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HEART MEDICATIONS & TREATMENTS

22 Elite Athletes Don't Tolerate Statins, issues

“Effective and well tolerated” is the mantra of PhARMA in selling the use of statins.  Quality of health is affected even among athletes.  Performance drops because statin medication lowers CoQ10 40% by blocking the pathway of its synthesis.   This is in the group of most healthy, the effect upon the elder are far, far worse.  A very highly motivated group because their cholesterol runs because of genetic mutation runs over 400 (the article give the European measurements) and major cardiac events typically occur before the age of 50.  Side effects are far more common and severe in the elderly.  Two major study have shown that at 2 years that between 75% and 80% of the elder stop taking prescribed statins—jk.

British Journal of Clinical Pharmacology  Volume 57, Issue 4, pages 525–528, April 2004

http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2125.2003.02044.x/full

Professional athletes suffering from familial hypercholesterolaemia  rarely tolerate statin treatment because of muscular problems

Keywords:

  • creatine phosphokinase;
  • familial hypercholesterolaemia;
  • muscle pains; 
  • oxidation injury;
  • professional athletes

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 [FH], 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.

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.      FH familial hypercholesterolaemia; CH cholesterol (mmol); A atorvastatin, F fluvastatin; L lovastatin; P pravastatin; S simvastatin.

 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

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.      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.

 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

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 [familial hypercholesterolemia] do not tolerate any of the statins available.

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: E1E7.

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: 5815.

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: 722.

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: 13839.

Witztum JL. Drugs used in the treatment of hyperlipoproteinemia. In Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th edn, eds HarrisonJG, et al. New York, McGraw-Hill, 1996.

  • 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: 45960.

Ucar M, Mjörndal T, Dahlqvist R. HMG-CoA reductase inhibitors and myotoxicity. Drug Safety 2000; 29: 44157.

Omar MA, Wilson JP, Cox TS. Rhabdomyolysis and HMG-CoA reductase inhibitors. Am Pharmacol Ther 2002; 35: 1096107.

Sinzinger H, Kritz H, Schwarz B. Austrian Cholesterol Consensus Conference. Richtlinien des Cholesterin-Konsens 1995. Wr Klin Wschr 1995; 107: 5379.

Thompson PD, Zmuda JM, Domalik LJ, Zimet RJ, Staggers J, Guyton JR. Lovastatin increases exercise-induced skeletal muscle injury. Metabolism 1997; 46: 120610.

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 Ther 2001; 26: 30310.

Direct Link:

Sinzinger H. Does vitamin E beneficially affect muscle pains during HMG-CoA enzyme reductase inhibitors without CK-elevation? Atherosclerosis 2000; 149: 225.

Oguogho A, Mehrabi M, Sinzinger H. Increased plasma, serum and urinary 8-epi-prostaglandin F in heterozygous hypercholesterolemia. Wr Klin Wschr 1999; 111: 1138.

Sinzinger H, Chehne F, Lupattelli G. Oxidation injury in patients receiving HMG-CoA reductase inhibitors. Drug Safety 2002; 25: 87783.

of these types of disease

^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^

 

 

 

Side effects are under reported (3/23-jk)

In the study of 22 elite athletes with familial hypercholesterolemia (over twice the normal LDL level), 73% did not tolerate the treatment; viz. they wouldn’t continue to take a statin, though there condition is life-shortening.   Most have a mutation in the gene ApoB and will develop cardiovascular disease between the age of 30 and 40, some earlier.  The article below found that:  “Regardless of the biochemical background statin therapy and top athletics seem to be almost incompatible.”  If we consider only those over the age of 17 who partook in the most physically intense sports, track, swimming, and cycling, none continued with their life-extending statin treatment. Those tested were the healthiest group possible--lowest incident side-effects.  Nevertheless, 73% stopped taking what they thought was a life-extending statins because its negative effect upon their physical well-being.  Yet medical textbooks write of statins “Safe, effective, and well-tolerated … that treat disorders of lipid metabolism” (Braunwald, Heart Diseases, 8th Ed, p 2286).    

