Abstract
Aims
Muscular problems are the major group of side-effects during statin treatment. They are known to occur much more frequently during and after exercise.
Methods and results
For the last 8 years we have monitored 22 professional athletes in whom, because of familial hypercholesterolaemia, treatment with different statins was attempted. Only six out of the 22 finally tolerated at least one member of this family of drugs. In three of these six the first statin prescribed allowed training performance without any limitation. Changing the drug demonstrated that only two tolerated all the four or five statins examined (atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin). Cerivastatin was not among the statins prescribed.
Conclusions
These findings indicate that in top sports performers only about 20% tolerate statin treatment without side-effects. Clinical decision making as to lipid lowering therapy thus becomes a critical issue in this small subgroup of patients.
Keywords: creatine phosphokinase, familial hypercholesterolaemia, muscle pains, oxidation injury, professional athletes
Introduction
Statins are one of the most widely used drugs worldwide because of their clinical effectiveness [1]. Although rare, top sports performers suffering from familial hypercholesterolaemia (FH) may require drug treatment even at a young age. Muscular symptoms are the major group of adverse side-effects among statin users, totaling about 5% in multicentre-controlled studies [2]. The HPS-Study reported muscular symptoms at a rate of 32.9% in the active treatment group and 33.2% in the placebo group [3]. The number of more severe side-effects is quite low, ranging below 0.1%[4, 5]. However, some years ago we found that muscular side-effects during exercise clearly are related to statin treatment even in the absence of elevated creatine kinase (CK) [6]. In another study examining the role of exercise in patients with statin treatment we realized that in those people performing regular strenuous exercise side-effects, characterized as ache- and cramp-like symptoms as well as muscular weakness, may increase, raising the possibility that as many as 25% may suffer. In recent reviews [7, 8] exercise-induced pain and the problem of statin use in top athletes is not even mentioned. Throughout the years we have monitored a number of professional athletes in whom FH had been diagnosed and at different stages statin treatment was initiated. In this paper we describe the individual cases and response to attempts to treat with various members of this family of compounds.
Methods
Patients were considered as professional athletes when they had attended an Austrian championship at any age class during the last 2 years or were playing in the top two leagues of their respective discipline (for characteristics of athletes see Table 1). They all were suffering from FH as diagnosed at the receptor level. No other drugs including vitamins were taken for at least 4 weeks. Testing for anabolic steroids was done in all athletes to exclude any possible influence. According to a recommendation of the Austrian Cholesterol Consensus [9] the starting dose of the respective statin was always the lowest available dose. Logic for switching patients who tolerated a statin was that they did not achieve target values. The shortest duration of treatment before switching was 8 weeks.
Table 1.
Athletes characteristics and the statin tolerated and not tolerated by each
