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Effect of Statins on Exercise Performance
Paul D. Thompson, MDDirector 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) Taylor, Jeff
Capizzi, Amanda Augieri, William Roman, Lindsay Lorson, 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
Conflicts of Interest
• Research Support: NHLBI, NIAMS, NCCAM,Genomas, Roche, Sanolfi, Regeneron, Esperion, Amarin and Pfizer.
• Consultant: Amgen, Astra Zenica, Regeneron, Merck , Genomas, Runners World, Sanolfi, Esperion, Amarin, Novartis
• Speaker Honoraria: Merck, Pfizer, Abbott, Astra Zenica, GlaxoSmithKline
• Stock Shareholder: Abbvie, Abbott Labs, J&J; General Electric, JA Wiley
Exercise & Statins Take Home Messages
1. Exercise Magnifies “Statin” Myalgia2. Exercise Causes & Magnifies Many of The
CK Elevations Attributed to Statins 3. Some Patients Report Weakness, But
There is Little Objective Data on Muscle in Asymptomatic Patients
4. Statins Appear to Block the Aerobic Training Response
5. Long Term Muscle Effects of Statins Are Not Defined
Exercise & Statins Take Home Messages
1. Exercise Magnifies “Statin” Myalgia
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
Bruckert CV Drugs & Therapy 2005
PRIMO Study• 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 & Statins Take Home Messages
1. Exercise Magnifies “Statin” Myalgia2. Exercise Causes & Magnifies Many of The
CK Elevations Attributed to Statins
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.
Thompson, et al Med & Science in Sports & Exercise. 2004: 36: 1132-1139.
NIH RO1-NS40606-01A1
10 Men
• Performed 45 Minutes Of Non-Dominant Arm Exercises
• Standing Curls, Preacher Curls, Triceps Extensions
• On Days 1 & 3• CK’s Obtained on Daily For 5 Days
0
1000
2000
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5000
6000
1 2 3 4 5Day
Plas
ma
Cre
atin
e K
inas
e (U
/L)
Subj 1 Subj 2Subj 3 Subj 4Subj 5 Subj 6Subj 7 Subj 8Subj 9 Subj 10
Bilbie SM, Seip RL, Bilbie CL, Clarkson, PM, Thompson, PD. Submitted.
Exercise - Induced CK Elevations With Statins
• 59 Men Aged 18-65• LDL > 130 mg/dl• Randomly to Placebo or Lova 40 mg• 5 Weeks of Treatment• At 4 Weeks: Maximal EXT, Downhill
Walking at 65% HR for 3 X 15 Min Bouts• At 5 Weeks: Biceps 1 RM, Then 4 X 10
Curls @ 50%Thompson et al Metabolism 1997
Thompson et al Metabolism 199
CK Elevations After Downhill Walking
Exercise - Induced CK Elevations -
Two Men Excluded Because of Marked CK Increases
Thompson et al Metabolism 1997
Thompson et al Metabolism 1997
CK Elevations After Eccentric Biceps Curls
0
100
200
300
400
Screen PreExerciseon Meds
24h 48h 72h 96h
Cre
atin
e K
inas
e (U
/L)
10 mg80 mg
Atorvastatin 10mg, n=42: 80 mg, n=37, 1 Month of Treatment1
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 & 13 Women
Am J Cardiol 2012;109:282–287
Exercise & Statins Take Home Messages
1. Exercise Magnifies “Statin” Myalgia2. Exercise Causes & Magnifies Many of The CK
Elevations Attributed to Statins 3. Some Patients Report Weakness, But There is
Little Objective Data on Muscle Strength
Weakness is Not An Uncommon Complaint…Complaints of
Decreased Exercise Tolerance Are Uncommon
Very Few Statin Studies Have Examined Exercise Performance or
Muscle Strength
A Systematic Review of Statin-Induced Muscle Problems in Clinical Trials
Identified 1012 Reports on Statin Trials - 42 Qualified for Analysis
4 Reported Average CK 26 Reported Muscle ProblemsOnly 1 Queried For Muscle Problems All Studies: Muscle Problems on Statin
(12.7%) vs Placebo (12.4%) (p=0.06).
