Expert opinion: the therapeutic challenges faced by statin intolerance

Expert Opinion on Pharmacotherapy

Volumn 17, Issue 11, 2016, Pages 1497-1507

  Patel, Jaideep ^a,b   Martin, Seth S ^a   Banach, Maciej ^c  

^a JOHNS HOPKINS UNIVERSITY   (United States)

^b VIRGINIA COMMONWEALTH UNIVERSITY MEDICAL CENTER   (United States)

^c MEDICAL UNIVERSITY OF LODZ   (Poland)

Author keywords

cardiovascular; Intolerance; myopathy; prevention; statin

Indexed keywords

ANTILIPEMIC AGENT; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR;

ALTERNATIVE MEDICINE; CONTROLLED CLINICAL TRIAL (TOPIC); DOCTOR PATIENT RELATION; DRUG EFFICACY; DRUG HYPERSENSITIVITY; DRUG RECHALLENGE; DRUG TOLERABILITY; DYSLIPIDEMIA; HUMAN; IMMUNE MEDIATED NECROTIZING MYOPATHY; MYOPATHY; PATIENT COUNSELING; PATIENT EDUCATION; PRACTICE GUIDELINE; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; RISK BENEFIT ANALYSIS; RISK FACTOR; CARDIOVASCULAR DISEASES; CHEMICALLY INDUCED; DOSE RESPONSE; MUSCULAR DISEASES;

CARDIOVASCULAR DISEASES; DOSE-RESPONSE RELATIONSHIP, DRUG; HUMANS; HYDROXYMETHYLGLUTARYL-COA REDUCTASE INHIBITORS; MUSCULAR DISEASES; RISK FACTORS;

EID: 84978663484     PISSN: 14656566     EISSN: 17447666     Source Type: Journal    
DOI: 10.1080/14656566.2016.1197202     Document Type: Review

References (122)

