Statin myopathy pdf

1. Statin Myopathy
Lisa Christopher-Stine, MD, MPH
Professor of Medicine and Neurology
Director, Johns Hopkins Myositis Precision Medicine Center of Excellence
Johns Hopkins University School of Medicine

2. Disclosures
• I have the following relevant financial relationship(s) to disclose:
Consultant: , Janssen, Boehringer-Ingelheim, Mallinckrodt, EMD Serono,
Roivant/Priovant, Pfizer, ArgenX, Horizon Therapeutics, and Allogene.
• Grant/Research Support: Pfizer, Corbus and Kezar
• Royalties: Inova Diagnostics
• Intellectual Property/Patents: Inova Diagnostics (Anti-HMGCR autoantibody testing)
All of the relevant financial relationships listed for this individual have been
mitigated.

3. Evidence-Based Medicine (EBM)
Key References
• Albayda J, Christopher-Stine L. Identifying statin-associated autoimmune necrotizing myopathy.
Cleve Clin J Med. 2014 Dec;81(12):736-41.
• Christopher-Stine L, Basharat P. Statin-associated immune-mediated myopathy: biology and clinical
implications. Curr Opin Lipidol. 2017 Apr;28(2):186-192.
• Wood FA, Howard JP, Finegold JA, Nowbar AN, Thompson DM, Arnold AD, Rajkumar CA, Connolly
S, Cegla J, Stride C, Sever P, Norton C, Thom SAM, Shun-Shin MJ, Francis DP. N-of-1 Trial of a
Statin, Placebo, or No Treatment to Assess Side Effects. N Engl J Med. 2020 Nov 26;383(22):2182-
2184.
• Herrett E, Williamson E, Beaumont D, Prowse D, Youssouf N, Brack K, Armitage J, Goldacre B,
MacDonald T, Staa TV, Roberts I, Shakur-Still H, Smeeth L. Study protocol for statin web-based
investigation of side effects (StatinWISE): a series of randomised controlled N-of-1 trials comparing
atorvastatin and placebo in UK primary care. BMJ Open. 2017 Dec 1;7(12):e016604.
• Writing Committee, Lloyd-Jones DM, Morris PB, Ballantyne CM, Birtcher KK, Covington AM,
DePalma SM, Minissian MB, Orringer CE, Smith SC Jr, Waring AA, Wilkins JT. 2022 ACC Expert
Consensus Decision Pathway on the Role of Nonstatin Therapies for LDL-Cholesterol Lowering in
the Management of Atherosclerotic Cardiovascular Disease Risk: A Report of the American College
of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2022 Oct 4;80(14):1366-1418.

4. Broad Objectives
• Review clinical presentation, laboratory assessment, and
treatment plans for statin myopathy
• Outline alternative treatments for hyperlipidemia in those who
cannot tolerate statins

5. What we will cover today…
• What is the definition of “statin intolerance”, and how many statins does
a patient need to fail before meeting this definition?
• What is the definition of “statin myopathy”?
• What is the difference between autoimmune statin myopathy and
a statin myopathy where the drug acts as a direct myotoxin (“toxic” statin
myopathy”)?
• How common is statin intolerance in the “real world?”
• Are muscle enzymes (e.g., CK) routinely checked prior to starting
a statin for cholesterol reduction in routine clinical practice? What is the
implication?
• In statin clinical trials, do patients on placebo report the
same statin intolerance that those on statins do?

6. What we will cover today… (continued)
• Can statin myopathy occur with a normal CK?
• Should you ever do a muscle biopsy in acute rhabdomyolysis
related to statins?
• Can a patient with myositis (inflammatory myopathy like
dermatomyositis) safely take a statin?
• Do you need a muscle biopsy to diagnose autoimmune statin
myopathy?
• What is the evidence for CoQ10 supplementation (and other
supplements) in statin myopathy?
• What are some pharmacologic options for lipid reduction in
statin intolerance (including statin myopathy)?

