Share this article on:

Muscular Side Effects of Statins

Sinzinger, Helmut*†; Wolfram, Roswitha; Peskar, Bernhard A.§

Journal of Cardiovascular Pharmacology: August 2002 - Volume 40 - Issue 2 - p 163-171

Lipid lowering has been shown to be effective in preventing primary and recurrent cardiovascular events and to save life. Statins almost exclusively used for this purpose meanwhile became one of the most widely prescribed families of drugs world-wide. Myopathies – mainly not well characterized – are the major group of side effects. We here review different types of clinical appearances, localizations, symptoms and the biochemical background. The data indicate that severe muscular side effects are rare. Patients and their doctors, however, easily overlook mild ones. Myopathic symptoms without any known biochemical correlate are not rare. No general guideline exists about exact diagnosis and differential diagnosis. Strict adherence to the measures of life-style change and performance of regular exercise can even further enhance significantly these side effects. Much more research should be directed onto the pathophysiological (genetic?) background to finally evaluate possible therapeutic consequences rather than simply to withdraw or change the respective statin.

*Department of Nuclear Medicine, University of Vienna; †Wilhelm Auerswald Atherosclerosis Research Group (ASF), Vienna; ‡Department of Angiology, University of Vienna; and §Department of Experimental and Clinical Pharmacology, University of Graz, Austria

Received October 1, 2001; accepted March 6, 2002.

Address correspondence and reprint requests to H. Sinzinger, M.D., Prof., Wilhelm Auerswald Atherosclerosis Research Group Vienna, Nadlergasse 1, A-1090 Vienna, Austria. E-mail:

DOI: 10.1097/01.FJC.0000019066.50377.90

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.

Back to Top | Article Outline


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.

Back to Top | Article Outline


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.

Back to Top | Article Outline


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.

Back to Top | Article Outline

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)F (35). IP (8-epi-PGF) 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-PGF 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-PGF, 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-PGF (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-PGF 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-PGF 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.

FIG. 1.

FIG. 2.

FIG. 2.

Back to Top | Article Outline


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.

Back to Top | Article Outline


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.

Back to Top | Article Outline


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.

Back to Top | Article Outline


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.

Back to Top | Article Outline


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.

Back to Top | Article Outline


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.

Back to Top | Article Outline


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.

Back to Top | Article Outline


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.

Back to Top | Article Outline


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).

Back to Top | Article Outline


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.

Back to Top | Article Outline


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).

Back to Top | Article Outline


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.

  1. Start always with the lowest available dose of the respective statin.
  2. Avoid combination with fibrates (if necessary, only under strict surveillance in a specialized center).
  3. Inform patient on muscle symptoms; if any of those occur, stop treatment immediately, contact physician, measure enzymes.
  4. 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.
  5. 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.

Back to Top | Article Outline


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.

Back to Top | Article Outline


The authors thank Eva Unger for her valuable help in preparing and typing the manuscript.

