What are statins
Statins are prescription medicines used to lower cholesterol in your blood. Statins are recommended for people who have or are at high risk of, cardiovascular disease. Most of the cholesterol in your blood is made by the liver. Statins (hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors) work by reducing the amount of cholesterol made by your liver and by helping your liver remove cholesterol that is already in your blood.
There are several different types of statins, including atorvastatin (Lipitor), rosuvastatin (Crestor), pravastatin, fluvastatin and simvastatin.
Most people who take statins do not notice any side effects. Side effects that can occur tend to be mild and temporary, and include muscle pain, abnormal liver enzyme levels and a slightly increased risk of diabetes. Serious side effects are rare.
Rarely, statins can cause more-serious side effects such as:
- Increased blood sugar or type 2 diabetes. It’s possible that your blood sugar (blood glucose) level may slightly increase when you take a statin, which can lead to type 2 diabetes. This is especially likely if your blood sugar is already high. However, the benefit of taking a statin may potentially outweigh the risk. Studies show that those with diabetes who take statins have much lower risks of heart attacks.
- Muscle cell damage. Very rarely, high-dose statin use can cause muscle cells to break down (rhabdomyolysis) and release a protein called myoglobin into the bloodstream. This can lead to severe muscle pain and kidney damage.
- Liver damage. Occasionally, statin use causes an increase in liver enzymes. If the increase is mild, you can continue to take the drug. Low to moderate doses of statins do not appear to severely raise liver enzyme levels. Contact your doctor immediately if you have unusual fatigue or weakness, loss of appetite, pain in your upper abdomen, dark-colored urine, or yellowing of your skin or eyes.
- Cognitive problems. Some people have reported memory loss and confusion after using statins. However, the U.S. Preventive Services Task Force has not found any evidence to prove that statins actually cause cognitive problems.
Balancing benefits and risks
There have been questions raised in the media over the benefits of statins. Two risks that patients may be aware of are muscle-related complaints and an increased risk of developing type 2 diabetes. Muscle complaints are quite common even among people not taking statins, so it is important to have your healthcare provider evaluate any symptoms before stopping your statin medication. It is rare for statins to cause serious muscle problems. Similarly, the risk of developing diabetes as a result of a statin is small. The benefits of statins in reducing heart attacks and strokes should generally outweigh this small increased risk.
Peak health organizations have urged people who take statins to consult their doctors before stopping any prescribed medicines. The benefits of statin treatment have been shown to outweigh the risk of possible side effects in most people at high risk of heart attack or stroke. If you are taking statins and have any concerns, an important first step is to have a discussion with your healthcare provider about your risk of having heart disease or a stroke, how a statin would reduce that risk, and any side effects that you should consider.
Many people who take statins experience no or very few side effects. Others experience some troublesome – but usually minor – side effects, such as an upset stomach, headache or feeling sick. Your doctor should discuss the risks and benefits of taking statins if they’re offered to you.
Cases that involve more serious side effects, such as kidney failure, tend to get a great deal of media coverage, but these are rare. The British Heart Foundation states than just 1 in every 10,000 people who take statins will experience a potentially dangerous side effect.
The risks of any side effects also have to be balanced against the benefits of preventing serious problems. A review of scientific studies into the effectiveness of statins found that around one in every 50 people who take the medication for five years will avoid a serious event, such as a heart attack or stroke, as a result.
International health guidelines, recommend that statins be used by:
- people who have had a heart attack, or been diagnosed with coronary heart disease
- people at high risk of a cardiovascular event, such as heart attack or stroke.
Factors that can put you at high risk of cardiovascular disease include:
- older age
- an inactive lifestyle
- poor general health
- raised cholesterol levels
- high blood pressure
- smoking
- diabetes
- overweight or obesity
- a family history of high cholesterol, heart attack or stroke.
Lifestyle measures that can reduce your cholesterol level
Lifestyle measures that can reduce your cholesterol level and cardiovascular disease risk include:
- Eating a healthy, balanced diet. A heart-healthy eating plan limits the amount of saturated and trans fats that you eat. It recommends that you eat and drink only enough calories to stay at a healthy weight and avoid weight gain. It encourages you to choose a variety of nutritious foods, including fruits, vegetables, whole grains, and lean meats. Examples of eating plans that can lower your cholesterol include the Therapeutic Lifestyle Changes diet and the DASH eating plan.