1. C.Baigent, A.Keech, P.M.Kearney, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005;366:1267–1278.
2. F.D.Hobbs, M.Banach, D.P.Mikhailidis, et al. Is statin-modified reduction in lipids the most important preventive therapy for cardiovascular disease? A pro/con debate. BMC Med. 2016;14:4.
3. C.S.Desai, S.S.Martin, R.S.Blumenthal Non-cardiovascular effects associated with statins. BMJ. 2014;349:g3743.
4. P.D.Thompson, P.Clarkson, R.H.Karas. Statin-associated myopathy. JAMA. 2003;289:1681–1690.
5. G.A.Nichols, C.E.Koro. Does statin therapy initiation increase the risk for myopathy? An observational study of 32,225 diabetic and nondiabetic patients. Clin Ther. 2007;29:1761–1770.• Provides a novel approach for the definition of statin intolerance.
6. M.Banach, M.Rizzo, P.P.Toth, et al. Statin intolerance - an attempt at a unified definition. Position paper from an international lipid expert panel. Expert Opin Drug Saf. 2015;14:935–955.•• Current European consensus statement on the management of statin intolerance.
7. E.S.Stroes, P.D.Thompson, A.Corsini, et al. European Atherosclerosis Society Consensus Panel. Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. Eur Heart J. 2015;36:1012–1022.
8. N.J.Stone, J.Robinson, A.H.Lichtenstein, et al. 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. Circulation. 2014;129(25 Suppl 2):S1–45.• Provides management strategies for patients with known intolerance.
9. R.S.Rosenson, S.K.Baker, T.A.Jacobson, et al. The National Lipid Association’s Muscle Safety Expert Panel. An assessment by the statin muscle safety task force: 2014 update. J Clin Lipidol. 2014;8:S58–71.
10. G.B.Mancini, A.Y.Tashakkor, S.Baker, et al. Diagnosis, prevention, and management of statin adverse effects and intolerance: Canadian Working Group Consensus update. Can J Cardiol. 2013;29:1553–1568.
11. J.P.Ioannidis. More than a billion people taking statins?: Potential implications of the new cardiovascular guidelines. JAMA. 2014;311:463–464.
12. N.Sattar, D.Preiss, H.M.Murray, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet. 2010;375:735–742.
13. D.Preiss, S.R.Seshasai, P.Welsh, et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. JAMA. 2011;305:2556–2564.
14. P.M.Ridker, A.Pradhan, J.G.MacFadyen, et al. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial. Lancet. 2012;380:565–571.
15. W.Vandiver, M.L.Hunter. Statin adverse effects: sorting out the evidence. Fam Pract. 2013;62:730.
16. T.Stulc, R.Ceška, A.M.GottoJr. Statin intolerance: the clinician’s perspective. Curr Atheroscler Rep. 2015;17:69.
17. S.Kopecky, S.Baum, J.M.Foody, et al. Statin intolerance roundtable participants. Insights into statin intolerance. Clin Cardiol. 2015;38:520–526.
18. S.B.Raju, K.Varghese, K.Madhu. Management of statin intolerance. Indian J Endocrinol Metab. 2013;17:977–982.
19. J.M.McKenney, M.H.Davidson, T.A.Jacobson, et al. National Lipid Association Statin Safety Assessment Task Force. Final conclusions and recommendations of the National Lipid Association Statin Safety Assessment Task Force. Am J Cardiol. 2006;97:89C–94C.
20. Z.Reiner, A.L.Catapano, G.De Backer, et al.; ESC Committee for Practice Guidelines (CPG) 2008-2010 and 2010-2012 Committees. ESC/EAS guidelines for the management of dyslipidaemias: the task force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J. 2011;32:1769–1818.
21. B.A.Parker, J.A.Capizzi, A.S.Grimaldi, et al. Effect of statins on skeletal muscle function. Circulation. 2013;127:96–103.
22. K.E.Hansen, J.P.Hildebrand, E.E.Ferguson, et al. Outcomes in 45 patients with statin-associated myopathy. Arch Intern Med. 2005;165:2671–2676.
23. E.Bruckert, G.Hayem, S.Dejager, et al. Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients—the PRIMO study. Cardiovasc Drugs Ther. 2005;19:403–414.