Back to Top | Article Outline


1. Shepherd J, Cobbe SM, Ford I, Isles CG, Larimer AR, Mac Farlane PW, McKillop JH, Packard CJ, for the West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. New Engl J Med 1995;333:1301–7.
2. Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Group. Lancet 1994;344:1383–9.
3. Gotto AM, Grundy SM. Lowering LDL-cholesterol: questions from recent meta-analysis and –subreb analysis of clinical trials data: issues from the Interdisciplinary Council of Reducing the Risk for Coronary Heart Disease. Circulation 1999; 99:E1–E7.
4. Kolovou G. The treatment of coronary heart disease. An update. Part 3: Statins beyond cholesterol lowering. Current Med Res and Opinion 2001; 17:34–7.
5. Schwandt P, Richter WO, Parhofer KG. Handbuch der Fettstoffwechselstörungen. Pathophysiologie, Diagnostik und Therapie der Dyslipoproteinämien – Prävention der Atherosklerose. 2nd ed. Schattauer, Stuttgart-New York, 2001.
6. Arad Y, Ramakrishnan R, Ginsberg HN. Lovastatin therapy reduces low-density lipoprotein apoB levels in subjects with combined hyperlipidemia by reducing the production of apoB-containing lipoproteins: implications for the pathophysiology of apoB production. J Lipid Res 1990; 31:567–82.
7. Bard JM, Dallongeville J, Hagen E, Pfister P, Rose L, Fruchart JC, Duriez P. Comparison of the effect of fluvastatin, an hydroxymethyl glutaryl conenzyme A reductase inhibitor, and cholestyramine, a bile acid sequestrant, on lipoprotein particles defined by apolipoprotein composition. Metabolism 1995; 44:1447–54.
8. Pedersen TR, Berg K, Cook TJ, Faergeman O, Haag T, Felt H, Kjekshus J, Miettinen T, Muslimer TA, Olsson AG, Pyörälä K, et al. Safety and tolerability of cholesterol lowering with simvastatin during 5 years in the Scandinavian Simvastatin Survival Study. Arch Intern Med 1996; 156:2085–92.
9. Witztum JL. Drugs used in the treatment of hyperlipoproteinemias. In: Harrison JG, et al. (eds). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. McGraw-Hill, 1996.
10. Gaist D, Carcía Rodríguez LA, Huerta C, Hallas J, Sindrup SH. Lipid-lowering drugs and risk of myopathy: a population-based follow-up study. Epidemiology 2001; 12:565–9.
11. Bradford RH, Shear CL, Chremos AN, Dujovne C, Downton M, Franklin FA, Gould AL, Hesney M, Higgins J, Hurley DP. Expanded clinical evaluation of lovastatin (EXCEL) study results. I. Efficacy in modifying plasma lipoproteins and adverse event profile in 8245 patients with moderate hypercholesterolemia. Arch Intern Med 1991; 151:43–9.
12. Bliznakov E, Wilkins DJ. Biochemical and clinical consequences of inhibiting coenzyme Q10 biosynthesis by lipid-lowering HMG-CoA reductase inhibitors (statins): a critical overview. Adv Therapy 1998; 15:218–28.
13. Sinzinger H, Lupattelli G, Chehne F. Increased lipid peroxidation in a patient with CK elevation and muscle pain during statin therapy. Atherosclerosis 2000; 153:255–6.
14. Sinzinger H, Chehne F, Lupattelli G. Oxidation injury may also occur in statin-treated patients without enzyme elevation and myopathy. J Cardiovasc Pharmacol 2002 (in press).
15. Bizzaro N, Bagolin E, Milani L, et al. Massive rhabdomyolysis and simvastatin. Clin Chem 1992; 38:1504–5.
16. Corpier CL, Jones PH, Suki WN, et al. Rhabdomyolysis and renal injury with lovastatin use. JAMA 1988; 260:239–41.
17. Sinzinger H. ACE-inhibitor rather than HMG-Co-enzyme-A-reductase inhibitor causative for CK-elevation? – A case report. Atherosclerosis 2000; 148:205–6.
