Statin Therapy as Primary Prevention in Exercising Adults: Best Evidence for Avoiding Myalgia

N. John Bosomworth

doi:10.3122/jabfm.2016.06.160085

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Figure 1.
Management of statin myopathy in exercising adults. *Lowers low-density lipoprotein (no evidence of cardiovascular disease event reduction¹⁰⁹). CK, creatine kinase; ULN, upper limit of normal.

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Table 1.

Strength of Recommendation Taxonomy

Strength of Recommendation	Definition
A	Based on consistent and good-quality, patient-oriented evidence^*
B	Based on inconsistent or limited-quality patient-oriented evidence^*
C	Based on consensus, usual practice, opinion, or case series

Study Quality	Definition	Examples
Level 1	Good-quality, patient-oriented evidence^*	High-quality RCT
		SR or MA of high-quality studies
		High-quality prospective cohort study or SR or MA of such studies
Level 2	Limited-quality, patient-oriented evidence^*	Lower-quality clinical trial
		Lower-quality cohort study
		Retrospective cohort study
		SR or MA of lower-quality studies or studies with inconsistent findings
		SR or MA of lower-quality cohort studies or studies with inconsistent results
		Case-control study
Level 3	Other evidence	Consensus guidelines
		Expert opinion
		Case series

Adapted from Ebell et al.²²
↵* Patient-oriented evidence measures outcomes that matter to patients, such as morbidity, mortality, symptom improvement, and quality of life. Measures of disease activity or surrogate outcomes may or may not matter to the patient.
MA, meta-analysis; RCT, randomized controlled trial; SR, systematic review.

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Table 2.

Definitions of Muscle Syndromes

	Myopathy	Myalgia	Myositis	Rhabdomyolysis
Canadian Working Group²³	General term for muscle events	Normal CK Aching or weakness	CK more than the ULN Aching or weakness	Aching or weakness CK >10× ULN ± Renal dysfunction
NLA Muscle Safety Task Force²⁴	Spectrum of muscle events	Muscle soreness, stiffness, cramps, tenderness	Muscle inflammation	CK >3× ULN with myoglobinuria or acute renal failure
ACC/AHA/NHLBI Clinical Advisory²⁵	General term for muscle events	Normal CK Aching or weakness	CK more than the ULN Aching or weakness	Aching or weakness Marked CK elevation + Elevated creatinine + Urine myoglobin

ACC, American College of Cardiology; AHA, American Heart Association; CK, creatine kinase; NHLBI, National Heart Lung and Blood Institute; NLA, National Lipid Association; ULN, upper limit of normal.

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Table 3.

Studies Relating Statin Use and Physical Activity

Reference, Year	Study Population	Design, Intervention	Findings	SORT Study Quality	Comments
Panza et al,⁴⁶ 2015	418 adults not taking statins Age 44 ± 16.1 years 50% men	RCT; high-dose statin vs placebo for 6 months	PA ↓ over time in placebo and statin arms equally	Level 1^*	Young; very few at high activity levels Used accelerometry
Parker et al,⁴⁰ 2013	420 healthy adults not taking statins 50% men	RCT; high-dose statin vs placebo for 6 months	PA ↓ over time in both placebo and statin arms; ↑ myalgia and CK in statin arm Statin arm had significant myalgia ↑, PA ↓ in >55-year-old age group vs controls	Level 1	Young; very few at high activity levels Used accelerometry
Golomb et al,⁴⁷ 2012	1016 adults No CVD or diabetes LDL 3.0 to 5.0 mmol/L Age ≥20 years 67% men	RCT; moderate-dose statin vs placebo for 6 months	Scale-rated energy levels ↓ and fatigue with exertion ↑ with statins Effects worse for women	Level 1	4 in 10 women noted some harm 2 in 10 noted harm overall
Mikus et al,⁴⁸ 2013	37 sedentary overweight or obese adults with ≥2 MS risk factors not taking statins Age 25–59 years 35% men	RCT; moderate-dose statin + PA vs PA alone for 12 weeks	Statin attenuated ↑ in cardiorespiratory fitness (↑ 1.5% with statin vs 10%)	Level 2	No placebo control Younger population
Scott et al,⁴⁹ 2009	774 noninstitutionalized older adults Age 62 ± 7 years 52% men	Prospective cohort study, 2.6 years	Statin users had reduced leg strength over 2.6 years vs controls	Level 2	Strength measured by dynamometry
Qureshi et al,⁵⁰ 2015	17,264 adults Age 59 ± 8 years 54% men	Prospective cohort study, 5.4 years	Statins did not affect peak treadmill performance Statin users were more sedentary	Level 2	Mortality study comparing the benefits of fitness and statins
Lee et al, ⁵¹2014	5994 elderly men Age ≥65 100% men	Prospective cohort study, 6.9 years	Men taking statins had a 10% ↓ in PA and showed more sedentary behavior New statin users had the most rapid decline in PA	Level 2	PA measured by accelerometry Moderate PA ↓ 9.6% and vigorous PA ↓ 9% among statin users
Williams et al,⁴⁵ 2015	66,377 runners and 12,031 walkers not taking statins Age 21–82 years 55% men	Prospective cohort study, 7.2 years	PA levels ↓ in all hypercholesterolemic people, whether taking statins or not ? Reverse causality (↓ PA may have led to high lipids)	Level 2	Majority age 40–50 years Rate of statin discontinuation was not recorded Low-dose statins
Bruckert et al,¹⁸ 2005	7924 unselected hyperlipidemic patients taking high-dose statins Age 18–75 years 70% men	Observational, cross-sectional study	Muscle symptoms in 10.5% 38% of these were unable to tolerate moderate activity	Level 3	Self-report of activity No placebo control 14% with high PA levels had muscle symptoms
Terpak et al,⁵² 2015	749 swimmers, 558 controls Age ≥35 years	Cross-sectional study	Statin use not associated with change in swimming activity	Level 3	Self-report of activity
Cham et al,⁵³ 2010	354 adults taking statins Age 34–86 years 53% men	Case series	One-third met causality criteria for statin myalgia^{^†} Activities most affected were running and walking	Level 3	Subjects were self-selected Self-report
Sinzinger et al,⁴³ 2004	22 elite athletes with familial hypercholesterolemia Age 13–35 years 68% men	Case series	80% were unable to tolerate any statin dose	Level 3	Series of professional athletes monitored in clinic for 8 years Young population

