Statin Therapy as Primary Prevention in Exercising Adults: Best Evidence for Avoiding Myalgia

References

1. 1.↵
   1. Stone NJ,
   2. Robinson JG,
   3. Lichtenstein AH,
   4. et al

   ; American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63(25 Pt B):2889–934.

   OpenUrlFREE Full Text
2. 2.↵
   1. Downs JR,
   2. O'Malley PG

   . Management of dyslipidemia for cardiovascular disease risk reduction: synopsis of the 2014 U.S. Department of Veterans Affairs and U.S. Department of Defense Clinical Practice Guideline. Ann Intern Med 2015;163:291–7.

   OpenUrlCrossRefPubMed
3. 3.↵
   1. Anderson TJ,
   2. Grégoire J,
   3. Hegele RA,
   4. et al

   . 2012 Update of the Canadian Cardiovascular Society guidelines for the diagnosis and treatment of dyslipidemia for the prevention of cardiovascular disease in the adult. Can J Cardiol 2013;29:151–67.

   OpenUrlCrossRefPubMed
4. 4.↵
   1. Han BH,
   2. Weinberger Y,
   3. Sutin D

   . Statinopause. J Gen Intern Med 2014;29:1702–6.

   OpenUrl
5. 5.↵
   1. Mihaylova B,
   2. Emberson J,
   3. Blackwell L,
   4. et al

   . The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 2012;380:581–90.

   OpenUrlCrossRefPubMedWeb of Science
6. 6.↵
   1. Savarese G,
   2. Gotto AM,
   3. Paolillo S,
   4. et al

   . Benefits of statins in elderly subjects without established cardiovascular disease: a meta-analysis. J Am Coll Cardiol 2013;62:2090–9.

   OpenUrlFREE Full Text
7. 7.↵
   1. Afilalo J,
   2. Duque G,
   3. Steele R,
   4. Jukema JW,
   5. de Craen AJM,
   6. Eisenberg MJ

   . Statins for secondary prevention in elderly patients: a hierarchical Bayesian meta-analysis. J Am Coll Cardiol 2008;51:37–45.

   OpenUrlFREE Full Text
8. 8.↵
   1. Soran H,
   2. Schofield JD,
   3. Durrington PN

   . Cholesterol, not just cardiovascular risk, is important in deciding who should receive statin treatment. Eur Heart J 2015;36:2975–83.

   OpenUrlAbstract/FREE Full Text
9. 9.↵
   1. Rose G

   . Sick individuals and sick populations. Bull World Health Organ 2001;79:990–6.

   OpenUrlPubMedWeb of Science
10. 10.↵
    1. Zulman DM,
    2. Vijan S,
    3. Omenn GS,
    4. Hayward RA

    . The relative merits of population-based and targeted prevention strategies. Milbank Q 2008;86:557–80.

    OpenUrlCrossRefPubMedWeb of Science
11. 11.↵
    1. Ioannidis JPA

    . More than a billion people taking statins? Potential implications of the new cardiovascular guidelines. JAMA 2013;94305:463–4.

    OpenUrl
12. 12.↵
    1. Powers Hannley P

    . Move more, eat less: it's time for Americans to get serious about exercise. Am J Med 2014;127:681–4.

    OpenUrl
13. 13.↵
    1. Pleis JR,
    2. Ward BW,
    3. Lucas JW

    . Summary health statistics for U.S. adults: National Health Interview Survey, 2009. Vital Health Stat 10 2010; 249:1–207.

    OpenUrl
14. 14.↵
    1. Running USA

    . Running USA's annual marathon report. March 23, 2014. Available from: http://www.runningusa.org/index.cfm?fuseaction=news.details&ArticleId=332&returnTo=annual-reports. Accessed February 18, 2016.
15. 15.↵
    1. Zingg M,
    2. Rüst CA,
    3. Lepers R,
    4. Rosemann T,
    5. Knechtle B

    . Master runners dominate 24-h ultramarathons worldwide-a retrospective data analysis from 1998 to 2011. Extrem Physiol Med 2013;2:21.

