STATINS AND
EXERCISE: THE
COMBINED EFFECT…
Christopher Paul Mckneely
2014 Doctor of Pharmacy Candidate
Preceptor: Dr. Ali Rahimi
Lets get our bearings:
• Dyslipidemia
• Statins
• Exercise
• Studies that may or may not be surprising
• Conclusion
Dyslipidemia:
Introduction1:
• Cholesterol, triglycerides, and phospholipids are the major
lipids in the body
• Transported in body as complexes of lipids and proteins
• Lipoproteins
• 3 major classes of lipoproteins
• LDL
• Is the major cholesterol transport lipoprotein
• HDL
• VLDL
• Dyslipidemia defined as elevation of total cholesterol,
elevation of LDL, elevation in triglycerides or low HDL, or
any combo of the above
• Based on AHA
Introduction
continued1:
• 46.8% or 10.2 million American
adults over age 20 years have total
cholesterol levels of 200 mg/dL or
higher.
• Abnormalities of plasma lipoproteins
can result in a predisposition to
coronary, cerebrovascular, and
peripheral vascular arterial disease and
constitutes one of the major risk
factors for coronary heart disease
(CHD)
• Evidence over the last decades
linked elevated total cholesterol and
LDL and decreased HDL to
development of CHD
Risk Factors:
Positive
• Age
• Male >45, female >55
• Family history
• Premature CHD in 1st degree
relative
• Male <55, female <65
• Smoking status
• HTN (>140/90 or on anti-
HTN meds)
• Low HDL (<40)
Negative
• High HDL (>60)
Metabolic Syndrome8:
• Cluster of inter-related factors
• Insulin resistance
• Central adiposity
• HTN
• Dyslipidemia
• All associated with increased risk of cardiovascular
disease, stroke, DM II, and premature death
• Currently 70% of adults are overweight or obese in the
U.S.A.
• 98% of these pts do not meet current physical activity guidelines
• Estimated 23% have metabolic syndrome
Goals2:
http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3_rpt.htm
Cholesterol Metabolism:
In vivo:
Acetyl CoA
HMG-CoA
HMG-CoA reductase
Mevalonate
Cholesterol
Treatment2:
TLC
• Therapeutic lifestyle
Pharmacologic
•
Statins (HMG-CoA Reductase Inhibitors)
•
•
•
changes
• Exercise
•
• 30 minutes per day/most days
of the week
•
• decreased intake of saturated
fat and total cholesterol;
increased soluble fiber intake;
plant stanols/sterols (veggies,
fruits, nuts, and/or seeds)
Fibrates
•
• Diet
•
•
•
• Smoking cessation
•
MOA: decreases LDL and VLDL synthesis
decrease LDL 5-25% and TG by 20-50%, HDL increase
by 15-35%
Bile Acid Sequestrants
•
• Weight reduction
MOA: decreases VLDL synthesis & increases VLDL
clearance
LDL decrease by 5-20%, TG 20-50%, HDL increase by
10-20%
Niacin
•
•
•
First line
MOA
LDL reduction of 18-60%, TG reduction of 7-30%, HDL
increase 5-15%
atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin
(Mevacor), pitavastatin (Livalo), pravastatin* (Pravachol),
simvastatin (Zocor), rosuvastatin (Crestor)
MOA: increase LDL catabolism and decrease cholesterol
absorption
Decease LDL by 15-30%, increase HDL by 3-5%, may
increase TGs
Ezetimibe (Zetia) (waste of money?)
•
•
MOA: blocks absorption of dietary cholesterol across the
brush border of the intestine
decrease LDL by18% and TG $8%
Statins MOA:
In vivo:
Acetyl CoA
HMG-CoA
HMG-CoA reductase
Mevalonate
Cholesterol
Statin Side Effects:
• Most reported effect
• Muscle pain and weakness
• Others
• Skeletal muscle cramping
• Pain
• Myalgia
• Rhabdomyolysis
• In rare cases
• All of these, if experienced in the patient, can reduce the quality
of life, limit the patients physical activity and more importantly
can affect medication compliance
• Has been found that the only way to treat statin-induced
myopathy is the discontinuation of statin use in the affected
individual9
• Shown to be reversible
Exercise4:
• Regular exercise helps improve your overall health and
fitness and reduces your risk for many chronic diseases
• Adults age 18-64
• 2 hours and 30 minutes (150 minutes) of moderate-intensity aerobic
activity (i.e., brisk walking) every week and muscle-strengthening
activities on 2 or more days a week that work all major muscle groups
(legs, hips, back, abdomen, chest, shoulders, and arms).
