Statins: Update on Clinical Issues and Adverse Effects
Statins: Update on Clinical Issues and Adverse Effects
Much of the data on the newer adverse effects of statins have come from observational studies of large administrative databases or anecdotal case reports. In clinical trials, the participants may be healthier and taking fewer drugs than patients seen in routine practice and thus at lower risk of adverse effects. In addition, data from observational studies reporting new adverse effects with statins may be subject to residual confounding rather than a true adverse effect. As a result, the challenge for practitioners is to find the balance between statins' established efficacy for cardiovascular disease and having an open, yet skeptical, mind to new and potentially important data from observational studies.
Muscle symptoms are the best known adverse effects of statins and may be related to a reduction in coenzyme Q10 that affects mitochondrial oxidative metabolism and impairs energy production in muscles. These syndromes include myopathy, myalgias in which muscle pain or weakness is present and serum CK concentrations are not elevated, and myositis in which muscle symptoms and increased CK levels are present. Rhabdomyolysis is characterized by the presence of muscle symptoms and an elevation in CK levels typically greater than 10 times the upper limit of normal. Fortunately, with appropriate management including prompt discontinuation of the statin, symptoms resolve, and most patients will return to their baseline function within several weeks to months. Patients should be counseled to report any symptoms of muscle pain or weakness to their provider at which time a decision to discontinue or alter therapy can be determined based on the severity of symptoms and CK level. Depending on symptom severity, patients may be restarted on a different statin, or an alternative dosing regimen may be substituted such as twice-weekly rosuvastatin.
Update. Drug interactions and genetic factors continue to be identified as major contributing risk factors for developing muscle symptoms with statins. Genetic variability in the CYP3A4 and CYP2D6 genes may result in potentially reduced metabolism of simvastatin and atorvastatin. In addition, preliminary evidence exists of ubiquinone deficiencies in patients with mutations in the COQ2 gene, which might increase the risk of developing muscle syndromes. Although the use of coenzyme Q10 and vitamin D has been promoted for preventing or lessening common muscle syndromes from statins, the evidence is inconsistent. The single most important consideration is to have an up-to-date list of all of the patient's drugs in order to minimize drug interactions that increase the risk of muscle syndromes.
New reports have indicated that a rare immune-mediated necrotizing myopathy may also be associated with the use of statins. Of note, this syndrome has not resolved with the discontinuation of the statin unlike the common muscle symptoms but instead may respond to the use of immunosuppressive drugs.
Hepatotoxicity has been a potential concern with the use of statins since the drugs were first undergoing clinical trials in the early 1980s. This concern originated in part from the use of elevations in hepatic transaminases of at least 3 times the upper limit of normal as a marker of drug-induced liver disease, although an 8-fold elevation would have been more specific. Large clinical trials of statins infrequently have noted elevations in alanine transaminase, but the frequency has been similar to that of participants receiving placebo. Although the mechanism is unclear, it may be the result of changes in the lipid components of hepatocyte membranes and subsequent release of liver enzymes. The prescribing information for most statins had recommended baseline monitoring of alanine transaminase with repeated measurements at 6 to 12 weeks after initiating therapy and periodically thereafter. In February 2012, the Food and Drug Administration (FDA) indicated that routine monitoring of hepatic transaminases is no longer necessary.
Established Adverse Effects
Much of the data on the newer adverse effects of statins have come from observational studies of large administrative databases or anecdotal case reports. In clinical trials, the participants may be healthier and taking fewer drugs than patients seen in routine practice and thus at lower risk of adverse effects. In addition, data from observational studies reporting new adverse effects with statins may be subject to residual confounding rather than a true adverse effect. As a result, the challenge for practitioners is to find the balance between statins' established efficacy for cardiovascular disease and having an open, yet skeptical, mind to new and potentially important data from observational studies.
Muscle Syndromes
Muscle symptoms are the best known adverse effects of statins and may be related to a reduction in coenzyme Q10 that affects mitochondrial oxidative metabolism and impairs energy production in muscles. These syndromes include myopathy, myalgias in which muscle pain or weakness is present and serum CK concentrations are not elevated, and myositis in which muscle symptoms and increased CK levels are present. Rhabdomyolysis is characterized by the presence of muscle symptoms and an elevation in CK levels typically greater than 10 times the upper limit of normal. Fortunately, with appropriate management including prompt discontinuation of the statin, symptoms resolve, and most patients will return to their baseline function within several weeks to months. Patients should be counseled to report any symptoms of muscle pain or weakness to their provider at which time a decision to discontinue or alter therapy can be determined based on the severity of symptoms and CK level. Depending on symptom severity, patients may be restarted on a different statin, or an alternative dosing regimen may be substituted such as twice-weekly rosuvastatin.
Update. Drug interactions and genetic factors continue to be identified as major contributing risk factors for developing muscle symptoms with statins. Genetic variability in the CYP3A4 and CYP2D6 genes may result in potentially reduced metabolism of simvastatin and atorvastatin. In addition, preliminary evidence exists of ubiquinone deficiencies in patients with mutations in the COQ2 gene, which might increase the risk of developing muscle syndromes. Although the use of coenzyme Q10 and vitamin D has been promoted for preventing or lessening common muscle syndromes from statins, the evidence is inconsistent. The single most important consideration is to have an up-to-date list of all of the patient's drugs in order to minimize drug interactions that increase the risk of muscle syndromes.
New reports have indicated that a rare immune-mediated necrotizing myopathy may also be associated with the use of statins. Of note, this syndrome has not resolved with the discontinuation of the statin unlike the common muscle symptoms but instead may respond to the use of immunosuppressive drugs.
Hepatotoxicity
Hepatotoxicity has been a potential concern with the use of statins since the drugs were first undergoing clinical trials in the early 1980s. This concern originated in part from the use of elevations in hepatic transaminases of at least 3 times the upper limit of normal as a marker of drug-induced liver disease, although an 8-fold elevation would have been more specific. Large clinical trials of statins infrequently have noted elevations in alanine transaminase, but the frequency has been similar to that of participants receiving placebo. Although the mechanism is unclear, it may be the result of changes in the lipid components of hepatocyte membranes and subsequent release of liver enzymes. The prescribing information for most statins had recommended baseline monitoring of alanine transaminase with repeated measurements at 6 to 12 weeks after initiating therapy and periodically thereafter. In February 2012, the Food and Drug Administration (FDA) indicated that routine monitoring of hepatic transaminases is no longer necessary.
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