Transcript consensus - University of Connecticut

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