Rhabdomyolysis from simvastatin triggered by infection and muscle exertion.

Abstract: A 42-year-old woman received a 6-month course of simvastatin (20 mg/d) for hypercholesterolemia. Despite an infection with fever, fatigue, myalgias, and lumbar pain, she continued to perform her regular sports activities. Neurologic examination revealed bilateral ptosis and slight upper limb weakness. Serum creatine kinase was 41,000 U/L. Needle electromyography was nonspecifically abnormal. Discontinuation of simvastatin and reduction of the sports activities was followed by a prompt continual lowering of the elevated muscle enzymes to normal values over a 2-week period. The patient's infection, regular sports activity despite the infection, and a suspected mitochondrial defect were regarded as triggers of rhabdomyolysis.

Key Words: Adverse reaction, hyperlipidemia, neuromuscular disorder, side effect, statin therapy

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Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) have been shown to cause dose-dependent myotoxicity, manifesting as myalgia, weakness, asymptomatic creatine kinase (CK) elevation, or rhabdomyolysis with or without renal failure. (1,2) Myotoxicity caused by statins is dependent on the type of statin, its dosage, and on the additional presence of conditions or drugs that are myotoxic or may interact with the metabolism and/or the excretion of statins. (2) Simvastatin has been frequently reported to be myotoxic alone or in combination with other enhancing conditions (Table 1). Simvastatin myopathy triggered by infection and muscle exertion has not, to our knowledge, been reported.

Case Report

The patient is a 42-year-old, HIV-negative woman (height, 164 cm; weight, 60 kg) who had been receiving simvastatin (20 mg/d) for approximately 6 months because of an elevated serum cholesterol of 300 mg/dL. In August 2004, 1 hour after swimming in a cold mountain lake for 1 hour, she had fever up to 37.8[degrees]C, tiredness, and myalgia. She self-medicated with diclofenac, and her symptoms gradually resolved within 2 weeks. Routine blood work later that month revealed elevated muscle function parameters (Table 2). Clinical neurologic examination revealed bilateral ptosis and weakness of elbow extension on the right side. Nerve conduction studies of the right median and left peroneal nerve were normal. Needle electromyography of the right anterior tibial muscle showed some unstable, distorted motor-unit action potentials with normal mean duration, increased percent polyphasia, and increased percent satellite potentials. Needle electromyography of the right brachial biceps muscle was normal. The serum aldolase level was 55.9 U/L (normal, 0 to 7 U/L). Other blood test results are shown in Table 2. After discontinuation of simvastatin, the patient's fatigue disappeared and serum muscle enzyme levels decreased to normal values within 14 days (Table 2). The patient made an uneventful, complete recovery.

Discussion

Statins are highly effective in lowering serum cholesterol levels and are well tolerated. (2) Occasionally, they can be myotoxic, even at normal dosages. The incidence of statin myopathy is reported to be 0.1 to 0.5%. (6) The incidence of rhabdomyolysis is approximately 0.001%. Statin myopathy may manifest within 1 week of statin use but in individual cases, after a single dosage of statin. (9) Myotoxicity of statins, at least CK elevation, is dose dependent (10) and manifests as myalgias, muscle cramps, weakness, asymptomatic CK elevation, or, rarely, rhabdomyolysis with reversible or irreversible renal failure. (3) Not all statins are equally myotoxic. The risk of myotoxicity has been ranked in decreasing rates as follows: cerivastatin, fluvastatin, simvastatin, atorvastatin, and pravastatin. (4) Statin myopathy may occur when the statin is used alone but particularly when combined with drugs that are myotoxic or elevate the statin concentration.

