Lipid lowering drugs all (fibrates, nicotinic acid derivatives, statins) have been associated with myopathy. 3-Hydroxy-3-methylglutaryl (HMG)-Co-enzyme-A-reductase inhibitors (statins) are widely and effectively used to lower LDL-cholesterol and thereby vascular events and to prolong patient survival. Since their introduction in 1987 they have been shown to be remarkably successful on a clinical base. Large-scale clinical trials have proven effectiveness both in primary (1) and secondary (2) prevention of coronary heart disease (3). Due to the discovery of a great number of additional non-lipid related benefits (4) this family of compounds has already become one of the most widely used ones world-wide. It is reasonable to believe that optimized use of this family of drugs (indication, compliance) will have a significant further impact on cardiovascular events and life-expectancy, optimized pharmacological profile may lead to the development of compounds with further improved effects with an identical or even better spectrum of side effects. The more severe ones, especially in combination with other drugs (e.g. fibrates, cyclosporine, etc.) are well documented. Beside extremely rare severe forms, such as rhabdomyolysis, the major groups of side effects of statins are various forms of myopathy presenting clinically either with muscle pain (myalgia) and/or creatine phosphokinase (CK) elevation. Almost all papers on statins simply refer to this side effect just in percentage numbers, without presenting any further information. The detailed literature, however, is rare. Even terminology (myopathy, myalgia, myotoxicity, myositis, etc.) is not (well) defined. A recent textbook (5) mentions that a mild increase in CK during statin therapy is quite frequent, and may persist or normalize during ongoing therapy. Assuming that the severe statin-induced side effects are well documented it is the aim of this review to deal with a so far rather neglected quite large group of more mild side effects of unknown origin and consequence.
In the large clinical trials with various statins, the rate of muscular side effects consistently has been reported to range at around 5% (6,7). No significant difference between simvastatin and placebo treatment with regard to the frequency of myalgia was found (8). Muscular skeletal side effects (total of all types of appearance) were monitored in 27.6% and myalgia in 3.7%. In a textbook (9) it is stressed that prevalence of mild elevations in CK activity may be 5 – 10%, myositis (CK-elevation plus muscle pain) is rare. Combination with fibrates significantly enhances the risk. In a large population-based cohort study (n = 17,219 vs. 28,974) Gaist et al. (10) found the incidence of myopathy 2.3 per 10,000 person-years (vs 0 in the non-treated hyperlipidemia cohort). Their definition of myopathy was the presence of at least 2 criteria out of 3, i.e. clinical diagnosis of myopathy, muscle weakness (or pain or tenderness) and elevated CK.
Schwandt (5) described the most severe form as “myopathy syndrome” or “weakness” with a concomitant >10 fold increase of CK. The prevalence rate of this form seems to range between about 0.1% (40 mg lovastatin) and 0.2% (80 mg lovastatin) (11). The prescribing information reports a prevalence of myopathy at 20 – 40 mg lovastatin of 1 : 5000, at 80 mg of 1 : 400. The most severe form, a myositis syndrome eventually resulting in rhabdomyolysis and renal failure seems to be rare with a prevalence rate of <1 °/oo as it can be recalculated from the large studies (11).
The mechanism of statin-induced skeletal injury is not well understood. Animal models show that type II white muscle fibers are mainly affected. Oxidation injury may be a central issue. Coenzyme-Q-biosynthesis is decreased (12) and at least in some patients increased levels of isoprostanes (IP; 13) have been found. The percentage of patients with elevated IP is higher in the presence of CK elevation, but can also be seen in the absence of elevated CK. The extent of IP elevation showed no correlation to CK and/or symptoms. An increase in IP has been reported in myopathy (14) and rhabdomyolysis (15,16). If IP appeared to be increased, there was a comparable elevation in serum, plasma and urine. Although vitamin E in single cases may cause alleviation of the symptoms (17), its general use does not result in clinical benefit.
PROBLEMS OF VERIFICATION
When the first patient reported muscle pains without CK-elevation to one of us, he was not believed. The same skepticism was apparent when I (H.S.) first presented preliminary data on this complicated issue. Looking on the available tests that could confirm the patients' problems, this issue becomes even more evident.
SCINTIGRAPHIC IMAGING
We are not aware of a systematic EMG study in statin users. Anecdotal cases show that patients suffering from any type of statin-induced myopathy do not develop an abnormal EMG (own unpublished results). However, as we monitored 2 patients, a normal EMG does not exclude myopathy.
