CHD morbidity and mortality rates have more than halved since their peak in the 1960s and 1970s. This trend is a result of many factors; however, primary prevention provides the bulk of this benefit. Despite this tremendous progress, cardiovascular disease remains the major cause of death and this trend is projected to persist given the continuous growth in those aged 65 years or greater. Although statin therapy has been a main contributor to a primary prevention strategy, there is still controversy about exposing a large healthy population to long-term statin therapy. Advocates contend the mortality benefits from an aggressive statin approach would remove heart disease from its perch as the greatest killer of Americans and stroke mortality would drop from third to fifth place. Those advocating a much more conservative approach contend the data are not available to expose a healthy population to lifelong statin therapy given limited data on mortality, potential adverse events, and considerable costs. Given these opposing views, this summary of the evolution of statin therapy for the primary prevention of cardiovascular disease will review the major factors fueling this debate.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease in men with hypercholesterolemia. N Engl J Med. 1995;333:1301–7.
Downs JR, Clearfield MB, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels. Results of AFCAPS/TexCAPS. JAMA. 1998;279:1615–22.
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.
Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomized controlled trial. Lancet. 2002;360:1623–30.
The ALLHAT Collaborative Research Group. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: the antihypertensive and lipid lowering treatment to prevent heart attack trial. JAMA. 2002;288:2998–3007.
Sever PS, Dalhof B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower than average cholesterol concentrations in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a multicenter randomized controlled trial. Lancet. 2003;361:1149–58.
Collins R, Armitage J, Parish S, et al. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 5963 people with diabetes: a randomized placebo controlled trial. Lancet. 2003;361:2005–16.
Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS); multicenter randomized placebo controlled trial. Lancet. 2004;364:685–96.
Thavendiranathan P, Bagai A, Brookhart MA, et al. Primary prevention of cardiovascular diseases with statin therapy: a meta-analysis of randomized controlled trials. Arch Int Med. 2006;166:2307–13.
Nakamuro H, Arakawa K, et al. Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA Study): a prospective randomized controlled trial. Lancet. 2006;368:1155–63.
Ridker PM, Rifai N, Clearfield M, et al. Measurement of C-reactive protein for the targeting of statin therapy in primary prevention of acute coronary events. N Engl J Med. 2001;344:1959–65.
Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation and cardiovascular disease: application to clinical public health practice. A statement for health care professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation. 2003;107:499–511.
Murphy SA, Cannon CP, Wiviott, et al. Effect of intensive lipid lowering therapy on mortality after acute coronary syndrome (a patient level analysis of the Aggrastat to Zocor and pravastatin or atorvastatin evaluation and infection therapy-thrombolysis in myocardial infarction 22 trials). Am J Cardiol. 2007;100:1047–51.
Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med. 2005;352:20–8.
Ridker PM, Danielson E, Fonseca AF, for the JUPITER study group, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2197–207.
Ridker PM, Danielson E, Fonseca F, et al. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. Lancet. 2009;373:1175–83.
• Hsia J, MacFadyen JG, Monyak J. Cardiovascular event reduction and adverse events among subjects attaining LDL-C < 50 mg/dl with rosuvastatin. J Am Coll Cardiol. 2011;57:1666–75. This substudy of JUPITER demonstrated those subjects treated with rosuvastatin who achieved LDL-C levels below 50 mg/dl continued to have lower rates of cardiovascular events without an increase in the rates of statin-induced adverse events.
Lee KH, Jeong MH, Kim HM, et al. Benefit of early statin therapy in patients with acute myocardial infarction who have extremely low LDL-C. J Am Coll Cardiol. 2011;58:1664–71.
Ray KK, Seshasai S, Erqou S, et al. Statins and all-cause mortality in high risk primary prevention. Arch Intern Med. 2010;170:1024–31.
Brugts JJ, Yetgin T, Hoeks SE, Gotto AM, et al. The benefits of statins in people without established cardiovascular disease but with cardiac risk factor: meta-analysis of randomized controlled trials. BMJ. 2009;338:b2376. doi:10.1136/bmj.b2376.
Taylor F, Ward K, Moore THM, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2011;(1):CD004816
Grammer TB. Are statins really useless in primary prevention? Recent Cochrane meta-analysis revisited. Int J Clin Pharmacol Ther. 2011;49:293–6.