7. A case... and a tale of two brothers
• ASM is a 71-year-old man with a history of ASCVD, hypertension,
hyperlipidemia, and type 2 diabetes mellitus
• The patient had been taking atorvastatin 80 mg daily for 37
months before it was stopped when the liver-associated enzymes
were found to be elevated initially.
• Sees his PCP for pre-procedural labs for a scheduled liver biopsy
to further evaluate persistently elevated liver-associated enzymes
(AST, ALT) for the past 4 months.
• The PCP realizes that a creatine kinase (CK) has never been
ascertained, so she also draws a CK which is markedly elevated.
• The patient wonders if he has “statin myopathy” like his brother.

8. • Patient History:
• Extreme fatigue and muscle soreness for the past 2 months;
reports difficulty climbing stairs, getting off low seated chairs,
and washing his hair in the shower.
• Denies frank dysphagia but has noticed occasionally having to
“double swallow” to swallow dry bread.
• Denies joint pain; no history of any autoimmune diseases
Exam: proximal weakness of deltoids and hip flexors
• CK: 5250 U/L ( normal range under 250 U/L)
• Anti-HMGCR testing is positive
• Family history- no known autoimmune diseases; brother (TSM)
had a diagnosis of self- limited (“toxic”) statin myopathy.

9. More about his brother (TSM)…
• Stopped atorvastatin 80 mg daily after 6 weeks of use because
his muscles were painful.
• Had calf and other diffuse muscle pain and fatigue but denied
true weakness
• Had a CK of 450 U/L; pre-statin CK was unknown.
• Anti-HMGCR testing is negative
• CK normalized after statin cessation but rose upon re-challenge
of atorvastatin at any dose and with rosuvastatin at higher doses
• Able to tolerate low-dose rosuvastatin with the addition of a
PCSK9 mAb inhibitor for excellent lipid control.

10. Do the two brothers (ASM and
TSM) have the same type of
statin myopathy?
ASM has autoimmume statin myopathy (a.k.a. statin- associated necrotizing autoimmune myopathy (SANAM) or anti-HMGCR associated IMNM)
TSM has toxic statin myopathy or self-limited statin myopathy

11. Statin Associated Autoimmune
Necrotizing Myopathy
Toxic (Self-Limited) Statin Myopathy
Incidence Rare (2-3 per 100K statin users) Common (13% of statin users
depending on definition)
Statin Atorvastatin overwhelmingly Any
Statin Duration Years (average 36 months) Days to weeks
Weakness Yes, almost always Varies
Myalgia Sometimes Often
Dysphagia Sometimes Never
CK range Usually >1000, rarely normal Varies
Clinical rhabdomyolysis Rare to Never Rare
New onset Raynaud’s Rare Never
HMGCR autoantibody Yes (sensitive and specific) No
Muscle Biopsy MHC class 1 upregulation;
degeneration, regeneration, necrosis
Degeneration, regeneration, Necrosis
Concomitant meds exacerbate it No Sometimes
Myopathy dissipates when statin
stopped
No Yes
Basharat PJ Am Coll Cardiol. 2016 Jul 12;68(2):234-5.
Albayda J. Cleve Clin J Med. 2014 Dec;81(12):736-41.
Christopher-Stine L, Arthritis Rheum. 2010 Sep;62(9):2757-66.
Mammen AL. Arthritis Rheum. 2011 Mar;63(3):713-21.
Christopher-Stine L,. Curr Opin Lipidol. 2017 Apr;28(2):186-192.

12. Statin Associated Autoimmune
Necrotizing Myopathy
Toxic (Self-Limited) Statin Myopathy
Incidence Rare (2-3 per 100K statin users) Common (13% of statin users
depending on definition)
Statin Atorvastatin overwhelmingly Any
Statin Duration Years (average 36 months) Days to weeks
Weakness Yes, almost always Varies
Myalgia Sometimes Often
Dysphagia Sometimes Never
CK range Usually >1000, rarely normal Varies
Clinical rhabdomyolysis Rare to Never Rare
Raynaud’s Rare Never
HMGCR autoantibody Yes (sensitive and specific) No
Muscle Biopsy MHC class 1 upregulation;
degeneration, regeneration, necrosis
Degeneration, regeneration, Necrosis
Concomitant meds exacerbate it No Sometimes
Myopathy dissipates when statin
stopped
No Yes