Although muscular metabolic abnormalities are frequently associated with an increased uptake of methoxyisobutylisonitrile (MIBI) into the diseased muscular segments (18), statin-induced myopathy in 8 patients during still ongoing therapy with 5 different compounds did not reveal any abnormal scintigraphic finding (19). Other cationic tracers (99mTc-tetrofosmin, 99mTc-furifosmin) did not image positively the affected muscles either. 201Thallium to our knowledge was not tested. One of the reasons of negative imaging might be that 99mTc-MIBI is associated with mitochondrial integrity and cellular viability, while the type II fibers in contrast contain much less mitochondria (16). PET-metabolic studies are not available yet. Therefore, nuclear medicine was of no help as to diagnosis and localization of statin-induced myopathies so far.
POSSIBLE MECHANISMS
Coenzyme Q10 (CoQ10)-ubiquinol
CoQ10 among others is a well-known scavenger of reactive oxygen species and membrane stabilizer, which in man is in part of exogenous and in part of endogenous origin. CoQ10 is a mevalonate derived compound that could explain the relationship between low levels of ubiquinone and statins as related to myopathy. It is an essential coenzyme for the optimal performance of a variety of intra- and extra-cellular metabolic processes, in particular in the cardiovascular system. It has thus been discussed, whether a decrease in ubiquinone could be the cause of myopathy-related side effects. Kontush (20) was the first to report that the reduced form of CoQ10 is significantly lower in patients with hyperlipoproteinemia. Following this line Mohr and coworkers (21) were able to show that supplementation with CoQ10 resulted in an increased CoQ10 level within the circulating human lipoproteins and in enhanced oxidation resistance. In 1990 Folkers et al. (22) demonstrated that treatment with lovastatin resulted in a decreased CoQ10 level in blood, which could be normalized by exogenous supplementation. Watts et al. (23) reported a similar decrease after simvastatin treatment in patients suffering from hyperlipidemia suggesting that this effect might eventually induce the adverse events. A similar finding was reported after pravastatin (24) in hypercholesterolemic patients. Tissue CoQ10 levels and LDL/ubiquinone ratio, however, were unchanged (25). Similarly, simvastatin was reported not to influence the ratio (26). Bargossi (27) showed a reduced level of CoQ10 in plasma and platelets after simvastatin treatment, which was normalized again by CoQ10 oral administration. Ghirlanda (28) described a similar decrease in CoQ10 by about 40% after pravastatin and simvastatin treatment. In an experimental study in rabbits, Fukami et al. (29) showed that there is no direct correlation between myopathy and the decrease in ubiquinone content in skeletal muscles. In a randomized cross-over study in 12 healthy volunteers, however, testing hydrophilic pravastatin (20 mg) and lipophilic atorvastatin (10 mg) for 4 weeks no decrease in circulating CoQ10 levels was monitored (30). In a review Dujovne (31) discussed the dose-dependent potential of statins to induce myotoxicosis and its reversal by mevalonate. Duration of treatment was different, and the number of cases too small to see, whether there are differences among the various statins on the market. No detailed data on patients with side effects (before vs after), however, are available. A genetical background can not be excluded. At an extremely high dose of up to 45 mg lovastatin/kg/day in cancer patients the dose-limiting myopathy could be prevented by ubiquinone supplementation (32). In our patients with mild forms a therapeutic attempt, however, in the great majority (> 80%) was unsuccessful. While the majority of papers (but not all) report a decrease in CoQ10 during statin therapy (22,29,33,34) its value as protecting agent is even more unclear and unlikely.
Isoprostanes (oxidation injury)
An anecdotal case with statin-induced muscle pains clinically responding to vitamin E treatment suggests that oxidation injury may play a major role (17). Usually, statins have an antioxidant effect, which besides other parameters was documented by analysis of antioxidant concentrations in LDL before and after statin treatment as well as a decrease in 8-epi-prostaglandin (PG)F2α (35). IP (8-epi-PGF2α) can be considered as biochemical markers of in-vivo oxidation injury (36). Patients with hypercholesterolemia exhibit increased levels of IP in plasma and urine (37). Increased lipid peroxidation in (not statin-induced) rhabdomyolysis via strikingly increased urinary F2-isoprostane excretion has been reported (38). In some patients on statin therapy an elevation of IP could be discovered (39) which disappeared immediately after drug withdrawal (40). Most patients respond only on a few statins (see for example a 56-years old female in Figure 1), while only very few (17 in our unit out from >1,000 with side effects) show an increase in IP 8-epi-PGF2α after all the statins (for example see a patient's response in Figure 2). As the day-to-day variations in IP levels are minimal (41), the data seem quite reliable. The increase in 8-epi-PGF2α, however, was not correlated to absence or presence of clinical symptoms and their extent or to elevation in CK (40). 11% of (hundred) statin-treated patients (34) without myalgia and CK elevation and normal pretherapeutic IP values exhibited increased 8-epi-PGF2α (in plasma and urine) indicating that there might be a small subgroup showing in-vivo oxidation injury during statin therapy. More than 50% of patients with myalgia showed elevated IP. Plasma and urinary 8-epi-PGF2α sometimes appeared to be more elevated as compared with the respective serum values. Interestingly, cigarette smoking with its severe influence on antioxidant status (42,43) is not associated with a higher rate of muscular side effects or more frequent increase in 8-epi-PGF2α as are other conditions with elevated IP, such as diabetes mellitus etc. No relation to type and/or extent of hyperlipoproteinemia can be assessed. No prooxidant effect of statins was observed on in-vitro induced LDL-oxidation in plasma samples from these patients. This parameter is, in fact, normally beneficially affected by the statins. As a matter of fact, no exact data on prevalence are available. No significant differences as to the various statins used therapeutically have been observed so far. From our findings, however, we attempted a very preliminary table of incidence summarizing all the compounds. The hypothesis that statins bring about some, if not all, of their actions by interacting with essential fatty acids and their metabolites, serving as endogenous second messenger, deserves further studies (44).