Goldfine AB. Statins: is it really time to reassess benefits and risk? NEJM. 2012;366(19):1752–5.
Minder CM, Blaha MJ, Horne A, et al. Evidence based use of statins for primary prevention of cardiovascular disease. Am J Med. 2012;125(5):440–6.
•• Cholesterol Treatment Trialists’ Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomized trials. Lancet. 2010;376:1670–11681. This is the most comprehensive meta-analysis on statin therapy for the prevention of cardiovascular disease. This analysis demonstrated there was no evidence for any threshold within the cholesterol range studied and suggested reductions in LDL-C levels by 2–3 mmol/l could reduce the risk of cardiovascular disease by 40-50%.
•• Cholesterol Treatment Trialists’ Collaborators. The effects of lowering LDL-C with statin therapy in people at low risk of vascular disease: a meta-analysis of individual data from 27 randomized trials. Lancet. 2012;380:581–90. This meta-analysis evaluating subjects at low risk of vascular disease demonstrated continued cardiovascular benefits from statins in lower-risk subgroups currently not recommended for statin therapy.
Redberg RF, Katz M, Grady D. To make the case: evidence is required. Comment on “making the case for selective use of statins in the primary prevention setting.”. Arch Int Med. 2011;171:1594.
Steinberg D. Earlier intervention in the management of hypercholesterolemia. What are we waiting for? J Am Coll Cardiol. 2010;56:627–9.
Roberts WC. It’s the cholesterol, stupid! Am J Cardiol. 2010;106:1364–6.
Forrester JS. Redefining normal low-density cholesterol. A strategy to unseat coronary disease as the Nation’s leading killer. J Am Coll Cardiol. 2010;56:630–6.
• Domanski M, Lloyd-Jones D, Fuster V, Grundy S. Can we dramatically reduce the incidence of coronary heart disease? Nat Rev Cardiol. 2011;8:721–5. This article outlines the feasibility and basic design for a new clinical trial to further assess an LDL-C-lowering strategy in men aged 35–50 years and women aged 35–59 years.
Girman CJ, Rhodes T, Mercuri M, et al. The metabolic syndrome and risk of major coronary events in the Scandinavian Simvastatin Survival Study (4S) and the Air Force/Texas Coronary Atherosclerosis Prevention Study. Am J Cardiol. 2004;93:136–41.
Clearfield M, Downs JR, Lee M, et al. Implications from the Air Force/Texas Coronary Atherosclerosis Prevention Study for the Adult Treatment Panel III guidelines. Am J Cardiol. 2005;96:1674–80.
Clearfield M. Statins and the primary prevention of cardiovascular events. Curr Atheroscler Reports. 2006;8:390–96.
Ridker PM, MacFadyen JG, Nordestgaard BG, et al. Rosuvstatin for primary prevention among individuals with elevated high sensitivity C-reactive protein and 5% to 10% and 10% to 20% 10 year risk. Circ Cardiovasc Qual Outcomes. 2010;3:447–52.
Sniderman A, Thanassoulis G, Couture P, et al. Is lower and lower better and better? A re-evaluation of the evidence from the Cholesterol Treatment Trialists’ Collaboration meta-analysis for LDL-C lowering. J Clin Lipidology. 2012;6:303–9.
Lloyd-Jones D, Adams R, Carnethon M, American Heart Association Statistics Committee and Stroke statistics subcommittee, et al. Heart disease and stroke statistics-2009 update: a report from the American Heart Association Statistics Committee and Stroke statistics subcommittee. Circulation. 2009;119(3):e21–e181.
Culver AL, Balasubramanian R, Olendzki BC, et al. Statin use and risk diabetes mellitus in postmenopausal women in the Women’s Health Initiative. Arch Int Med. 2012;172:144–52.
Preiss D, Seshasai RK, Welsh P, et al. Risk of incident diabetes with intensive dose compared with moderate dose statin therapy. A meta-analysis. JAMA. 2011;305:2556–64.
Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy of cholesterol lowering therapy in 18,686 people with diabetes in 14 randomized trials of statins: a meta-analysis. Lancet. 2008;371:117–25.