13. Self-limited (‘toxic”)statin myopathy
(Statin Associated Muscle Symptoms)

14. Stroes ES.Eur Heart J. 2015 May 1;36(17):1012-22

16. Statin Intensity
HIGH INTENSITY (Lower LDL by ≥ 50%)
Atorvastatin 40-80 mg
Rosuvastatin 20 mg-40 mg
MODERATE INTENSITY(Lower LDL by 30-49%)
Atorvastatin 10 -20 mg
Rosuvastatin 5-10 mg
Simvastatin 20-40 mg
Pravastatin 40- 80 mg
Fluvastatin 80 mg BID
Lovastatin 40 mg
Pitvastatin 2-4 mg
LOW INTENSITY (Lower LDL by ≤30%)
Simvastatin 10 mg
Pravastatin 10-20 mg
Fluvastatin 20-40 mg
Lovastatin 20 mg
Pitvastatin 1 mg Hydrophilic statins
Bansal AB., Cassagnoi M. HMG-CoA Reductatse Inhibitors [Updated July 4 2022] . In: StatPearls: StatPearls Publishing

17. Lipophilic versus hydrophilic
• Meta-analysis: with the exception of the GAUSS-3* study, no
significant association between lipophilic or hydrophilic statins
and risk of skeletal muscle events.
• Another meta-analysis of statin randomized controlled trials
(RCTs) also found limited evidence that lipophilic statins were
associated with a greater risk of statin-associated muscle
symptoms (SAMS).
Irwin JCPharmacol Res. 2018 Feb;128:264-273.
Iwere R.B. Br. J. Clin. Pharmacol. 2015;80:363–371..
* Goal Achievement after Utilizing an anti-PCSK9 antibody in Statin Intolerant Subjects-3

18. Statin Compliance
• Evidence from RCTs :adverse cardiovascular event risk lowered by atherogenic
lipoprotein level reduction
• Benefit proportionate to degree of reduction and the length of time lower level is
maintained
• Despite benefits on cardiovascular outcomes, compliance to statin therapy often
inadequate
• Non-adherence to treatment up to 50% of patients
Gislason G.H., Eur. Heart J. 2006;27:1153–1158.
Blackburn D.F., Can. J. Cardiol. 2005;21:485–488.

19. Statin intolerance
• Statin-associated muscle symptoms (SAMS) are the most common side
effect (>80%) associated with statin discontinuation.
• Symptoms range from mild-to-moderate muscle pain, weakness, or
fatigue to rhabdomyolysis
• Reported by 10% to 25% of patients receiving statin therapy.
• Due to lack of “gold standard”, diagnostic test for SAMS is based on a
clinical index score (SAMS-CI), which is independent of creatine kinase
(CK) elevation.

20. Rosenson RS.Cardiovasc Drugs Ther Apr;31(2):2017;
31(2):179-186.
SAMS-CI
[from the Statin
Muscle
Safety Task Force
of the National
Lipid Association
(NLA)]

21. Medication interactions with Statins
Alagona, Peter S. Core Evidence 5 (2010): 91 - 105.
HIV
HIV Protease

22. What about Exercise and Statins?
• Exercise together with statins can exacerbate /trigger SAMS
• After a training session, CK levels appear to increase more
in statin-treated athletes than in athletes not on therapy
• Association between high CK levels and age found only in
athletes on statin therapy
• Systematic review of the literature reports conflicting results on
the ability of statins to impair performance during exercise
Mendes P. Physiother. Can. 2014;66:124–132.
Parker B.A.. Exerc. Sport Sci. Rev. 2012;40:188–194.
Parker B.A. Am. J. Cardiol. 2012;109:282–287.
Noyes A.M. J. Clin. Lipidol. 2017;11:1134–1144.

23. CK in self-limited statin myopathy
• CK levels are frequently normal in symptomatic patients
taking statins, while also may be increased in asymptomatic
patients
• For these reasons, CK is a non-sensitive biomarker for statin-
induced myopathy, but is currently used in the evaluation of
SAMS due to the absence of other specific laboratory tests.
MRC/BHF Heart Protection Study Collaborative Group. BMC Clin. Pharmacol. 2009;9:6.
Downs J.R.,. Am. J. Cardiol. 2001;87:1074–1079.

