Canadian Journal of Cardiology

An Evidence-Based Guide to Cholesterol-Lowering Guidelines

Published:October 24, 2016DOI:


      Since 2014, guidelines for the management of lipid disorders to reduce cardiovascular (CV) events have been updated in the United States, the United Kingdom, Europe, and Canada. Some of these guidelines are almost entirely evidence-based whereas others are a mix of evidence and expert opinion. Guidelines differ on such simple questions as to whether blood samples should be fasting or nonfasting, and whether low-density lipoprotein cholesterol (LDL-C) or another lipid parameter should be the primary focus of treatment. Different risk assessment tools are recommended by different guidelines. Lifetime risk is highlighted in some guidelines, with the suggestion that earlier treatment will reduce lifetime risk in younger people even when short-term risk is low. Some guidelines have numerical treatment targets that differ according to level of risk, while others eschew targets but recommend statins at high or moderate intensity to reduce LDL-C by ≥ 50% or 30%-50%, respectively. Statins are the backbone of therapy in all guidelines. Ezetimibe produced a 6.4% relative risk reduction in the only large clinical outcomes trial in which it was tested, and is recommended for high-risk patients with an inadequate response to statins, despite the high number needed to treat to prevent 1 CV event. Proprotein convertase subtilisin/kexin 9 inhibitors lack outcome data to support their use, but are approved for patients with familial hypercholesterolemia or clinical atherosclerotic CV disease who require additional LDL-C lowering beyond statins. All these new guidelines are aimed at improving the problem of undertreatment of high-risk groups, leading to better outcomes for these patients.


      Depuis 2014, les États-Unis, le Royaume-Uni, l’Europe et le Canada ont procédé à l’actualisation des lignes directrices sur la prise en charge des anomalies lipidiques pour réduire les événements cardiovasculaires (CV). Certaines de ces lignes directrices sont presque entièrement fondées sur les données probantes, tandis que les autres constituent une combinaison de données probantes et d’opinions d’experts. Les lignes directrices diffèrent sur de simples questions quant à savoir si les échantillons de sang devraient être prélevés à jeun ou non à jeun, et si l’objectif principal du traitement devrait porter sur le cholestérol à lipoprotéines de faible densité (cholestérol LDL) ou sur un autre paramètre du bilan lipidique. Les diverses lignes directrices recommandent différents outils d’évaluation des risques. Certaines lignes directrices mettent en relief les risques à vie, et suggèrent qu’un traitement plus précoce les réduira chez les personnes plus jeunes même lorsque les risques à court terme sont faibles. Certaines lignes directrices ont des cibles numériques de traitement qui diffèrent selon le niveau de risque, tandis que d’autres évitent les cibles, mais recommandent un traitement par statines d’intensité élevée ou modérée pour réduire respectivement le cholestérol LDL de ≥ 50 % ou de 30 % à 50 %. Les statines sont le pilier de traitement de toutes les lignes directrices. L’ézétimibe entraînait une réduction du risque relatif de 6,4 % dans la seule grande étude sur les résultats cliniques au cours de laquelle il était testé, et est recommandé chez les patients exposés à un risque élevé qui ont une réponse inadéquate aux statines, en dépit du nombre élevé de sujets à traiter pour empêcher 1 événement CV. Les inhibiteurs de la proprotéine convertase subtilisine/kexine de type 9 manquent de données sur les résultats cliniques pour soutenir leur utilisation, mais sont approuvés chez les patients atteints d’une hypercholestérolémie familiale ou d’une maladie CV athérosclérotique clinique qui nécessitent un hypocholestérolémiant pour abaisser le cholestérol LDL en plus des statines. Toutes ces nouvelles lignes directrices visent l’amélioration du problème de l’insuffisance de traitement des groupes exposés à un risque élevé afin d’entraîner de meilleurs résultats cliniques chez ces patients.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Canadian Journal of Cardiology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


      1. US Department of Health and Human Services. Agency for Healthcare Research and Quality. National Guideline Clearinghouse. Available at: Accessed April 28, 2016.