| Number | Age (years) | Sex (M/F) | Height (cm) | Weight (kg) | Discipline | FH (years) | Total CH (mmol) | Lp(a) (mg/dl) | Statins adverse event | Statins tolerated |
|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 15 | F | 160 | 38 | Running | 10 | 8.78 | 9 | L, P, S | F, A |
| 2 | 13 | M | 150 | 38 | Fencing | 8 | 10.63 | 13 | P, L, S | F, A |
| 3 | 17 | F | 172 | 70 | Swimming | 6 | 7.71 | 69 | P, S, A, F, L | None |
| 4 | 23 | M | 196 | 93 | Volleyball | 4 | 7.92 | 106 | P, S, A, F, L | None |
| 5 | 19 | M | 194 | 91 | Basketball | 4 | 8.26 | 17 | P, S, A | L, F |
| 6 | 33 | M | 180 | 83 | Skiing | 14 | 7.63 | 21 | P, S, A, F, L | None |
| 7 | 26 | M | 174 | 73 | Soccer | 9 | 8.97 | 4 | P, L, S, A, F | None |
| 8 | 29 | F | 174 | 67 | Handball | 7 | 9.47 | 165 | P, L, S, A, F | None |
| 9 | 20 | M | 174 | 76 | Skiing | 5 | 7.78 | 51 | L, P, S, F, A | None |
| 10 | 17 | M | 175 | 75 | Bicycling | 10 | 9.68 | 44 | P, L, S, A, F | None |
| 11 | 26 | M | 194 | 102 | Football | 6 | 9.73 | 124 | – | L, S, A, P, F |
| 12 | 29 | F | 175 | 70 | Handball | 7 | 7.94 | 171 | S, A, P, F, L | None |
| 13 | 24 | M | 169 | 71 | Soccer | 4 | 7.83 | 16 | S, P, A, L, F | None |
| 14 | 25 | M | 167 | 57 | Running | 8 | 7.50 | 207 | S, P, A | None |
| 15 | 32 | M | 190 | 92 | Basketball | 11 | 9.13 | 71 | – | L, P, S, A |
| 16 | 35 | M | 178 | 74 | Soccer | 10 | 8.81 | 9 | A, S, P, L, F | None |
| 17 | 28 | F | 166 | 69 | Skating | 9 | 8.47 | 41 | A, S, P, F, L | None |
| 18 | 23 | M | 186 | 83 | Tennis | 8 | 9.34 | 94 | A, S, P, F | None |
| 19 | 21 | F | 166 | 57 | Hockey | 6 | 9.05 | 3 | A, S, P, F | None |
| 20 | 26 | M | 177 | 76 | Soccer | 8 | 8.18 | 7 | L, S | P, A |
| 21 | 22 | F | 177 | 71 | Tennis | 7 | 8.52 | 83 | S, A, P, F, L | None |
| 22 | 27 | M | 188 | 93 | Ice hockey | 14 | 9.65 | 9 | A, S, P, F, L | None |
FH familial hypercholesterolaemia; CH cholesterol (mmol); A atorvastatin, F fluvastatin; L lovastatin; P pravastatin; S simvastatin.
Blood samples for CK and liver enzymes (GOT, GPT, γGT) were regularly drawn at each monitoring interval.
Results
Except for cerivastatin all the other statins available were tried. Some of the athletes refused to try a further compound (Table 2). When initiating a statin therapy only three (numbers 5, 11, 15) out of 22 athletes (11%) tolerated the chosen drug (Table 2). Another three patients (numbers 1, 2, 20) tolerated at least one statin, while only two athletes (numbers 11 and 15) tolerated all the compounds used. Switching to other compounds we realized that toleration was rare and 16 (78%) athletes did not tolerate any of the compounds tested (Table 2). Symptoms experienced on the different statins in one and the same athlete were very similar. The delay in reporting onset of symptoms was longer during the first drug attempt, possibly because the athletes were more alert to the possible emergence of muscle problems. After drug withdrawal, symptoms in most of the patients disappeared within a few days (< 1 week) and in all of them within 3 weeks. Patients 1 and 2 were already reported in part in our earlier work describing statin associated exercise-induced muscle pain without CK-alteration for the first time [6]. An increase in CK above the value usually found in professional athletes was not seen. In the present study an increase in any of the liver enzymes was not observed in any of the athletes. Testing for anabolic steroids was negative in all of them. Fenofibrate given finally mainly to those athletes with extremely elevated Lp(a) did not produce any adverse reaction in the six athletes treated so far.
Table 2.
