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High-Intensity Statins Benefit High-Risk Patients: Why and How to Do Better

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Grundy, Scott M., Stone, Neil J., Blumenthal, Roger S., Braun, Lynne T., Heidenreich, Paul A., Lloyd-Jones, Donald, Orringer, Carl E., Saseen, Joseph J. +3 more·2021·Mayo Clinic Proceedings
DOI 10.1016/j.mayocp.2021.02.032
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Abstract

Review of the US and European literature indicates that most patients at high risk for atherosclerotic cardiovascular disease (ASCVD are not treated with high-intensity statins, despite strong clinical-trial evidence of maximal statin benefit. High-intensity statins are recommended for 2 categories of patients: those with ASCVD (secondary prevention) and high-risk patients without clinical ASCVD. Most patients with ASCVD are candidates for high-intensity statins, with a goal for low-density lipoprotein cholesterol reduction of 50% or greater. A subgroup of patients with ASCVD are at very high risk and can benefit by the addition of nonstatin drugs (ezetimibe with or without bile acid sequestrant or bempedoic acid and/or a proprotein convertase subtilisin/kexin type 9 inhibitor). High-risk primary prevention patients are those with severe hypercholesterolemia, diabetes with associated risk factors, and patients aged 40 to 75 years with a 10-year risk for ASCVD of 20% or greater. In patients with a 10-year risk of 7.5% to less than 20%, coronary artery calcium scoring is an option; if the coronary artery calcium score is 300 or more Agatston units, the patient can be up-classified to high risk. If high-intensity statin treatment is not tolerated in high-risk patients, a reasonable approach is to combine a moderate-intensity statin with ezetimibe. In very high-risk patients, proprotein convertase subtilisin/kexin type 9 inhibitors lower low-density lipoprotein cholesterol levels substantially and hence reduce risk as well.

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  • Statin prescriptions also appeared among important predictors, consistent with their indication for patients with diabetes and cardiovascular risk factors whose greater clinical complexity increases the likelihood of experiencing acute events requiring emergency care.

    “Statin prescriptions also appeared among important predictors, consistent with their indication for patients with diabetes and cardiovascular risk factors whose greater clinical complexity [86,87] increases the likelihood of experiencing acute events requiring emergency care [88–90].”

    From Machine learning-driven risk prediction for post-hospitalization diabetes case management: Integrating clinical and social determinants of health (2026) · cites this paper as [90]

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Research works printed but not linked: 58