        • Tricoci P.
        • Allen J.M.
        • Kramer J.M.
        • Califf R.M.
        • Smith S.C.
        Scientific evidence underlying the ACC/AHA clinical practice guidelines.
        JAMA. 2009; 301: 831-841
        • Institute of Medicine
        Graham R. Mancher M. Wolman D.M. Greenfield S. Steinberg E. Clinical Practice Guidelines We Can Trust. National Academies Press, Washington, DC2011
      2. Nix MP. What a difference a year makes: 1 year after implementing the AHRQ National Guideline Clearinghouse's revised inclusion criteria. Available at: Accessed April 28, 2016.

        • Mora S.
        Nonfasting for routine lipid testing. From evidence to action.
        JAMA Intern Med. 2016; 176: 1005-1006
        • Reiner Z.
        • Catapano A.L.
        • De Backer G.
        • et al.
        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
      3. NICE. National Institute for Health and Care and Excellence. Lipid modification: cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease. Available at: Accessed April 30, 2016.

        • Stone N.J.
        • Robinson J.G.
        • Lichtenstein A.H.
        • 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: S1-S45
        • Anderson T.J.
        • Grégoire J.
        • Pearson G.J.
        • et al.
        2016 Canadian Cardiovascular Society guidelines for the management of dyslipidemia for the prevention of cardiovascular disease in the adult.
        Can J Cardiol. 2016; 32: 1263-1282
        • Catapano A.L.
        • Graham I.
        • De Backer G.
        • et al.
        2016 ESC/EAS Guidelines for the Management of Dyslipidaemias: the Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR).
        Eur Heart J. 2016; 37: 2999-3058
        • Verbeek R.
        • Hovingh G.K.
        • Boekholdt S.M.
        Non-high-density lipoprotein cholesterol: current status as cardiovascular marker.
        Curr Opin Lipidol. 2015; 26: 502-510
        • Wilson P.W.
        • D'Agostino R.B.
        • Levy D.
        • et al.
        Prediction of coronary heart disease using risk factor categories.
        Circulation. 1998; 97: 1837-1847
        • D'Agostino Sr., R.B.
        • Vassan R.S.
        • Pencina M.J.
        • et al.
        General cardiovascular risk profile for use in primary care: the Framingham Heart Study.
        Circulation. 2008; 117: 743-753
        • Eichler K.
        • Puhan M.A.
        • Steurer J.
        • Bachmann L.M.
        Prediction of first coronary events with the Framingham score: a systematic review.
        Am Heart J. 2007; 153: 722-731
        • Sivapalaratnam S.
        • Boekholdt S.M.
        • Trip M.D.
        • et al.
        Family history of premature coronary heart disease and risk prediction in the EPIC-Norfolk prospective population study.
        Heart. 2010; 96: 1985-1989
        • Goff D.C.
        • Lloyd-Jones D.M.
        • Bennett G.
        • et al.
        2013 ACC/AHA guideline on the assessment of cardiovascular risk. A report of the American College of Cardiology/American Heart Association task force on practice guidelines.
        Circulation. 2014; 129: S49-S73
        • Hippisley-Cox J.
        • Coupland C.
        • Vinogradova Y.
        • et al.
        Predicting cardiovascular risk in England and Wales: prospective derivation and validation of QRISK2.
        BMJ. 2008; 336: 1475-1482
        • Ference B.A.
        • Yoo W.
        • Alesh I.
        • et al.
        Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease. A Mendelian randomization analysis.
        J Am Coll Cardiol. 2012; 60: 631-639
        • Khera A.V.
        • Won H.H.
        • Peloso G.M.
        • et al.
        Diagnostic yield and clinical utility of sequencing familial hypercholesterolemia genes in patients with severe hypercholesterolemia.
        J Am Coll Cardiol. 2016; 67: 2578-2589
        • 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 randomised trials.
        Lancet. 2010; 376: 1670-1681
        • Bangalore S.
        • Fayyad R.
        • Kastelein J.J.
        • et al.
        2013 Cholesterol guidelines revisited: percent LDL cholesterol reduction or attained LDL cholesterol level or both for prognosis?.
        Am J Med. 2016; 129: 384-391
        • Robinson J.G.
        • Ray K.
        Counterpoint: low-density lipoprotein cholesterol targets are not needed in lipid treatment guidelines.
        Arterioscler Thromb Vasc Biol. 2016; 36: 586-590
        • Lloyd-Jones D.M.
        • Morris P.B.
        • et al.
        • Writing committee
        2016 ACC expert consensus decision pathway on the role of non-statin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk: a report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents.
        J Am Coll Cardiol. 2016; 68: 92-125
        • Boekholdt S.M.
        • Hovingh G.K.
        • Mora S.
        • et al.
        Very low levels of atherogenic lipoproteins and the risk for cardiovascular events: a meta-analysis of statin trials.
        J Am Coll Cardiol. 2014; 64: 485-494
        • Ridker P.M.
        • Mora S.
        • Rose L.
        • JUPITER Trial Study Group
        Percent reduction in LDL cholesterol following high-intensity statin therapy: potential implications for guidelines and for the prescription of emerging lipid-lowering agents.
        Eur Heart J. 2016; 37: 1373-1379
        • Soran H.
        • Schofield J.D.
        • Durrington P.N.
        Cholesterol, not just cardiovascular risk, is important in deciding who should receive statin treatment.
        Eur Heart J. 2015; 36: 2975-2983
        • Robinson J.G.
        Lower might be better – it matters how you get there, and in whom.
        Eur Heart J. 2016; 37: 1380-1383
        • Thanassoulis G.
        • Williams K.
        • Altobelli K.K.
        • et al.
        Individualized statin benefit for determining statin eligibility in the primary prevention of cardiovascular disease.
        Circulation. 2016; 133: 1574-1581
        • Steel N.
        Thresholds for taking antihypertensive drugs in different professional and lay groups: questionnaire survey.
        BMJ. 2000; 320: 1446-1447
        • Collins R.
        • Reith C.
        • Emberson J.
        • et al.
        Interpretation of the evidence for the efficacy and safety of statin therapy.
        Lancet. 2016; 388: 2532-2561
        • Cannon C.P.
        • Blazing M.A.
        • Giugliano R.P.
        • et al.
        Ezetimibe added to statin therapy after acute coronary syndromes.
        N Engl J Med. 2015; 372: 2387-2397
      4. FDA Briefing Document. Endocrinologic and Metabolic Drugs Advisory Committee, December 14, 2015. Available at: Accessed December 10, 2016.