Individual problems top athletes exhibited on the respective statins, time to onset and the drug prescribed finally
| Patient | 1st statin | 2nd | 3rd | 4th | |
|---|---|---|---|---|---|
| 1 | L: MP(a), D7 | P: MP(a), D7 | S: MP(a), D3 | F, A: tolerated | A → |
| 2 | P: MP(a), D10 | L: MP(a), D7 | S: MP(a), D5 | F, A: tolerated | A → |
| 3 | P: CK,MP(a), D6 | S: CK,MP(a), D3 | A: CK,MP(a),D2 | F: MP(a), D5 | L: MP(a), D5 → 0 |
| 4 | P: MP(w), D18 | S: MP(w,a), D12 | A: MP(w), D11 | F: MP(w), D17 | L: MP(w), D14→ 0 |
| 5 | L: tolerated | P: MP(c,o), D3 | F: tolerated | S: MP(w,a), D12 | A: MP(c,o) → L |
| 6 | P: MP(c), D6 | S: MP(c), D9 | A: MP(c), D6 | F: MP(c), D5 | L: MP(c), D7 → 0 |
| 7 | P: MP(w), D16 | L: MP(w), D14 | S: MP(w), D10 | A: MP(w), D10 | F: MP(w), D7 → 0 |
| 8 | P: MP(o), D12 | L: MP(o), D14 | S: MP(o), D8 | A: MP(o), D5 | F: MP(o), D4 → Fe |
| 9 | L: CK,MP(a), D4 | P: CK,MP(a), D4 | S: MP(a), D4 | F: MP(a), D3 | A: MP(a); D3 → Fe |
| 10 | P: MP(a,w), D18 | L: MP(a,w), D14 | S: MP(a), D9 | A: MP(a), D8 | F: MP(a), D7 → 0 |
| 11 | L: tolerated | S: tolerated | A: tolerated | P: tolerated | F: tolerated; → A |
| 12 | S: MP(a), D6 | A: MP(a), D8 | P: MP(a), D10 | F: MP(a), D7 | L: MP(a), D6 → Fe |
| 13 | S: MP(c), D3 | P: MP(c), D3 | A: MP(a), D8 | L: MP(w), D12 | F: MP(a,w), D5 → 0 |
| 14 | S: MP(w,a), D9 | P: MP(w,a), D7 | A: MP(a), D5 | – | → Fe |
| 15 | L: tolerated | P: tolerated | S: tolerated | A: tolerated | → A |
| 16 | A: MP(a), D6 | S: MP(a), D8 | P: MP(a), D9 | L: MP(a), D5 | F: MP(a), D4 → 0 |
| 17 | A: MP(w,c), D11 | S: MP(w,c), D14 | P: MP(w), D10 | F: MP(w,c), D8 | L: MP(w), D10 → Co |
| 18 | S: MP(w), D5 | A: MP(w), D7 | P: MP(w), D9 | F: MP(w), D6 | → Fe |
| 19 | A: MP(o), D16 | S: MP(o), D13 | P: MP(o,w) D8 | F: MP(o), D12 | → 0 |
| 20 | L: MP(c,w), D5 | P: tolerated | A: tolerated | S: MP(c,w), D4 | → A |
| 21 | S: CK,MP(a,c),D4 | A: MP(a,c), D5 | P: MP(a), D6 | F: MP(a), D8 | L: MP(a,c), D5 → 0 |
| 22 | A: MP (w,o), D12 | S: MP(w,o), D10 | P: MP(w), D8 | F: MP(o), D10 | L: MP(o,w), D7 → Fe |
A atorvastatin; Co colestyramine; F fluvastatin; Fe fenofibratre; L lovastatin; P pravastatin; S simvastatin; 0 no drug; CK CK-elevation; MP muscle pain (a = ache-like,c = cramp-like, w = weakness, o = others); Dx onset in × days.
Discussion
Thompson et al. first described exercise-induced skeletal muscle injury with CK-elevation but in the absence of symptoms after lovastatin [10]. Prevalence of muscle pain without exercise may increase in hobby athletes and even further in professional athletes. Regardless of the biochemical background statin therapy and top athletics seem to be almost incompatible. Whether top athletes are more likely to report side-effects affecting the results remains open. Switching to nonstatin lipid reduction therapy or (in less severe FH) to postpone treatment seemed to be the only options available. As biopsy studies [2] and blood examination [11] revealed an oxidation injury which may be further aggravated by heavy exercise (the underlying pathogenesis being unknown), withdrawal of statins until after finishing an athletic career considering the usually high HDL these patients have may be advisable. The decision, however, remains a very individual one based only on experience and risk calculation rather than facts or recommendations available.
The case report that incidental vitamin E administration improved statin-induced muscle pains [12] led to the discovery that many of these patients show increased lipid peroxidation while normally statin therapy causes a decrease [13]. It has been described that in patients with muscle problems on all the statins a withdrawal of the drug results in cessation in muscular symptoms [14] as also seen in the athletes.
In the original description on exercise-induced muscle pain on statins [6] problems in all the eight patients (six of them performing hobby sports activities) disappeared after fluvastatin; in our group of top athletes, however, the prevalence of side-effects on all the compounds examined seemed to be comparable. The limitation of this observation is the lack of a control. However, at least six of them tolerated some statin. Our data are raising a concern on the use of statins in elite professional athletics. In order to definitely test the hypothesis, however, there is a strong need for a placebo-controlled trial of statins in subjects undergoing intensive exercise.