  1. Cholesterol Treatment Trialists' (CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 rando- mised trials. Lancet. 2010;376(9753):1670-1681.
  2. Rodriguez F, Maron DJ, Knowles JW, Virani SS, Lin S, Heidenreich PA. Association between intensity of statin ther- apy and mortality in patients with atherosclerotic cardiovascular disease. JAMA Cardiol. 2017;2(1):47-54.
  3. Rodriguez F, Maron DJ, Knowles JW, Virani SS, Lin S, Heidenreich PA. Association of statin adherence with mortality in patients with atherosclerotic cardiovascular disease. JAMA Cardiol. 2019;4(3):206-213.
  4. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/ AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/ PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines [published correction appears in Circulation. 2019;139(25): e1182-e1186]. Circulation. 2019;139(25):e1082-e1143.
  5. Kazi DS, Moran AE, Coxson PG, et al. Cost-effectiveness of PCSK9 inhibitor therapy in patients with heterozygous familial hypercholesterolemia or atherosclerotic cardiovascular disease. JAMA. 2016;316(7):743-753.
  6. Maddox TM, Borden WB, Tang F, et al. Implications of the 2013 ACC/AHA cholesterol guidelines for adults in contempo- rary cardiovascular practice: insights from the NCDR PINNACLE registry. J Am Coll Cardiol. 2014;64(21):2183-2192.
  7. Rosenson RS, Kent ST, Brown TM, et al. Underutilization of high-intensity statin therapy after hospitalization for coronary heart disease. J Am Coll Cardiol. 2015;65(3):270-277.
  8. Reiner Z, De Backer G, Fras Z, et al; EUROASPIRE Investiga- tors. Lipid lowering drug therapy in patients with coronary heart disease from 24 European countriesdfindings from the EUROASPIRE IV survey. Atherosclerosis. 2016;246:243-250.
  9. Virani SS, Akeroyd JM, Smith SC, et al. Very high-risk ASCVD and eligibility for nonstatin therapies based on the 2018 AHA/ACC cholesterol guidelines [letter]. J Am Coll Cardiol. 2019;74(5):712-714.
  10. Virani SS, Akeroyd JM, Nambi V, et al. Applicability and cost im- plications for proprotein convertase subtilisin/kexin type 9 in- hibitors based on the ODYSSEY Outcomes trial [letter]. Circulation. 2019;139(3):410-412.
  11. McBride CL, Akeroyd JM, Ramsey DJ, et al. Statin prescription rates and their facility-level variation in patients with peripheral artery disease and ischemic cerebrovascular disease: insights from the Department of Veterans Affairs. Vasc Med. 2018; 23(3):232-240.
  12. Hirsh BJ, Smilowitz NR, Rosenson RS, Fuster V, Sperling LS. Utilization of and adherence to guideline-recommended lipid-lowering therapy after acute coronary syndrome: op- portunities for improvement. J Am Coll Cardiol. 2015;66(2): 184-192.
  13. Stroes ES, Thompson PD, Corsini A, et al; European Atherosclerosis Society Consensus Panel. Statin-associated muscle symptoms: impact on statin therapydEuropean Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. Eur Heart J. 2015;36(17):1012-1022.
  14. Newman CB, Preiss D, Tobert JA, et al; American Heart Asso- ciation Clinical Lipidology, Lipoprotein, Metabolism and Thrombosis Committee, a Joint Committee of the Council on Atherosclerosis, Thrombosis and Vascular Biology and Council on Lifestyle and Cardiometabolic Health; Council on Cardiovascular Disease in the Young; Council on Clinical Car- diology; and Stroke Council. Statin safety and associated adverse events: a scientific statement from the American Heart Association [published correction appears in Arterioscler Thromb Vasc Biol. 2019;39(5):e158]. Arterioscler Thromb Vasc Biol. 2019; 39(2):e38-e81.
  15. Virani SS, Akeroyd JM, Ahmed ST, et al. The use of structured data elements to identify ASCVD patients with statin-associated side effects: insights from the Department of Veterans Affairs. J Clin Lip- idol. 2019;13(5):797-803.e1.
  16. Thompson PD, Clarkson P, Karas RH. Statin-associated myop- athy. JAMA. 2003;289(13):1681-1690.
  17. Turner RM, Pirmohamed M. Statin-related myotoxicity: a comprehensive review of pharmacokinetic, pharmacogenomic and muscle components. J Clin Med. 2019;9(1):22.
  18. Pasternak RC, Smith SC Jr, Bairey-Merz CN, Grundy SM, Cleeman JI, Lenfant C. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. J Am Coll Cardiol. 2002;40(3): 567-572.
  19. Chan JCN, Kong APS, Bao W, Fayyad R, Laskey R. Safety of atorvastatin in Asian patients within clinical trials. Cardiovasc Ther. 2016;34(6):431-440.
  20. Lau TW, Tan KEK, Choo JCJ, Ng T-G, Tavintharan S, Chan JCN. Regional evidence and international recommendations to guide lipid management in Asian patients with type 2 diabetes with special reference to renal dysfunction. J Diabetes. 2018;10(3): 200-212.
  21. Parker BA, Thompson PD. Effect of statins on skeletal muscle: exercise, myopathy, and muscle outcomes [published correc- tion appears in Exerc Sport Sci Rev. 2013;41(1):71]. Exerc Sport Sci Rev. 2012;40(4):188-194.
  22. Vodnala D, Rubenfire M, Brook RD. Secondary causes of dys- lipidemia. Am J Cardiol. 2012;110(6):823-825.
  23. Saxon DR, Eckel RH. Statin intolerance: a literature review and management strategies. Prog Cardiovasc Dis. 2016;59(2):153- 164.
  24. Morioka TY, Lee AJ, Bertisch S, Buettner C. Vitamin D status modifies the association between statin use and musculoskel- etal pain: a population based study. Atherosclerosis. 2015; 238(1):77-82.
  25. Red yeast rice. Med Lett Drugs Ther. 2009;51(1320):71-72.
  26. Mammen AL, Chung T, Christopher-Stine L, et al. Autoanti- bodies against 3-hydroxy-3-methylglutaryl-coenzyme A reduc- tase in patients with statin-associated autoimmune myopathy. Arthritis Rheum. 2011;63(3):713-721.
  27. Nissen SE, Stroes E, Dent-Acosta RE, et al; GAUSS-3 Investiga- tors. Efficacy and tolerability of evolocumab vs ezetimibe in pa- tients with muscle-related statin intolerance: the GAUSS-3 randomized clinical trial. JAMA. 2016;315(15):1580-1590.
  28. LaRosa JC, Grundy SM, Waters DD, et al; Treating to New Tar- gets (TNT) Investigators. Intensive lipid lowering with atorvasta- tin in patients with stable coronary disease. N Engl J Med. 2005; 352(14):1425-1435.
  29. Pedersen TR, Faergeman O, Kastelein JJP, et al; Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) Study Group. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarc- tion: the IDEAL study; a randomized controlled trial [published correction appears in JAMA. 2005;294(24):3092]. JAMA. 2005; 294(19):2437-2445.
