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Exercise And Statin – Associated Myopathy

Exercise And Statin – Associated Myopathy. Paul D. Thompson, MD Director of Cardiology Henry Low Heart Center Hartford Hospital Hartford, CT. Collaborators. Brown University – Peter Herbert , Eileen Cullinane, Stan Sady,

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Exercise And Statin – Associated Myopathy

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  1. Exercise And Statin – Associated Myopathy Paul D. Thompson, MD Director of Cardiology Henry Low Heart Center Hartford Hospital Hartford, CT

  2. Collaborators • Brown University – Peter Herbert, Eileen Cullinane, Stan Sady, • University of Pittsburgh – Joe Zmuda, Rich Zimet, Susan Yurgalevitch • Duke University – John Guyton • Hartford Hospital - Beth Parker, Jeff Capizzi, Amanda Augieri, William Roman, Lindsay Lorson, Mauren Yuscavitch, Brenda Foxen, Mary Beth Moran, Cherie Biblie, Rick Seip, Gualberto Ruano • Umass - Priscilla Clarkson, Maria Urso, Amy Kearns • Tufts University – Richard Karas • Washington Children’s Medical Center - Eric Hoffman • UConn – Linda Pescatello

  3. Thompson - Conflicts of Interest • Grant / Research Support: GlaxoSmithKline / Merck / Roche / Pfizer / AstraZeneca / NIH / B. Braun / Genomas • Consultant: Astra Zenica / Merck / Schering-Plough / Takeda / Roche / Genomas /Abbott / Runners World • Speaker’s Bureau: Merck / Pfizer / Abbott / Astra Zenica / Schering-Plough • Stock Shareholder: Zoll / General Electric / JA Wiley Publishing / Zimmer / Medtronic / Abbott /

  4. Peripheral Cells High-Affinity Uptake Low-Affinity Uptake FFA Capillary LPL Low-Affinity VLDL Uptake High-Affinity Uptake Acetyl CoA HMG-CoA Reductase Bile Acids Cholesterol Bile ACAT Cholesterol Esters Bile Acids Cholesterol Fecal Excretion

  5. Capillary Increased High-Affinity LDL Uptake Decreased LDL Cholesterol ß-hydroxy-ß-methylglutaryl CoA Inhibition of Cholesterol Synthesis Mevalonate Cholesterol HMG-CoA REDUCTASE INHIBITORS

  6. There Are Three Principles of Managing Lipids With Medications

  7. First Principle of Lipid Drug Management Start a Statin

  8. They Produce Remarkable Reductions in LDL Levels

  9. LDL-C Reductions with Different Statin Strategies 10 mg 20 mg 40 mg 20 mg 40 mg 80 mg 10 mg 20 mg 40 mg 10 mg 80 mg 40 mg 10 mg 20 mg P<0.002 vs CRESTOR 20 mg P<0.002 vs CRESTOR 40 mg P<0.002 vs CRESTOR 10 mg Change in LDL-C from baseline (%) -5 -10 -15 20 -25 -30 -35 -40 -45 -50 -55 -60 0 rosuvastatin atorvastatin simvastatin pravastatin Adapted from Jones PH et alAm J Cardiol 2003;92:152–160

  10. Second Principle of Lipid Drug Management Start a Statin

  11. They Cure Almost Every Lipid Problem That Ails You • LDL – Cholesterol • Triglycerides • HDL – Cholesterol • LDL Particle Size • Hs CRP

  12. Simvastatin Expanded-Dose Study Lipid Changes 10 0 -10 -20 -30 -40 -50 -60 +8 +7 +6 % change from baseline (median) -21 -23 -30 -33 -35 Simvastatin 40mg Simvastatin 80mg Simvastatin 100mg -40 -41 -47 -53 N=156 HDL Cholesterol Triglycerides Total Cholesterol LDL Cholesterol Am J Cardiol 1997;79:38-42

  13. Third Principle of Lipid Drug Management Start a Statin

  14. They Have Incredible Outcome DATA

  15. London WOSCOPS 100 Oslo CARE MRC LIPID AF/TexCAPS Los Angeles 80 Upjohn HPS LRC ALERT PROSPER NHLBI POSCH ASCOT-LLA 60 4S CARDS Nonfatal MI and CHD death relative risk reduction, % 40 20 0 –20 15 20 25 30 35 40 LDL-C reduction, % Multiple Studies Showed a Relationship BetweenLDL-C Reduction and CHD Relative Risk MI = myocardial infarction. Adapted with permission from Robinson JG et al. J Am Coll Cardiol. 2005;46:1855–1862.

