Exercise And Statin – Associated Myopathy Paul D. Thompson, MD Director of Cardiology Henry Low...

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

CholesterolEsters

BileAcids

Bile Acids

Cholesterol

FecalExcretion

Low-AffinityVLDL Uptake

High-AffinityUptake

Low-AffinityUptake

PeripheralCells

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

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

P<0.002 vs CRESTOR 10 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

TotalCholesterol

LDLCholesterol

HDLCholesterol

Triglycerides

+6 +7 +8

-30-35

-40 -41-47

-21 -23

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

LDL-C reduction, %

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

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

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

1 2 3 4 5Day

/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.

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

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

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

3.4Statin Control

* p = 0.02

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

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

Decreases in Serum Q10 & LDL-C With Statin Therapy

-54-50

Pravastatin Simvastatin Placebo

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

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

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

Subject

PreStatin Exercise Post Statin Exercise

Hanai ... Lecker. J. Clin. Invest. 2007

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

Exercise And Statin – Associated Myopathy Paul D. Thompson, MD Director of Cardiology Henry Low...

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