  30. Cannon CP, Braunwald E, McCabe CH, et al; Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus mod- erate lipid lowering with statins after acute coronary syndromes [published correction appears in N Engl J Med. 2006;354(7): 778]. N Engl J Med. 2004;350(15):1495-1504.
  31. Ridker PM, Danielson E, Fonseca FAH, et al; JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008; 359(21):2195-2207.
  32. Jacobson TA. The safety of aggressive statin therapy: how much can low-density lipoprotein cholesterol be lowered? Mayo Clin Proc. 2006;81(9):1225-1231.
  33. O'Malley PG, Arnold MJ, Kelley C, et al. Management of dysli- pidemia for cardiovascular disease risk reduction: synopsis of the 2020 updated U.S. Department of Veterans Affairs and U.S. Department of Defense clinical practice guideline. Ann Intern Med. 2020;173(10):822-829.
  34. Preiss D, Seshasai SRK, Welsh P, et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin ther- apy: a meta-analysis. JAMA. 2011;305(24):2556-2564.
  35. Robinson JG. Statins and diabetes risk: how real is it and what are the mechanisms? Curr Opin Lipidol. 2015;26(3):228-235.
  36. Ballantyne CM, Houri J, Notarbartolo A, 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(19):2409- 2415.
  37. Lakoski SG, Xu F, Vega GL, et al. Indices of cholesterol meta- bolism and relative responsiveness to ezetimibe and simvastatin [published correction appears in J Clin Endocrinol Metab. 2011; 96(5):1582]. J Clin Endocrinol Metab. 2010;95(2):800-809.
  38. Jones MR, Nwose OM. Role of colesevelam in combination lipid-lowering therapy. Am J Cardiovasc Drugs. 2013;13(5): 315-323.
  39. Bays HE, Davidson M, Jones MR, Abby SL. Effects of colesevelam hydrochloride on low-density lipoprotein cholesterol and high- sensitivity C-reactive protein when added to statins in patients with hypercholesterolemia [published correction appears in Am J Cardiol. 2006;98(3):428]. Am J Cardiol. 2006;97(8): 1198-1205.
  40. Vega GL, Dunn FL, Grundy SM. Effect of colesevelam hydro- chloride on glycemia and insulin sensitivity in men with the metabolic syndrome. Am J Cardiol. 2011;108(8):1129-1135.
  41. Rivers SM, Kane MP, Busch RS, Bakst G, Hamilton RA. Colese- velam hydrochloride-ezetimibe combination lipid-lowering therapy in patients with diabetes or metabolic syndrome and a history of statin intolerance. Endocr Pract. 2007;13(1):11-16.
  42. Mach F, Baigent C, Catapano AL, et al; ESC Scientific Docu- ment Group. 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk [published correction appears in Eur Heart J. 2020;41(44): 4255]. Eur Heart J. 2020;41(1):111-188.
  43. Mason RP, Libby P, Bhatt DL. Emerging mechanisms of car- diovascular protection for the omega-3 fatty acid eicosa- pentaenoic acid. Arterioscler Thromb Vasc Biol. 2020;40(5): 1135-1147.
  44. Bowen KJ, Harris WS, Kris-Etherton PM. Omega-3 fatty acids and cardiovascular disease: are there benefits? Curr Treat Op- tions Cardiovasc Med. 2016;18(11):69.
  45. Goldberg AC, Leiter LA, Stroes ESG, et al. Effect of bempedoic acid vs placebo added to maximally tolerated statins on low- density lipoprotein cholesterol in patients at high risk for cardio- vascular disease: the CLEAR Wisdom randomized clinical trial [published correction appears in JAMA. 2020;323(3):282]. JAMA. 2019;322(18):1780-1788.
  46. Ballantyne CM, Laufs U, Ray KK, et al. Bempedoic acid plus eze- timibe fixed-dose combination in patients with hypercholester- olemia and high CVD risk treated with maximally tolerated statin therapy. Eur J Prev Cardiol. 2020;27(6):593-603.
  47. Grundy SM, Cleeman JI, Merz CN, et al; Coordinating Commit- tee of the National Cholesterol Education Program. Implica- tions of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. J Am Coll Cardiol. 2004;44:720-732.
  48. Smith SC Jr, Benjamin EJ, Bonow RO, et al. AHA/ACCF second- ary prevention and risk reduction therapy for patients with coro- nary and other atherosclerotic vascular disease: 2011 update; a guideline from the American Heart Association and American College of Cardiology Foundation endorsed by the World Heart Federation and the Preventive Cardiovascular Nurses Association [published correction appears in J Am Coll Cardiol. 2015;65(14): 1495]. J Am Coll Cardiol. 2011;58(23):2432-2446.
  49. Thompson PD, Panza G, Zaleski A, Taylor B. Statin-associated side effects. J Am Coll Cardiol. 2016;67(20):2395-2410.
  50. Cannon CP, Sanchez RJ, Klimchak AC, et al. Simulation of the impact of statin intolerance on the need for ezetimibe and/or proprotein convertase subtilisin/kexin type 9 inhibitor for meeting low-density lipoprotein cholesterol goals in a popula- tion with atherosclerotic cardiovascular disease. Am J Cardiol. 2019;123(8):1202-1207.
  51. Stroes E, Colquhoun D, Sullivan D, et al; GAUSS-2 Investiga- tors. Anti-PCSK9 antibody effectively lowers cholesterol in pa- tients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol. 2014;63(23):2541-2548.
  52. Nissen SE, Dent-Acosta RE, Rosenson RS, et al; GAUSS-3 In- vestigators. Comparison of PCSK9 inhibitor evolocumab vs ezetimibe in statin-intolerant patients: design of the Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin-Intolerant Subjects 3 (GAUSS-3) trial. Clin Cardiol. 2016;39(3):137-144.
  53. Arrieta A, Hong JC, Khera R, Virani SS, Krumholz HM, Nasir K. Updated cost-effectiveness assessments of PCSK9 inhibitors from the perspectives of the health system and private payers: insights derived from the FOURIER trial. JAMA Cardiol. 2017; 2(12):1369-1374.
  54. Fonarow GC, van Hout B, Villa G, Arellano J, Lindgren P. Updated cost-effectiveness analysis of evolocumab in patients with very high-risk atherosclerotic cardiovascular disease. JAMA Cardiol. 2019;4(7):691-695.
  55. National Cholesterol Education Program (NCEP) 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(25):3143-3421.
  56. Santos RD, Stein EA, Hovingh GK, et al. Long-term evolocu- mab in patients with familial hypercholesterolemia. J Am Coll Cardiol. 2020;75(6):565-574.
  57. Orringer CE, Blaha MJ, Blankstein R, et al. The National Lipid Association scientific statement on coronary artery calcium scoring to guide preventive strategies for ASCVD risk reduc- tion. J Clin Lipidol. 2021;15(1):33-60.
  58. Greenland P, LaBree L, Azen SP, Doherty TM, Detrano RC. Coronary artery calcium score combined with Framingham score for risk prediction in asymptomatic individuals [published correction appears in JAMA. 2004;291(5):563]. JAMA. 2004; 291(2):210-215.