Drugs that inhibit the CYP450 metabolism are likely to raise the serum levels of statins eliminated through this system. These include lovastatin, simvastatin, atorvastatin, cerivastatin, and fluvastatin. (3) If therapy with a potent CYP450 inhibitor such as itraconazole is inevitable, a statin without significant CYP450 metabolism such as pravastatin should be administered. (5) Some statins, such as lovastatin, simvastatin, or atorvastatin, are also eliminated through the P-glycoprotein drug efflux system, and the concomitant administration of inhibitors of this system increase the risk of myopathy. Another factor for potential serious statin drug interaction is the presence of single-nucleotide polymorphisms in the gene encoding for the organic anion transporting polypeptide C (OATP-C).

Mechanisms of statin-induced myotoxicity are not well understood. Studies in rats suggest increased muscle membrane fluidity, abundant hypercontractility, or fiber necrosis. (6) Other studies suggest that the myotoxicity is due to CoQ10 deficiency in tissue mitochondria. (7) Mitochondrial dysfunction as a cause of statin myopathy is supported by muscle biopsy findings, showing increased lipid storage, COX-negative muscle fibers, and ragged-red fibers. (8)

Simvastatin is moderately myotoxic. (4) Some studies report no muscular side effects at dosages between 20 and 80 mg/d, (11) whereas others report muscle symptoms or signs of hyper-CK-emia (greater than 10 times the upper reference limit) in 0.4% of the patients receiving 40 mg or 80 mg of simvastatin per day. (12) Simvastatin may cause myotoxicity or rhabdomyolysis even after a single dose. (9) Whether or not the myotoxic effect of simvastatin is dose-dependent is debatable. Some reports demonstrate dose dependence of the myotoxic effect, (13) whereas one study showed muscular side effects only at dosages of 10 to 20 mg per day but no muscular side effects at higher dosages. Muscular side effects of simvastatin are particularly frequent in patients with excessive sports activity, (15) renal failure, hepatic insufficiency, hypothyroidism, or diabetes or in patients who receive certain drugs in addition to simvastatin (Table 1).

Conclusion

This case suggests that infection in combination with sporting activities and possibly an underlying mitochondrial defect promoted myotoxicity from simvastatin. Which of these triggers had the most significant effect remains speculative. The elevated serum levels of CK, lactate dehydrogenase, glutamate-oxalate transaminase, glutamate-pyruvate transaminase, and aldolase were attributed to the myotoxic effect of simvastatin, since they normalized shortly after discontinuation of the statin.

References

1. Finsterer J. Fibrat-/StatinMyopathie. Nervenarzt 2003;74:115-22.

2. Hamilton-Craig I. Statin-associated myopathy. Med J Aust 2001;175:486-489.

3. Andreou ER, Ledger S. Potential drug interaction between simvastatin and danazol causing rhabdomyolysis. Can J Clin Pharmacol 2003;10:172-174.

4. Matzno S, Tazuya-Murayama K, Tanaka H, et al. Evaluation of the synergistic adverse effects of concomitant therapy with statins and fibrates on rhabdomyolysis. J Pharm Pharmacol 2003;55:795-802.

5. Roten L, Schoenenberger RA, Krahenbuhl S, et al. Rhabdomyolysis in association with simvastatin and amiodarone. Ann Pharmacother 2004;38:978-981.

6. Riesco-Eizaguirre G, Arpa-Gutierrez FJ, Gutierrez M, et al. Severe polymyositis with simvastatin use. Rev Neurol 2003;37:934-936.

7. Goli AK, Goli SA, Byrd RP Jr, et al. Simvastatin-induced lactic acidosis: a rare adverse reaction? Clin Pharmacol Ther 2002;72:461-464.

8. Phillips PS, Haas RH, Bannykh S, et al. Statin-associated myopathy with normal creatine kinase levels. Ann Intern Med 2002;137:581-585.

9. Jamil S, Iqbal P. Rhabdomyolysis induced by a single dose of a statin. Heart 2004;90:e3.

10. Matsuyama K, Nakagawa K, Nakai A, et al. Evaluation of myopathy risk for HMG-CoA reductase inhibitors by urethane infusion method. Biol Pharm Bull 2002;25:346-350.