Ganga, Slim, Thompson. Am H J (in press)
Don’t Ask….Don’t Tell
Current Opinion in Lipidology 2010
• 6 Studies Examined Statins & Muscle Strength
• 9 Studies Examined Statins & Exercise Tolerance
• Studies Were Small & Used Crude Measues• Insufficient Data to Determine if Statins
Affect Strength and Exercise Performance
Tasmanian Older Adults Cohort Study
Prospective Cohort Design Statins in 402 men, 372 women, Aged 50–79
Statin Users at 2.6 yr Had Lower Leg Strength
Strength in Users was Decreased vs StoppersSuggests Statins Decrease Strength in Older
Subjects Decrease is Reversible with Statin Cessation
Scott D, Blizzard L, Fell J, Jones G. QJM 2009; 102:625–633
The STOMP StudyThe Effect of STatins On Skeletal
Muscle PerformanceNHLBI (NIH): R01HL081893
STOMP Recruitment Sites
• Hartford Hospital:– PI: Paul D. Thompson, MD
• University of Connecticut (Storrs):– PI: Linda Pescatello, PhD
• University of Massachusetts (Amherst):– PI: Pricilla Clarkson, PhD
Experimental Design
• Subjects (n=440)– Men and women– >20 yr– No prior statin use
• Design– Randomized, double blind
• 80 mg dose of Atorva or placebo for six months
• Muscle function– Handgrip strength– Elbow flexor/extensor– Knee flexor/extensor
• Aerobic performance (VO2Max)
• Physical activity (accelerometer)
• Muscle symptoms
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
Study Definition of Statin-Related Myopathy
1. They report new or increased myalgia, cramps, or muscle aching,
2. These symptoms have persisted for at least 2 weeks,
3. The symptoms resolve within 2 weeks of stopping the study drug, and
4. The symptoms reoccur within 4 weeks of restarting the medication
STOMP Myalgia Results
23 Atorva & 14 Placebo Developed Pain X2=3.16; p = 0.08
19 Atorva & 10 Placebo Met Myalgia DefinitionX2=3.74; p = 0.05
There Were No Differences in
Maximal Exercise Capacity or
Handgrip, Arm or Leg Strength
Between the Atorva & Placebo
Groups With 6 Mos of Therapy
Average CK Increased 20.8±141.1 U/L (P<0.0001) with
Atorvastatin
Spontaneous Physical Activity
Decreased in The >55 Year
Group
Statins and Physical Activity in Older Men: The Osteoporotic Fractures in Men
Study
Lee et al Arch IM
1,801 Non Users1,195 New Users1,801 Users
Exercise & Statins Take Home Messages
1. Exercise Magnifies “Statin” Myalgia2. Exercise Causes & Magnifies Many of The
CK Elevations Attributed to Statins 3. Some Patients Report Weakness, But
There is Little Objective Data on Muscle Strength in Asymptomatic Patients
4. Statins Appear to Block the Aerobic Training Response
JACC 2013
• Overweight Adults With 2 Metabolic Risk Factors• 12 wks Exercise Training With (18) / Wo (19)
Simvastatin (40)• VO2 Increased 10% Wo Statin; 1.5% With Statin• Citrate Synthase Increased 13% Wo & Decreased
by 4.5% With Statin
Exercise & Statins Take Home Messages
1. Exercise Magnifies “Statin” Myalgia2. Exercise Causes & Magnifies Many of The
CK Elevations Attributed to Statins 3. Some Patients Report Weakness, But
There is Little Objective Data on Muscle Strength in Asymptomatic Patients
4. Statins Appear to Block the Aerobic Training Response
5. Long Term Muscle Effects of Statins Are Unknown
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)
• Glycine Amidinotransferase• Rate Limiting Enzyme in
Creatine Synthesis• Less Creatine = Less
Rhabdo with Statins
Ballard & Thompson – Cell Metab Previews 2013
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)
Hoffman EP, Nader GA. Nat Med. 2004;10:584-5.