        • Waters D.D.
        • Hsue P.Y.
        PCSK9 inhibitors to lower LDL-cholesterol and reduce cardiovascular risk. Great expectations.
        Circ Res. 2015; 116: 1643-1645
        • Waters D.D.
        • Hsue P.Y.
        • Bangalore S.
        PCSK9 inhibitors for statin intolerance?.
        JAMA. 2016; 315: 1571-1572
        • Kazi D.S.
        • Moran A.E.
        • Coxson P.G.
        • et al.
        Cost-effectiveness of PCSK9 inhibitor therapy in patients with heterozygous familial hypercholesterolemia or atherosclerotic cardiovascular disease.
        JAMA. 2016; 316: 743-753
        • Grimshaw J.M.
        • Russell I.T.
        Effect of clinical guidelines on medical practice: a systematic review of rigorous evaluations.
        Lancet. 1993; 342: 1317-1322
        • Yusuf S.
        • Islam S.
        • Chow C.K.
        • et al.
        Use of secondary prevention drugs for cardiovascular disease in the community in high-income, middle-income, and low-income countries (the PURE Study): a prospective epidemiological survey.
        Lancet. 2011; 378: 1231-1243
        • Jeffery R.A.
        • To M.J.
        • Hayduk-Costa G.
        • et al.
        Interventions to improve adherence to cardiovascular disease guidelines: a systematic review.
        BMC Fam Pract. 2015; 16: 147
        • Nichols M.
        • Townsend N.
        • Scarborough P.
        • Rayner M.
        Cardiovascular disease in Europe 2014: epidemiological update.
        Eur Heart J. 2014; 35: 2950-2959
        • Sidney S.
        • Quesenberry Jr., C.P.
        • Jaffe M.G.
        • et al.
        Recent trends in cardiovascular mortality in the United States and public health goals.
        JAMA Cardiol. 2016; 1: 594-599
        • Tu J.V.
        • Khan A.M.
        • Ng K.
        • Chu A.
        Recent temporal changes in atherosclerotic cardiovascular diseases in Ontario: clinical and health systems impact.
        Can J Cardiol. 2017; 33: 378-384