    OpenUrlCrossRefPubMed
16. 16.↵
    1. Harper CR,
    2. Jacobson TA

    . Evidence-based management of statin myopathy. Curr Atheroscler Rep 2010;12:322–30.

    OpenUrlCrossRefPubMed
17. 17.↵
    1. Fernandez G,
    2. Spatz ES,
    3. Jablecki C,
    4. Phillips PS

    . Statin myopathy: a common dilemma not reflected in clinical trials. Cleve Clin J Med 2011;78:393–403.

    OpenUrlAbstract/FREE Full Text
18. 18.↵
    1. Bruckert E,
    2. Hayem G,
    3. Dejager S,
    4. Yau C,
    5. Bégaud B

    . Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients–the PRIMO study. Cardiovasc Drugs Ther 2005;19:403–14.

    OpenUrlCrossRefPubMedWeb of Science
19. 19.↵
    1. Sofi F,
    2. Capalbo A,
    3. Cesari F,
    4. Abbate R,
    5. Gensini GF

    . Physical activity during leisure time and primary prevention of coronary heart disease: an updated meta-analysis of cohort studies. Eur J Cardiovasc Prev Rehabil 2008;15:247–57.

    OpenUrlCrossRefPubMedWeb of Science
20. 20.↵
    1. Hamer M,
    2. Chida Y

    . Walking and primary prevention: a meta-analysis of prospective cohort studies. Br J Sports Med 2008;42:238–43.

    OpenUrlAbstract/FREE Full Text
21. 21.↵
    1. Kokkinos PF,
    2. Faselis C,
    3. Myers J,
    4. Panagiotakos D,
    5. Doumas M

    . Interactive effects of fitness and statin treatment on mortality risk in veterans with dyslipidaemia: a cohort study. Lancet 2013;381:394–9.

    OpenUrlCrossRefPubMedWeb of Science
22. 22.↵
    1. Ebell MH,
    2. Siwek J,
    3. Weiss BD,
    4. et al

    . Strength of recommendation taxonomy (SORT): a patient-centered approach to gathering evidence in the medical literature. J Am Board Fam Pract 2004;17:59–67.

    OpenUrlAbstract/FREE Full Text
23. 23.↵
    1. Mancini GBJ,
    2. Tashakkor AY,
    3. Baker S,
    4. et al

    . Diagnosis, prevention, and management of statin adverse effects and intolerance: Canadian working group consensus update. Can J Cardiol 2013;29:1553–68.

    OpenUrlCrossRefPubMed
24. 24.↵
    1. Rosenson RS,
    2. Baker SK,
    3. Jacobson TA,
    4. Kopecky SL,
    5. Parker BA

    . An assessment by the Statin Muscle Safety Task Force: 2014 update. J Clin Lipidol 2014;8:S58–71.

    OpenUrlCrossRefPubMed
25. 25.↵
    1. Pasternak RC,
    2. Smith SC Jr.,
    3. Bairey-Merz CN,
    4. Grundy SM,
    5. Cleeman JI,
    6. Lenfant C

    ; American College of Cardiology; American Heart Association; National Heart, Lung and Blood Institute. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. Am Coll Cardiol 2002;40:1024–8.

    OpenUrl
26. 26.↵
    1. Clarkson PM,
    2. Hubal MJ

    . Exercise-induced muscle damage in humans. Am J Phys Med Rehabil 2002;81(11 Suppl):S52–69.

    OpenUrlCrossRefPubMedWeb of Science
27. 27.↵
    1. Phillips PS,
    2. Haas RH,
    3. Bannykh S,
    4. et al

    . Statin-associated myopathy with normal creatine kinase levels. Ann Intern Med 2002;137:581–5.

    OpenUrlCrossRefPubMedWeb of Science
28. 28.↵
    1. Draeger A,
    2. Monastyrskaya K,
    3. Mohaupt M,
    4. et al

    . Statin therapy introduces ultrastructural damage in skeletal muscle in patients without myalgia. J Pathol 2006;210:94–102.