• Ridker PM, Pradham A, MacFaden JG, et al. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial. Lancet. 2012;380:565–71. The JUPITER analysis noted an increased risk of new onset of diabetes in those treated with rosuvastatin versus placebo; however, this risk was almost entirely isolated to those with risk factors for diabetes or in a prediabetic state.
Wang KL, Liu CJ, Chao TF, et al. Statins, Risk of diabetes and implications on outcome in the general population. J Am Coll Cardiol. 2012;60:1231–8.
• Kizer JR, Madias C, Wilner B, et al. Relation of different measures of LDL-C to risk of coronary artery disease and death in a meta-regression analysis of large scale trials of statin therapy. Am J Cardiol. 2010;105:11289–1296. This analysis suggests the absolute reduction in LDL-C level by comparing the control and treatment groups was the predominant determinant for mortality reduction from treatment with statins.
Lloyd-Jones DM, Dyer AR, Wang R, et al. Risk factor burden in middle age and lifetime risks for cardiovascular and non-cardiovascular death. (Chicago Heart Association Detection Project in Industry). Am J Cardiol. 2007;99:535–40.
Lloyd-Jones DM, Leip EP, Larson MG, et al. Prediction of lifetime risk for cardiovascular disease by risk factor burden at 50 years of age. Circulation. 2006;113:791–8.
Cohen JC, Boerwinkle E, Mosely TH, Hobbs HH. Sequence variations in PCSK9, low LDLand protection against coronary heart disease. N Engl J Med. 2006;354:1264–72.
Martin SS, Metkus TS, Horne A, et al. Waiting for the National Cholesterol Education Program Adult Treatment Panel IV Guidelines, and in the meantime, some challenges and recommendations. Am J Cardiol. 2012;110:307–13.
• Kostis WJ, Moreyra AE, Cheng JQ, et al. Continuation of mortality reduction after the end of randomized therapy in clinical trials of lipid lowering therapy. J Clin Lipidology. 2011;5:97–104. A meta-analysis of eight lipid-lowering trials (including five statin trials) showed a continuous cardiovascular benefit after the trials concluded and suggested a legacy effect may be possible where curves continued to diverge after discontinuation of the blinded therapy.
Simpson RJ, Mendys P. The effect of adherence and persistence on clinical outcomes in patients treated with statins: A systematic review. J Clin Lipidiology. 2010;4:462–71.
LaRosa JC, Deedwania PC, Shepherd JM, et al. Comparison of 80 vs 10 mg of atorvastatin on occurrence of cardiovascular events after first event (from the Treating to New Targets [TNT] trial). Am J Cardiol. 2010;105:283–87.
Choudhry NK, Patrick AR, Glynn RJ, et al. The cost-effectiveness of C-reactive protein and rosuvastatin treatment for patients with normal cholesterol. J Am Coll Cardiol. 2011;57:784–91.
Pletcher MJ, Lazar L, Bibbins-Domingo K, et al. Comparing impact and cost-effectiveness of primary prevention strategies for lipid lowering. Ann Intern Med. 2009;150:243–54.
LaRosa JC, Grundy SM, Kastelein JP, et al. Safety and efficacy of atorvastatin induced very low LDL-C levels patients with coronary heart disease (a post hoc analysis of the Treating to New Target (TNT) study. Am J Cardiol. 2007;100:747–52.
Sever P, Poulter NR, Chang C, et al. Evaluation of CRP prior to and on-treatment as a predictor of benefit from the Anglo-Scandanavian Cardiac Outcomes Trial. Eur Heart J. 2012;33:486–94.
Braunwald E. Creating controversy where none exists: the important role of CRP in CARE, AFCAPS/TexCAPS, PROVE-IT, REVERSAL, A to A, JUPITER, HEART PROTECTION and ASCOT trials. Eur Heart J. 2012;33:430–2.
Mottillo SM, Filion KB, Genest J, et al. The metabolic syndrome and cardiovascular risk: A systemic review and meta-analysis. J Am Coll Cardiol. 2010;56:1113–32.
Robinson JG, Smith B, Maheshwari, et al. Pleiotropic effects of statins: benefit beyond cholesterol reduction? A meta-regression analysis. J Am Coll Cardiol. 2005;46:1855–62.
Robinson JG. Models for describing relations among various statin drugs, lowering LDL-C, pleiotropic effects, and cardiovascular risk. Am J Cardiol. 2008;101:1009–15.