- Exercising regularly. Everyone should get regular physical activity (30 minutes on most, if not all, days).
- Maintaining a healthy weight. If you are overweight, losing weight can help lower your LDL (bad) cholesterol. This is especially important for people with metabolic syndrome. Metabolic syndrome is a group of risk factors that includes high triglyceride levels, low HDL (good) cholesterol levels, and being overweight with a large waist measurement (more than 40 inches for men and more than 35 inches for women).
- Limiting the amount of alcohol you drink.
- Stopping smoking. Quitting smoking can raise your HDL “good” cholesterol. Since HDL “good” cholesterol helps to remove LDL “bad” cholesterol from your arteries, having more HDL “good” cholesterol can help to lower your LDL “bad” cholesterol.
- Managing stress. Research has shown that chronic stress can sometimes raise your LDL “bad” cholesterol and lower your HDL “good” cholesterol.
Statins may be recommended if these measures don’t help.
Taking statins
Statins come as tablets that are taken once a day. The tablets should normally be taken at the same time each day – most people take them just before going to bed. In most cases, treatment with statins continues for life, as stopping the medication causes your cholesterol to return to a high level within a few weeks.
If you ever forget to take your dose, don’t take an extra one to make up for it. Just take your next dose as usual the following day. If you accidentally take too many statin tablets (more than your usual daily dose), contact your doctor or pharmacist for advice.
Do statins increase the risk of diabetes?
US regulators have decided that product information leaflets for statins will advise people they carry a small increased risk of developing diabetes and memory problems.
However, evidence reviewed by the main regulator for medicines in the US – the Food and Drug Administration (FDA) – still suggests that for people who are at high risk of cardiovascular events (heart attack or stroke), the risk of developing diabetes with statins is small compared with the effectiveness of statins in reducing the risk of cardiovascular events.
For example, in an analysis of statin trials involving more than 90,000 people, new diabetes cases occurred in people taking statins as well as those who didn’t. This shows that some people at risk of cardiovascular disease may develop diabetes anyway, although the number of new diabetes cases was 9% higher in those people taking statins.
Do statins cause memory loss or amnesia?
Despite statins being widely prescribed and taken by millions of people worldwide, there are only a relatively small number of reports of minor memory loss in people taking statins. The symptoms were reversed when the statins were stopped. People who are concerned about memory loss with statins should also discuss this with their doctor.
Do statins cause amyotrophic lateral sclerosis (ALS)?
There’s no good evidence that statins cause or trigger ALS, also known as Lou Gehrig’s disease. However, there have been reports of people who have developed ALS while taking statins. Other studies have shown a decreased risk of ALS in people who take statins.
ALS is a serious neurological disorder that causes disease and death in the nerve cells in the brain and spinal cord that control voluntary muscles. ALS may begin with muscle twitching, weakness in an arm or leg, or changes in speech (dysarthria). Eventually, it affects the ability to control the muscles needed to move, speak, eat and breathe.
Statins are medications prescribed for the treatment of high cholesterol. These medications can sometimes cause muscle pain (myalgia), muscle weakness or, very rarely, severe muscle damage (rhabdomyolysis). But these occur as a result of direct muscle damage, not damage to nerve cells.
Who needs cholesterol medicines?
Your health care provider may prescribe medicine if:
- You have already had a heart attack or stroke, or you have peripheral arterial disease
- Your LDL (bad) cholesterol level is 190 mg/dL or higher
- You are 40-75 years old, you have diabetes, and your LDL cholesterol level is 70 mg/dL or higher
- You are 40-75 years old, you have a high risk of developing heart disease or stroke, and your LDL cholesterol level is 70 mg/dL or higher
Not everyone with a heart condition needs to use a statin. Guidelines from the U.S. Preventive Services Task Force, American College of Cardiology and American Heart Association outline four main groups of people who may be helped by statins:
- People without cardiovascular disease who have risk factors for the disease and a higher 10-year risk of a heart attack. This group includes people who have diabetes, high cholesterol, high blood pressure, or who smoke and whose 10-year risk of a heart attack is 7.5 percent or higher.
- People who already have cardiovascular disease related to hardening of the arteries (atherosclerosis). This group includes people who have had heart attacks, strokes caused by blockages in a blood vessel, ministrokes (transient ischemic attacks), peripheral artery disease, or prior surgery to open or replace coronary arteries.
- People who have very high LDL (bad) cholesterol. This group includes adults who have LDL cholesterol levels of 190 mg/dL (4.9 mmol/L) or higher.
