Statins are a group of medicines widely used in the treatment of high cholesterol. Among the best known drugs of this group, we can mention simvastatin, rosuvastatin, pravastatin and atorvastatin.
Statins, besides being the most effective drugs for cholesterol control, are also the ones with the best results in the studies prevention of cardiovascular diseases, and are therefore currently prescribed for tens of millions of people throughout the world. world.
Despite being effective and safe drugs, about 5% to 10% of patients develop myopathy (muscular injury), characterized clinically by muscle pain, weakness and / or cramps. Patients receiving high doses are those at highest risk.
Muscle-origin complaints are the major side effect of statins and the most common cause of discontinuation of treatment.
In this article we will review the myopathy of statins, addressing their symptoms, risk factors and treatment options.
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The role of creatine phosphokinase (CPK or CK)
The severity of a muscle injury is defined not only by the symptoms, which include pain and loss of muscle strength, but also by changes in laboratory tests.
Muscle cells are rich in an enzyme called creatine phosphokinase, better known by the acronym CK or CPK. When there is injury of the muscle tissue, part of the CK enzyme contained in the muscles extravasates into the blood, causing the blood levels of CK to rise. While small increases in CK can occur in benign situations, such as after intense physical exertion, large elevations of blood levels are a sign of severe muscle disease.
The CK reference value usually varies with each laboratory. In general, the upper limit of normality is around 100 to 200 U / L. Whenever the CK value is at least 3 times the normal value, we say that the patient has myonecrosis (death of muscle cells).
The severity of myonecrosis is usually divided as follows:
- Mild muscle injury: CK elevated 3 to 9 times the normal value.
- Moderate muscle injury: CK elevated 10 to 50 times the normal value.
- Severe muscle injury: CK raised more than 50 times the normal value.
Therefore, a patient with CK around 400 or 500 U / L has only mild muscle injury, whereas a patient with CK levels around 7, 00 U / L has a severe and extensive muscle injury. If, in addition to myonecrosis, the patient also has loss of muscle proteins in the urine, an event called of myoglobinuria, we say that he has rhabdomyolysis, a serious condition that can lead to renal failure acute
Statins generally cause mild muscle injury, with small increases in CK values. However, about 1 in , 00 patients given these drugs may develop moderate or severe muscle damage with rhabdomyolysis.
Symptoms of Statin Myopathy
Statins can trigger a constellation of muscle symptoms, which include: discomfort, stiffness, tiredness, increased sensitivity, weakness or cramps. Symptoms generally appear after some physical exertion, but may also be present even at rest.
The intensity of the symptoms is not always directly related to the blood level of CK. Some patients with severe pain may have low or even normal CK levels, while others with mild to moderate complaints may have very high rates. Without dosing the blood CK you can not precisely define the degree of muscle damage. Therefore, every patient on statin who starts muscle pain should have a blood test to know the degree of elevation of CK.
The most common symptom of statin myopathy is muscle pain (myalgia), which may or may not be accompanied by reduced strength. In general, statins muscle damage causes pain and weakness, which in the lower limbs symmetrically affects pelvis and upper limbs attacks the muscles around the scapula, clavicle, and the initial portion of the arms (see illustration below). side).
Loss of muscle strength from myopathy of statins may make it difficult for the patient to raise his arms above his head, to rise from a chair or to climb stairs. These symptoms can also be described by the patient as fatigue or fatigue of the limbs.
Usually myopathy of statins develops within the first 6 months of use of the drug, but there are cases of patients who only developed it after a few years of use of the drug.
Complications of statin myopathy
Statin muscle damage occurs in about 5 to 10% of users, and even then, the vast majority of cases are mild, without major harm to the patient's health.
Despite the rarity, there may be cases of severe muscle damage by statins. The rhabdomyolysis is the most dangerous because the muscle proteins can clog the renal tubules, leading to acute renal failure. It is not uncommon for patients with rhabdomyolysis to require hemodialysis treatment for a few days (read: WHAT IS HEMODIALYSIS).
Risk Factors for Statin Myopathy
As already mentioned, although muscle injury is the most common side effect of statins, it is a problem that only affects some users.
We still do not fully understand the mechanisms that lead statins to be toxic to certain individuals, but some risk factors are already well known, as Next.