OR
• 1 hour and 15 minutes (75 minutes) of vigorous-intensity aerobic
activity (i.e., jogging or running) every week and muscle-strengthening
activities on 2 or more days a week that work all major muscle groups
(legs, hips, back, abdomen, chest, shoulders, and arms).
OR
• An equivalent mix of moderate- and vigorous-intensity aerobic activity
and muscle-strengthening activities on 2 or more days a week that
work all major muscle groups (legs, hips, back, abdomen,
chest, shoulders, and arms).
Statins and Exercise:
The Evidence
Disclaimer: Very limited amount of data
actually exists in clinical trials of the
combined effect
Interactive Effects of Fitness and Statin
Treatment on Mortality risk in Veterans with
Dyslipidaemia[sic]: a Cohort Study6:
• Looked at health benefits of fitness and statin treatment
• Dyslipidemic veterans from Veterans Affairs Medical Centers
in Palo Alto, Ca and Washington DC
• Pts had exercise tolerance test (stress test) between 1986 and 2011
• Symptom limited
• 20,000+ veterans
• Prospective cohort study
• Divided up into 4 arms based on metabolic equivalents
(MET) and eight arms based off of fitness status and statin
treatment
• Fitness arms based off of MET
• Least fit group was the “control”
• Statin groups – received statin or did not receive statin
• Those who did not receive statins were the “control”
Interactive Effects of Fitness and Statin
Treatment on Mortality risk in Veterans
with Dyslipidaemia[sic]: a Cohort Study6:
• Duration of statin treatment was based on first
and last date that statins were prescribed for
each patient
• Exercise capacity was assessed (pts exercised
until volitional fatigue)
• Standard treadmill via Bruce Protocol (Washington DC)
• Individualized ramp protocol (Palo Alto, Ca)
• Primary end point
• Death from any cause
Interactive Effects of
Fitness and
Statin…Cohort
Study6:
“Muscle
complaints
caused by statin
treatment affect
25% of statin
users, but can
be easily
dismissed by
the doctor and
the patient”
Results:
• Supports the notion that both statin
treatment and increased fitness lower
mortality and independently from other
clinical characteristics
• Suggest that statin treatment combined
with moderate fitness offers additional
protection against premature mortality in
individuals with dyslipidemia
• Absence of either or both  significantly
increases the risk of mortality
Atorvastatin Treatment Reduces Exercise
Capacities in Rats: Involvement of Mitochondrial
Impairments and Oxidative Stress7:
• “Demonstrated that atorvastatin treatment in rats
decreased exercise capacities and muscular glycogen
content, exacerbated muscular oxidative stress, and
inhibited activation of mitochondrial respiration after
exhaustive exercise.”
• Materials and Methods
• Adult male Wistar rats
• Atorvastatin active drug
• Treadmill exercise
• TC, HDL, and CPK
• Study of muscle mitochondrial respiration
• ROS measurements via dihydroethidium staining
Atorvastatin
Treatment
Reduces
Exercise…Oxid
ative Stress7:
4 Treatment
arms:
1. Resting
control
(CONT)
2. Exercise
(CONT +
EXE)
3. Resting
(ATO)
4. Exercise
(ATO + EXE)
• Results:
• Atorvastatin treatment decreased
endurance capacities
• Treadmill exercise
• P<0.05
• Oxidative stress was increased in
the glycolytic plantaris muscle
after atorvastatin treatment
• ROS increased by %60 in the ATO
group v CONT
• ATO + EXE increased by %110 v ATO
and %226 in the ATO + EXE v CONT
+ EXE
• Atorvastatin impaired
mitochondrial function in the
glycolytic plantaris muscle
Results continued7:
Simvastatin Impairs Exercise Training
Adaptions8
• Statins are poorly tolerated among elite athletes and can
increase susceptibility to muscle damage during exercise
• Shown to reduce mitochondrial content and oxidative capacity
in humans
• This was a randomized control trial designed to compare the
effects of exercise training to those of simvastatin in
combination with exercise on changes in cardiorespiratory
fitness and skeletal muscle citrate synthase activity
• Blocked randomized design
• 12 week supervised aerobic exercise training program or exercise with
combination with daily simvastatin use (40mg)
• Participants
• 25-59 years of age
• BMI (26-39)
• Sedentary
• Weight stable
• Had at least 2 of 5 metabolic syndrome risk factors
Simvastatin Impairs Exercise Training
Adaptions8
• Assessments at baseline and 12 week interventions
• Biopsies were obtained from the vastus lateralis muscle
using the modified Bergstrom needle technique