- People who have diabetes. This group includes adults who have diabetes and an LDL between 70 and 189 mg/dL (1.8 and 4.9 mmol/L), especially if they have evidence of vascular disease or other risk factors for heart disease such as high blood pressure, smoking or being older than age 40.
Statins precautions and interactions
Statins shouldn’t be taken if you have severe liver disease or blood tests suggest that your liver may not be working properly.
This is because statins can affect your liver, and this is more likely to cause serious problems if you already have a severely damaged liver.
Before you start taking statins, your doctor should carry out a blood test to ensure your liver is in a relatively good condition. You should also have a routine blood test to check the health of your liver three months after treatment begins, and undergo another after 12 months.
Pregnancy and breastfeeding
Statins shouldn’t be taken by women who are pregnant or breastfeeding, as there’s no firm evidence on whether it’s safe to do so.
If you do become pregnant while taking statins, contact your doctor for advice.
People at an increased risk of side effects
Statins should be taken with caution if you’re at an increased risk of developing a rare side effect called myopathy, which is where the tissues of your muscles become damaged and painful. This can lead to kidney damage (rhabdomyolysis).
Things that can increase this risk include:
- being over 70 years old
- having a history of liver disease
- regularly drinking large quantities of alcohol
- having a history of muscle-related side effects when taking a statin or fibrate (another type of medicine for high cholesterol)
- having a family history of myopathy or rhabdomyolysis
If one or more of these apply to you, there’s a chance that frequent monitoring may be needed to check for complications. A lower dose of statin may also be recommended.
If you have an underactive thyroid (hypothyroidism), treatment may be delayed until this problem is treated. This is because having an underactive thyroid can lead to an increased cholesterol level, and treating hypothyroidism may cause your cholesterol level to decrease, without the need for statins. Statins are also more likely to cause muscle damage in people with an underactive thyroid.
Statin interactions
Statins can react unpredictably with certain other substances (known as “interacting”), potentially increasing the risk of serious side effects, such as muscle damage.
Medications that can interact with some types of statin include:
- certain antibiotics and antifungals
- certain HIV medications
- warfarin – a medication commonly use to prevent blood clots
- ciclosporin – a medication that suppresses the immune system, which is used to treat a wide range of conditions, including psoriasis and rheumatoid arthritis
- danazol – a synthetic hormone medication used to treat conditions such as endometriosis
- verapamil and diltiazem – types of medication called calcium channel blockers, which are used to treat various conditions affecting the heart and blood vessels
- amiodarone – a medication sometimes used to treat irregular heartbeats
- fibrates – medications that, like statins, help to reduce cholesterol levels in the blood
If you are taking statins and need to take one of these medications, your doctor may prescribe an alternative statin or prescribe your current statin at a lower dosage. In some cases, they may recommend that you temporarily stop taking your statin.
Food and alcohol
Grapefruit juice can affect some statins and increase your risk of side effects. Your doctor may advise you to avoid it or to only consume it in small quantities.
There are no known interactions between statins and alcohol.
Grapefruit juice and statins
Grapefruit juice and fresh grapefruit can affect the way some medicines work. That’s true with certain statins, too—but only some of them. For example, if you drink a lot of grapefruit juice while taking certain statin drugs to lower cholesterol, too much of the drug may stay in your body, increasing your risk for liver and muscle damage that can lead to kidney failure. Some drugs, like statins are broken down by enzymes. Grapefruit juice can block the action of these enzymes, increasing the amount of statin drug in your body and may cause more side effects. Seville oranges (often used to make orange marmalade), pomelos, and tangelos (a cross between tangerines and grapefruit) may have the same effect as grapefruit juice. Do not eat those fruits if your medicine interacts with grapefruit juice.
Many drugs are broken down (metabolized) with the help of a vital enzyme called CYP3A4 in the small intestine. Grapefruit juice can block the action of CYP3A4, so instead of being metabolized, more of the statin drug enters the blood and stays in the body longer. The result is too much statin drug in your body.
The amount of the CYP3A4 enzyme in the intestine varies from person to person. Some people have a lot of enzymes and others just a little. So grapefruit juice may affect people differently even when they take the same statin drug.
Here are examples of some statin drugs that grapefruit juice can cause problems with (interact): atorvastatin, lovastatin, and simvastatin 1. The severity of the interaction can be different depending on the person, the statin drug, and the amount of grapefruit juice you drink. Talk to your doctor, pharmacist or other health care provider and read any information provided with your prescription.