;)
FIG. 1.:
Some but not all statins enhance 8-epi-PGF2α. 8-epi-PGF2α-response after various statins; 56 years female (156/57; familial isolated hypercholesterolemia since 20 a). P, prevalue; follow-up in days; D, day of drug withdrawal (after 12 days of therapy); IP was measured in plasma (P, pg/ml), serum (S, pg/ml) and urine (U, pg/mg creatinine). Drugs (P, pravastatin, S, simvastatin, L, lovastatin, A, atorvastatin) were tested. y-axis, isoprostane values; x-axis, follow-up period. While the patient responded on P and S, she did not on L and A.
FIG. 2.:
Isoprostane increase on statins is comparable in all compartments. Patient responds with an IP-increase after all the statins examined (43-year-old woman, survivor of myocardial infarction). F, fluvastatin; further abbreviations as in
Figure 1. After stopping therapy the IP-values fast return back to prevalues within a few days only.
APPEARANCE/TYPE
Apparently there are at least two types of muscle pains. These are either ache- or cramp-like with a ratio of about 3:1. In rare cases we saw both types in a particular patient at the same time (45). Interestingly, they may show different times of onset after start of statin therapy ranging from days to weeks. Starting regular physical exercise may manifest these symptoms even after years. Recently, we separated a third type of “flue-like” symptoms including myalgia, weakness, exhaustion, paining joints elevated acute phase response markers and sometimes subfebrile temperature (46). This type of side effects might be dose-dependent. Concerning appearance or type of muscle pains we are not aware of different responses to the various statins. A certain type of muscle weakness seen mainly in older patients (> 70 a) after statin therapy of >1 year is not yet definitely attributed to the treatment.
TIME OF ONSET
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.
DURATION
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.
LOCALIZATION
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.
CREATINE PHOSPHOKINASE
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.
PHYSICAL ACTIVITY
Thompson et al. (47) were the first to report, that HMG-Co-enzyme-A-reductase inhibitors exacerbate exercise-related skeletal muscle injury. Thompson et al. (47) reported a patient treated with lovastatin that experienced a significant CK elevation after physical exercise in the absence of clinical symptoms. The fact that many of the milder symptoms are exercise-dependent probably results in a mis-interpretation by the patient and the doctor and is not related to the statin treatment. The by far most prevalent finding in those doing regular exercise is tennis-induced myopathy, at least in our country. The prevalence of myopathy during and after exercise is significantly enhanced as compared with sedentary life style. Preliminary own data indicate that up to about 25% of statin users may suffer from any of the problems described if they do vigorous physical exercise. Top athletes very rarely tolerate treatment with statins. So far, we could not detect differences between the various statins.
DOSE-DEPENDENCY
With lovastatin 40 and 80 mg/d there was a 100% difference of myopathy (11), although at a very low level (0.1 vs 0.2%). Cytochrome P450-induced muscular side effects in combination with other drugs, in particular fibrates, may well be dose-dependent. Although personal experience varies among specialists, with the exception of cerivastatin we did not have any indication for a dose-dependency so far with any of the compounds, in particular in those patients without CK-elevation. At higher doses, however, not used in our country there may be well a dose-dependency of symptoms (Phillips P.S., San Diego, personal communication 2001). Dujovne (31) reported a dose-dependent potential of statins to induce myositis and its reversal by mevalonic acid. In our experience there was no evidence of dose-dependency for muscle pain with any of the statins except for two cases on cerivastatin. With cerivastatin, in contrast, in two patients we saw a clear dose-dependency of pains in absence of a change in CK.