24. A.Pineda, L.X.Cubeddu. Statin rebound or withdrawal syndrome: does it exist? Curr Atheroscler Rep. 2011;13:23–30.
25. FDA announces safety changes in labeling for some cholesterol-lowering drugs. FDA public health advisory. Washington, DC: FDA; 2012; [cited 2016 March06]. Available from: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm293623.htm
26. A.Alfirevic, D.Neely, J.Armitage, et al. Phenotype standardization for statin-induced myotoxicity. Clin Pharmacol Ther. 2014;96:470–476.
27. H.Zhang, J.Plutzky, S.Skentzos, et al. Discontinuation of statins in routine care settings: a cohort study. Ann Intern Med. 2013;158:526–534.
28. W.M.Mampuya, D.Frid, M.Rocco, et al. Treatment strategies in patients with statin intolerance: the Cleveland clinic experience. Am Heart J. 2013;166:597–603.
29. C.J.Glueck, D.Aregawi, M.Agloria, et al. Rosuvastatin 5 and 10 mg/d: a pilot study of the effects in hypercholesterolemic adults unable to tolerate other statins and reach LDL cholesterol goals with nonstatin lipid-lowering therapies. Clin Ther. 2006;28:933–942.
30. E.A.Stein, C.M.Ballantyne, E.Windler, et al. Efficacy and tolerability of fluvastatin XL 80 mg alone, ezetimibe alone, and the combination of fluvastatin XL 80 mg with ezetimibe in patients with a history of muscle-related side effects with other statins. Am J Cardiol. 2008;101:490–496.
31. T.R.Joy, A.Monjed, G.Y.Zou, et al. N-of-1 (single-patient) trials for statin-related myalgia. Ann Intern Med. 2014;160:301–310.
32. B.D.Mackie, S.Satija, C.Nell, et al. Monday, Wednesday, and Friday dosing of rosuvastatin in patients previously intolerant to stain therapy. Am J Cardiol. 2007;99:291.
33. B.H.Gopalagowda, C.Cutchins, D.C.Cutchins, et al. Alternate day rosuvastatin, an underutilized option in statin intolerant hyperlipidemic patients: a case report and literature review. Tenn Med. 2011;104:49–51.
34. J.M.Backes, C.V.Venero, C.A.Gibson, et al. Effectiveness and tolerability of every-other-day rosuvastatin dosing in patients with prior statin intolerance. Ann Pharmacother. 2008;42:341–346.
35. J.M.Backes, P.M.Moriarty, J.F.Ruisinger, et al. Effects of once weekly rosuvastatin among patients with a prior statin intolerance. Am J Cardiol. 2007;100:554–555.
36. J.F.Ruisinger, J.M.Backes, C.A.Gibson, et al. Once-a-week rosuvastatin (2.5 to 20 mg) in patients with a previous statin intolerance. Am J Cardiol. 2009;103:393–394.
37. S.P.Kennedy, G.P.Barnas, M.J.Schmidt, et al. Efficacy and tolerability of once-weekly rosuvastatin in patients with previous statin intolerance. J Clin Lipidol. 2011;5:308–315.
38. C.Meek, A.S.Wierzbicki, C.Jewkes, et al. Daily and intermittent rosuvastatin 5 mg therapy in statin intolerant patients: an observational study. Curr Med Res Opin. 2012;28:371–378.
39. M.Gadarla, A.K.Kearns, P.D.Thompson. Efficacy of rosuvastatin (5 mg and 10 mg) twice a week in patients intolerant to daily statins. Am J Cardiol. 2008;101:1747–1748.
40. S.H.Lennerna. Clinical pharmacokinetics of atorvastatin. Clin Pharmacokinet. 2003;42(13):1141–1160.
41. C.Piamsomboon, P.Laothavorn, S.Saguonwong, et al. Efficacy and safety of atorvastatin 10 mg every other day in hypercholesterolemia. J Med Assoc Thai. 2002;85:297–300.
42. M.A.Juszczyk, R.L.Seip, P.D.Thompson. Decreasing LDL cholesterol and medication cost with every-other-day statin therapy. Prev Cardiol. 2005;8:197–199.
43. M.S.Matalka, M.C.Ravnan, M.D.Deedwania. Is alternate daily dose of atorvastatin effective in treating patients with hyperlipidemia? The Alternate Day versus Daily Dosing of Atrovastatin Study (ADDAS). Am Heart J. 2002;144:674–677.
44. M.Jafari, R.Ebrahimi, M.Ahmadi-Kashani, et al. Efficacy of alternate-day dosing versus daily dosing of atorvastatin. J Cardiovasc Pharmacol Ther. 2003;8:123–126.