  16. Statins Lower Risk - Even if the Risk Factor is Not LDL-Cholesterol

  17. Statins In the Water ?

  18. Not So Fast • There Are No Long Term Studies of Continuous Statin Treatment • The Number Needed to Treat for Low Risk Patients is Huge • Statins Have Side Effects • That No Pharmaceutical Company Wants to Study

  19. I Came Here Not To Bury Statins But To Praise Them But There Is A Problem

  20. Statin – Associated Myopathy

  21. Exercise & Statin Myopathy - Take Home Messages • Statins Are Remarkably Effective at Reducing CAD Risk • But Can Produce Myopathic (and Possibly Neurological) Side Effects • Exercise Causes Many of The CK Elevations Attributed to Statins • Exercise Magnifies Statin Myalgia & CK Increases • Some Patients Report Weakness, But There is Little Objective Data on Muscle Strength • Long Term Muscle Effects of Statins Are Unknown

  22. Exercise & Statin Myopathy - Take Home Messages • Statins Are Remarkably Effective at Reducing CAD Risk • But Can Produce Myopathic (and Possibly Neurological) Side Effects • Exercise Causes Many of The CK Elevations Attributed to Statins • Exercise Magnifies Statin Myalgia & CK Increases • Some Patients Report Weakness, But There is Little Objective Data on Muscle Strength • Long Term Muscle Effects of Statins Are Unknown

  23. Statin - Related Muscle Complaints • Myositis and Rhabdomyolysis - CK > 10 X ULN • Increased CK < 10 X ULN  Symptoms • Myalgia With No CK Increases • Muscle Weakness - Virtually Unstudied • Muscle Cramps • Persistent Myalgia ± CK ’s Even After Withdrawal

  24. Exercise & Statin Myopathy - Take Home Messages • Statins Are Remarkably Effective at Reducing CAD Risk • But Can Produce Myopathic (and Possibly Neurological) Side Effects • Exercise Causes Many of The CK Elevations Attributed to Statins • Exercise Magnifies Statin Myalgia & CK Increases • Some Patients Report Weakness, But There is Little Objective Data on Muscle Strength • Long Term Muscle Effects of Statins Are Unknown

  25. Exercise ALONE Can Produce Remarkable CK Increases So That Many CK Increases Attributed to Statins Are Due to Exercise

  26. Siegel AJ, Silverman LM, Lopez RE. Yale J Biol Med. 1980 Jul-Aug;53(4):275-9.

  27. Functional SNPs Associated with Human Muscle Size and Strength FAMuSS NIHRO1-NS40606-01A1 Study Thompson, et al Med & Science in Sports & Exercise. 2004: 36: 1132-1139.

  28. Bilbie SM, Seip RL, Bilbie CL, Clarkson, PM, Thompson, PD. Submitted.

  29. Exercise & Statin Myopathy - Take Home Messages • Statins Are Remarkably Effective at Reducing CAD Risk • But Can Produce Myopathic (and Possibly Neurological) Side Effects • Exercise Causes Many of The CK Elevations Attributed to Statins • Exercise Magnifies Statin Myalgia & CK Increases • Some Patients Report Weakness, But There is Little Objective Data on Muscle Strength • Long Term Muscle Effects of Statins Are Unknown

  30. Collected Cases • Among 22 Professional Athletes • With LDL Receptor Defects • Only 6 Could Tolerate Statins • Despite Multiple Attempts With Fluva, Lova, Prava, Atorva, & Simva Sinzinger Br J Clin Phar 2004

  31. PRedIction of Muscular Risk in Observational Conditions orPRIMO Study • 7,924 French Patients on Fluva 80, Atorva 40-80, Prava 40, Simva 40-80, for 3 mos • 10.5% Reported Muscular Symptoms • The Rate was 14.7% in Patients Practicing “Intense Form of Sport” vs 10.8% Who Did “Only Leisure Time Activities” • Pain Was Triggered in 41% - 53% by “Unusual Physical Activity” Bruckert CV Drugs & Therapy 2005

  32. Exercise & Statin Myopathy - Take Home Messages • Statins Are Remarkably Effective at Reducing CAD Risk • But Can Produce Myopathic (and Possibly Neurological) Side Effects • Exercise Causes Many of The CK Elevations Attributed to Statins • Exercise Magnifies Statin Myalgia & CK Increases • Some Patients Report Weakness, But There is Little Objective Data on Muscle Strength • Long Term Muscle Effects of Statins Are Unknown

  33. Exercise - Induced CK Elevations - • 59 Men Aged 18-65 • LDL > 130 mg/dl • Randomly to Placebo or Lova 40 mg • At 4 Weeks: Maximal EXT, Downhill Walking at 65% HR for 3 X 15 Min Bouts Thompson et al Metabolism 1997