How do statins work?
Statins block how your liver makes cholesterol. Cholesterol can stick to the walls of your arteries and narrow or block them.
Statins work by:
- Lowering LDL (bad) cholesterol
- Raising HDL (good) cholesterol in your blood
- Lowering triglycerides, another type of fat in your blood
What do statins do?
Statins are powerful inhibitors of 3-hydroxy-3-methyl glutaryl coenzyme A reductase (HMG-CoA reductase), which is the enzyme responsible for the conversion of HMG-CoA to mevalonate in the cholesterol synthesis pathway, which leads to a decrease in cholesterol synthesis in the liver 2. By reducing hepatic cholesterol synthesis, an upregulation of LDL-receptors and increased hepatic uptake of LDL-cholesterol from the circulation occurs.
In addition to effects on lipid metabolism statins also have additional effects that may not be directly related to alterations in lipid metabolism 3. For example, statins are anti-inflammatory and consistently decrease C-reactive protein (CRP) levels 4. Other additional effects of statins include anti-proliferative effects, antioxidant properties, anti-thrombosis, improving endothelial dysfunction, and attenuating vascular remodeling 3. Whether these pleiotropic effects contribute to the beneficial effects of statins in preventing cardiovascular disease is uncertain and much of the beneficial effect of statins on cardiovascular disease can be attributed to reductions in lipid levels.
List of statins
There are currently seven statins (HMG-CoA reductase inhibitors) approved for lowering cholesterol levels and they are the first line drugs for treating lipid disorders and can lower LDL “bad” cholesterol levels by as much as 60% 5.
There are seven types of statin available via prescription:
- atorvastatin (Lipitor)
- fluvastatin (Lescol)
- lovastatin (Mevacor)
- pitavastatin (Livalo)
- pravastatin (Lipostat)
- rosuvastatin (Crestor)
- simvastatin (Zocor)
Most of these statins are now generic drugs and therefore they are relatively inexpensive. Which particular statin one elects to use may depend on the degree of cholesterol lowering needed and the potential of drug-drug interactions.
What are statins used for?
Having high levels of ‘bad’ cholesterol (low-density lipoprotein, or LDL) in your blood can increase your risk of cardiovascular disease, such as heart attack and stroke. Statins are used to lower LDL “bad” cholesterol, and this helps lower your risk of cardiovascular disease. Statins may be recommended if you have cardiovascular disease or have a high risk of developing it in the next 10 years.
Statins are considered the most effective group of cholesterol-lowering medicines available and work by blocking cholesterol production in your liver.
Statins are used in combination with other ways of lowering cholesterol, including eating a healthy diet, managing your weight and exercising.
Having a high level of LDL “bad” cholesterol is potentially dangerous, as it can lead to a hardening and narrowing of the arteries (atherosclerosis) and cardiovascular disease.
Cardiovascular disease is a general term that describes a disease of the heart or blood vessels. It’s the most common cause of death in the US. The main types of cardiovascular disease are:
- Coronary heart disease (coronary artery disease) – when the blood supply to the heart becomes restricted as a result of the hardening and narrowing of the arteries (atherosclerosis)
- Angina – sharp chest pain, caused by coronary heart disease
- Heart attacks – when the supply of blood to the heart is suddenly blocked
- Strokes and transient ischaemic attacks (TIAs) – when the supply of blood to the brain becomes blocked or disrupted
- Peripheral arterial disease – when a build-up of fatty deposits in the arteries restricts blood supply to the limbs
Your doctor may recommend taking statins if:
- You have already had a heart attack or stroke, or you have peripheral arterial disease
- Your LDL (bad) cholesterol level is 190 mg/dL or higher
- You are 40-75 years old, you have diabetes, and your LDL cholesterol level is 70 mg/dL or higher
- You are 40-75 years old, you have a high risk of developing heart disease or stroke, and your LDL cholesterol level is 70 mg/dL or higher.
- Your personal and family medical history suggests you’re likely to develop cardiovascular disease at some point over the next 10 years and lifestyle measures haven’t reduced this risk
Statins can’t cure these conditions, but they can help prevent them from getting worse or recurring in people who have been diagnosed with them.
They can also reduce the chance of these conditions developing in the first place in people at risk (see below).
