Poškození svalů při léčbě inhibitory HMG CoA reduktázy - statiny

Cor Vasa 2003, 44(7-8):376-386

Muscle damage during therapy with statins, HMG CoA reductase inhibitors

Jiří Widimský: Klinika kardiologie, Institut klinické a experimentální medicíny, Subkatedra kardiologie IPVZ, Praha, Česká republika

Muscle damage associated with statin therapy is one of the most serious side effects of statins. These include myalgia (muscle pain without an increase in creatine kinase /CK/), with myositis being a more serious stage (muscle symptoms associated with an increase in CK), which may be accompanied by fever and malaise. The most serious stage is rhabdomyolysis characterized by the presence of muscle symptoms, a marked increase in CK levels (as a rule, substantially more than a tenfold of the upper limit of the norm) associated with an increase in creatinine levels (a condition accompanied usually by brown urine and urinary myoglobin) and the development of acute renal failure.
However, the incidence of rhabdomyolysis is not high; not a single case was reported in the Pravastatin Pooling Project study summarizing the results of CARE and LIPID, two secondary prevention trials, and WOSCOPS, a primary prevention trial. In the 4S trial, rhabdomyolysis was reported in one patient.
A summary of all reported fatal cases of rhabdomyolysis and the numbers of prescriptions for all statins in the US (from the time they received marketing authorization for the US) demonstrates that the incidence of muscle damage-with the exception of cerivastatin (withdrawn from the market)-is low being about 0.04-0.19 cases per 1 million prescriptions.
The basic mechanisms of statin-produced myopathy are not well understood. Myotoxicity may be due to interaction with the cytochrome P-450 (CYP-450) enzyme system; the system is involved in the metabolism of numerous drugs and occurs predominantly in the hepatocytes. The toxic effect may manifest itself especially in situations whereby a substance metabolized by a specific CYP-450 isoform is administered concomitantly with another substance inhibiting the same CYP-450 isoform, or metabolized by the same CYP-450 isoform. CYP-450 3A4 is the main isoform for lovastatin, simvastatin, and atorvastatin metabolism. Fluvastatin has not been shown to interact with CYP3A4 inhibitors and is metabolized mainly by the CYP2C9 isoform. An advantage of pravastatin is that it is not metabolized via CYP-450; the exact metabolic pathway is still a subject of debate. However, muscle damage also occurs during fibrate therapy.
Transplant recipients are at increased risk for myotoxic effects.
To explain, cyclosporin-the most widely used immunosuppressive agent-shows interaction with some drugs including statins. The review reports muscle damage during treatment of patients after heart or kidney transplantation. Given the interaction of statins in cyclosporin-treated transplant recipients, fluvastatin and pravastatin seem to be the most suitable drugs as they are not primarily metabolized by CYP3A, and their relatively hydrophilic nature makes these statins enter less intensively cells other than hepatic, e. g., muscle cells.
The review includes a recommendation to monitor side effects of stations, as suggested by ACC/AHA/NHLBI 2002. Evidence on the beneficial action of statins on the survival of heart transplant recipients and on the beneficial modulation of graft vasculopathy is also provided.
Potent CYP 3A4 inhibitors which, when combined with some statins (except for pravastatin and fluvastatin), may cause myopathy include azole antifungals such as itraconazole and ketoconazole; macrolides such as erythromycin, claritromycin; and antivirals such as ritonavir. The summary concludes by reviewing management of combined hyperlipidemia using a combination of statins and fibrates, and the potential for myopathy occurrence. Among fibrates, gemfibrozil seems to be the least suitable drug for combination therapy with statins. By contrast, the safety of the fluvastatin-fenofibrate combination has been supported even by Czech data.