Genest J. C-reactive protein: risk factor, biomarker and/or therapeutic target? Can J Cardiol. 2010;26:A41–4.
Ridker P. Testing the inflammatory hypothesis of atherothrombosis: scientific rationale for the cardiovascular inflammation reduction trial. (CIRT). J Thrombo Heamost. 2009;7 Suppl 1:332–9.
Ridker PM, Thuren T, Zalewski A, Libby P. Interleukin-1β inhibition and the prevention of recurrent cardiovascular events: rationale and design of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS). Am Heart J. 2011;162:597–605.
Young F, Capewell S, Ford E, et al. Coronary mortality declines in the U.S. between 1980 and 2000. Quantifying the contributions from primary and secondary prevention. Am J Prev Med. 2010;39:228–34.
Kerr AJ, Broad J, Wells S, Riddell T, Jackson R. Should the first priority in cardiovascular risk management be those with prior cardiovascular disease? Heart. 2009;95:125–9.
Roger VL, Go AS, Lloyd-Jones, et al. Executive summary: heart disease and stroke statistics-2102 update. A report from the American Heart Association. Circ. 2012;125:188–97.
Barter PJ, Caulfield M, Eriksson M, Grundy SM, Kastelein JP, Komajda M, Lopez-Sendon J, Mosca L, Tardif JC, Waters D, Shear CL, Revkin JH, Buhr KA, Fisher M, Tall AR, Brewer B, for the ILLUMINATE Investigators. Effects of torcetrapib in patients at high risk for coronary events. New Engl J Med. 2007;357:2109–22.
ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes mellitus. New Engl J Med. 2010;362:1563–74.
Cannon CP, Shah S, Dansky HM, Davidson M, Brinton E, Gotto AM, Stepanavage M, Liu SX, Gibbons P, Ashraf TB, Zafarino J, Mitchel Y, Barter P, for the DEFINE investigators. Safety of anacetrapib in patients with or at high risk for coronary heart disease. New Engl J Med. 2010;363:2406–15.
Ridker PM, Fonseca F, Genest J, et al. Baseline characteristics of participants in the JUPITER, a randomized placebo-controlled primary prevention trial of statin therapy among individuals with low LDL-C and elevated hs-CR. Am J Cardiol. 2007;100:1659–64.
Glynn RJ, Koenig W, Nordestgaard BG, Shepherd J, Ridker PM. Rosuvastatin for primary prevention in older persons with elevated C-reactive protein and low to average LDL-C levels: exploratory analysis of a randomized trial. Ann Int Med. 2010;152:488–96.
Rahilly-Tierney CR, Lawler EV, Scranton RE, Gaziano M. Cardiovascular benefit of magnitude of LDL-C reduction. A comparison of subgroups by age. Circulation. 2009;120:1491–7.
Rodenburg J, Vissers MN, Wiegman A, van Trotsenburg AS, van der Graaf A, de Groot E, Wijburg FA, Kastelein JJP, Hutten BA. Statin treatment in children with familial hypercholesterolemia: the younger, the better. Circulation. 2007;116:664–8.
Vermissen J, Oosterveer D, Yazdanpanah M, Defesche JC, Basart D, Liem AH, Heeringa J, Witteman JC, Lansberg PJ, Kastelein JP, Sijbrands EJ. Efficacy of statins in familial hypercholesterolemia: a long term cohort study. BMJ. 2008;337:a2423. doi:10.1136/bmj.a2423.
Genest J, McPherson R, Frohlich J, et al. 2009 Canadian Cardiovascular Society/Canadian guidelines for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease in the adult-2009 recommendations. Can J Cardiol. 2009;25(10):567–79.
P. Rehfield: none, C. Kopes-Kerr: none, and M. Clearfield: consultancy, honoraria received from and has travel/accommodation expenses covered or reimbursed by Astra Zeneca and Daiichi Sankyo.
This article is part of the Topical Collection on Statin Drugs
About this article
Cite this article
Rehfield, P., Kopes-Kerr, C. & Clearfield, M. The Evolution or Revolution of Statin Therapy in Primary Prevention: Where Do We Go From Here?. Curr Atheroscler Rep 15, 298 (2013). https://doi.org/10.1007/s11883-012-0298-0
- Primary prevention
- LDL target
- C-reactive protein