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

Introduction continued1:

• Based on AHA• 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 changes• Exercise

• 30 minutes per day/most days of the week

• Diet• decreased intake of saturated

fat and total cholesterol; increased soluble fiber intake; plant stanols/sterols (veggies, fruits, nuts, and/or seeds)

• Weight reduction• Smoking cessation

Pharmacologic

• Statins (HMG-CoA Reductase Inhibitors)• 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)

• Fibrates• MOA: decreases VLDL synthesis & increases VLDL

clearance • LDL decrease by 5-20%, TG 20-50%, HDL increase by 10-

20%• Niacin

• MOA: decreases LDL and VLDL synthesis • decrease LDL 5-25% and TG by 20-50%, HDL increase

by 15-35%

• Bile Acid Sequestrants• 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:

Acetyl CoA

HMG-CoA

HMG-CoA reductase

Mevalonate

Cholesterol

In vivo:

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:

Results:

“Muscle complaints caused by statin treatment affect 25% of statin users, but can be easily dismissed by the doctor and the patient”

• 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…Oxidative Stress7:

• 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

4 Treatment arms:1.Resting control (CONT)2.Exercise (CONT + EXE)3.Resting (ATO)4.Exercise (ATO + EXE)

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/S0140-6736(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