Hypercholesterolemia

• condition characterized by elevated serum levels of total cholesterol, low-density lipoprotein cholesterol or non-high-density lipoprotein cholesterol^1,2,3
• this topic deals with nonfamilial forms of hypercholesterolemia; see also Familial hypercholesterolemia

• dyslipidemia (broader term for abnormal amounts of fat or cholesterol in the blood)
• hypercholesterolemia may also be called
  • hypercholesterolaemia
  • pure hypercholesterolemia
  • Fredrickson Type IIa hyperlipoproteinemia
  • hyperbetalipoproteinemia
  • group A hyperlipidemia
  • low-density lipoprotein hyperlipoproteinemia
• mixed hypercholesterolemia (hypercholesterolemia with hypertriglyceridemia) may also be called
  • broad-betalipoproteinemia
  • floating-betalipoproteinemia
  • Fredrickson Type IIb hyperlipoproteinemia
  • Fredrickson Type III hyperlipoproteinemia
  • hypercholesterolemia with endogenous hyperglyceridemia
  • hyperbetalipoproteinemia with prebetalipoproteinemia
  • combined hyperlipidemia

• Table 1. Fredrickson Classification of Dyslipidemias*

  Phenotype	Lipoproteins(s) Elevated	Serum Cholesterol Level	Serum Triglyceride Level	Atherogenicity
  I	Chylomicrons	Normal to mildly increased	Very severely increased	None
  IIa	LDL	Moderately increased	Normal	Severe
  IIb	LDL and VLDL	Moderately increased	Moderately increased	Severe
  III	IDL	Moderately increased	Severely increased	Severe
  IV	VLDL	Normal to mildly increased	Moderately increased	Mild to Moderate
  V	VLDL and chylomicrons	Normal to mildly increased	Very severely increased	Mild to Moderate
  Abbreviations: HDL, high-density lipoprotein; IDL,                                     intermediate-density lipoprotein; LDL, low-density lipoprotein;                                     VLDL, very-low-density lipoprotein. * HDL cholesterol levels not considered. Reference -                                     14262568Circulation 1965 Mar;31:321

1. 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 Dec 17;106(25):3143-421PDF or at NHLBI 2002 Sep PDF, editorial can be found in Circulation 2002 Dec 17;106(25):3140
2. Grundy SM, Cleeman JI, Merz CN, et al; National Heart, Lung, and Blood Institute, American College of Cardiology Foundation, American Heart Association. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004 Jul 13;110(2):227-39full-text, correction can be found in Circulation 2004 Aug 10;110(6):763
3. National Institute for Health and Care Excellence (NICE). Lipid modification: cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease. NICE 2014 Jul:CG181PDF, summary can be found in BMJ 2014 Jul 17;349:g4356
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. J Am Coll Cardiol. 2018 Nov 8 early online
5. Goff DC Jr, Lloyd-Jones DM, 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 Jun 24;129(25 Suppl 2):S49-73 or in J Am Coll Cardiol 2014 Jul 1;63(25 Pt B):2935full-text (correction can be found in J Am Coll Cardiol 2014 Jul 1;63(25 Pt B):3026), commentary can be found in Mayo Clin Proc 2014 Jun;89(6):722
6. Eckel RH, Jakicic JM, Ard JD, et al. 2013 AHA/ACC Guideline on Lifestyle Management to Reduce Cardiovascular Risk: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014 Jun 24;129(25 Suppl 2):S76-99 or in J Am Coll Cardiol 2014 Jul 1;63(25 Pt B):2960PDF
7. Catapano AL, Graham I, De Backer G, et al. 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias. Eur Heart J. 2016 Oct 14;37(39):2999-3058

• Canadian Cardiovascular Society (CCS) uses Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system
  • strength of recommendations
    • Strong recommendation - high confidence that desirable effects of recommendation outweigh undesirable effects
    • Conditional recommendation - less confidence that desirable effects of recommendation probably outweigh undesirable effects, or benefits and harms are finely balanced, or appreciable uncertainty
  • quality of evidence
    • High - further research very unlikely to change confidence in estimate of effect
    • Moderate - further research likely to have important impact on confidence in estimate of effect and may change estimate
    • Low - further research very likely to have important impact on confidence in estimate of effect and likely to change estimate
    • Very low - any estimate of effect very uncertain
  • Reference - 2016 CCS guideline on management of dyslipidemia for prevention of cardiovascular disease in adults (27712954Can J Cardiol 2016 Nov;32(11):1263)