24. SAMSON and STATINWise
and
-the “Nocebo”effect

25. Self-Assessment Method for Statin Side-
effects Or Nocebo (SAMSON) trial
• 12 month study of 60 UK patients with statin-associated
adverse events within 2 weeks of statin initiation (excl CK<5x
ULN+ of CK increase + myalgia)
• Double-blind, three-group, n-of-1 trial
• Test whether symptoms would be induced by a statin (atorva 20
mg) or placebo.
• 4 bottles contained statin tablets, 4 placebo tablets, and 4 empty
• Each bottle was to be used for a 1-month period ;random sequence.
• Smartphone application to report symptom intensity daily.
• Symptom scores ranged from 0 to 100
Wood FA. N Engl J Med 2020; 383:2182-2184

26. SAMSON trial (continued)
• Overall symptom severity scores:
• 8 for no-tablet months (95% CI, 4.7-11.3);
• 15.4 for placebo (95% CI, 12.1-18.7); and
• 16.3 for statin therapy (95% CI, 13-19.6).
• Difference in symptom severity reported for placebo compared with
statin therapy was not clinically significant (P < .388);
• Side effect severity was significant for both statin and placebo compared with
no- tablet months (P for both < .001).
• 90% developed the same symptoms on placebo using random monthly
crossover sequences over 12 months
• Half of the participants successfully re-started statins
• May reassure physicians and patients to pursue statin re-challenges

27. STATIN: Web-based Investigation of Side
Effects (STATINWISE)
• 151 of 200 randomized patients with statin intolerance from England and
Wales provided at least one VAS score on placebo and one on statin
active comparator
• A series of randomized, double blind, placebo controlled n-of-1 trials.
• Six two-month treatment periods
• three of active treatment (atorvastatin 20 mg)
• three of matching placebo
• randomly allocated order.
• Daily atorvastatin (20 mg) was compared with matching placebo
• Primary outcome measured daily by validated VAS 0-10 for last 7days of
each treatment period
• Secondary outcomes three months after the end of the final treatment
period:
• Restart statins?
• Trial useful in decision making? Herrett E. BMJ Open. 2017 Dec 1;7(12):e016604.

28. STATINWISE (continued)
• No evidence of difference in muscle symptom scores between statin and
placebo periods
• mean difference statin minus placebo -0.11, 95% confidence interval -0.36 to
0.14; p = 0.398).
• Withdrawals, adherence and missing data were similar during the statin
periods and the placebo periods.
• Few withdrew because of muscle symptoms
• Of the participants who completed six treatment periods and received their
results during an end of trial discussion, 3 months later:
• 88% said that the trial had been helpful
• 66% said that they had already resumed or intended to resume taking statins.

29. Statin therapy and underlying
neuromuscular disorders
• Statin therapy may exacerbate underlying neuromuscular
disorders
• myasthenia gravis
• dermato/polymyositis
• inclusion body myositis
• motor neuron disease,
• MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like
episodes)
• Note : Regarding the inflammatory myopathies, the only absolute
contraindication to statins are patients with myositis who are HMGCR
ab+, (PCSK9 mAb inhibitors are safe in this population) Tay S.K. Pediatr. Neurol. 2008;39:426–428.
Alonso R.J. Atheroscler. Thromb. 2019;26:207–215.
Brunham L.R. Cardiovasc. Res. 2018;114:1073–1081
Thomas J.E. Eur. Neurol. 2007;57:232–235.
Tiniakou E. Arthritis Rheumatol. 2019 Oct;71(10):1723-1726.

30. Muscle Biopsy in Statin Myopathy
Statin Associated Necrotizing
Autoimmune Myopathy
• Muscle biopsy falling out of
favor with widely available
autoantibody testing in the
right clinical scenario
• HMGCR Ab testing positive
• High CK
• Proximal weakness
• +/- Myalgias
• Statin exposure (atorvastatin)
Self-limited Statin Myopathy
• No reason to biopsy when
rhabdomyolysis is acute.
• A clinical diagnosis
• HMGCR antibody testing
negative
• Acute increase in CK
• Urine myoglobin
• +/- Proximal Weakness
• Myalgias
• Statin exposure (any)

31. Are CKs checked at statin initiation?
What about when LFTS rise?
• No longer recommended to check CK at initiation of statin
therapy
• Routinely, PCPs and others never check CK after LFTS rise in
patients taking statins