Statins are usually used in combination with lifestyle measures such as:
- eating a healthy diet low in saturated fat
- exercising regularly
- stopping smoking
- moderating your alcohol consumption
People at risk of cardiovascular disease
If you don’t have any form of cardiovascular disease, statins may still be recommended if you’re thought to be at a high risk of developing the condition in the future.
The current recommendation is that you should be offered statins if:
- there’s at least a 1 in 10 chance of you developing cardiovascular disease at some point in the next 10 years
- lifestyle measures, such as exercising regularly and eating a healthy diet, haven’t reduced this risk
Your doctor may recommend carrying out a formal assessment of your cardiovascular disease risk if they think you may be at an increased risk of cardiovascular disease, based on your personal and family medical history.
For this formal assessment, your doctor will use special cardiovascular disease risk assessment computer software that takes into account factors such as:
- your age
- your gender
- your ethnic group, as some have an increased risk of cardiovascular disease
- your weight and height
- if you smoke or have previously smoked
- if you have a family history of cardiovascular disease
- your blood pressure
- your blood cholesterol levels
- if you have certain long-term conditions – such as diabetes, chronic kidney disease, rheumatoid arthritis and atrial fibrillation (a heart condition that causes an irregular and often abnormally fast heart rate)
Other uses
Statins can also be used to treat people with a condition called familial hypercholesterolemia. This is an inherited condition caused by a genetic fault that leads to high cholesterol levels, even in people who have a generally healthy lifestyle.
Who should take statins to lower cholesterol?
Having low LDL “bad” cholesterol and total cholesterol reduces your risk of heart disease. But not everyone needs to take statins to lower cholesterol.
Your health care provider will decide on your treatment based on:
- Your total, HDL (good), and LDL (bad) cholesterol levels
- Your age
- Your history of diabetes, high blood pressure, or heart disease
- Other health problems that may be caused by high cholesterol
- Whether or not you smoke
- Your risk of heart disease
- Your ethnicity
You should take statins if you are 75 or younger, and you have a history of:
- Heart problems due to narrowed arteries in the heart
- Stroke or TIA (mini stroke)
- Aortic aneurysm (a bulge in the main artery in your body)
- Narrowing of the arteries to your legs
If you are older than 75, your provider may prescribe a lower dose of a statin. This may help lessen possible side effects.
You should take statins if your LDL “bad” cholesterol is 190 mg/dL or higher. You should also take statins if your LDL “bad” cholesterol is between 70 and 189 mg/dL and:
- You have diabetes and are between ages 40 and 75
- You have diabetes and a high risk of heart disease
- You have a high risk of heart disease
You and your doctor may want to consider statins if your LDL cholesterol is 70 to 189 mg/dL and:
- You have diabetes and a medium risk for heart disease
- You have a medium risk for heart disease.
How low should my LDL cholesterol be?
Doctors used to set a target level for your LDL “bad” cholesterol. But now the focus is reducing your risk for problems caused by narrowing of your arteries. Your provider may monitor your cholesterol levels. But frequent testing is rarely needed.
Adding other drugs along with statins provides little to no benefit in most cases.
You and your doctor will decide what dose of a statin you should take. If you have risk factors, you may need to take higher doses. Factors that your provider will consider when choosing the dose include:
- Your total, HDL, and LDL cholesterol levels before treatment
- Whether you have coronary artery disease (history of angina or heart attack), a history of stroke, or narrowed arteries in your legs
- Whether you have diabetes
- Whether you smoke or have high blood pressure
Higher doses may lead to side effects over time. So your provider will also consider your age and risk factors for side effects.
What are the different types of medicines for cholesterol?
There are several types of cholesterol-lowering drugs available, including
- Statins, which block the liver from making cholesterol
- Bile acid sequestrants, which decrease the amount of fat absorbed from food
- Cholesterol absorption inhibitors, which decrease the amount of cholesterol absorbed from food and lower triglycerides.
- Nicotinic acid (niacin), which lowers LDL (bad) cholesterol and triglycerides and raises HDL (good) cholesterol. Even though you can buy niacin without a prescription, you should talk to your health care provider before taking it to lower your cholesterol. High doses of niacin can cause serious side effects.
- PCSK9 inhibitors, which block a protein called PCSK9. This helps your liver remove and clear LDL cholesterol from your blood.
- Fibrates, which lower triglycerides. They may also raise HDL (good) cholesterol. If you take them with statins, they may increase the risk of muscle problems.