  34. CK Elevations After Downhill Walking Thompson et al Metabolism 1997

  35. Exercise - Induced CK Elevations - Two Men Excluded Because of Marked CK Increases Thompson et al Metabolism 1997

  36. Med Sci Sports Exercise 2009

  37. Study Design • 3 blood draws • CK isoenzymes EXPO: 24 HRS PRE FINISH LINE: POST 24 HOURS POST

  38. Study Population • 43 controls • 51 ± 7 yrs • 29 men and 8 women • 37 statin users • 56 ± 8 yrs • 30 men and 13 women

  39. Log Transformed CK Response * p = 0.02

  40. Exercise & Statin Myopathy - Take Home Messages • Statins Are Remarkably Effective at Reducing CAD Risk • But Can Produce Myopathic (and Possibly Neurological) Side Effects • Exercise Causes Many of The CK Elevations Attributed to Statins • Exercise Magnifies Statin Myalgia & CK Increases • Some Patients Report Weakness, But There is Little Objective Data on Muscle Strength • Long Term Muscle Effects of Statins Are Unknown

  41. The Effect of Statins on Skeletal Muscle FunctionNIH RO1 081893 • 440 Subjects • Randomized to Atorvastatin 80 or Placebo • 6 Months • Strength - Handgrip, Biceps, Quadriceps - Static & Dynamic Strength • Quadriceps Endurance • Exercise Oxygen Uptake & Respiratory Quotient

  42. What Causes Statin Myopathy ?

  43. I DON’T KNOW

  44. Possible Mechanisms of Statin Induced Muscle Injury 1.Reduced Sarcolemmal Cholesterol 2. Reduced T-Tubule & Sarcoplamic Recticulum Cholesterol Draeger JPath 2006 3. Reduced Isoprenoids: Ubiquinone - Co-enzy Q10 4. Reduced Prenylation of GTP Binding Proteins - Ras, Rac and Rho - Cell Maintenance, Growth & Reduced ApoptosisColeman Cell Death Differ 2002 5. Changes in Fat Metabolism (Phillips P Atherosclerosis 2005) 6.  Increased Muscle Cholesterol & ? Plant Sterol 2nd to LDL Receptor Activity (Paiva Clin Pharmacol Ther 2005) • Failure to Appropriately Repair Damaged Muscle(Urso …. Thompson ATVB 2005) • Vitamin D Deficiency • Inflammation (Inflammatory Myopathy)

  45. Possible Mechanisms of Statin Induced Muscle Injury 1.Reduced Sarcolemmal Cholesterol 2. Reduced T-Tubule & Sarcoplamic Recticulum CholesterolDraeger JPath 2006 3. Reduced Isoprenoids: Ubiquinone - Co-enzy Q10 4. Reduced Prenylation of GTP Binding Proteins - Ras, Rac and Rho - Cell Maintenance, Growth & Reduced ApoptosisColeman Cell Death Differ 2002 5. Changes in Fat Metabolism (Phillips P Atherosclerosis 2005) 6.  Increased Muscle Cholesterol & ? Plant Sterol 2nd to LDL Receptor Activity (Paiva Clin Pharmacol Ther 2005) • Failure to Appropriately Repair Damaged Muscle(Urso …. Thompson ATVB 2005) • Vitamin D Deficiency • Inflammation (Inflammatory Myopathy)

  46. Coenzyme Q10 in Statin Myopathy 1 RC1 AT005836-01 NIH/NCCAM

  47. 135 Subjects with Prior Statin Complaints Run-In: Initial – Simvastatin Simvastatin 20 mg for 8 weeks or Until Symptoms Persist for 1 Week or are Intolerable Run-In: Initial - Placebo Placebo for 8 Weeks or Until Symptoms Persist for 1 Week or are Intolerable 4 week washout Run-In: Initial - Placebo Placebo for 8 Weeks or Until Symptoms Persist for 1 Week or are Intolerable Run-In: Initial – Simvastatin Simvastatin 20 mg for 8 weeks or Until Symptoms Persist for 1 Week or are Intolerable 4 week washout 100 Subjects Symptomatic on Statins Only: Baseline Strength and Exercise Performance Testing, Accelerometer, Pain Questionnaire Randomization to Treatment: Placebo or 600 mg CoQ10 Load Subjects for 2 weeks on Treatment Simvastatin 20mg + Placebo (N=50) Simvastatin 20mg + CoQ10 (N=50) At 8 Weeks or Until Symptoms Persist 1 Week or are Intolerable:Strength and Exercise Performance Testing, Accelerometer, Pain Questionnaire Weekly phone calls: Pain Questionnaires used to assess muscle symptoms and document myalgia

  48. Total & LDL Reductions Were Greatest in “True Myalgics” True = 12 Non = 19 D-C Morales, B Parker, L Lorson, D Polk, PD Thompson. ACC 2011

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