11. Morales D, Chung N, Zhu JR, et al. Efficacy and safety of simvastatin in Asian and non-Asian coronary heart disease patients: a comparison of the GOALLS and STATT studies. Curr Med Res Opin 2004;20:1235-1243.

12. de Lemos JA, Blazing MA, Wiviott SD, et al. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA 2004;292:1307-1316.

13. Skrabal MZ, Stading JA, Monaghan MS. Rhabdomyolysis associated with simvastatin-nefazodone therapy. South Med J 2003;96:1034-1035.

14. Aboulafia DM, Johnston R. Simvastatin-induced rhabdomyolysis in an HIV-infected patient with coronary artery disease. AIDS Patient Care STDS 2000;14:13-18.

15. Sinzinger H, O'Grady, J. Professional athletes suffering from familial hypercholesterolaemia rarely tolerate statin treatment because of muscular problems. Br J Clin Pharmacol 2004;57:525-528.

16. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239-245.

17. Caldwell SH, Hespenheide EE, von Borstel RW. Myositis, microvesicular hepatitis, and progression to cirrhosis from troglitazone added to simvastatin. Dig Dis Sci 2001;46:376-378.

Science is organized knowledge. Wisdom is organized life.
--Immanuel Kant

Josef Finsterer, MD, PHD, and Georg Zuntner, MD

From the Department of Neurology, Krankenanstalt Rudolfstiftung, and the Third Medical Department, Krankenanstalt Rudolfstiftung, Vienna, Austria.

Reprint requests to Univ. Doz. DDr. J. Finsterer, Schindlergasse 9/10, 1180 Wien, Austria. Email: [e-mail]

Accepted March 4, 2005.

RELATED ARTICLE: Key Points

* The myotoxic effect of simvastatin may be enhanced by viral infection.

* The myotoxic effect of simvastatin may be enhanced by sport activity.

* Withdrawal of simvastatin results in immediate, complete recovery from rhabdomyolysis.

Table 1. Factors triggering simvastatin myopathy

Factor                                    NP  CK  Myalgia  Weakness

Drugs
  Colchicine                              1   +                +
  Fusidic acid                            1   +
  Verapamil/cyclosporine                  1   +
  Cortisone azathioprine, cyclosporine    1   +
  Amiodarone                              2   +      +         +
  Nefazodone                              1   +
  Danazol/renal failure                   1   +
  Clarithromycin                          2   +      +         +
  Itraconazole/cyclosporine               1   +
  Itraconazole/gemfibrozil, cyclosporine  1   +
  Tacrolimus/fusidic acid                 1   +
  Diltiazem                               1   +
  Fibrates                                1   +
  Fluconazole                             1   +                +
  Nelfinavir                              1   +                +
  Ritonavir                               1   +      ng        ng
  Indomethacin/renal failure              1   +      ng        ng
  Troglitazone                            1   +
Conditions
  Diabetes                                1   +                +
  Renal insufficiency                     ng  +
  Hepatic insufficiency                   ng  +
  Hypothyroidism                          ng  +
Muscle activity                           ng  +

NP, Number of patients; CK, creatine kinase; ng, not given.

Table 2. Serum muscle enzymes during and after simvastatin in the
patient

Date/reference      CK           LDH         GOT         GPT

                (< 145 U/L)  (< 249 U/L)  (6-31 U/L)  (< 35 U/L)
08/26/04          36,000        1,062        481         160
08/27/04          41,000           nd        830         258
08/28/04          25,338           nd        502         181
08/29/04          11,338           nd         nd          nd
08/30/04           4,680           nd        153         139
08/31/04           1,947           nd         nd          nd
09/01/04             932           nd         nd          nd
09/16/04              75          169         17          23

CK, Creatine kinase; LDH, lactate dehydrogenase; GOT, glutamate-oxalate
transaminase; GPT, glutamate-pyruvate transaminase; nd, not determined.