32. Remember to check the CK if LFTS
are elevated! (Abstract #1283)
• Explored how frequently clinicians check CK in patients with elevated
transaminases to look for muscle injury
• Outpatient retrospective chart review May 2017 to May 2022
• 731 randomly selected patients taking statins
• Diagnosed with elevated transaminases (ICD code: R74.01)
• Records were reviewed to ascertain if subjects had a CK level checked
within one month of diagnosis of elevated transaminases
Only 169, (23%), had their CK checked within one month
• Of these 169 subjects, 26 (15%), had CK flagged as high
• 65 % had CK level >400 U/L and 19 % had CK level >1000 U/L
• 562 patients (77%) did not have their CK checked
Nidhaan A, Hastings A, Gonzalez D, Joshi R gilbert N, O'connor C. Frequency of Checking Creatine Kinase in Patients on Statins with Elevated Transaminase for Early
Detection of Statin Induced Myopathy [abstract]. Arthritis Rheumatol. 2022; 74 (suppl 9).

33. Treatment:
Toxic Statin Myopathy
Lipid Lowering Options

34. Toxic Statin Myopathy Acute Management
Newman CB. Endocrinol Metab Clin North Am.
2022,Sep; 51(3):655-679

35. Strategies to increase statin tolerance
• Try “N of 1” personal trial off and on statin with symptom diary
• Switch brands
• Lower the dose
• Every other day or 3x/week dosing
• Lower dose of statin plus other non-statin

36. 2022 ACC Expert Consensus Decision
Pathway for Statin Intolerance
• Builds on the 2018 AHA/ACC/Multi-society cholesterol guideline
• Provides helpful guidance in several key areas on the use of
newer (approved since 2018) non-statin therapies for primary
and secondary prevention
• In patients with clinical ASCVD and partial or
complete statin intolerance;
• ezetimibe or a PCSK9 mAb inhibitor (evolocumab, alirocumab)
first-line non-statin therapy.
• bempedoic acid and inclisiran second line non-statin therapy
J Am Coll Cardiol. 2022 Oct 4;80(14):1366-1418.

37. What about CoQ10?
• Several studies have shown that statins reduce CoQ10 plasma levels in skeletal muscle tissue
(humans and rodents)
• A deficit of CoQ10 does not seem to be associated with:
-statin type
-intensity
-treatment duration
• Statins may interfere with mitochondrial function, causing an impaired muscle performance,
resulting in muscle damage.
• Structural abnormalities were detected in muscle biopsies of patients treated with statins, even
when they did not experience any symptoms
• 60 Patient RCT: The addition of CoQ10 (100 mg/day) x 3 months with
half dosage statin in patients with previous intolerance to statins improves
the perception of clinical symptoms such as asthenia, myalgia or pain.
Vladutiu G.D., Muscle Nerve. 2006;34:153–162.
Marcoff L. J. Am. Coll. Cardiol. 2007;49:2231–2237.
Mohaupt M.G. CMAJ. 2009;181:E11–E18.
Derosa G, Drug Des Devel Ther. 2019 Oct 21;13:3647-3655.

38. What about supplements?
The SPORT study
• ¾ of US citizens take a supplement ; 20 % for “heart health” or “cholesterol
health”
• Daily rosuvastatin (5 mg) lowered LDL, total cholesterol and serum
triglycerides significantly more than placebo and 6 common supplements
• No supplement lowered LDL more than placebo
• Over-the-counter dietary supplements
• Fish oil
• Cinnamon
• Garlic
• Turmeric
• Plant sterols
• Red yeast rice*
28 day 8-arm randomized, double-blind trial; 190 adults aged 40 to 75 years
who had LDL between 70 and 189 mg/dL, no history of atherosclerotic CVD and
an increased 10-year risk of ASCVD Laffin LJ, et al. J Am Coll Cardiol. 2022;doi:10.1016/j.jacc.2022.10.013.