    OpenUrlCrossRefPubMedWeb of Science
29. 29.↵
    1. Thompson PD,
    2. Zmuda JM,
    3. Domalik LJ,
    4. Zimet RJ,
    5. Staggers J,
    6. Guyton JR

    . Lovastatin increases exercise-induced skeletal muscle injury. Metabolism 1997;46:1206–10.

    OpenUrlCrossRefPubMedWeb of Science
30. 30.↵
    1. Taylor BA,
    2. Lorson L,
    3. White CM,
    4. Thompson PD

    . A randomized trial of coenzyme Q10 in patients with confirmed statin myopathy. Atherosclerosis 2015;238:329–35.

    OpenUrlCrossRefPubMed
31. 31.↵
    1. Skarlovnik A,
    2. Janić M,
    3. Lunder M,
    4. Turk M,
    5. Šabovič M

    . Coenzyme Q10 supplementation decreases statin-related mild-to-moderate muscle symptoms: a randomized clinical study. Med Sci 2014;20:2183–8.

    OpenUrl
32. 32.↵
    1. Tomaszewski M,
    2. Stêpieñ KM,
    3. Tomaszewska J,
    4. Czuczwar SJ

    . Statin-induced myopathies. Pharmacol Rep 2011;63:859–66.

    OpenUrlCrossRefPubMed
33. 33.↵
    1. Urso ML

    . Changes in ubiquitin proteasome pathway gene expression in skeletal muscle with exercise and statins. Arterioscler Thromb Vasc Biol 2005;25:2560–6.

    OpenUrlAbstract/FREE Full Text
34. 34.↵
    1. Thompson PD,
    2. Clarkson P,
    3. Karas RH

    . Statin associated myopathy. JAMA 2003;289:1681–90.

    OpenUrlCrossRefPubMedWeb of Science
35. 35.↵
    1. Kashani A,
    2. Phillips CO,
    3. Foody JM,
    4. et al

    . Risks associated with statin therapy: a systematic overview of randomized clinical trials. Circulation 2006;114:2788–197.

    OpenUrlAbstract/FREE Full Text
36. 36.↵
    1. Jacobson TA

    . Toward “pain-free” statin prescribing: clinical algorithm for diagnosis and management of myalgia. Mayo Clin Proc 2008;83:687–700.

    OpenUrlCrossRefPubMedWeb of Science
37. 37.↵
    1. Bulbulia R,
    2. Bowman L,
    3. Wallendszus K,
    4. et al

    . Effects on 11-year mortality and morbidity of lowering LDL cholesterol with simvastatin for about 5 years in 20 536 high-risk individuals: a randomised controlled trial. Lancet 2011;378:2013–20.

    OpenUrlCrossRefPubMedWeb of Science
38. 38.↵
    1. McClure DL,
    2. Valuck RJ,
    3. Glanz M,
    4. Hokanson JE

    . Systematic review and meta-analysis of clinically relevant adverse events from HMG CoA reductase inhibitor trials worldwide from 1982 to present. Pharmacoepidemiol Drug Saf 2007;16:132–43.

    OpenUrlCrossRefPubMed
39. 39.↵
    1. Tobert JA,
    2. Newman CB

    . Statin tolerability: in defence of placebo-controlled trials. Eur J Prev Cardiol 2016;23:891–6.

    OpenUrlAbstract/FREE Full Text
40. 40.↵
    1. Parker BA,
    2. Capizzi JA,
    3. Grimaldi AS,
    4. et al

    . Effect of statins on skeletal muscle function. Circulation 2013;127:96–103.

    OpenUrlAbstract/FREE Full Text
41. 41.↵
    1. Macedo A,
    2. Taylor F,
    3. Casas JP,
    4. Adler A,
    5. Prieto-Merino D,
    6. Ebrahim S

    . Unintended effects of statins from observational studies in the general population: systematic review and meta-analysis. BMC Med 2014;12:51.

