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Statins and exercise: the combined effect…

Statins and exercise: the combined effect…. Christopher Paul Mckneely 2014 Doctor of Pharmacy Candidate Preceptor: Dr. Ali R ahimi. Lets get our bearings:. Dyslipidemia Statins Exercise Studies that may or may not be surprising Conclusion. Dyslipidemia: Introduction 1 :.

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Statins and exercise: the combined effect…

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  1. Statins and exercise: the combined effect… Christopher Paul Mckneely 2014 Doctor of Pharmacy Candidate Preceptor: Dr. Ali Rahimi

  2. Lets get our bearings: • Dyslipidemia • Statins • Exercise • Studies that may or may not be surprising • Conclusion

  3. 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

  4. 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

  5. Risk Factors: Positive Negative High HDL (>60) • 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)

  6. 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

  7. Goals2: http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3_rpt.htm

  8. Cholesterol Metabolism: In vivo: Acetyl CoA HMG-CoA HMG-CoA reductase Mevalonate Cholesterol

  9. Treatment2: TLC 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% • 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

  10. Statins MOA: In vivo: Acetyl CoA HMG-CoA HMG-CoA reductase Mevalonate Cholesterol

  11. 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

  12. 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 andmuscle-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 activityandmuscle-strengthening activities on 2 or more days a week that work all major muscle groups (legs, hips, back, abdomen, chest,  shoulders, and arms).

  13. Statins and Exercise:The EvidenceDisclaimer: Very limited amount of data actually exists in clinical trials of the combined effect

  14. 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 armsbased 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”

  15. 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

  16. Interactive Effects of Fitness and Statin…Cohort Study6: • 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 Results: “Muscle complaints caused by statin treatment affect 25% of statin users, but can be easilydismissedby the doctor and the patient”

  17. 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

  18. 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: Resting control (CONT) Exercise (CONT + EXE) Resting (ATO) Exercise (ATO + EXE)

  19. Results continued7:

  20. 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

  21. Simvastatin Impairs Exercise Training Adaptions8 • Assessments at baseline and 12 week interventions • Biopsies were obtained from the vastuslateralis 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

  22. 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

  23. 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

  24. Conclusions…

  25. 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

  26. 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 JoffreyZoll. Atorvastatin treatment reduces exercise capacities in rats: involvement of mitochondrial impairments and oxidative stress. J ApplPhysiol111:1477-1483, 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

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