Exercise And Statin – Associated Myopathy Paul D. Thompson, MD Director of Cardiology Henry Low Heart Center Hartford Hospital Hartford, CT
Apr 01, 2015
Exercise And Statin – Associated
MyopathyPaul 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 / 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 /
Acetyl CoA
HMG-CoAReductase
Cholesterol
ACAT
CholesterolEsters
BileAcids
Bile
Bile Acids
Cholesterol
FecalExcretion
Low-AffinityVLDL Uptake
High-AffinityUptake
High-AffinityUptake
Low-AffinityUptake
PeripheralCells
FFA
LPL
Capillary
Capillary
IncreasedHigh-AffinityLDL Uptake
Inhibition ofCholesterol Synthesis
ß-hydroxy-ß-methylglutaryl CoA
Mevalonate
Cholesterol
DecreasedLDL Cholesterol
HMG-CoA REDUCTASEINHIBITORS
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
10mg
10mg
10mg
10mg
Adapted from Jones PH et alAm J Cardiol 2003;92:152–160
Change in LDL-C from baseline (%)
0 -10 20 -30 -40 -50 -60-5 -15 -25 -35 -45 -55
rosuvastatin
atorvastatin
simvastatin
pravastatin
40mg
40mg
40mg
40mg
20mg
20mg
20mg
20mg
80 mg
80mg
P<0.002 vs CRESTOR 10 mg
P<0.002 vs CRESTOR 20 mg
P<0.002 vs CRESTOR 40 mg
LDL-C Reductions with Different Statin LDL-C Reductions with Different Statin StrategiesStrategies
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
Am J Cardiol 1997;79:38-42
% c
hang
e fr
om b
asel
ine
(med
ian)
TotalCholesterol
LDLCholesterol
HDLCholesterol
Triglycerides
10
0
-10
-20
-30
-40
-50
-60
+6 +7 +8
-30-35
-40 -41-47
-53
-21 -23
-33
N=156
Simvastatin 40mg
Simvastatin 80mg
Simvastatin 100mg
Third Principle of Lipid Drug Management
Start a Statin
They Have Incredible Outcome DATA
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.
15 20 25 30 35 40
–20
0
20
40
60
80
100
LDL-C reduction, %
No
nfa
tal
MI
and
CH
D d
eath
re
lati
ve r
isk
red
uct
ion
, %
4S CARDSPOSCH ASCOT-LLANHLBI PROSPERLRC ALERTUpjohn HPSLos Angeles AF/TexCAPSMRC LIPIDOslo CARELondon WOSCOPS
Statins Lower Risk - Even if the Risk Factor is Not LDL-
Cholesterol
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 Increases5. Some Patients Report Weakness, But There is
Little Objective Data on Muscle Strength6. Long Term Muscle Effects of Statins Are
Unknown
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 Increases5. Some Patients Report Weakness, But There is
Little Objective Data on Muscle Strength6. Long Term Muscle Effects of Statins Are
Unknown
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 Increases5. Some Patients Report Weakness, But There is
Little Objective Data on Muscle Strength6. Long Term Muscle Effects of Statins Are
Unknown
Exercise ALONE Can Produce Remarkable CK
IncreasesSo 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.
Thompson, et al Med & Science in Sports & Exercise. 2004: 36: 1132-1139.
NIHNIH RO1-NS40606-01A1RO1-NS40606-01A1
0
1000
2000
3000
4000
5000
6000
1 2 3 4 5Day
Pla
sma
Cre
atin
e K
inas
e (U
/L) Subj 1 Subj 2
Subj 3 Subj 4Subj 5 Subj 6Subj 7 Subj 8Subj 9 Subj 10
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 Increases5. Some Patients Report Weakness, But There is
Little Objective Data on Muscle Strength6. Long Term Muscle Effects of Statins Are
Unknown
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
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
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 Increases5. Some Patients Report Weakness, But There is
Little Objective Data on Muscle Strength6. Long Term Muscle Effects of Statins Are
Unknown
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
Thompson et al Metabolism 1997
CK Elevations After Downhill Walking
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
Before Finish Line 24 Hour
CK
(L
og
Bas
e 10
Tra
nsf
orm
ed)
2.0
2.2
2.4
2.6
2.8
3.0
3.2
3.4Statin Control
* p = 0.02
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 Increases5. Some Patients Report Weakness, But There is
Little Objective Data on Muscle Strength6. Long Term Muscle Effects of Statins Are
Unknown
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 Cholesterol2. Reduced T-Tubule & Sarcoplamic Recticulum
Cholesterol Draeger JPath 2006
3. Reduced Isoprenoids: Ubiquinone - Co-enzy Q104. Reduced Prenylation of GTP Binding Proteins - Ras, Rac and
Rho - Cell Maintenance, Growth & Reduced Apoptosis 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 9. Inflammation (Inflammatory Myopathy)
Possible Mechanisms of Statin Induced Muscle Injury
1. Reduced Sarcolemmal Cholesterol2. Reduced T-Tubule & Sarcoplamic Recticulum
Cholesterol Draeger JPath 2006
3. Reduced Isoprenoids: Ubiquinone - Co-enzy Q104. Reduced Prenylation of GTP Binding Proteins - Ras, Rac and