- Combination medicines, which include more than one type of cholesterol-lowering medicine
There are also a few other cholesterol medicines (lomitapide and mipomersen) that are only for people who have familial hypercholesterolemia (FH). FH is an inherited disorder that causes high LDL cholesterol.
How does my health care provider decide which cholesterol medicine I should take?
When deciding which medicine you should take and which dose you need, your health care provider will consider
- Your cholesterol levels
- Your risk for heart disease and stroke
- Your age
- Any other health problems you have
- Possible side effects of the medicines. Higher doses are more likely to cause side effects, especially over time.
Medicines can help control your cholesterol, but they don’t cure it. You need to keep taking your medicines and get regular cholesterol checks to make sure that you cholesterol levels are in a healthy range.
Are statins bad for you?
Statins and Liver Injury
The incidence of true liver injury caused by statin therapy is low (about 1 percent) 6. The dose-related elevations of alanine transaminase (ALT) and aspartate transaminase (AST) levels observed in patients taking statins do not exceed those in patients taking placebo at low to moderate dosages (one-half the maximal dosage or less) and are modest at higher dosages 6. Many preexisting conditions that cause elevations in transaminase levels (e.g., chronic viral hepatitis, nonalcoholic fatty liver disease) were once thought to be contraindications to statin therapy; however, statins do not worsen liver function in most patients with chronic liver disease 7.
Elevations in transaminase levels do not reflect hepatic injury per se; the best indicator of true liver injury is the serum bilirubin level 7. Meta-analyses of randomized placebo controlled trials demonstrate that low to moderate dosages of statins are not associated with clinically significant (i.e., greater than three times the upper limit of normal) elevations in transaminase levels 8. Maximal recommended dosages of lovastatin (Mevacor) 9, pravastatin (Pravachol) 10, simvastatin (Zocor) 1, atorvastatin (Lipitor) 8 and rosuvastatin (Crestor) 8 were associated with modest but notable increases in transaminase levels. Many of these elevations will resolve with continued therapy 11.
Nonalcoholic fatty liver disease
The presence of nonalcoholic fatty liver disease or nonalcoholic steatohepatitis should not deter physicians from using statins in patients with hyperlipidemia. Some studies even suggest that statins may have a beneficial effect on underlying liver disease 12.
Two retrospective studies examining 7,473 patients with mildly elevated transaminase levels found fewer severe increases in transaminase levels in patients using statins than in patients not using them over a 12-month period 13. In another matched study of 2,264 patients, those taking statins showed no differences in liver enzyme levels or progression of steatohepatitis compared with patients not taking statins 14. A small study of 68 patients with biopsy-proven nonalcoholic fatty liver disease showed no change in liver enzymes but a statistically significant 46 percent reduction in the quantitative steatosis on repeat biopsy in the 17 patients taking statins at follow-up 15. Two small studies evaluating patients with nonalcoholic steatohepatitis showed no change (seven patients) 16 or a reduction (five patients) 1 in liver enzymes among those taking statins; both studies also demonstrated some degree of improvement in liver pathology.
Chronic viral hepatitis
Evidence suggests that patients with chronic hepatitis B and C infections may safely use statins, although supporting data are not as strong as those for patients with nonalcoholic fatty liver disease. A retrospective cohort study of 13,492 patients taking lovastatin 17 and a prospective study of 320 patients taking pravastatin 18 found no evidence of increased hepatotoxicity among those with chronic liver disease (including hepatitis B and C infections). A cohort study showed that patients with hepatitis C infection who took statins had less severe elevations in transaminase levels than patients with hepatitis C infection who were not on statins or those who took statins but tested negative for hepatitis C infection 19.
An expert consensus panel of hepatologists convened by the National Lipid Association concluded that chronic liver disease is not a contraindication to statin use. Although the panel also concluded that routine monitoring of liver function was not supported by the literature, for medicolegal reasons they recommended checking transaminase levels before initiating therapy, 12 weeks after initiating therapy or increasing the dosage, and periodically thereafter 11.
Statins and Muscle Toxicity
Myopathy is a general term describing any disease of the muscles. Myalgia is defined as muscle ache or weakness without elevated creatine kinase (CK) levels, whereas myositis denotes muscle symptoms with elevated creatine kinase levels. Rhabdomyolysis indicates muscle symptoms with a creatine kinase elevation greater than 10 times the upper limit of normal associated with creatinine elevation (usually with brown urine and urinary myoglobin) 20. Myalgias are common with statin use. However, myositis and rhabdomyolysis are far less common, with rates of 5.0 and 1.6 per 100,000 patient-years, respectively; these rates appear to be similar with all statins, although well-designed comparative studies are lacking 21. The mechanism of statininduced muscle injury is uncertain 22.