• Citrate synthase was measured
• Quantification of mitochondrial oxidative phosphorylation proteins
was also determined by immunoblotting
• Expired gases were analyzed by a metabolic cart during a
ramped treadmill test (Bruce Protocol) to determine
cardiorespiratory fitness
• The effects of time (baseline v post-intervention),
treatment (exercise v exercise + treatment) and time by
treatment interactions (between group differences) was
measured by ANOVA
Results8:
• Effects of intervention on cardiorespiratory fitness
• Increased significantly in response to exercise training alone but
not in response to exercise plus statin
• P<0.005
• Indicates that simvastatin significantly attenuated exercise-
mediated increases in cardiorespiratory fitness
• Effects of intervention on skeletal muscle citrate synthase
activity
• Simvastatin prevented exercise training induced increases in
skeletal muscle citrate synthase activity
• Increased by 13% in the exercise group
• Decreased by 4.5% in the exercise + statin group
• Similar results stood for the mitochondrial complexes
Discussion
• During exercise
• Skeletal muscle energy flux and mitochondrial respiration
are increased  needed for ATP  muscle contractions
• Exercise also increases mitochondrial numbers
(biogenesis)
• Also increases mitochondrial oxidative capacity
• All these lead to greater capacity for skeletal muscle
oxygen consumption  key components for improvements
in cardiorespiratory fitness
• Simvastatin was found to disrupt mitochondrial respiration,
increase oxidative stress, and activate mitochondrial
apoptotic pathways in isolated skeletal muscle fibers
CONCLUSIONS…
References
• 1. Talbert R.L. (2011). Chapter 28. Dyslipidemia. In J.T. DiPiro, R.L. Talbert, G.C. Yee, G.R.
•
•
•
•
Matzke, B.G. Wells, L.M. Posey (Eds), Pharmacotherapy: A Pathophysiologic Approach, 8e.
Retrieved June 4, 2013 from http://www.accesspharmacy.com/content.aspx?aID=7974214.
2. . National Cholesterol Education Program Expert Panel on Detection Evaluation and Treatment
of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National
Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of
High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation
2002;106:3143–421.
3. Maria L. Urso, Priscilla M. Clarkson, Dustin Hittel, Eric P. Hoffman and Paul D. Thompson.
Changes in Ubiquitin Proteasome Pathway Gene Expression in Skeletal Muscle with Exercise
and Statins. Arteriosclerosis, Thrombosis, and Vascular Biology. 2005; 25: 2560-2566. Accessed
on 6/2/13. http://atvb.ahajournals.org/content/25/12/2560.full.pdf+html
4. Centers for Disease Control and Prevention. Physical Activity: How much physical activity do
Adults Need?. Last updated December 1, 2011. Accessed on 6/3/13.
http://www.cdc.gov/physicalactivity/everyone/guidelines/adults.html.
5. Peter F Kokkinos, PhD, Charles Faselis, MD, Jonathan Myers, PhD, Demosthenes
Panagiotakos, PhD, Michael Doumas, MDInteractive effects of fitness and statin treatment on
mortality risk in veterans with dyslipidaemia: a cohort studyThe Lancet, Volume 381, Issue 9864,
2–8 February 2013, Pages 394–399http://dx.doi.org.proxy.mercer.edu/10.1016/S01406736(12)61426-3
References
• 6. Peter F Kokkinos, PhD, Charles Faselis, MD, Jonathan Myers, PhD,
Demosthenes Panagiotakos, PhD, Michael Doumas, MD. Interactive effects of
fitness and statin treatment on mortality risk in veterans with dyslipidaemia: a
cohort study. The Lancet, Volume 381, Issue 9864, 2–8 February 2013, Pages
394–399http://dx.doi.org.proxy.mercer.edu/10.1016/S0140-6736(12)61426-3
• 7. Jamal Bouitbir, Anne-Laure Charles, Laurence Rasseneur, Stéphane Dufour,
François Piquard, Bernard Geny and Joffrey Zoll. Atorvastatin treatment reduces
exercise capacities in rats: involvement of mitochondrial impairments and
oxidative stress. J Appl Physiol 111:1477-1483, 2011. First published 18 August
2011; doi: 10.1152/japplphysiol.00107.2011
• 8. Catherine R. Mikus, Ph.D, Leryn J. Boyle, M.Sc., Sarah J. Borengasser, Ph.D.,
Douglas J. Oberlin, M.Sc., Scott P. Naples, M.Sc., Justin Fletcher, M.Sc., et al.
Simvastatin impairs exercise training adaptations. Journal of the American
College of Cardiology, Available online 10 April 2013
http://dx.doi.org/10.1016/j.jacc.2013.02.074
• 9. Amie J. Dirks and Kimberly M. Jones. Statin-induced apoptosis and skeletal
myopathy. Am J Physiol Cell Physiol 291:C1208-C1212, 2006. First published 2
August 2006; doi: 10.1152/ajpcell.00226.2006