Atrogin 1 Background #1Hanai ... Lecker. J. Clin. Invest. 2007
• Ubiquitin Proteosome Pathway Breaks Down Skeletal Muscle
• Ubiquitin Protein Ligase E3 or Atrogin 1 (AT-1)
• AT-1 Increases in Failing Hearts, PP Uteri
4 wks
8h 8hStatin/ PlaceboStatin/
Placebo
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
C a t e g o ry P r o b e S e t ID F o ld p - V a lu e G e n e T i t le G e n e S y m b o l
S ig n a l in g H o r m o n e M e d ia te d 2 0 6 4 0 4 _ a t 2 .3 4 0 .0 1 f ib r o b la s t g r o w th fa c to r 9 F G F 9
G T P 2 1 4 3 5 2 _ s _ a t 1 .9 7 0 .0 0 K i r s te n r a t s a r c o m a 2 v i r a l o n c o g e n e h o m o lo g K R A S 2
2 1 2 5 8 9 _ a t 1 .7 8 0 .0 0 r e la te d R A S v ir a l ( r - ra s ) o n c o g e n e h o m o lo g 2 R R A S 2
2 1 1 6 6 5 _ s _ a t - 1 .7 6 0 .0 1 s o n o f s e v e n le s s h o m o lo g 2 ( D r o s o p h ila ) S O S 2
P r o te in K in a s e 2 1 4 9 7 8 _ s _ a t 2 .1 5 0 .0 0 p r o te in ty r o s in e p h o s p h a ta s e P P F IA 4
2 1 2 1 8 1 _ s _ a t 2 .0 2 0 .0 0 n u d ix - ty p e m o t i f 4 N U D T 4
2 0 2 3 5 1 _ a t 1 .8 1 0 .0 0 in te g r in , a lp h a V IT G A V
2 0 4 8 3 1 _ a t 1 .6 0 0 .0 0 c y c l in -d e p e n d e n t k in a s e 8 C D K 8
2 2 8 5 5 5 _ a t 1 .4 5 0 .0 1 c a lm o d u lin -d e p e n d e n t p r o te in k in a s e C A M K 2 D
2 2 6 0 4 6 _ a t - 1 .8 9 0 .0 0 m i to g e n - a c tiv a te d p r o te in k in a s e 8 M A P K 8
T r a n s c r ip t io n 2 3 8 3 2 4 _ a t 3 3 .4 2 0 .0 0 p 6 6 A lp h a p 6 6 a lp h a
P ro t e o ly s is , U b iq u it in a t io n 2 3 8 6 8 6 _ a t 3 .2 4 0 .0 0 F - b o x o n ly p r o te in 3 F B X O 3
2 3 0 6 2 3 _ x _ a t 1 .5 2 0 .0 1 u b iq u i t in s p e c i f i c p r o te a s e 2 8 U S P 2 8
2 0 3 1 0 9 _ a t 1 .4 7 0 .0 1 u b iq u i t in - c o n ju g a t in g e n z y m e E 2 M ( U B C 1 2 ) U B E 2 M
2 1 3 2 7 5 _ x _ a t 1 .3 2 0 .0 2 c a th e p s in B C T S B
2 4 2 3 4 9 _ a t 1 .3 2 0 .0 2 H E C T d o m a in - 1 H E C T D 1
2 2 5 1 3 2 _ a t 1 .3 1 0 .0 2 F - b o x p r o te in 3 A F B X L 3 A
2 0 1 6 4 9 _ a t 1 .2 9 0 .0 3 u b iq u i t in - c o n ju g a tin g e n z y m e E 2 L 6 U B E 2 L 6
2 0 2 3 3 5 _ s _ a t 1 .1 9 0 .0 9 u b iq u i t in - c o n ju g a tin g e n z y m e E 2 B U B E 2 B
2 1 2 2 1 9 _ a t 1 .1 7 0 .0 9 p r o te a s o m e a c t iv a to r s u b u n i t 4 P S M E 4
2 0 8 7 7 6 _ a t 1 .1 6 0 .0 9 p r o te a s o m e 2 6 S s u b u n i t1 1 P S M D 1 1