40. References (I)
• Christopher-Stine L, Casciola-Rosen LA, Hong G, Chung T, Corse AM, Mammen AL. A novel autoantibody recognizing 200-kd
and 100-kd proteins is associated with an immune-mediated necrotizing myopathy. Arthritis Rheum. 2010 Sep;62(9):2757-66.
• Mammen AL, Chung T, Christopher-Stine L, Rosen P, Rosen A, Doering KR, Casciola-Rosen LA. Autoantibodies against 3-
hydroxy-3-methylglutaryl-coenzyme A reductase in patients with statin-associated autoimmune myopathy. Arthritis Rheum. 2011
Mar;63(3):713-21.
• Basharat P, Lahouti AH, Paik JJ, Albayda J, Pinal-Fernandez I, Bichile T, Lloyd TE, Danoff SK, Casciola-Rosen L, Mammen AL,
Christopher-Stine L. Statin-Induced Anti-HMGCR-Associated Myopathy. J Am Coll Cardiol. 2016 Jul 12;68(2):234-5
• Albayda J, Christopher-Stine L. Identifying statin-associated autoimmune necrotizing myopathy. Cleve Clin J Med. 2014
Dec;81(12):736-41.
• Christopher-Stine L, Basharat P. Statin-associated immune-mediated myopathy: biology and clinical implications. Curr Opin
Lipidol. 2017 Apr;28(2):186-192.
• Stroes ES, Thompson PD, Corsini A, et al. Statin-associated muscle symptoms: impact on statin therapy-European
Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. Eur Heart J. 2015 May
1;36(17):1012-22.
• Bansal AB., Cassagnoi M. HMG-CoA Reductatse Inhibitors [Updated July 4 2022] . In: StatPearls: StatPearls Publishing
• Irwin JC, Khalesi S, Fenning AS, Vella RK. The effect of lipophilicity and dose on the frequency of statin-associated muscle
symptoms: A systematic review and meta-analysis. Pharmacol Res. 2018 Feb;128:264-273.
• Iwere R.B., Hewitt J. Myopathy in older people receiving statin therapy: A systematic review and meta-analysis. Br. J. Clin.
Pharmacol. 2015;80:363–371..
• Newman CB, Preiss D, Tobert JA, Jacobson TA, Page RL 2nd, Goldstein LB, Chin C, Tannock LR, Miller M, Raghuveer G, Duell
PB, Brinton EA, Pollak A, Braun LT, Welty FK; American Heart Association Clinical Lipidology, Lipoprotein, Metabolism and
Thrombosis Committee, a Joint Committee of the Council on Atherosclerosis, Thrombosis and Vascular Biology and Council on
Lifestyle and Cardiometabolic Health; Council on Cardiovascular Disease in the Young; Council on Clinical Cardiology; and
Stroke Council. Statin Safety and Associated Adverse Events: A Scientific Statement From the American Heart Association.
Arterioscler Thromb Vasc Biol. 2019 Feb;39(2):e38-e81

41. References (II)
• Newman CB. Safety of Statins and Nonstatins for Treatment of Dyslipidemia. Endocrinol Metab Clin North Am. 2022
Sep;51(3):655-679.
▪ Gislason G.H., Rasmussen J.N., Abildstrøm S.Z., Gadsbøll N., Buch P., Friberg J., Rasmussen S., Køber L., Stender S., Madsen
M., et al. Long-term compliance with beta-blockers, angiotensin-converting enzyme inhibitors, and statins after acute myocardial
infarction. Eur. Heart J. 2006;27:1153–1158.
▪ Blackburn D.F., Dobson R.T., Blackburn J.L., Wilson T.W., Stang M.R., Semchuk W. Adherence to statins, beta-blockers and
angiotensin-converting enzyme inhibitors following a first cardiovascular event: A retrospective cohort study. Can. J. Cardiol.
2005;21:485–488
• Rosenson RS, Miller K, Bayliss M, Sanchez RJ, Baccara-Dinet MT, Chibedi-De-Roche D, Taylor B, Khan I, Manvelian G, White
M, Jacobson TA. The Statin-Associated Muscle Symptom Clinical Index (SAMS-CI): Revision for Clinical Use, Content
Validation, and Inter-rater Reliability. Cardiovasc Drugs Ther. 2017 Apr;31(2):179-186.
• Alagona, Peter S.. “Pitavastatin: evidence for its place in treatment of hypercholesterolemia.” Core Evidence 5 (2010): 91 - 105.
• Mendes P., Robles P.G., Mathur S. Statin-Induced Rhabdomyolysis: A Comprehensive Review of Case Reports. Physiother.
Can. 2014;66:124–132.
• Parker B.A., Thompson P.D. Effect of statins on skeletal muscle: Exercise, myopathy, and muscle outcomes. Exerc. Sport Sci.
Rev. 2012;40:188–194.
• Parker B.A., Augeri A.L., Capizzi J.A., Ballard K.D., Troyanos C., Baggish A.L., D’Hemecourt P.A., Thompson P.D. Effect of
statins on creatine kinase levels before and after a marathon run. Am. J. Cardiol. 2012;109:282–287
• Noyes A.M., Thompson P.D. The effects of statins on exercise and physical activity. J. Clin. Lipidol. 2017;11:1134–1144.
• Alfirevic A., Neely D., Armitage J., Chinoy H., Cooper R.G., Laaksonen R., Carr D., Bloch K.M., Fahy J., Hanson A., et al.
Phenotype Standardization for Statin-Induced Myotoxicity. Clin. Pharmacol. Ther. 2014;96:470–476.
• Phillips PS, Haas RH, Bannykh S, Hathaway S, Gray NL, Kimura BJ, Vladutiu GD, England JD; Scripps Mercy Clinical Research
Center. Statin-associated myopathy with normal creatine kinase levels. Ann Intern Med. 2002 Oct 1;137(7):581-5.