CK, creatine kinase; CVD, cardiovascular disease; LDL, low-density lipoprotein; MS, metabolic syndrome; PA, physical activity; RCT, randomized controlled trial.
↵* SORT represents the Strength of Recommendation Taxonomy rating of study quality determined by Ebell et al.²²
↵† Muscle symptoms improved upon reducing or discontinuing the statin dose and resumed upon restarting the drug.

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Table 4.

Meta-Analyses: Statin Treatment Effects in Primary Prevention

Meta-analyses	Duration (Years)	Coronary Events (HR)	Total CVD Events (HR)	CV Mortality (HR)	All-Cause Mortality (HR)
Thavendiranathan et al,⁸⁴ 2006	4.3	0.78 (NNT, 60)		NS	NS
Mills et al,⁸⁵ 2008	1.8–5.2	0.85		0.89	0.93
Petretta et al,⁸⁶ 2010	3.9	Men: 0.59 Women: NS			Men: NS Women: NS
Bruckert et al,¹⁸ 2005	4.1	0.70 (NNT, 77)			0.88 (NNT, 167)
Ray et al,⁸⁷ 2010	3.7				NS
Mora et al,⁸⁸ 2010	Not stated		Women: 0.63		Women: NS
Kostis et al,⁸⁹ 2012	4.0	Men: 0.73 Women: 0.85			Men: NS Women: 0.87
Savarese et al,⁶ 2013	3.5	0.61		NS	NS
Taylor et al,⁹⁰ 2013	1–5.3	0.73		0.65 (NNT, 56)	0.86 (NNT, 96)

CV, cardiovascular; CVD, cardiovascular disease; HR, hazard ratio; NNT, number needed to treat; NS, not significant.

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Table 5.

Exercise Benefit in Primary Prevention: Meta-analyses of Prospective Cohort Studies

Authors	Time Interval (Years)	Moderate Exercise (HR)	Vigorous Exercise (HR)	Pooled Exercise (HR) (Data Source)
Mortality studies
Hamer and Chida,²⁰ 2008	4–31	0.68
Löllgen et al,⁹⁴ 2009	5–26	Men: 0.81 Women: 0.76	Men: 0.78 Women: 0.69
Nocon et al,⁹⁵ 2008	4–20			Overall: 0.67 (fitness test: 0.59; self-report: 0.71)
Cardiovascular event studies
Sofi et al,¹⁹ 2008	4–25	0.88	0.73
Li and Siegrist,⁹⁶ 2012	>5	0.89	0.76
Sattelmair et al,⁹⁷ 2011	No record	0.86	0.80
Hamer and Chida,²⁰ 2008	4–31	0.69
Nocon et al,⁹⁵ 2008	4–20			Overall: 0.65 (fitness test: 0.43; self-report: 0.70)

HR, hazard ratio.

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Table 6.

Conclusions Regarding Statin Use in Exercising Adults

Conclusion	SORT Categorization	References
Myopathy is a significant adverse outcome of exposure to statins.	A	40
Addition of statins in exercising adults significantly increases myopathy risk.	B	18
Addition of statins may present special risk for reduction in physical activity in:
Very high levels of activity	C	43
The elderly	B	40, 44, 49
High-dose statin therapy	B	18
Statins added to exercise can provide additional protection against cardiovascular events and mortality.	B	21
A stable level of physical activity should be established before starting a statin.	B	58, 59
If statins are used, low doses can provide similar protection to high doses in primary prevention.	B	60, 61
Fluvastatin may be the least myotoxic of the statins and the least likely to cause myalgia with exercise.	B	18, 35
Ezetimibe and colesevelam do not cause myopathy and may be useful in combination or when added to a statin.	B	82, 86
Other measures to improve statin tolerance may be useful, but evidence is of low quality and confounded by a considerable nocebo effect.	C	53, 62, 63, 69, 70
If a choice needs to be made between drug and exercise interventions, continued exercise is the better option.	B	21