Tolerated is a very low standard:  it counts only those who stopped taking the drug because of side-effects-- grossly under reports the severity & number of side-effects.   The highest standard would be an active search.  This would include physical and mental tests (such as treadmill and memory test) and analysis for proteins such as CoQ10 whose production is effected by statins.  The next highest standard is self-reporting based on having the subject fill-out questionnaire that list likely side-effects.  An even lower standard is tolerated, the discontinuation of a treatment because of severe side effects.   The lowest standard is to rely upon hospital admissions for major events.  A study of Warfarin took this to even a lower level, by counting as a major stomach bleed only those who required a transfusion of 2 or more pints of blood.  The Warfarin sales reps will use this result, without mentioning the transfusions, to inform the physician that Warfarin is safer than alternatives.  Duration is an issue since most Phase-III studies are under 6 months--too short for side effects such as cancer and cardiovascular disease.  Those physicians selected to run a study are known to be PhARMA friendly—another cause for deliberate under reporting.  Drugs are studied for marketing.   Hiding reports is the norm:  Roche in 2011 failed to report 80,000 notices they received from U.S. of physicians on patient side effects including 15,161, deaths.  In June of 2012 the European Medicines Agency began its investigation.  Approval by the FDA does not insure that the drug is worth taking since side effects in Phase III studies are NOT part of the evaluation of the drug’s effectiveness—with very few exceptions.  Since the industry controls research, publication, and continuing education, physicians must rely on PhARMA for info.  Our drug-testing system since Regan lacks meaningful oversight.    

The problem goes further than just how PhARMA (a term here used to collectively indicate major drug companies) reports side-effects.  Allow me to explain, the vast majority of clinical patient studies published in journal are phase IV which are designed by PhARMA’s marketing departments solely for promotion sales, and have even greater bias.  Phase III studies (also owned and funded by PhARMA) generate raw data that will be submitted to the FDA--or like regulatory agency in the country of origin.  Phase III studies are done for the sake of gaining a patent of exclusivity from the FDA.  Once the drug is approved, the study is published for the sake of marketing the new drug (phase IV studies are done after approval).  Unfortunately the FDA does not review the journal articles that are based upon the raw data submitted to the FDA in the phase III studies.  Moreover, the journals never receive the raw data (like is done with other sciences).  This leaves the marketing departments of drug manufacturer free to manipulate the published results to promote the just approved drug.  An independent review of 37 phase III studies based upon the raw data (which was obtained from the FDA under the freedom of information act) compared the actual findings based on this same data to the journal articles.  The five scientists who did this investigation of raw data found for phase III an average bias of 32%, range 11% to 69% (at (http://healthfully.org/dnd/id10.html, NEJM Jan 2008).  I can only assume that the favorable bias is even greater for phase IV studies, since only the drug manufacturer has the raw data and they write the journal articles.  No wonder only a few doctors turn to journal articles.  This is only one of the ways PhARMA controls drug education .   

This does not entail that all journal articles suffer from major bias.  Some are based on biological in vivo and in vitro research; a few are by critics who, though marginalized, are published.  Most doctors and researchers lament the replacement of medical science by marketing science, but they don’t go public about the state of their business, and the corporate press would marginalize it.  The article below is one of those rare, low-budget, published examples.  It tarnishes the golden egg, statins, for the evidence contradicts PhARMA’s claim that Statins are well tolerated-jk.

Studies need to have long term windows of following patients to pick up consequences which can take a decade or more to show up in low risk patients such as cancer and atherosclerosis; they don’t.  One way to ferret out these health risk would be test the drug in high-risk groups.  That happened with the Advantage study.  While this works for patients who already have atherosclerosis, and increases death and heart attacks, this doesn’t work for cancer because except for very limited conditions, such as tobacco and lung cancer, patient aren’t high risk for a particular caner.   What would be the increased risk of heart attack if patients in their 20’s take long-term celebrex or these athletes a statin for coronary heart disease?  It doesn’t begin showing up until the 5th decade of life.    Particular attention must be paid as to the conditions of a study especially duration and group selected, and this does not preclude gross irregularities creating a positive bias which has been found when compared to raw data to average 32% for neuroleptic drugs.. 

 

 

 


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