    OpenUrlCrossRefPubMed
42. 42.↵
    1. Stroes ES,
    2. Thompson PD,
    3. Corsini A,
    4. et al

    . Statin-associated muscle symptoms: impact on statin therapy–European Atherosclerosis Society Consensus Panel statement on assessment aetiology and management. Eur Heart J 2015;36:1012–22.

    OpenUrlAbstract/FREE Full Text
43. 43.↵
    1. Sinzinger H,
    2. O'Grady J

    . Professional athletes suffering from familial hypercholesterolaemia rarely tolerate statin treatment because of muscular problems. Br J Clin Pharmacol 2004;57:525–8.

    OpenUrlCrossRefPubMedWeb of Science
44. 44.↵
    1. Lee D-C,
    2. Pate RR,
    3. Lavie CJ,
    4. Sui X,
    5. Church TS,
    6. Blair SN

    . Leisure-time running reduces all-cause and cardiovascular mortality risk. J Am Coll Cardiol 2014;64:472–81.

    OpenUrlFREE Full Text
45. 45.↵
    1. Williams PT,
    2. Thompson PD

    . Effects of statin therapy on exercise levels in participants in the National Runners' and Walkers' Health Study. Mayo Clin Proc 2015;90:1338–47.

    OpenUrlCrossRefPubMed
46. 46.↵
    1. Panza GA,
    2. Taylor BA,
    3. Thompson PD,
    4. et al

    . The effect of atorvastatin on habitual physical activity among healthy adults. Med Sci Sports Exerc 2015;48:1–6.

    OpenUrl
47. 47.
    1. Golomb BA,
    2. Evans MA,
    3. Dimsdale JE,
    4. White HL

    . Effects of statins on energy and fatigue with exertion: results from a randomized controlled trial. Arch Intern Med 2012;172:1180–2.

    OpenUrlPubMedWeb of Science
48. 48.
    1. Mikus CR,
    2. Boyle LJ,
    3. Borengasser SJ,
    4. et al

    . Simvastatin impairs exercise training adaptations. J Am Coll Cardiol 2013;62:709–14.

    OpenUrlFREE Full Text
49. 49.
    1. Scott D,
    2. Blizzard L,
    3. Fell J,
    4. Jones G

    . Statin therapy, muscle function and falls risk in community-dwelling older adults. QJM 2009;102:625–33.

    OpenUrlAbstract/FREE Full Text
50. 50.
    1. Qureshi WT,
    2. Keteyian SJ,
    3. Brawner CA,
    4. Dardari Z,
    5. Blaha MJ,
    6. Al-Mallah MH

    . Impact of statin use on cardiorespiratory fitness in multi-racial men and women: the Henry Ford Exercise Testing (FIT) Project. Int J Cardiol 2015;197:76–7.

    OpenUrl
51. 51.
    1. Lee DS,
    2. Markwardt S,
    3. Goeres L,
    4. et al

    . Statins and physical activity in older men: the Osteoporotic Fractures in Men Study. JAMA Intern Med 2014;174:1263–70.

    OpenUrlCrossRefPubMed
52. 52.
    1. Terpak K,
    2. Guthrie S,
    3. Erickson S

    . Statin use and self-reported swimming performance in US masters swimmers. J Sports Sci 2015;33:286–92.

    OpenUrl
53. 53.↵
    1. Cham S,
    2. Evans MA,
    3. Denenberg JO,
    4. Golomb BA

    . Statin-associated muscle-related adverse effects: a case series of 354 patients. Pharmacotherapy 2010;30:541–53.

    OpenUrlCrossRefPubMed
54. 54.↵
    1. Ridker PM,
    2. Rose L,
    3. Cook R

    . A proposal to incorporate trial data into a hybrid ACC/AHA algorithm for the allocation of statin therapy in primary prevention. J Am Coll Cardiol 2015;65:942–8.

    OpenUrlFREE Full Text
55. 55.↵
    1. Glueck CJ,
    2. Rawal B,
    3. Khan NA,
    4. Yeramaneni S,
    5. Goldenberg N,
    6. Wang P

    . Should high creatine kinase discourage the initiation or continuance of statins for the treatment of hypercholesterolemia? Metabolism 2009;58:233–8.

