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, • 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 Thompson - Conflicts of Interest • Grant / Research Support: GlaxoSmithKline / Merck / Roche / Pfizer / AstraZeneca / NIH / B. Braun / Genomas • Consultant: Astra Zenica / Merck / ScheringPlough / 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 / Peripheral Cells High-Affinity Uptake Low-Affinity Uptake FFA Capillary LPL Low-Affinity VLDL Uptake High-Affinity Uptake Acetyl CoA HMG-CoA Reductase Cholesterol ACAT Cholesterol Esters Bile Acids Bile Bile Acids Cholesterol Fecal Excretion Capillary Increased High-Affinity LDL Uptake Decreased LDL Cholesterol ß-hydroxy-ßmethylglutaryl CoA Inhibition of Cholesterol Synthesis Mevalonate Cholesterol HMG-CoA REDUCTASE INHIBITORS There Are Three Principles of Managing Lipids With Medications First Principle of Lipid Drug Management Start a Statin They Produce Remarkable Reductions in LDL Levels LDL-C Reductions with Different Statin Strategies Change in LDL-C from baseline (%) 0 -5 -10 -15 20 -25 -30 -35 -40 -45 10 mg 20 mg 20 mg 10 mg 20 mg 10 mg 10 mg 20 mg -50 -55 40 mg 40 mg 40 mg 80 mg 80 mg 40 mg -60 rosuvastatin atorvastatin simvastatin pravastatin P<0.002 vs CRESTOR 10 mg P<0.002 vs CRESTOR 20 mg P<0.002 vs CRESTOR 40 mg Adapted from Jones PH et al Am J Cardiol 2003;92:152–160 Second Principle of Lipid Drug Management Start a Statin They Cure Almost Every Lipid Problem That Ails You • LDL – Cholesterol • Triglycerides • HDL – Cholesterol • LDL Particle Size • Hs CRP Simvastatin Expanded-Dose Study Lipid Changes +6 +7 +8 % change from baseline (median) 10 0 -10 -20 -21 -30 -23 -30 -40 -33 -35 -40 -50 Simvastatin 40mg -41 Simvastatin 80mg -47 Total Cholesterol Am J Cardiol 1997;79:38-42 LDL Cholesterol Simvastatin 100mg N=156 -53 -60 HDL Cholesterol Triglycerides Third Principle of Lipid Drug Management Start a Statin They Have Incredible Outcome DATA Multiple Studies Showed a Relationship Between LDL-C Reduction and CHD Relative Risk London Oslo MRC Los Angeles Upjohn LRC NHLBI POSCH 4S Nonfatal MI and CHD death relative risk reduction, % 100 80 60 WOSCOPS CARE LIPID AF/TexCAPS HPS ALERT PROSPER ASCOT-LLA CARDS 40 20 0 –20 15 20 25 30 LDL-C reduction, % MI = myocardial infarction. Adapted with permission from Robinson JG et al. J Am Coll Cardiol. 2005;46:1855–1862. 35 40 Statins Lower Risk - Even if the Risk Factor is Not LDLCholesterol Statins In the Water ? 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 I Came Here Not To Bury Statins But To Praise Them But There Is A Problem Statin – Associated Myopathy Exercise & Statin Myopathy Take Home Messages 1. Statins Are Remarkably Effective at Reducing CAD Risk 2. But Can Produce Myopathic (and Possibly Neurological) Side Effects 3. Exercise Causes Many of The CK Elevations Attributed to Statins 4. Exercise Magnifies Statin Myalgia & CK Increases 5. Some Patients Report Weakness, But There is Little Objective Data on Muscle Strength 6. Long Term Muscle Effects of Statins Are Exercise & Statin Myopathy Take Home Messages 1. Statins Are Remarkably Effective at Reducing CAD Risk 2. But Can Produce Myopathic (and Possibly Neurological) Side Effects 3. Exercise Causes Many of The CK Elevations Attributed to Statins 4. Exercise Magnifies Statin Myalgia & CK Increases 5. Some Patients Report Weakness, But There is Little Objective Data on Muscle Strength 6. Long Term Muscle Effects of Statins Are 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 Exercise & Statin Myopathy Take Home Messages 1. Statins Are Remarkably Effective at Reducing CAD Risk 2. But Can Produce Myopathic (and Possibly Neurological) Side Effects 3. Exercise Causes Many of The CK Elevations Attributed to Statins 4. Exercise Magnifies Statin Myalgia & CK Increases 5. Some Patients Report Weakness, But There is Little Objective Data on Muscle Strength 6. Long Term Muscle Effects of Statins Are Exercise ALONE Can Produce Remarkable CK Increases So That Many CK Increases Attributed to Statins Are Due to Exercise Siegel AJ, Silverman LM, Lopez RE. Yale J Biol Med. 1980 Jul-Aug;53(4):275-9. NIH RO1-NS40606-01A1 Thompson, et al Med & Science in Sports & Exercise. 