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Authors
Grundy, S. M., Stone, N. J., Blumenthal, R. S., Braun, L. T., Heidenreich, P. A., Lloyd-Jones, D., Orringer, C. E., Saseen, J. J., Smith, S. C., Sperling, L. S., & Virani, S. S.
Affiliations
  • The University of Texas Southwestern Medical Center (US)
  • Northwestern University (US)
  • Johns Hopkins University (US)
  • Rush University Medical Center (US)
  • Stanford University (US)
  • University of Miami (US)
  • University of Colorado Anschutz (US)
  • University of North Carolina at Chapel Hill (US)
  • Emory University (US)
  • Michael E. DeBakey VA Medical Center (US)
Corresponding author
Grundy, Scott M.
ORCID
Venue
Mayo Clinic Proceedings
Publisher
Elsevier BV
Published
2021-10
Volume
96
Issue
10
Pages
2660-2670
ISSN
0025-6196 (ISSN-L)
DOI
10.1016/j.mayocp.2021.02.032
OpenAlex
W3199734561
Cited by
20
References
14
Citations by year
2026: 2 · 2025: 4 · 2024: 7 · 2023: 5 · 2022: 2
FWCI
0.84
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Mayo Clinic Proceedings (publishedVersion)
  • PubMed (publishedVersion)
  • Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
  • eCommons - AKU (Aga Khan University) (submittedVersion)
  • UNC Libraries
Topics
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
Keywords
high-intensity statins, atherosclerotic cardiovascular disease, secondary prevention, primary prevention, LDL cholesterol lowering, ezetimibe, bile acid sequestrants, bempedoic acid, PCSK9 inhibitors, coronary artery calcium scoring, 10-year cardiovascular risk, severe hypercholesterolemia, diabetes mellitus, statin intolerance, treatment gap
MeSH terms
Ezetimibe, Anticholesteremic Agents, Coronary Artery Disease, Humans, Hypercholesterolemia, Cholesterol, LDL, Primary Prevention, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Secondary Prevention

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