    OpenUrlPubMed
56. 56.↵
    1. Lenz TL

    . Are physically active individuals taking statins at increased risk for myopathy? Am J Lifestyle Med 2009;3:287–9.

    OpenUrlAbstract/FREE Full Text
57. 57.↵
    1. Semple SJ

    . Statin therapy, myopathy and exercise - a case report. Lipids Health Dis 2012;11:40.

    OpenUrlPubMed
58. 58.↵
    1. Evans WJ,
    2. Meredith CN,
    3. Cannon JG,
    4. et al

    . Metabolic changes following eccentric exercise in trained and untrained men. J Appl Physiol 1986;61:1864–8.

    OpenUrlAbstract/FREE Full Text
59. 59.↵
    1. Bonfim MR,
    2. Oliveira ASB,
    3. do Amaral SL,
    4. Monteiro HL

    . Treatment of dyslipidemia with statins and physical exercises: recent findings of skeletal muscle responses. Arq Bras Cardiol 2015;324–32.
60. 60.↵
    1. Kearns AK,
    2. Bilbie CL,
    3. Clarkson PM,
    4. et al

    . The creatine kinase response to eccentric exercise with atorvastatin 10mg or 80mg. Atherosclerosis 2008;200:121–5.

    OpenUrlPubMed
61. 61.↵
    1. Josan K,
    2. Majumdar SR,
    3. McAlister FA

    . The efficacy and safety of intensive statin therapy: a meta-analysis of randomized trials. CMAJ 2008;178:576–84.

    OpenUrlAbstract/FREE Full Text
62. 62.↵
    1. Ruisinger JF,
    2. Backes JM,
    3. Gibson CA,
    4. Moriarty PM

    . Once-a-week rosuvastatin (2.5 to 20 mg) in patients with a previous statin intolerance. Am J Cardiol 2009;103:393–4.

    OpenUrlCrossRefPubMed
63. 63.↵
    1. Gadarla M,
    2. Kearns AK,
    3. Thompson PD

    . Efficacy of rosuvastatin (5 mg and 10 mg) twice a week in patients intolerant to daily statins. Am J Cardiol 2008;101:1747–8.

    OpenUrlCrossRefPubMedWeb of Science
64. 64.↵
    1. Mampuya WM,
    2. Frid D,
    3. Rocco M,
    4. et al

    . Treatment strategies in patients with statin intolerance: the Cleveland Clinic experience. Am Heart J 2013;166:597–603.

    OpenUrlCrossRefPubMedWeb of Science
65. 65.↵
    1. Stein EA,
    2. Ballantyne CM,
    3. Windler E,
    4. et al

    . Efficacy and tolerability of fluvastatin XL 80 mg alone, ezetimibe alone, and the combination of fluvastatin 80 mg with ezetimibe in patients with a history of muscle-related side effects with other statins. Am J Cardiol 2008;101:480–96.

    OpenUrl
66. 66.↵
    1. Cannon CP,
    2. Blazing MA,
    3. Giugliano RP,
    4. et al

    . Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015;372:2387–97.

    OpenUrlCrossRefPubMed
67. 67.↵
    1. Lee P,
    2. Greenfield JR,
    3. Campbell LV

    . Vitamin D insufficiency - a novel mechanism of statin-induced myalgia? Clin Endocrinol 2009;71:154–5.

    OpenUrlCrossRefPubMed
68. 68.↵
    1. Michalska-Kasiczak M,
    2. Sahebkar A,
    3. Mikhailidis DP,
    4. et al

    ; Lipid and Blood Pressure Meta-analysis Collaboration (LBPMC) Group. Analysis of vitamin D levels in patients with and without statin-associated myalgia - a systematic review and meta-analysis of 7 studies with 2420 patients. Int J Cardiol 2014;178:111–6.

    OpenUrlPubMed
69. 69.↵
    1. Khayznikov M,
    2. Hemachrandra K,
    3. Pandit R,
    4. Kumar A,
    5. Wang P,
    6. Glueck CJ

    . Statin intolerance because of myalgia, myositis, myopathy or myonecrosis can in most cases be safely resolved by vitamin D supplementation. North Am J Med Sci 2015;7:86–93.