In conclusion, our findings demonstrate that the great majority of professional athletes with severe FH do not tolerate any of the statins available.
Acknowledgments
The valuable help of Eva Unger in preparing and typing the manuscript is gratefully acknowledged.
References
- 1.Gotto AM, Grundy SM. Lowering LDL-cholesterol: questions from recent analysis of clinical trials. Data from the Interdisciplinary Council of Reducing the Risk for Coronary Heart Disease. Circulation. 1999;99:E1–E7. doi: 10.1161/01.cir.99.8.e1. [DOI] [PubMed] [Google Scholar]
- 2.Phillips PS, Haas RH, Bannykh S, Hathaway S, Gray NL, Kimura BJ, England JDF. Statin-associated myopathy with normal creatine kinase levels. Ann Int Med. 2002;137:581–5. doi: 10.7326/0003-4819-137-7-200210010-00009. [DOI] [PubMed] [Google Scholar]
- 3.Heart Protection Study Collaborative Group. MRC/BHF Heart protection study of cholesterol lowering with simvastatin in 20536 high-risk individuals: a randomized placebo-controlled trial. Lancet. 2002;360:7–22. doi: 10.1016/S0140-6736(11)61125-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S) Lancet. 1994;344:1383–9. [PubMed] [Google Scholar]
- 5.Witztum JL. Drugs used in the treatment of hyperlipoproteinemia. In: Harrison JG, et al., editors. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9. New York: McGraw-Hill; 1996. [Google Scholar]
- 6.Sinzinger H, Schmid P, O'Grady J. 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. doi: 10.1016/s0021-9150(98)00310-4. [DOI] [PubMed] [Google Scholar]
- 7.Ucar M, Mjörndal T, Dahlqvist R. HMG-CoA reductase inhibitors and myotoxicity. Drug Safety. 2000;29:441–57. doi: 10.2165/00002018-200022060-00003. [DOI] [PubMed] [Google Scholar]
- 8.Omar MA, Wilson JP, Cox TS. Rhabdomyolysis and HMG-CoA reductase inhibitors. Am Pharmacol Ther. 2002;35:1096–107. doi: 10.1345/aph.10228. [DOI] [PubMed] [Google Scholar]
- 9.Sinzinger H, Kritz H, Schwarz B. Austrian Cholesterol Consensus Conference. Richtlinien des Cholesterin-Konsens 1995. Wr Klin Wschr. 1995;107:537–9. [PubMed] [Google Scholar]
- 10.Thompson PD, Zmuda JM, Domalik LJ, Zimet RJ, Staggers J, Guyton JR. Lovastatin increases exercise-induced skeletal muscle injury. Metabolism. 1997;46:1206–10. doi: 10.1016/s0026-0495(97)90218-3. [DOI] [PubMed] [Google Scholar]
- 11.Sinzinger H, Lupattelli G, Chehne F, Oguogho A, Furberg CD. Isoprostane 8-epi-PGF2α is frequently increased in patients with muscle pain and/or CK-elevation after HMG-Co-enzyme-A-reductase inhibitor therapy. J Clin Pharm Ther. 2001;26:303–10. doi: 10.1046/j.1365-2710.2001.00360.x. [DOI] [PubMed] [Google Scholar]
- 12.Sinzinger H. Does vitamin E beneficially affect muscle pains during HMG-CoA enzyme reductase inhibitors without CK-elevation? Atherosclerosis. 2000;149:225. doi: 10.1016/s0021-9150(99)00422-0. [DOI] [PubMed] [Google Scholar]
- 13.Oguogho A, Mehrabi M, Sinzinger H. Increased plasma, serum and urinary 8-epi-prostaglandin F2α in heterozygous hypercholesterolemia. Wr Klin Wschr. 1999;111:113–8. [PubMed] [Google Scholar]
- 14.Sinzinger H, Chehne F, Lupattelli G. Oxidation injury in patients receiving HMG-CoA reductase inhibitors. Drug Safety. 2002;25:877–83. doi: 10.2165/00002018-200225120-00005. [DOI] [PubMed] [Google Scholar]