45. T.Keles, N.Akar Bayram, T.Kayhan, et al. The comparison of the effects of standard 20 mg atorvastatin daily and 20 mg atorvastatin every other day on serum LDL-cholesterol and high sensitive C-reactive protein levels. Anadolu Kardiyol Derg. 2008;8:407–412.
46. J.C.Ferrer-Garcia, J.Perez-Silvestre, I.Martinez-Mir, et al. Alternate-day dosing of atorvastatin: effects in treating type 2 diabetic patients with dyslipidemia. Acta Diabetol. 2006;43:75–78.•• Review of the safety and efficacy of alternative intermittent statin-dosing regimens in patients with previous intolerance due to myopathy.
47. S.Wongwiwatthananukit, N.Sansanayudh, R.Dhummauppakorn, et al. Efficacy and safety of rosuvastatin every other day compared with once daily in patients with hypercholesterolemia. Ann Pharmacother. 2006;40:1917–1923.
48. A.J.Keating, K.B.Campbell, J.R.Guyton. Intermittent nondaily dosing strategies in patients with previous statin-induced myopathy. Ann Pharmacother. 2013;47:398–404.
49. I.F.Gazi, S.S.Daskalopoulou, D.R.Nair, et al. Effect of ezetimibe in patients who cannot tolerate statins or cannot get to the low density lipoprotein cholesterol target despite taking a statin. Curr Med Res Opin. 2007;23:2183–2192.
50. A.Pandor, R.M.Ara, I.Tumur, et al. Ezetimibe monotherapy for cholesterol lowering in 2,722 people: systematic review and meta-analysis of randomized controlled trials. J Intern Med. 2009;265:568–580.
51. H.Slim, P.D.Thompson. Ezetimibe-related myopathy: a systematic review. J Clin Lipidol. 2008;2:328–334.
52. L.Luo, X.Yuan, W.Huang, et al. Safety of coadministration of ezetimibe and statins in patients with hypercholesterolaemia: a meta-analysis. Intern Med J. 2015;45:546–547.
53. C.A.Dujovne, M.P.Ettinger, J.F.McNeer, et al.; Ezetimibe Study Group. Efficacy and safety of a potent new selective cholesterol absorption inhibitor, ezetimibe, in patients with primary hypercholesterolemia. Am J Cardiol. 2002;90:1092–1097.
54. R.H.Knopp, C.A.Dujovne, A.Le Beaut, et al. Ezetimbe Study Group. Evaluation of the efficacy, safety, and tolerability of ezetimibe in primary hypercholesterolaemia: a pooled analysis from two controlled phase III clinical studies. Int J Clin Pract. 2003;57:363–368.
55. R.Fux, K.Mörike, U.F.Gundel, et al. Ezetimibe and statin-associated myopathy. Ann Intern Med. 2004;140:671–672.
56. J.Perez-Calvo, F.Civeira-Murillo, A.Cabello. Worsening myopathy associated with ezetimibe in a patient with McArdle disease. QJM. 2005;98:461–462.
57. C.Simard, P.Poirier. Ezetimibe-associated myopathy in monotherapy and in combination with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Can J Cardiol. 2006;22:141–144.
58. J.M.Havranek, A.R.Wolfsen, G.A.Warnke, et al. Monotherapy with ezetimibe causing myopathy. Am J Med. 2006;119:285–286.
59. T.Meas, C.Cimadevilla, J.Timsit, et al. Elevation of CKP induced by ezetimibe in monotherapy: report on two cases. Diabetes Metab. 2006;32:364–366.
60. C.M.Ballantyne, J.Houri, A.Notarbartolo, et al.; Ezetimibe Study Group. Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial. Circulation. 2003;107:2409–2415.
61. M.H.Davidson, D.Maccubbin, M.Stepanavage, et al. Striated muscle safety of ezetimibe/simvastatin (Vytorin). Am J Cardiol. 2006;97:223–228.
62. L.Masan, P.Mata, C.Gagné, et al. Ezetimibe Study Group. Long-term safety and, tolerability profiles and lipid-modifying efficacy of ezetimibe coadministered with ongoing simvastatin treatment: a multicenter, randomized, double-blind, placebo-controlled, 48-week extension study. Clin Ther. 2005;27:174–184.
63. C.P.Cannon, M.A.Blazing, R.P.Giugliano, et al.; IMPROVE-IT Investigators. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372:2387–2397.
64. S.E.Nissen, E.Stroes, R.E.Dent-Acosta, et al.; GAUSS-3 Investigators. Efficacy and tolerability of Evolocumab vs Ezetimibe in patients with muscle-related statin intolerance: the GAUSS-3 randomized clinical trial. JAMA. 2016;315:1580–1590.