Characteristics of statins
The risk of muscle damage is not equal for all statins and increases with dose. THEpravastatinand thefluvastatinseem to be the drugs of this group with lower incidence of muscular pain. The 40 mg dose of pravastatin was shown to be quite safe and with a low incidence of muscle damage. THErosuvastatinat a dose of 20 mg / day has also been shown to be safe in the studies, however, doses starting at 40 mg / day have been reported as responsible for rhabdomyolysis.
As patients with hypothyroidism often have elevated cholesterol levels, it is not uncommon to prescribe statins in this group of patients. The problem is that hypothyroidism alone can cause myopathy, and when associated with a statin, the risk becomes even greater.
Clinical control of hypothyroidism through levothyroxine medications decreases the risk of muscle pain (read: LEVOTIROXINE (Puran T4) - Indications and side effects).
Genetic factors appear to play a relevant role in the genesis of statin myopathy. This is the reason why in one family, myopathy is frequent in more than one person.
Women and individuals over 60 are also at higher risk. Other factors that may influence are the frequent consumption of alcoholic beverages, intense physical activity, lack of vitamin D, dehydration and the existence of kidney or liver disease. People with a history of frequent cramps are also at increased risk of myopathy due to statins.
One of the factors that most influence the appearance of muscle damage by statins is the association with other drugs. THEsimvastatinand thelovastatinare the statins that suffer the most drug interaction capable of provoking myopathy. THEatorvastatin, arosuvastatinand thepitavastatinmay also experience interaction of some medications, but with a somewhat lower frequency.
Medications such as: amiodarone, fluconazole, ketoconazole, itraconazole, cyclosporine, gemfibrozil, warfarin, verapamil, amlodipine, erythromycin, clarithromycin, ritonavir, colchicine and niacin significantly increase the risk of muscle statins. If possible, this association should be avoided.
The list provided above is far from complete, so if you take multiple medications and have muscle pain by the statin, take a look at the package insert to see if there is any drug interaction that may be triggering the of pain.
What to do with the patient who has statin muscle pain
As there are no drugs on the market as effective as statins in preventing cardiovascular disease, the decision whether or not to suspend treatment should be well considered. Drugs like ezetimibe are not as effective as statins and should not be regarded as a substitute for height. Ezetimibe can even be usedtogetherwith the statin, in order to allow a lower dosage of the latter.
Rare patients who develop severe muscle damage should permanently stop treatment with statins because the risk to health is greater than the potential benefit of the drug. We treated myopathy with a CK elevation greater than 10 times the reference value (CK greater than 1500-2000 U / L in most laboratories) as severe myopathy.
In cases that do not fall under the concept of severe myopathy, which are actually the majority, there are some strategies that can be implemented.
1- Problems to correct
The first point is to identify possible drug interactions that may be increasing the risk of muscle injury. The association of a statin with gemfibrozil, although not indicated, is still widely used by some doctors, when the goal is to lower triglyceride levels (read: WHAT ARE THE TRIGLYCERIDES?). If the patient has high cholesterol and triglycerides, and the statin alone is not enough to control the values, the drug with the least risk of myopathy is fenofibrate.
In addition to reviewing medications the patient uses, an evaluation of thyroid function is also important. In many cases, a simple optimization of the treatment of hypothyroidism is sufficient to control muscle pain.
Dosing of blood vitamin D levels is also indicated. If the values are low, the replacement, which can be done very simply and cheaply, usually softens the pain.
2- Changes in statin
With no problems to correct, the next step is to try to optimize treatment with statins. In patients who take high doses of statin, simple reduction of the daily dose may be sufficient. If needed, the doctor may associate a drug such as ezetimibe so that the LDL cholesterol value does not rise again after the statin is reduced.
Statin doses considered moderate are: 40 mg of lovastatin, pravastatin or simvastatin; 20 mg atorvastatin; or 10 mg of rosuvastatin. Only patients who have previously had a heart attack or who have a very high risk of heart attack usually have been indicated for higher doses of statins, usually atorvastatin 40 mg / day or 20 mg / day rosuvastatin.
An alternative is the use of statins on alternate days. Rosuvastatin at doses up to 20 mg / day can be taken 3 times a week, which still maintains a good action against LDL.
Another option is to switch statin. As already mentioned, pravastatin and fluvastatin usually have a lower incidence of myopathy and may be the solution, especially for patients taking simvastatin or lovastatin, which are the most common statins that cause pain muscular.