Patients who have disease states or are taking concomitant medications known to independently cause myalgias are more likely to experience muscle injury when statin therapy is initiated. Untreated hypothyroidism 23 and alcohol abuse 24 may predispose patients to myopathic symptoms from statin therapy. Gemfibrozil and niacin, often used in patients taking statins, have their own associated risks of myopathy 25, although these appear to be rare and have not been confirmed by large, welldesigned studies 22. Evidence does not support the hypothesis that lipophilic statins (e.g., lovastatin, simvastatin, atorvastatin), which penetrate muscle fibers more easily, are more likely to cause muscle toxicity than hydrophilic statins (e.g., pravastatin, rosuvastatin) 22.
Risk factors for muscle toxicity
Several factors may increase the likelihood of statin-induced myopathy (see the list below) 20. Multiple clinical trials have found that the risk of myopathy is dose-dependent, especially with simvastatin 21. The U.S. Food and Drug Administration recently cautioned about the increased risk of muscle injury from the 80-mg dose of simvastatin 26. A systematic review of placebo-controlled trials found that the incidence of statin-related myopathy from low to moderate dosages (40 mg per day or less) is similar to that with placebo (approximately 5 percent) 21. High dosages (more than 40 mg per day) are associated with myopathic symptoms in 5 to 18 percent of patients 27.
Risk factors for statin-induced myopathy 20
Factors associated with increasing statin plasma concentration
- Age older than 70 years
- Drug-drug interactions
- Female sex
- High-dose therapy (greater than one-half the maximal recommended dosage)
- Impaired liver/renal function (creatinine clearance < 30 mL per minute per 1.73 m2 [0.50 mL per second per m2])
- Low body mass
- Untreated hypothyroidism
Factors predisposing muscle to injury
- Additive drug adverse effects
- Alcohol abuse
- Substance abuse (e.g., cocaine, amphetamines, heroin)
- Untreated hypothyroidism
Myopathy risk increases when statins are taken with medications known to inhibit their metabolism (Table 1). Serum levels of simvastatin and lovastatin are increased four- to sixfold in conjunction with erythromycin and verapamil therapy, and 10- to 20-fold with itraconazole (Sporanox) and cyclosporine (Sandimmune) therapy 1. Simvastatin and lovastatin levels are increased threefold and rosuvastatin levels are increased twofold in patients also taking gemfibrozil (Lopid) 1. The rate of rhabdomyolysis was 0.44 per 10,000 patient-years with statin monotherapy versus 5.98 when the statin was combined with a fibrate. This interaction appears to be more notable with gemfibrozil than fenofibrate (Tricor) 25.
Table 1. Summary of the Major Interactions with Statins
Non-statin drug/substance | Statins affected | Recommendation | |
---|---|---|---|
CYP3A4 inhibitors | |||
Azole antifungals |
|
| |
Itraconazole (Sporanox) | |||
Ketoconazole | |||
Calcium channel blockers | |||
Diltiazem (Cardizem) |
| ||
Verapamil |
| ||
Other | |||
Grapefruit juice (more than 1 quart per day) |
| ||
CYP3A4/organic anion transporting polypeptide inhibitors | |||
Cyclosporine (Sandimmune) |
|
| |
Macrolide antibiotics |
|
| |
Clarithromycin (Biaxin) | |||
Erythromycin | |||
Protease inhibitors |
|
| |
Atazanavir (Reyataz) | |||
Ritonavir (Norvir) | |||
Lopinavir/ritonavir (Kaletra) | |||
CYP3A4/CYP2C9 inhibitor | |||
Amiodarone (Cordarone) |
|
| |
CYP2C9, CYP2C19, glucuronidation, and organic anion transporting polypeptide inhibitors | |||
Gemfibrozil (Lopid) |
|
| |
CYP2C9 inhibitor | |||
Fluconazole (Diflucan) |
|
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Statin induced muscle injury prevention
Strategies to reduce the risk of statin-induced myopathy include using the lowest effective dosage, identifying patient risk factors, monitoring adverse effects and creatine kinase (CK) levels in symptomatic patients, avoiding serious drug interactions, and educating patients. Although the third report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults recommends measuring baseline creatine kinase (CK) levels in all patients, other experts recommend obtaining baseline creatine kinase levels only in patients at high risk of muscle toxicity 11. Asymptomatic patients do not require routine measurement of creatine kinase levels. Figure 1 provides an algorithm for the evaluation and treatment of patients with myopathic symptoms 28. These usually resolve approximately two months after discontinuing statin therapy; patients can then restart the statin at a lower dosage or try a different statin. In a retrospective cohort study, 43 percent of patients remained asymptomatic on statin rechallenge, with 32 percent of patients tolerating a different statin and 11 percent tolerating a lower dosage of the same statin 29.