65. V.G.Athyros, K.Tziomalos, A.I.Kakafika, et al. Effectiveness of ezetimibe alone or in combination with twice a week atorvastatin (10 mg) for statin intolerant high-risk patients. Am J Cardiol. 2008;101:483–485.
66. C.V.Venero, J.V.Venero, R.L.Seip, et al. Effectiveness of thrice weekly ezetimibe. Am J Cardiol. 2008;102:1205–1206.
67. J.Guo, F.Meng, N.Ma, et al. Meta-analysis of safety of the coadministration of statin with fenofibrate in patients with combined hyperlipidemia. Am J Cardiol. 2012;110:1296–1301.
68. M.C.Serban, M.Banach, D.P.Mikhailidis. Clinical implications of the IMPROVE-IT trial in the light of current and future lipid-lowering treatment options. Expert Opin Pharmacother. 2016;17:369–380.
69. American College of Cardiology/American Heart Association Task Force on Practice Guidelines, N.J.Stone, J.G.Robinson, A.H.Lichtenstein, et al. 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(25PtB):2889–2934.
70. J.M.McKenney, M.Farnier, K.W.Lo, et al. Safety and efficacy of long-term co-administration of fenofibrate and ezetimibe in patients with mixed hyperlipidemia. J Am Coll Cardiol. 2006;47:1584–1587.
71. M.H.Davidson, M.A.Dillon, B.Gordon, et al. Colesevelam hydrochloride(cholestagel): a new, potent bile acid sequestrant associated with a low incidence of gastrointestinal side effects. Arch Intern Med. 1999;159:1893–1900.
72. R.C.Heel, R.N.Brogden, G.E.Pakes, et al. Colestipol: a review of its pharmacological properties and therapeutic efficacy in patients with hypercholesterolaemia. Drugs. 1980;19:161–180.
73. S.Rivers, M.Kane, R.Busch, et al. Colesevelam hydrochloride-ezetimibe combination lipid-lowering therapy in patients with diabetes or metabolic syndrome and a history of statin intolerance. Endocr Pract. 2007;13:11–16.
74. R.H.Knopp, W.V.Brown, C.A.Dujovne, et al. Effects of fenofibrate on plasma lipoproteins in hypercholesterolemia and combined hyperlipidemia. Am J Med. 1987;83:50–59.
75. D.M.Capuzzi, J.R.Guyton, J.M.Morgan, et al. Efficacy and safety of an extended-release niacin (Niaspan): a long-term study. Am J Cardiol. 1998;82:74U–81U.
76. E.Stroes, D.Colquhoun, D.Sullivan, et al.; GAUSS-2 Investigators. Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol. 2014;63:2541–2548.
77. D.Sullivan, A.G.Olsson, R.Scott, et al. Effect of a monoclonal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statin-intolerant patients: the GAUSS randomized trial. JAMA. 2012;308:2497–2506.
78. P.M.Moriarty, P.D.Thompson, C.P.Cannon, et al.; ODYSSEY ALTERNATIVE Investigators. Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: the ODYSSEY ALTERNATIVE randomized trial. J Clin Lipidol. 2015;9:758–769.
79. E.A.Stein, R.P.Giugliano, M.J.Koren, et al. Efficacy and safety of evolocumab AMG 145., a fully human monoclonal antibody to PCSK9, in hyperlipidaemic patients on various background lipid therapies: pooled analysis of 1359 patients in 4 Phase 2 trials. Eur Heart J. 2014;35:2249–2259.
80. H.Tavori, M.Melone, S.Rashid. Alirocumab: PCSK9 inhibitor for LDL cholesterol reduction. Expert Rev Cardiovasc Ther. 2014;12:1137–1144.
81. Y.Li, L.Jiang, Z.Jia, et al. A meta-analysis of red yeast rice: an effective and relatively safe alternative approach for dyslipidemia. PLoS One. 2014;9:e98611.
82. D.J.Becker, R.Y.Gordon, S.C.Halbert, et al. Red yeast rice for dyslipidemia in statin-intolerant patients: a randomized trial. Ann Intern Med. 2009;150:830–839.
83. S.C.Halbert, B.French, R.Y.Gordon, et al. Tolerability of red yeast rice (2,400 mg twice daily) versus pravastatin (20 mg twice daily) in patients with previous statin intolerance. Am J Cardiol. 2010;105:198–204.
84. M.Banach, C.Serban, S.Ursoniu, et al.; Lipid and Blood Pressure Meta-analysis Collaboration (LBPMC) Group. Statin therapy and plasma coenzyme Q10 concentrations–A systematic review and meta-analysis of placebo-controlled trials. Pharmacol Res. 2015;99:329–336.