2004: 36: 1132-1139. Subj 1 Subj 3 Subj 5 Subj 7 Subj 9 Plasma Creatine Kinase (U/L) 6000 5000 Subj 2 Subj 4 Subj 6 Subj 8 Subj 10 4000 3000 2000 1000 0 1 2 3 Day 4 5 Bilbie SM, Seip RL, Bilbie CL, Clarkson, PM, Thompson, PD. Submitted. Exercise & Statin Myopathy Take Home Messages 1. Statins Are Remarkably Effective at Reducing CAD Risk 2. But Can Produce Myopathic (and Possibly Neurological) Side Effects 3. Exercise Causes Many of The CK Elevations Attributed to Statins 4. Exercise Magnifies Statin Myalgia & CK Increases 5. Some Patients Report Weakness, But There is Little Objective Data on Muscle Strength 6. Long Term Muscle Effects of Statins Are 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 PRedIction of Muscular Risk in Observational Conditions or PRIMO 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 Bruckert CV Drugs & Therapy 2005 “Unusual Physical Activity” Exercise & Statin Myopathy Take Home Messages 1. Statins Are Remarkably Effective at Reducing CAD Risk 2. But Can Produce Myopathic (and Possibly Neurological) Side Effects 3. Exercise Causes Many of The CK Elevations Attributed to Statins 4. Exercise Magnifies Statin Myalgia & CK Increases 5. Some Patients Report Weakness, But There is Little Objective Data on Muscle Strength 6. Long Term Muscle Effects of Statins Are 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 CK Elevations After Downhill Walking Thompson et al Metabolism 199 Exercise - Induced CK Elevations Two Men Excluded Because of Marked CK Increases Thompson et al Metabolism 1997 Med Sci Sports Exercise 2009 Study Design • 3 blood draws – CK isoenzymes EXPO: 24 HRS PRE FINISH LINE: POST 24 HOURS POST Study Population • 43 controls – 51 ± 7 yrs – 29 men and 8 women • 37 statin users – 56 ± 8 yrs – 30 men and 13 women Log Transformed CK Response * p = 0.02 CK (Log Base 10 Transformed) 3.4 Statin Control 3.2 3.0 2.8 2.6 2.4 2.2 2.0 Before Finish Line 24 Hour Exercise & Statin Myopathy Take Home Messages 1. Statins Are Remarkably Effective at Reducing CAD Risk 2. But Can Produce Myopathic (and Possibly Neurological) Side Effects 3. Exercise Causes Many of The CK Elevations Attributed to Statins 4. Exercise Magnifies Statin Myalgia & CK Increases 5. Some Patients Report Weakness, But There is Little Objective Data on Muscle Strength 6. Long Term Muscle Effects of Statins Are The Effect of Statins on Skeletal Muscle Function NIH 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 What Causes Statin Myopathy ? I DON’T KNOW 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 and Rho - Cell Maintenance, Growth & Reduced Apoptosis Ras, Rac Coleman 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) 7. Failure to Appropriately Repair Damaged Muscle (Urso …. Thompson ATVB 2005) 8. Vitamin D Deficiency 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 and Rho - Cell Maintenance, Growth & Reduced Apoptosis Ras, Rac Coleman 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) 7. Failure to Appropriately Repair Damaged Muscle (Urso …. Thompson ATVB 2005) 8. Vitamin D Deficiency Coenzyme Q10 in Statin Myopathy 1 RC1 AT005836-01 NIH/NCCAM 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 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 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 and Rho - Cell Maintenance, Growth & Reduced Apoptosis Ras, Rac Coleman 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) 7. Failure to Appropriately Repair Damaged Muscle (Urso …. Thompson ATVB 2005) 8. Vitamin D Deficiency Decreases in Serum Q10 & LDL-C With Statin Therapy 0 -10 -11 -20 -17 -21 LDL-CHO -30 -29 -40 -50 -50 -54 -60 Pravas tatin CoQ10 Simvas tatin Place bo Ghirlanda J Clin Pharmacol 1993 Most (me Marcoff & Thompson, JACC 2007) Attributed the Q10 Decrease to Decreases in LDL/VLDL….But Kawashiri et. al. Clin Pharm & Therapeutics Co Q10 ? • Muscle Biopsies From 132 Patients With “Statin Myopathies” • 50% - Co Q10 Levels - 2-4 SD’s < Normal Vladutiu et al Am C Rheum 2004 Abstract 1784 Is The Reduced Q10 The Cause or The Result of Mitochondrial / Muscle Problems Something Else Could Be Hurting The Muscle, Decreasing Mitochondria Numbers, and Q10 Levels There Are Two Appropriately Designed (& Published) Trials Ubiquinone or Co Enzyme Q10 ? There is No Convincing Evidence Coenzyme Q10 in Statin Myopathy 1 RC1 AT005836-01 NIH/NCCAM 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 and Rho - Cell Maintenance, Growth & Reduced Apoptosis Ras, Rac Coleman 