    OpenUrl
70. 70.↵
    1. Banach M,
    2. Serban C,
    3. Sahebkar A,
    4. et al

    . Effects of coenzyme Q10 on statin-induced myopathy: a meta-analysis of randomized controlled trials. Mayo Clin Proc 2014;90:1–11.

    OpenUrl
71. 71.↵
    1. Canner PL,
    2. Furberg CD,
    3. McGovern ME

    . Benefits of niacin in patients with versus without the metabolic syndrome and healed myocardial infarction (from the Coronary Drug Project). Am J Cardiol 2006;97:477–9.

    OpenUrlCrossRefPubMedWeb of Science
72. 72.↵
    1. Tenkanen L,
    2. Mänttäri M,
    3. Mannien V

    . Some coronary risk factors related to insulin resistance syndrome and treatment with gemfibrozil. Circulation 1995;92:1779–85.

    OpenUrlAbstract/FREE Full Text
73. 73.↵
    1. Magarian GJ,
    2. Lucas LM,
    3. Colley C

    . Gemfibrozil-induced myopathy. Arch Intern Med 1991;151:1873–4.

    OpenUrlCrossRefPubMedWeb of Science
74. 74.↵
    1. Slim H,
    2. Thompson PD

    . Ezetimibe-related myopathy: a systematic review. J Clin Lipidol 2008;2:328–34.

    OpenUrlPubMed
75. 75.↵
    1. Pandor A,
    2. Ara RM,
    3. Tumur I,
    4. et al

    . Ezetimibe monotherapy for cholesterol lowering in 2,722 people: systematic review and meta-analysis of randomized controlled trials. J Intern Med 2009;265:568–80.

    OpenUrlCrossRefPubMed
76. 76.↵
    1. Robinson JG,
    2. Farnier M,
    3. Krempf M,
    4. et al

    . Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1489–99.

    OpenUrlCrossRefPubMed
77. 77.
    1. Rivers SM,
    2. Kane MP,
    3. Busch RS,
    4. Bakst G,
    5. Hamilton RA

    . Colesevelam hydrochloride-ezetimibe combination lipid-lowering therapy in patients with diabetes or metabolic syndrome and a history of statin intolerance. Endocr Pract 2007;13:11–6.

    OpenUrlPubMed
78. 78.↵
    1. Ford ES,
    2. Bergmann MM,
    3. Kröger J,
    4. Schienkiewitz A,
    5. Weikert C,
    6. Boeing H

    . Healthy living is the best revenge: findings from the European Prospective Investigation Into Cancer and Nutrition – Potsdam Study. Arch Intern Med 2009;169:1355–62.

    OpenUrlCrossRefPubMedWeb of Science
79. 79.↵
    1. Opie LH

    . Exercise-induced myalgia may limit the cardiovascular benefits of statins. Cardiovasc Drugs Ther 2013;27:569–72.

    OpenUrlPubMed
80. 80.↵
    1. Downs JR,
    2. Clearfield M,
    3. Weis S,
    4. et al

    . Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels. JAMA 1998;279:1615–22.

    OpenUrlCrossRefPubMedWeb of Science
81. 81.↵
    1. Nakamura H,
    2. Arakawa K,
    3. Itakura H,
    4. et al

    . Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA Study): a prospective randomised controlled trial. Lancet 2006;368:1155–63.

    OpenUrlCrossRefPubMedWeb of Science
82. 82.↵
    1. Ridker PM,
    2. Danielson E,
    3. Fonseca FAH,
    4. et al

    . Rosuvastatin to prevent vascular events in men and women with elevated c-reactive protein. N Engl J Med 2008;359:2195–207.

    OpenUrlCrossRefPubMedWeb of Science
83. 83.↵
    1. Yusuf G,
    2. Bosch J,
    3. Dagenais G,
    4. et al

    . Cholesterol lowering in intermediate-risk persons without cardiovascular disease. N Engl J Med 2016;374:2021–31.