85. B.A.Taylor, L.Lorson, C.M.White, et al. A randomized trial of Coenzyme Q10 in patients with confirmed statin myopathy. Atherosclerosis. 2015;238:329–335.
86. M.Banach, C.Serban, A.Sahebkar, et al.; Lipid and Blood Pressure Meta-analysis Collaboration (LBPMC) Group. Effects of Coenzyme Q10 on statin-induced myopathy: a meta-analysis of randomized controlled trials. Mayo Clinic Proc. 2015;90:24–34.
87. D.A.Bookstaver, N.Burkhalter, C.Hatzigeorgiou. Effect of Coenzyme Q10 supplementation on statin-induced myalgias. Am J Cardiol. 2012;110:526–529.
88. G.Caso, P.Kelly, M.A.McNurlan, et al. Effect of CoenzymeQ10 on myopathic symptoms in patients treated with statins. Am J Cardiol. 2007;99:1409–1412.
89. M.Banach, C.Serban, A.Sahebkar, et al. Futility of supplementation with Coenzyme Q10 for statin-induced myopathy: an updated meta-analysis of randomized controlled trials. Eur Heart J. 2015;36(suppl 1.):1047.
90. M.Michalska-Kasiczak, A.Sahebkar, D.P.Mikhailidis, 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;178C:111–116.
91. S.E.Gryn, R.A.Hegele. Pharmacogenomics, lipid disorders, and treatment options. Clin Pharmacol Ther. 2014;96:36–47.
92. A.L.Mammen, T.Chung, L.Christopher-Stine, et al. Autoantibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase in patients with statin-associated autoimmune myopathy. Arthritis Rheum. 2011;63:713–721.
93. RDL Reference Library. Anti-HMGCR autoantibodies, (PDF). 2014; [cited 2016 May01].Availablefrom: http://www.rdlinc.com/rdlinc/wp-content/uploads/2014/02/Anti-HMGCR_Autoantibodies_February_2014.pdf
94. J.Patel, H.R.Superko, S.S.Martin, et al. Genetic and immunologic susceptibility to statin-related myopathy. Atherosclerosis. 2015;240:260–271.
95. P.Grable-Esposito, H.D.Katzberg, S.A.Greenberg, et al. Immune-mediated necrotizing myopathy associated with statins. Muscle Nerve. 2010;41:185–190.
96. J.L.Werner, L.Christopher-Stine, S.R.Ghazarian, et al. Antibody levels correlate with creatine kinase levels and strength in anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase-associated autoimmune myopathy. Arthritis Rheum. 2012;64:4087–4093.
97. R.Grimm, M.Malik, C.Yunis, et al. Simultaneous treatment to attain blood pressure and lipid goals and reduced CV risk burden using amlodipine/atorvastatin single-pill therapy in treated hypertensive participants in a randomized controlled trial. Vasc Health Risk Manag. 2010;6:261–271.
98. F.Malekzadeh, T.Marshall, A.Pourshams, et al. A pilot double-blind randomised placebo-controlled trial of the effects of fixed-dose combination therapy (‘polypill’) on cardiovascular risk factors. Int J Clin Pract. 2010;64:1220–1227.
99. J.M.Neutel, W.H.Bestermann, E.M.Dyess, et al. The use of a single-pill calcium channel blocker/statin combination in the management of hypertension and dyslipidemia: a randomized, placebo-controlled, multicenter study. J Clin Hypertens. 2009;11:22–30.
100. A.Rodgers, A.Patel, O.Berwanger, et al. An international randomised placebo-controlled trial of a four-component combination pill (“polypill”) in people with raised cardiovascular risk. PLoS ONE. 2011;6:e19857.
101. S.Yusuf, P.Pais, R.Afzal, et al.; Indian Polycap Study (TIPS). Effects of a polypill (Polycap) on risk factors in middle-aged individuals without cardiovascular disease (TIPS): a phase II, double-blind, randomised trial. Lancet. 2009;373:1341–1351.
102. D.S.Wald, J.K.Morris, N.J.Wald. Randomized polypill crossover trial in people aged 50 and over. PLoS ONE. 2012;7:e41297.
103. E.Z.Soliman, S.Mendis, W.P.Dissanayake, et al. A Polypill for primary prevention of cardiovascular disease: a feasibility study of the World Health Organization. Trials. 2011;12:3.