18. Sarikaya A, Sen S, Cermik TF, Birtane M, Berkarda S. Evaluation of skeletal muscle metabolism and response to erythropoietin treatment in patients with chronic renal failure using 99Tcm-sestamibi leg scintigraphy. Nucl Med Commun 2000; 21:83–7.
19. Lupattelli G, Palumbo B, Sinzinger H. Statin-induced myopathy does not show up in MIBI-scintigraphy. Nucl Med Commun 2001; 22:575–578.
20. Kontush A, Reich A, Baum K, et al. Plasma ubiquinol-10 is decreased in patients with hyperlipidemia. Atherosclerosis 1997; 129:119–26.
21. Mohr D, Bowry VW, Stocker R. Dietary supplementation with coenzyme Q10 results in increased levels of ubiquinol-10 within circulating lipoproteins and increased resistance of human low-density lipoprotein to the initiation of lipid peroxidation. Biochim Biophys Acta 1992; 1126:247–54.
22. Folkers K, Langsjoen P, Willis R, et al. Lovastatin decreases coenzyme Q levels in humans. Proc Natl Acad Sci USA 1990; 87:8931–4.
23. Watts GF, Castelluccio C, Riceevans C, Taub NA, Baum H, Quinn PJ. Plasma coenzyme Q (ubiquinone) concentration in patients treated with simvastatin. J Clin Pathol 1995; 46:1055–7.
24. Scalvini T, Marocolo D, Cerudelli B, Sleiman I, Balestrieri GP, Giustina G. Pravastatin-associated myopathy. Report of a case. Recent Prog Med 1995; 86:198–200.
25. Hanaki Y, Sugiyama S, Ozawa T, Ohno M. Coenzyme Q10 and coronary artery disease. Clin Investig 1993; 71:112–5.
26. Human JA, Ubbink JB, Jerling JJ, Delport R, Vermaak WJ, Vorster HH, Lagendijk J, Potgieter HC. The effect of simvastatin on the plasma antioxidant concentrations in patients with hypercholesterolaemia. Clin Chim Acta 1997; 263:67–77.
27. Bargossi AM, Grossi G, Fioletta PL, Gaddi A, DiGiulio R, Battino M. Exogenous CoQ10 supplementation prevents plasma ubiquinone reduction induced by HMG-CoA reductase inhibitors. Mol Aspects Med 1994; 15:187–93.
28. Ghirlanda G, Oradei A, Manto A, et al. Evidence of plasma CoQ10-lowering effect by HMG-CoA reductase inhibitors: a double-blind, placebo-controlled study. J Clin Pharmacol 1993; 33:226–9.
29. Fukami M, Maeda N, Fukushige J, Kogure Y, Shimada Y, Ogawa T, Tsujita Y. Effects of HMG-CoA reductase inhibitors on skeletal muscles of rabbits. Res Exp Med 1993; 193:263–73.
30. Bleske BE, Willis RA, Anthony M, Casselberry N, Datwani M, Uhley VE, Secontine SG, Shea MJ. The effect of pravastatin and atorvastatin on coenzyme Q10. Am Heart J 2001; 142:E2.
31. Dujovne CA. New lipid lowering drugs and new effects of old drugs. Curr Opin Lipidol 1997; 8: 362–8.
32. Thibault A, Samid D, Tompkins AC, Figg WD, Cooper MR, Hohl RJ, Trepel J, Liang B, Patronas N, Venzon DJ, Reed E, Myers CE. Phase I study of lovastatin, an inhibitor of the mevalonate pathway, in patients with cancer. Clin Cancer Res 1996; 2: 483–91.
33. Laaksonen R, Ojala JP, Tikkanen MJ, et al. Serum ubiquinone concentrations after short- and long-term treatment with HMG-CoA reductase inhibitors. Eur J Clin Pharmacol 1994; 46:313–7.
34. Mortensen SA, Leth A, Agner E, et al. Dose-related decrease of serum coenzyme Q10 during treatment with HMG-CoA reductase inhibitors. Mol Aspect Med 1997; 18:137–44.
35. Sinzinger H. Does vitamin E beneficially affect muscle pains during HMG-Co-enzyme-A reductase inhibitors without CK-elevation? Atherosclerosis 2000; 149:225.
36. Morrow JD, Robert II LJ. The isoprostanes: current knowledge and direction of future research. Biochem Pharmacol 1996; 51:1–9.
37. Oguogho A, Mehrabi M, Sinzinger H. Increased plasma, serum and urinary 8-epi-prostaglandin F in heterozygous hypercholesterolemia. Wr klin Wschr 1999; 111:113–8.