PREDISPOSING FACTORS
Gaist et al. (10) reported a higher myopathy risk in people above 65 a, smokers as well as ex-smokers and individuals with a BMI >24 kg/m2. In our group of patients these factors did not predispose.
RISK OF DIFFERENT STATINS
Under experimental conditions (48) cerivastatin was ranked the most risky compound to increase CK, followed by fluvastatin, atorvastatin, simvastatin, lovastatin and pravastatin. In their large cohort study Gaist et al. (10) reported the highest risk for pravastatin (27.3 relative risk) followed by simvastatin (6.1); this was lower as compared with fibrates (164.0 fenofibrate, 39.0 bezafibrate, respectively).
PATHOPHYSIOLOGY
In-vitro myotoxicity is well defined (49). Differential sensitivity of striated muscle for various statins (50) in-vitro as many other tests, however, has no in-vivo predictive value. In-vivo mechanisms remain mainly obscure. In severe cases of myopathy a non-inflammatory process with focal degeneration of myocytes and formation of vacuoles has been described (51). In one patient who developed myopathy while treated with pravastatin endo- and perimyolytic inflammatory infiltration with mainly CD4+-lymphocytes has been reported (13). During pravastatin and simvastatin treatment (52) mitochondrial myopathies have been seen. In patients with pain symptoms in the absence of CK elevation, light and electron microscopy revealed completely normal findings, although they were still taking the drug at the time of biopsy. Recently, muscle biopsy in patients with muscle symptoms muscle biopsy revealed evidence of mitochondrial dysfunction including abnormally increased lipid stores and signs of a defect in mitochondrial respiratory chain function (53). This would fit very well with the observed increase in IP indicating oxidation injury. While simvastatin and lovastatin reduce cholesterol content in striated muscle by >90%, pravastatin does not (53). Apparently, hydro- and lipophilicity and the quantitative differences in reduction of muscle cholesterol (content) do not correlate with any quantitative differences in the occurrence of muscular side effects (50).
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.
TREATMENT
What to do with mildly elevated CK, muscle pains and elevated isoprostanes? What is the evidence to stop treatment in patients with only one abnormal biochemical parameter without other symptoms? Especially, as only the association but not a causative mechanism has been assessed yet. Is not in these patients the benefit risk ratio sufficient to continue this therapy? What to do when myalgia is mild and tolerable? Should one advise the patient not to perform more strenuous exercise? Should a statin been withdrawn in a top athlete in case muscle pains appear? Withdrawal of the respective statin is definitely the measure of choice in case of more severe symptoms. Once the statin is withdrawn, usually the symptoms disappear within days or a week. Again, however, we saw one patient where pains persisted for more than a month. There are no guidelines available for this situation. No recommendation of the producing companies is available. Recently, FDA recommended that patients should watch for muscle aches and pains. And what then? Stop or continue? When? Is an attempt to interrupt the drug intake justified? Is a positive result meaningful? Several case reports suggest, that CoQ10 supplementation might reverse muscle injury (12). Anecdotal reports show also a benefit of vitamin E (35) and other antioxidants such as vitamin C. Although most findings indicate an oxidation injury, our results are discouraging.
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).
PREDICTABILITY
Nakai et al. (48) proposed a urethane infusion testing for assessing the risk of myopathy. This test is based upon the original finding that CK dramatically increases after bezafibrate during urethane infusion, a finding confirmed for other lipid lowering agents. Histochemical analysis revealed a concomitant increase in myoglobin in renal tissue. The pathophysiological background of the test is unknown. CK elevation, however, is only one type of side effects in men. In rats this testing worked and showed that the most risky compound is cerivastatin followed by fluvastatin, atorvastatin, simvastatin, pravastatin. However, we are not aware on human data. The authors claim that myopathy risk is proportional to lipophilicity at least in men cannot be confirmed.
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.
- Start always with the lowest available dose of the respective statin.
- Avoid combination with fibrates (if necessary, only under strict surveillance in a specialized center).
- Inform patient on muscle symptoms; if any of those occur, stop treatment immediately, contact physician, measure enzymes.
- If a new additional drug is prescribed, ask physician on the possibility of combination before. If this is impossible and the new drug urgent, discontinue statin temporarily until consulting.
- If antibiotics are used, ask physician before. If impossible, discontinue statin therapy for the period of antibiotics intake.
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.
CONCLUSION
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.
Acknowledgments:
The authors thank Eva Unger for her valuable help in preparing and typing the manuscript.
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