104. S.Thom, N.Poulter, J.Field, et al.; UMPIRE Collaborative Group. Effects of a fixed-dose combination strategy on adherence and risk factors in patients with or at high risk of CVD: the UMPIRE randomized clinical trial. JAMA. 2013;310:918–929.
105. A.Patel, A.Cass, D.Peiris, et al.; Kanyini Guidelines Adherence with the Polypill (Kanyini GAP) Collaboration. A pragmatic randomized trial of a polypill-based strategy to improve use of indicated preventive treatments in people at high cardiovascular disease risk. Eur J Prev Cardiol. 2015;22:920–930.
106. V.Selak, C.R.Elley, S.Crengle, et al. IMProving Adherence using Combination Therapy (IMPACT): design and protocol of a randomised controlled trial in primary care. Contemp Clin Trials. 2011;32:909–915.
107. G.Sanz, V.Fuster, L.Guzmán, et al. The fixed-dose combination drug for secondary cardiovascular prevention project: improving equitable access and adherence to secondary cardiovascular prevention with a fixed-dose combination drug. Study design and objectives. Am Heart J. 2011;162:811–817.
108. S.Yusuf, J.Bosch, G.Dagenais, et al., HOPE-3 Investigators. Cholesterol lowering in intermediate-risk persons without cardiovascular disease. N Engl J Med. 2016;374:2021–2031.
109. C.R.Elley, A.K.Gupta, R.Webster, et al. The efficacy and tolerability of ‘polypills’: meta-analysis of randomised controlled trials. PLoS One. 2012;7:e52145.
110. S.Yusuf, P.Pais, A.Sigamani, et al. Comparison of risk factor reduction and tolerability of a full-dose polypill (with potassium) versus low-dose polypill (polycap) in individuals at high risk of cardiovascular diseases: the Second Indian Polycap Study TIPS-2. investigators. Circ Cardiovasc Qual Outcomes. 2012;5:463–471.
111. M.Y.Wei, M.K.Ito, J.D.Cohen, et al. Predictors of statin adherence, switching, and discontinuation in the USAGE survey: understanding the use of statins in America and gaps in patient education. J Clin Lipidol. 2013;7:472–483.
112. D.C.Chan, W.H.Shrank, D.Cutler, et al. Patient, physician, and payment predictors of statin adherence. Med Care. 2010;48:196–202.
113. D.M.Mann, M.Woodward, P.Muntner, et al. Predictors of nonadherence to statins: a systematic review and meta-analysis. Ann Pharmacother. 2010;44:1410–1421.
114. A.H.Taylor, J.A.Schmittdiel, C.S.Uratsu, et al. Adherence to cardiovascular disease medications: does patient-provider race/ethnicity and language concordance matter? J Gen Intern Med. 2010;25:1172–1177.
115. D.G.Pittman, W.Chen, S.J.Bowlin, et al. Adherence to statins, subsequent healthcare costs, and cardiovascular hospitalizations. Am J Cardiol. 2011;107:1662–1666.
116. S.S.Martin, L.S.Sperling, M.J.Blaha, et al. Clinician-patient risk discussion for atherosclerotic cardiovascular disease prevention: importance to implementation of the 2013 ACC/AHA Guidelines. J Am Coll Cardiol. 2015;65:1361–1368.
117. T.A.Jacobson. Toward “pain-free” statin prescribing: clinical algorithm for diagnosis and management of myalgia. Mayo Clin Proc. 2008;83:687–700.
118. H.Hays, D.E.Cohen, N.Chalasani, et al. The National Lipid Association’s Statin Safety Task Force. An assessment by the statin liver safety task force: 2014 update. J Clin Lipidol. 2014;8(3 Suppl):S47–57.
119. S.Dragan, M.C.Serban, M.Banach. Proprotein convertase subtilisin/kexin 9 inhibitors: an emerging lipid-lowering therapy? J Cardiovasc Pharmacol Ther. 2015;20:157–168.
120. E.Link, S.Parish, J.Armitage, et al.; SEARCH Collaborative Group. SLCO1B1 variants and statin-induced myopathy–a genomewide study. N Engl J Med. 2008;359:789–799.
121. L.M.Mangravite, B.E.Engelhardt, M.W.Medina, et al. A statin-dependent QTL for GATM expression is associated with statin-induced myopathy. Nature. 2013;502:377–380.
122. D.F.Carr, A.Alfirevic, R.Johnson, et al. GATM gene variants and statin myopathy risk. Nature. 2014;513:E1.