38. Holt S, Reeder B, Wilson M, Harvey S, Morrow JD, Roberts II, LJ Moore K. Increased lipid peroxidation in patients with rhabdomyolysis. Lancet 1999; 353:358–9.
39. Sinzinger H, Lupattelli G, Chehne F, Oguogho A, Furberg CD. Isoprostane 8-epi-PGF is frequently increased in patients with muscle pain and/or CK-elevation after HMG-Co-enzyme-A-reductase inhibitor therapy. J Clin Pharm Therapeutics 2001; 26:303–10.
40. Sinzinger H, Lupattelli G, Chehne F. Increased isoprostane 8-epi-PGF in statin-induced myopathy. in: Advances in Prostaglandin and Leukotriene Research. R. Paoletti, B. Samuelsson (eds) Kluwer Acad Publ 2002 (in press).
41. Helmersson J, Basu S. F2-isoprostane excretion rate and diurnal variation in human urine. Prostagl Leukotr Essent Fatty Acids 1999; 61:203–5.
42. Chehne F, Oguogho A, Lupattelli G, Budinsky AC, Palumbo B, Sinzinger H. Increase of isoprostane 8-epi-PGF after restarting smoking. Prostagl Leukotr Essent Fatty Acids 2001; 64:307–10.
43. Morrow JD, Frei B, Longmore AW, Graziano JM, Lynchz SM, Shyr Y, Strauss WE, Oates JA, Roberts II LJ. Increase in circulating products of lipid peroxidation (F2-isoprostanes in smokers). Smoking as a cause of oxidative damage. New Engl J Med 1995; 332:1198–203.
44. Das UN. Essential fatty acids as possible mediators of the action of statins. Prostagl Leukotr Essent Fatty Acids 2001; 65:37–40.
45. Sinzinger H. Two different types of exercise-induced muscle pain without myopathy and CK-elevation during HMG-Co-enzyme-A-reductase inhibitor treatment. Atherosclerosis 1999; 143:459–60.
46. Sinzinger H. Flue-like response on statins. Brit J Clin Pharmacol 2002 (submitted for publication).
47. Thompson PD, Zmuda JM, Domalik LJ, Zimet RJ, Staggers J, Guyton JR. Lovastatin increases exercise-induced skeletal muscle injury. Metabolism 1997; 46:1206–10.
48. Nakai A, Nishikota M, Uchida T, Ichikawa M, Metsuyama K. Enhanced myopathy following administration of hypolipidemic agents under methane anesthesia. Chem Pharm Bull 1997; 20:104–6.
49. Masters BA, I'Almoski MG, Flint OP, Wang-Iversen D, Durham SK. In vitro myotoxicity of the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, pravastatin, lovastatin and simvastatin, using neonatal rat skeletal myocytes. Toxicol Appl Pharmacol 1995; 13:163–74.
50. Gadbut AP, Caruso AP, Galper JB. Differential sensitivity of C2-C12 striated muscle cells to lovastatin and pravastatin. J Mol Cell Cardiol 1995; 27:2397–402.
51. Manoukian AA, Bhagavan NV, Hayashi T, Nestor TA, Rios C, Scottolini AG. Rhabdomyolysis secondary to lovastatin therapy. Clin Chem 1990; 36;2145–7.
52. England JD, Walsh JC, Stewart P, Boyd I, Rohan A, Halmagyi GM. Mitochondrial myopathy developing on treatment with the HMG CoA reductase inhibitors simvastatin and pravastatin. Aust N Z J Med 1995; 25:374–5.
53. Phillips PS, Haas RH, Bannykh S, Hathaway S, Gray NL, Kimura BJ, England JDF, and the Scripps Mercy Clinical Research Center. Statin associated myopathy with normal and abnormal creatine kinase: clinical, pathologic and biochemical features. Lancet 2002 (in press).
54. Crane FL, Hatefi Y, Lester RL, Widmer C. Isolation of a quinone from beef heart mitochondria. Biochim Biophys Acta 1957; 25:220–1.
55. Silberbauer K, Sinzinger H. Vern)nftiger Umgang mit Medikamenten. Blutfette. Initiative Arznei & Vernunft, 1998.
56. Sinzinger H, Hoppichler F, Toplak H, Laimer H, Kritz H. Statine – einige Monate danach. Wr klin Wschr 2002 (in press).

Creatine phosphokinase; Muscle pains; Myopathy; Oxidation injury; Physical activity; Statins

© 2002 Lippincott Williams & Wilkins, Inc.