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) 7. Failure to Appropriately Repair Damaged Muscle (Urso …. Thompson ATVB 2005) 8. Vitamin D Deficiency Fat Myopathy ?? Damage to Type 1 Fibers STATIN NO STATIN Patients who experienced muscle symptoms with normal CK levels Statins withdrawn for 3 mo When placebo was used, Symptoms disappeared Stained For Lipid Phillips et al., 2003 Capillary Increased High-Affinity LDL Uptake Decreased LDL Cholesterol ß-hydroxy-ßmethylglutaryl CoA Inhibition of Cholesterol Synthesis Mevalonate Cholesterol HMG-CoA REDUCTASE INHIBITORS 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 and Rho - Cell Maintenance, Growth & Reduced Apoptosis Ras, Rac Coleman 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) 7. Failure to Appropriately Repair Damaged Muscle (Urso …. Thompson ATVB 2005) 8. Vitamin D Deficiency Failure to Repair Damaged Muscle The Ubiquitin Proteosome Pathway (Urso …. Thompson ATVB 2005) Hoffman EP, Nader GA. Nat Med. 2004;10:584-5. Our Gene Expression Studies Also Suggest a Role for Atrogin EXPERIMENTAL DESIGN Exercise Right Leg D1 4 wks D31 8h Statin/ Placebo 8h Biopsy Right & Left Vastus Lateralis Exercise Left Leg Biopsy Right & Left Vastus Lateralis GENE EXPRESSION •GeneChip® Human Genome U133 plus 2.0 array •47,000 transcripts and variants •38,500 genes There Are Few Changes With Statin Treatment & No Exercise, But Lots of Gene Change With Statin & Exercise qRT-PCR ResultsAtrogin-1 FBX032 (Atrogin) Gene Expression 1.6 1.4 1.2 1 0.8 0.6 0.4 0.2 0 1 4 7 Subject PreStatin Exercise Post Statin Exercise Hanai ... Lecker. J. Clin. Invest. 2007 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 and Rho - Cell Maintenance, Growth & Reduced Apoptosis Ras, Rac Coleman 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) 7. Failure to Appropriately Repair Damaged Muscle (Urso …. Thompson ATVB 2005) 8. Vitamin D Deficiency 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 and Rho - Cell Maintenance, Growth & Reduced Apoptosis Ras, Rac Coleman 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) 7. Failure to Appropriately Repair Damaged Muscle (Urso …. Thompson ATVB 2005) 8. Vitamin D Deficiency Exercise & Statin Myopathy Take Home Messages 1. Statins Are Remarkably Effective at Reducing CAD Risk 2. But Can Produce Myopathic (and Possibly Neurological) Side Effects 3. Exercise Causes Many of The CK Elevations Attributed to Statins 4. Exercise Magnifies Statin Myalgia & CK Increases 5. Some Patients Report Weakness, But There is Little Objective Data on Muscle Strength 6. Long Term Muscle Effects of Statins Are Statins and Cognition Pilot Studies of Cognitive Side Effects It All Started With A Case Case Study #1 • 65-year-old Caucasian • On atorvastatin 10 mg/day – Mood alteration, memory difficulties • Cognitive evaluation and fMRI of the brain • On and off (2 months) statin therapy • Significant improvement in cognitive function off statins fMRI Results Neuronal activation during the difficult version of the Sternberg Task, depicted by colored regions on the 3Drendered brains, during encoding (left) and response selection (right) while the subject was on 10 mg atorvastatin (bottom) and 2 months following atorvastatin cessation (top). Pilot Study #2 • fMRI during two tasks – Sternberg Task – Figural Memory Test • 19 adults from 6 month statin study – 14 on atorvastatin and 5 on placebo • Pre-post scans FMRI Results: FIG MEM Figure 2. FMRI activation on 3D-rendered brain showing changes in activation with statin use displayed at p=0.005 uncorrected level during the encoding (left) and recognition (right) phase of the Figural Memory Test. Now…Don’t Get Crazy • I Came Here Not to Bury Statins, But to Praise Them • But We Should Only Use Them When Their is Likely to Be Benefit • And Not Put Them in the Drinking Water • Until We Are Sure There is no Harm Myalgia Treatment ? • • • • • • • • • • Are Symptoms Tolerable? Measure CK Stop Drug Until No SX Try Another Statin Try Lower Doses Plus Minus Ezetimibe Try Another Class of Drug Try Chinese Red Rice Yeast 2 Tabs HS Try Atorva or Rosuva QOD or BIW Use Tonic (Quinine) Water HS for Cramps Do “Pulse Therapy” Use Q10 Supplements Rosuvastatin (5 mg or 10 mg) Twice a Week in Patients Intolerant to Daily Statins Gadarla, Kearns, Thompson: Am J Cardiol 2008 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