk of experiencing muscle problems when taking statins:

• Older age especially over 80 years, and older women more than older men
• Small body frame and frailty
• Diabetic-related kidney problems
• Taking multiple medications
• Drinking large quantities of grapefruit juice (more than 1 quart/day)
• Alcohol abuse

Rosuvastatin Side Effects & Dosing

Rosuvastatin (Crestor) is the most potent statin currently on the market. It was approved by the FDA in August 2003 at doses of 5 to 40 mg. Very high dose (80 mg) rosuvastatin was not approved by the FDA because it has a relatively high risk of the potentially fatal muscle-wasting side effect (rhabdomyolysis).⁴² A consumer group asked that rosuvastatin be banned after reports of this side effect with the approved doses.⁴³ The FDA denied the request for a ban stating that Crestor does not pose a greater risk of muscle problems or rhabdomyolysis than the other statins when prescribed correctly. The FDA asked the manufacturers to revise the label for rosuvastatin to emphasize the increased risk at higher doses and in certain groups of patients including those taking fibrates. Specifically, patients taking the fibrate gemfibrozil (Lopid) should not take more than 10 mg of rosuvastatin, and the 40 mg dose should only be used in people who have already tried the 20 mg dose but their LDL cholesterol is still too high.⁴⁴ Because studies show that Asians and Asian-Americans absorb almost twice as much of this drug into their blood than Caucasians (potentially increasing their risk for side effects), the FDA recommend a 5 mg starting dose for people of this race. Blood levels of rosuvastatin do not seem to differ between Caucasian, African American,,or Hispanic people.

Liver-related Side Effects

The other main side effect seen with statins is liver damage.⁴⁵ Before you are prescribed a statin, your doctor will test your liver enzymes. These tests will be repeated at 12 weeks and then twice a year assuming no problems are found. If the blood tests show signs of liver damage, you will be taken off the statin; this usually resolves the problem.

Can statins prevent Alzheimer's Disease & Dementia?

Fatty plaque buildup in the arteries of the brain and neck play a role in the development of dementia and Alzheimer's disease (AD), and cholesterol is linked to the plaques found in the brains of people with AD. This led to theories that statins could help lower the risk of mental decline and AD. However, research shows that very low cholesterol levels appears to increase the risk of mental decline,⁴⁶ and it is not clear whether statins have any affect (positive, negative) on mental function.

Some of the research so far suggests that statins reduce the risk of cognitive decline;^{47, 48} in other studies, people taking statins experienced increased memory loss.⁴⁹ Small trials suggest that statins may slightly lower attention and mental speed.^{50, 51}

It is also unclear whether statins affect Alzheimer's disease.⁵² The Cache County study followed more than 5,000 elderly residents (65 years or older) and saw no difference in the rates of dementia or AD between statin users and nonusers.⁵³ Two large studies on the heart health benefits of statins have not shown any significant impact (either negative or positive) on mental function or dementia.^14,54 The National Institues of Health (NIH) is sponsoring a large study on statins, mental function, and behavior that should shed more light on this issue.⁵⁵

Do statins increase the risk of cancer?

No. Studies from the early 1990s suggested—but did not prove—a link between low cholesterol and a higher risk of dying from cancer.^{56 54, 57} However, the Heart Protection Study, which included 20,000 people (25% were women), found that those taking simvastatin had no increased risk of cancer.⁵⁸ In addition, researchers combined the results of studies using various statins and found no increased risk of cancer for people who took statins for 5 years.^{54, 59, 60} It has also been shown that taking statins for 10 years does not increase your risk of cancer either.⁶¹ Now there is even a suggestion that taking statins may protect against some cancers, including colorectal cancer; however, this needs to be investigated more.⁶²

Is red yeast rice the same as a statin?

Red yeast rice is rice that is fermented with red yeast and used in Chinese cooking and herbal medicine. Red yeast rice is sold by many names, including the dietary supplements Cholestin and HypoCol, which claim to lower cholesterol. These preparations may contain a chemical (mevinolin) that is identical to the cholesterol-lowering drug lovastatin (Mevacor). In1998, the FDA banned Cholestin, deeming it an unapproved drug rather than a dietary supplement.⁶³ In August 2007, the FDA warned customers to avoid red yeast rice products promoted on the internet because they could lead to severe muscle problems and kidney problems and interfere with other medications.⁶⁴ Dietary supplements are not allowed to make claims to treat or cure disease. Drug manufacturers must prove to the FDA that their products are safe and effective before they can be sold in the US. Dietary supplements are not subject to such approval and there are no guarantees that they contain the ingredients listed on the label or that they have the promised effects. In small studies Cholestin has been shown to lower LDL (bad) cholesterol.⁶⁵ An analysis of 10 commercially available red yeast rice products found that some did not contain any cholesterol-lowering ingredients.⁶⁶ You should talk to your doctor before taking any dietary supplements. High cholesterol is a major risk factor for heart disease that should be treated with scientifically proven strategies (lifestyle changes and approved medications when necessary).