42. References (III)
• MRC/BHF Heart Protection Study Collaborative Group Effects of simvastatin 40 mg daily on muscle and liver adverse effects in
a 5-year randomized placebo-controlled trial in 20,536 high-risk people. BMC Clin. Pharmacol. 2009;9:6.
• Downs J.R., Clearfield M., Tyroler H.A., Whitney E.J., Kruyer W., Langendorfer A., Zagrebelsky V., Weis S., Shapiro D.R., Beere
P.A., et al. Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS). Additional perspectives on tol-
erability of long-term treatment with lovastatin. Am. J. Cardiol. 2001;87:1074–1079.
• Wood FA, Howard JP, Finegold JA, Nowbar AN, Thompson DM, Arnold AD, Rajkumar CA, Connolly S, Cegla J, Stride C, Sever
P, Norton C, Thom SAM, Shun-Shin MJ, Francis DP. N-of-1 Trial of a Statin, Placebo, or No Treatment to Assess Side Effects. N
Engl J Med. 2020 Nov 26;383(22):2182-2184.
• Herrett E, Williamson E, Beaumont D, Prowse D, Youssouf N, Brack K, Armitage J, Goldacre B, MacDonald T, Staa TV, Roberts
I, Shakur-Still H, Smeeth L. Study protocol for statin web-based investigation of side effects (StatinWISE): a series of
randomised controlled N-of-1 trials comparing atorvastatin and placebo in UK primary care. BMJ Open. 2017 Dec
1;7(12):e016604.
• Tay S.K., Di Mauro S., Pang A.Y., Lai P.-S., Yap H.-K. Myotoxicity of Lipid-Lowering Agents in a Teenager with MELAS Mutation.
Pediatr. Neurol. 2008;39:426–428.
• Alonso R., Cuevas A., Cafferata A. Diagnosis and Management of Statin Intolerance. J. Atheroscler. Thromb. 2019;26:207–215.
• Brunham L.R., Baker S., Mammen A., Mancini G.B.J., Rosenson R.S. Role of genetics in the prediction of statin-associated
muscle symptoms and optimization of statin use and adherence. Cardiovasc. Res. 2018;114:1073–1081
• Thomas J.E., Lee N., Thompson P.D. Statins Provoking MELAS Syndrome. Eur. Neurol. 2007;57:232–235.
• NIDHAAN A, Hastings A, Gonzalez D, Joshi R gilbert N, O'connor C. Frequency of Checking Creatine Kinase in Patients
on Statins with Elevated Transaminase for Early Detection of Statin Induced Myopathy [abstract]. Arthritis Rheumatol. 2022; 74
(suppl 9).

43. References (IV)
• Writing Committee, Lloyd-Jones DM, Morris PB, Ballantyne CM, Birtcher KK, Covington AM, DePalma SM, Minissian MB,
Orringer CE, Smith SC Jr, Waring AA, Wilkins JT. 2022 ACC Expert Consensus Decision Pathway on the Role of Nonstatin
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