effect of statins on exercise performance · effect of statins on exercise performance paul d....

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

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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

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24h 48h 72h 96h

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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

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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