    OpenUrlCrossRefPubMed
84. 84.↵
    1. Thavendiranathan P,
    2. Bagai A,
    3. Brookhard MA,
    4. Choudhry NK

    . Primary prevention of cardiovascular diseases with statin therapy: a meta-analysis of randomized controlled trials. Arch Intern Med 2006;166:2307–13.

    OpenUrlCrossRefPubMedWeb of Science
85. 85.↵
    1. Mills EJ,
    2. Rachlis B,
    3. Wu P,
    4. Devereaux PJ,
    5. Arora P,
    6. Perri D

    . Primary prevention of cardiovascular mortality and events with statin treatments: a network meta-analysis involving more than 65,000 patients. J Am Coll Cardiol 2008;52:1769–81.

    OpenUrlFREE Full Text
86. 86.↵
    1. Petretta M,
    2. Costanzo P,
    3. Perronne-Filardi P,
    4. Chiariello M

    . Impact of gender in primary prevention of coronary heart disease with statin therapy: a meta-analysis. Int J Cardiol 2010;138:25–31.

    OpenUrlCrossRefPubMedWeb of Science
87. 87.
    1. Ray KK,
    2. Seshasai SRK,
    3. Erqou S,
    4. et al

    . Statins and all-cause mortality in high-risk primary prevention. Arch Intern Med 2010;170:1024–31.

    OpenUrlCrossRefPubMedWeb of Science
88. 88.↵
    1. Mora S,
    2. Glynn RJ,
    3. Hsia J,
    4. MacFayden JG,
    5. Genest J,
    6. Ridker P

    . Statins for the primary prevention of cardiovascular events in women with elevated high-sensitivity c-reactive protein or dyslipidemia: results from the Justification for the Use of Statins for Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) and meta-analysis of women from primary prevention trials. Circulation 2010;121:1069–77.

    OpenUrlAbstract/FREE Full Text
89. 89.↵
    1. Kostis WJ,
    2. Cheng JQ,
    3. Dobrzynski JM,
    4. Cabera J,
    5. Kostis JB

    . Meta-analyis of statin effects in women versus men. J Am Coll Cardiol 2012;59:572–82.

    OpenUrlFREE Full Text
90. 90.↵
    1. Taylor F,
    2. Huffman MD,
    3. Macedo AF,
    4. et al

    . Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst 2013;(1):CD004816.
91. 91.↵
    1. Brugts JJ,
    2. Yetgin T,
    3. Hoeks SE,
    4. et al

    . The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomized controlled trials. BMJ 2009;338:b2376.

    OpenUrlAbstract/FREE Full Text
92. 92.↵
    1. Yan YL,
    2. Qiu B,
    3. Hu LJ,
    4. et al

    . Efficacy and safety evaluation of intensive statin therapy in older patients with coronary heart disease: a systematic review and meta-analysis. Eur J Clin Pharmacol 2013;69:2001–9.

    OpenUrlCrossRefPubMed
93. 93.↵
    1. Cannon CP,
    2. Steinberg BA,
    3. Murphy SA,
    4. Mega JL,
    5. Braunwald E

    . Meta-analysis of cardiovascular outcomes trials comparing intensive versus moderate statin therapy. J Am Coll Cardiol 2006;48:438–45.

    OpenUrlFREE Full Text
94. 94.↵
    1. Löllgen H,
    2. Böckenhoff A,
    3. Knapp G

    . Physical activity and all-cause mortality: an updated meta-analysis with different intensity categories. Int J Sports Med 2009;30:213–24.

    OpenUrlCrossRefPubMedWeb of Science
95. 95.↵
    1. Nocon M,
    2. Hiemann T,
    3. Müller-Riemenschneider F,
    4. Thalau F,
    5. Roll S,
    6. Willich S

    . Association of physical activity with all-cause and cardiovascular mortality: a systematic review and meta-analysis. Eur J Cardiovasc Prev Rehabil 2008;15:239–46.

