Usually, elevations of CK and IP as well as muscular symptoms occur early, within a few days after start of statin therapy, most of them during the initial month of treatment. However, late onset (even after 6 months of therapy with the same statin) in single rare cases is documented. Muscle pains may appear either as continuous or exercise-induced. If they are exercise-induced, they appear immediately in the majority (mainly the ache-type), while the less frequent cramp-type can occur up to 24 hours after exercise. Once manifested pains persist in the majority of cases, even if exercise is stopped.
The duration of muscular side effects is difficult to estimate, as once enzymes become elevated or patients report side effects, the respective statin will be withdrawn. Rapid remission of symptoms after discontinuation of therapy has frequently been reported. Biochemical and histopathologic data, however, are not widely available. In cases of milder CK-elevation during treatment statin therapy may be cautiously continued. In 2 of these cases we found a normalization of CK after 2 (simvastatin) and 6 (pravastatin) weeks, respectively, as similarly described by Schwandt (5), while in the great majority of cases no relevant alteration of either CK or pains with ongoing therapy seems to occur.
No systematic report on the localization of neither the types of symptoms nor their intensity is available. We are preparing at present a kind of an anatomic atlas, showing that symptoms seem to be localized predominantly in the pectoralis muscle, the quadriceps and to a lesser extent the biceps, abdominal musculature, but also the masseter and the muscles in the lower back. Information as to different subtypes of pain (with or without CK elevation, with or without oxidation injury, exercise-induced, etc.) is lacking completely. Exercise seems to enlarge the number of muscles involved as well as severity of symptoms, but does not change the pattern of the affected musculature.
The occurrence of CK elevation during statin therapy is well documented and may range from 0.1 to 10% depending on the extent. Controlled data on exercise-induced CK-elevation during statin therapy are not available. Underestimation of the prevalence of statin-induced myopathy may be due to the fact that many of the symptoms are not associated with a change in CK. In fact, in the majority of cases CK remains normal. Muscle pain reported by a particular patient may thus be misinterpreted or (rather) correlated to physical exercise and sports.
The claim that statin-induced muscle injury is related to mitochondrial dysfunction (54) is unproven and unlikely at least for the cases without CK elevation, which represent the vast majority in clinical routine. A decreased rate of glycogen synthesis after fibrate exposure has been reported in-vitro in rat striated muscle; no data on statins are available yet.
How difficult the assessment of the various agents might be is reflected by a female patient with elevated CK and ache-like pain in the masseter muscle who tolerated various statins given alone, but not in combination with different ACE-inhibitors (17).
The withdrawal of cerivastatin from the market in summer 2001 may be an important date in the recognition of statin-associated side effects. Especially the high doses (based on the mentality “the higher the better”) and combination with fibrates were responsible for the life-threatening consequence. In Austria a position (VUMA) paper (55) in 1998 already issued by national health authorities recommended to start statin treatment always with the lowest respective available dose and to avoid concomitant fibrate therapy, or if, perform only at specialized centers under strict surveillance.
The 5 golden Austrian rules for statin use (56; recently proposed as a consequence of cerivastatin withdrawal) include the following.
According to present knowledge they would have avoided all the clinically relevant side effects. They do not offer, however, a proposal how to deal with the much more frequent mild ones.
Due to the lack of specific biochemistry, pathophysiology and pharmacology recommendation of general guidelines is difficult. Our data indicate, that mild side effects of statins may be by far more prevalent than so far suspected (56). More and more so far unknown subtypes of myopathy are identified. Mechanisms and consequences remain still to be investigated. In view of the fast growing number of patients taking statins on a life-long basis, more emphasis on diagnostic criteria, pathophysiology and possible treatment should be focused.
The authors thank Eva Unger for her valuable help in preparing and typing the manuscript.
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