Figure 1. Evaluation and treatment algorithm of patients with statin-induced myopathic symptoms
[Source 6 ]Management of statins toxicity
There is no antidote to reverse the myopathy or rhabdomyolysis caused by statins 30. The general treatment is supportive and comprises immediate discontinuation of the offending drug. Aggressive fluid management is the cornerstone of treatment. The urine output needs to be monitored, and a Foley catheter insertion may be required. Other supportive measures include correction of any electrolyte disturbances and monitoring the patient with continuous ECG if hyperkalemia is present.
All patients need continual examination to monitor for hyperkalemia and acute renal failure. The patient may be discharged once electrolytes are normal and there is no renal dysfunction. The decision on restarting a statin requires good clinical judgment. Only the lowest dose of another statin should be used, and one should avoid concomitant use of fibrates. The patient should be closely monitored for muscle pain and routine urine and blood tests to ensure that muscle breakdown is not recurring.
Statins side effects
Like all medications, statins can cause side effects. However, most people tolerate them well and don’t experience any problems. You should discuss the benefits and risks of taking statins with your doctor before you start taking the medication.
If you find certain side effects particularly troublesome, you should talk to the doctor in charge of your care. Your dose may need to be adjusted or you may need a different type of statin.
Some of the main side effects of statins are described below; however, this isn’t a complete list and some of these won’t necessarily apply to the specific statin you’re taking. For information on the side effects of a particular statin, check the information leaflet that comes with your medication.
Common side effects
Although side effects can vary between different statins, common side effects (which affect up to 1 in 10 people) include:
- nosebleeds
- sore throat
- a runny or blocked nose (non-allergic rhinitis)
- headache
- feeling sick
- problems with the digestive system, such as constipation, diarrhea, indigestion or flatulence
- muscle and joint pain (see below)
- increased blood sugar level (hyperglycaemia)
- an increased risk of diabetes
However, it’s not clear whether most of the common problems people experience when taking statins are actually caused by the medication itself.
Uncommon side effects
Uncommon side effects of statins (which may affect up to 1 in 100 people) include:
- being sick
- loss of appetite or weight gain
- difficulty sleeping (insomnia) or having nightmares
- dizziness – if you experience this, do not drive or use tools and machinery
- loss of sensation or tingling in the nerve endings of the hands and feet (peripheral neuropathy)
- memory problems
- blurred vision – if you experience this, do not drive or use tools and machinery
- ringing in the ears
- inflammation of the liver (hepatitis), which can cause flu-like symptoms
- inflammation of the pancreas (pancreatitis), which can cause stomach pain
- skin problems, such as acne or an itchy red rash
- feeling unusually tired or physically weak
Rare side effects
Rare side effects of statins (which may affect up to 1 in 1,000 people) include:
- visual disturbances
- bleeding or bruising easily
- yellowing of the skin and eyes (jaundice)
Muscle effects
Statins can occasionally cause muscle inflammation (swelling) and damage. Speak to your doctor if you experience muscle pain, tenderness or weakness that can’t be explained (for example, pain that isn’t caused by physical work).
Your doctor will carry out a blood test to measure a substance in your blood called creatine kinase (CK), which is released into the blood when your muscles are inflamed or damaged. If the level of creatine kinase in your blood is more than five times the normal level, your doctor may advise you to stop taking the statin. Regular exercise can sometimes lead to a rise in creatine kinase so tell your doctor if you’ve been exercising a lot.
Once your creatine kinase level has returned to normal, your doctor may suggest that you start taking the statin again, but at a lower dose.
Tell your doctor right away if you have:
- Muscle or joint pain or tenderness
- Weakness
- Fever
- Dark urine
- Other new symptoms
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