    OpenUrlCrossRefPubMedWeb of Science
96. 96.
    1. Li J,
    2. Siegrist J

    . Physical activity and risk of cardiovascular disease - a meta-analysis of prospective cohort studies. Int J Environ Res Public Health 2012;9:391–407.

    OpenUrlCrossRefPubMed
97. 97.
    1. Sattelmair J,
    2. Pertman J,
    3. Kohl HW III.,
    4. Haskell W,
    5. Lee I-M

    . Dose-response between physical activity and risk of coronary heart disease: a meta-analysis. Circulation 2011;124:789–95.

    OpenUrlAbstract/FREE Full Text
98. 98.↵
    1. Colley RC,
    2. Garriguet D,
    3. Janssen I,
    4. Craig CL,
    5. Clarke J,
    6. Tremblay MS

    . Physical activity of Canadian adults: accelerometer results from the 2007 to 2009 Canadian Health Measures Survey. Health Rep 2011;22:7–14.

    OpenUrlPubMed
99. 99.↵
    1. Naci H,
    2. Ioannidis JPA

    . Comparative effectiveness of exercise and drug interventions on mortality outcomes: metaepidemiological study. BMJ 2013;347:f5577.

    OpenUrlAbstract/FREE Full Text
100. 100.↵
     1. Hupin D,
     2. Roche F,
     3. Gremeaux V,
     4. et al

     . Even a low-dose of moderate-to-vigorous physical activity reduces mortality by 22% in adults aged ≥60 years: a systematic review and meta-analysis. Br J Sports Med 2015;49:1262–7.

     OpenUrlAbstract/FREE Full Text
101. 101.↵
     1. Chakravarty EF,
     2. Hubert HB,
     3. Lingala VB,
     4. Fries JF

     . Reduced disability and mortality among ageing runners: a 21-year longitudinal study. Arch Intern Med 2008;168:1638–46.

     OpenUrlCrossRefPubMedWeb of Science
102. 102.↵
     1. Vos E,
     2. Rose CP,
     3. Biron P

     . Rebuttal: why statins have failed to reduce mortality in just about anybody. J Clin Lipidol 2013;7:228.

     OpenUrl
103. 103.↵
     1. Tomlinson SS,
     2. Mangione KK

     . Potential adverse effects of statins on muscle. Phys Ther 2005;85:459–65.

     OpenUrlFREE Full Text
104. 104.↵
     1. Soverow J,
     2. Watson K

     . Is there sufficient enhancement of the reduction in CVD rates after a decade of statin therapy to justify continuation? Curr Atheroscler Rep 2014;16:432.

     OpenUrl
105. 105.↵
     1. Knowler WC,
     2. Barrett-Connor E,
     3. Fowler SE,
     4. et al

     ; Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393–403.

     OpenUrlCrossRefPubMedWeb of Science
106. 106.↵
     1. Cederberg H,
     2. Stancakova A,
     3. Yaluri N,
     4. Modi S,
     5. Kuusisto J,
     6. Laakso M

     . Increased risk of diabetes with statin treatment is associated with impaired insulin sensitivity and insulin secretion: a 6 year follow-up study of the METSIM cohort. Diabetologia 2015;58:1109–17.

     OpenUrlCrossRefPubMed
107. 107.↵
     1. Rissanen AM,
     2. Heliövaara M,
     3. Knekt P,
     4. Reunanen A,
     5. Aromaa A

     . Determinants of weight gain and overweight in adult Finns. Eur J Clin Nutr 1991;45:419–30.

     OpenUrlPubMedWeb of Science
108. 108.↵
     1. Martin CK,
     2. Church TS,
     3. Thompson AM,
     4. Earnest CP,
     5. Blair SN

     . Exercise dose and quality of life: a randomized controlled trial. Arch Intern Med 2009;169:269–78.

     OpenUrlCrossRefPubMedWeb of Science
109. 109.↵
     1. Franklin BA,
     2. Lavie CJ

     . Impact of statins on physical activity and fitness: ally or adversary? Mayo Clin Proc 2015;90:1314–9.

     OpenUrlCrossRefPubMed