2 0 8 5 9 8 _ s _ a t - 1 .2 3 0 .0 6 u p s t r e a m r e g u la to r y e le m e n t b in d in g p r o te in 1 U R E B 1
2 2 0 3 7 0 _ s _ a t - 1 .3 0 0 .0 6 u b iq u i t in s p e c i f i c p r o te a s e 3 6 U S P 3 6
2 0 3 1 1 7 _ s _ a t - 1 .3 1 0 .0 5 u b iq u i t in s p e c i f i c p r o te a s e 5 2 U S P 5 2
2 0 9 4 5 6 _ s _ a t - 1 .3 2 0 .0 3 F - b o x a n d W D - 4 0 d o m a in p r o te in 1 B F B X W 1 B
1 5 5 4 4 2 3 _ a _ a t - 1 .4 0 0 .0 1 F - b o x o n ly p r o te in 7 F B X O 7
2 0 3 8 7 1 _ a t - 1 .4 6 0 .0 1 S M T 3 s p e c i f i c p r o te a s e 3 S E N P 3
2 0 1 0 0 1 _ s _ a t - 1 .5 2 0 .0 1 u b iq u i t in - c o n ju g a tin g e n z y m e E 2 v a r ia n t 1 U B E 2 V 1
2 4 1 7 6 2 _ a t - 6 .8 5 0 .0 0 F - b o x o n ly p r o t e in 3 2 ( A t r o g in ) F B X O 3 2
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 Urso et al ATVB2006
Hanai ... Lecker. J. Clin. Invest. 2007
Do Statins Cause Diabetes ?
• Jupiter Trial - 20 of Rosuva v. Placebo• CRP > 2….in 17,603 Subjects• Among Those with Diabetes Risk Factors
(Metabolic S, Fasting Glucose > 100, BMI > 30, A1c > 6)…Risk Increased 25% (5-49%)
• New Diabetics: 270 v 216….54 More New Diabetics• But…39% < CV Events, 36% < VTE, 18% < Deaths
!!!!• 134 < CV Events vs 54 New Diabetics in 17,603
Subjects• If No DM Risk Factors, No New Diabetes
Lancet 380: 565, 2012
Jupiter is not the First or Last
Why Diabetes ?
Something Is Going On In the Muscle
Statins Decrease P13k / AktIncreasing the Forkhead Box Gene Group (FOXO)FOXO Increases the 2 Muscle SpecificUbiquitin E3 Ligases
Mu Atrophy F Box (MAFbx)Mu RING Finger –1 (MURF-1)
They Conjugate to Protein SubstrateInitiating Protein Degradation
FOXO Also Activates Pyruvate Dehydrogenase Kinase (PDK) TranscriptionUpregulating PDK Inactivates Muscle Pyruvate Dehydrogenase Complex.Which Limits CHO & Promotes Fat Oxidation.
Exercise & Statins Take Home Messages
1. Exercise Magnifies “Statin” Myalgia2. Exercise Causes & Magnifies Many of The
CK Elevations Attributed to Statins 3. Some Patients Report Weakness, But
There is Little Objective Data on Muscle in Asymptomatic Patients
4. Statins Appear to Block the Aerobic Training Response
5. Long Term Muscle Effects of Statins Are
Can Statins Cause Tendonopathy ?
Tenocytes Degrade Type I Collagen to Repair Tendons
Using Matrix Metalproteinases (MMP) 2 & 9Statins Reduce MMP – 9 mRNA
Am J Cardiol 2007;100:152–153
Thank You
Paul D. Thompson, MDChief of CardiologyHartford Hospital
Hartford, CT