Rho - Cell Maintenance, Growth & Reduced Apoptosis 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 9. Inflammation (Inflammatory Myopathy)
Coenzyme Q10 in Statin Myopathy
1 RC1 AT005836-01 NIH/NCCAM
Run-In: Initial – Simvastatin Simvastatin 20 mg for 8 weeks or Until Symptoms Persist for 1 Week or are Intolerable
100 Subjects Symptomatic on Statins Only: Baseline Strength and Exercise Performance Testing, Accelerometer, Pain Questionnaire
Randomization to Treatment: Placebo or 600 mg CoQ10Load Subjects for 2 weeks on Treatment
Simvastatin 20mg + Placebo (N=50) Simvastatin 20mg + CoQ10 (N=50)
4 week washout
At 8 Weeks or Until Symptoms Persist 1 Week or are Intolerable: Strength and Exercise Performance Testing, Accelerometer, Pain Questionnaire
Run-In: Initial - PlaceboPlacebo for 8 Weeks or Until Symptoms Persist for 1 Week or are Intolerable
4 week washout
Run-In: Initial - PlaceboPlacebo 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
Weekly phone calls: Pain Questionnaires used to assess muscle symptoms and document myalgia
135 Subjects with Prior Statin Complaints
Total & LDL Reductions Were Greatest in “True
Myalgics”
D-C Morales, B Parker, L Lorson, D Polk, PD Thompson. ACC 2011
True = 12Non = 19
Possible Mechanisms of Statin Induced Muscle Injury
1. Reduced Sarcolemmal Cholesterol2. Reduced T-Tubule & Sarcoplamic Recticulum
Cholesterol Draeger JPath 2006
3. Reduced Isoprenoids: Ubiquinone - Co-enzy Q104. Reduced Prenylation of GTP Binding Proteins - Ras, Rac and
Rho - Cell Maintenance, Growth & Reduced Apoptosis 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 9. Inflammation (Inflammatory Myopathy)
Decreases in Serum Q10 & LDL-C With Statin Therapy
-17
-54-50
-11
-29
-21
-60
-50
-40
-30
-20
-10
0
Pravastatin Simvastatin Placebo
CoQ10
LDL-CHO
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
ProblemsSomething 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 Cholesterol2. Reduced T-Tubule & Sarcoplamic Recticulum
Cholesterol Draeger JPath 2006
3. Reduced Isoprenoids: Ubiquinone - Co-enzy Q104. Reduced Prenylation of GTP Binding Proteins - Ras, Rac and
Rho - Cell Maintenance, Growth & Reduced Apoptosis 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 9. Inflammation (Inflammatory Myopathy)
Fat Myopathy ??
Damage to Type 1 Fibers
Phillips et al., 2003
Patients who experienced muscle symptoms withnormal CK levels
Statins withdrawn for 3 mo
When placebo was used,Symptoms disappeared
Stained For Lipid
STATIN NO STATIN
Capillary
IncreasedHigh-AffinityLDL Uptake
Inhibition ofCholesterol Synthesis
ß-hydroxy-ß-methylglutaryl CoA
Mevalonate
Cholesterol
DecreasedLDL Cholesterol
HMG-CoA REDUCTASEINHIBITORS
Possible Mechanisms of Statin Induced Muscle Injury
1. Reduced Sarcolemmal Cholesterol2. Reduced T-Tubule & Sarcoplamic Recticulum
Cholesterol Draeger JPath 2006
3. Reduced Isoprenoids: Ubiquinone - Co-enzy Q104. Reduced Prenylation of GTP Binding Proteins - Ras, Rac and
Rho - Cell Maintenance, Growth & Reduced Apoptosis 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 9. Inflammation (Inflammatory Myopathy)
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
4 wks4 wks
8h8h 8h8hStatin/ Statin/ PlaceboPlaceboStatin/ Statin/
PlaceboPlacebo
EXPERIMENTAL DESIGN
ExerciseRightLeg
BiopsyRight & Left
Vastus Lateralis
ExerciseLeftLeg
BiopsyRight & Left
Vastus Lateralis
D1 D31
GENE EXPRESSION
•GeneChip®
Human Genome U133plus 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 Results- Atrogin-1FBX032 (Atrogin) Gene Expression
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
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 Cholesterol2. Reduced T-Tubule & Sarcoplamic Recticulum
Cholesterol Draeger JPath 2006
3. Reduced Isoprenoids: Ubiquinone - Co-enzy Q104. Reduced Prenylation of GTP Binding Proteins - Ras, Rac and
Rho - Cell Maintenance, Growth & Reduced Apoptosis 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 9. Inflammation (Inflammatory Myopathy)
Possible Mechanisms of Statin Induced Muscle Injury
1. Reduced Sarcolemmal Cholesterol2. Reduced T-Tubule & Sarcoplamic Recticulum
Cholesterol Draeger JPath 2006
3. Reduced Isoprenoids: Ubiquinone - Co-enzy Q104. Reduced Prenylation of GTP Binding Proteins - Ras, Rac and
Rho - Cell Maintenance, Growth & Reduced Apoptosis 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 9. Inflammation (Inflammatory 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 Increases5. Some Patients Report Weakness, But There is
Little Objective Data on Muscle Strength6. Long Term Muscle Effects of Statins Are
Unknown
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 3D-rendered 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
Hoffman