• American College of Cardiology/American Heart Association (ACC/AHA) grading system for recommendations
  • classifications of recommendations
    • Class I - procedure or treatment should be performed or administered
    • Class IIa - reasonable to perform procedure or administer treatment, but additional studies with focused objectives needed
    • Class IIb - procedure or treatment may be considered; additional studies with broad objectives needed, additional registry data would be useful
    • Class III - procedure or treatment should not be performed or administered because it is not helpful or may be harmful
      • Class III ratings may be subclassified as Class III No Benefit or Class III Harm
  • levels of evidence
    • Level A - data derived from multiple randomized clinical trials or meta-analyses
    • Level B - data derived from single randomized trial or nonrandomized studies
    • Level C - only expert opinion, case studies, or standard of care
  • Reference - 2013 ACC/AHA guideline on treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults (24222016Circulation 2014 Jun 24;129(25 Suppl 2):S1), also published in 24239923J Am Coll Cardiol 2014 Jul 1;63(25 Pt B):2889PDF
• American College of Cardiology/American Heart Association (ACC/AHA) grading system for recommendations
  • classifications of recommendations
    • Class I - procedure or treatment should be performed or administered
    • Class IIa - reasonable to perform procedure or administer treatment, but additional studies with focused objectives needed
    • Class IIb - procedure or treatment may be considered; additional studies with broad objectives needed, additional registry data would be useful
    • Class III - procedure or treatment should not be performed or administered because it is not helpful or may be harmful
      • Class III ratings may be subclassified as Class III No Benefit or Class III Harm
  • levels of evidence
    • Level A - high-quality evidence from > 1 randomized controlled trial or meta-analysis of high-quality randomized controlled trials
    • Level B-R - moderate-quality evidence from ≥ 1 randomized controlled trial or meta-analysis of moderate-quality randomized controlled trials
    • Level B-NR - moderate-quality evidence from ≥ 1 well-designed nonrandomized trial, observational studies, or registry studies, or meta-analysis of such studies
    • Level C-LD - randomized or nonrandomized studies with methodological limitations or meta-analyses of such studies
    • Level C-EO - consensus of expert opinion based on clinical experience
  • Reference - AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on management of blood cholesterol (30423393J Am Coll Cardiol 2018 Nov 8 early online)
• European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) grading system for recommendations
  • classes of recommendations
    • Class I - evidence and/or general agreement that given treatment or procedure is beneficial, useful, and effective
    • Class II - conflicting evidence and/or divergence of opinion about usefulness/efficacy of given treatment or procedure
      • Class IIa - weight of evidence/opinion in favor of usefulness/efficacy
      • Class IIb - usefulness/efficacy less well established by evidence/opinion
    • Class III - evidence or general agreement that given treatment or procedure is not useful/effective, and in some cases may be harmful
  • levels of evidence
    • Level A - data derived from multiple randomized clinical trials or meta-analyses
    • Level B - data derived from single randomized clinical trial or large nonrandomized studies
    • Level C - consensus of opinion of experts and/or small studies, retrospective studies, registries
  • Reference - ESC/EAS guideline on management of dyslipidemias (Eur Heart J 2016 Oct 14;37(39):2999full-text)

• United States Preventive Services Task Force (USPSTF) grades of recommendation (June 2007 to June 2012)
  • Grade A - USPSTF recommends the service with high certainty of substantial net benefit
  • Grade B - USPSTF recommends the service with high certainty of moderate net benefit or moderate certainty of moderate-to-substantial net benefit
  • Grade C - clinicians may provide the service to select patients depending on individual circumstances; however, only small benefit is likely for most individuals without signs or symptoms
  • Grade D - USPSTF recommends against providing the service with moderate-to-high certainty of no net benefit or harms outweighing benefits
  • Grade I - insufficient evidence to assess balance of benefits and harms
  • Reference - USPSTF Grade Definitions

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