Author(s)/Faculty: W. Virgil Brown, MD, FNLA; Yehuda Handelsman, MD, FACP, FACE, FNLA; Seth S. Martin, MD, MHS; Pamela B. Morris, MD, FNLA
Source: Healio - Cardiology Education Lab
Type: VideoArticles/Items: 9
Release Date: 4/19/2017Expiration Date: 4/18/2018
Credit Type: CME / CNE / CPE / ParticipationNumber of Credits: 1.75
Cost: FreeProvider: National Lipid AssociationPostgraduate Institute for Medicine

Past-President of the National Lipid Association and Editor-in-Chief of the Journal of Clinical Lipidology, Dr. W. Virgil Brown is joined by Drs. Yehuda Handelsman, Pamela Morris, and Seth Martin to discuss new issues in lipoprotein management, including assessment of treatment targets, documenting and using new targets of treatment and the setting of goals-setting for these lipoprotein targets. This included the use of clinical trial data, and the feasibility of applying new laboratory measures into guidelines for clinical practice. Finally, the discussion led to the importance of developing new data management and analysis systems to make the summative effect of the laboratory measurements relevant to the individual patient.

Early and frequent follow-up by physicians, especially utilizing lipid testing, has been shown to be associated with improved adherence to lipid-lowering therapy,1 but while the standard lipid panel provides important clinical information, it may not fully characterize a patients’ cardiovascular (CV) risk. In these cases, some believe that advanced lipid testing may be useful. A standard lipid panel includes total cholesterol (TC), triglycerides (TG), and high-density lipoprotein cholesterol (HDL-C). Low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C). These all depend on cholesterol assessment. However, we know that it is the specific lipoproteins that carry cholesterol that determine risk relationships and that define them as potential targets of treatment. It is also possible to measure apolipoprotein B (apoB) and A-I levels, LDL and HDL size, LDL and HDL particle number, and the specific protein component of lipoprotein(a) (Lp(a)). Data providing strong evidence that improvements in the accuracy of risk prediction can be made by using these new measures, particularly apoB. The move to develop this as a more commonly used tool in practice as a target of treatment and for goal setting is now in active discussion in the medical literature.

Because LDL-C has been our major target of treatment over the past 30 years,2 its accurate assessment has been important for therapeutic decisions. In routine clinical practice, LDL-C is typically calculated using the Friedewald formula (FF),3 but several studies have shown that this equation becomes less reliable in patients who have TG more than 200 mg/dL and an LDL-C less than 70 mg/dL.4-5 In a study published in the Journal of the American College of Cardiology in 2013, Martin et al. examined 1,340,614 adults who underwent lipid profiling by vertical spin density gradient ultracentrifugation from 2009 to 2011. Of these, 191,333 patients had LDL-C levels estimated by the Friedewald equation of <70 mg/dL. Researchers reported that 23% of individuals with a Friedewald-calculated LDL-C level <70 mg/dL actually had a directly measured LDL-C level >70 mg/dL. If the TG levels were 150 to 199 mg/dL, 39% of those with a Friedewald-calculated LDL <70 mg/dL had directly measured LDL-C of <70 mg/dL. The percentage of misclassified low-LDL-C patients rose to 59% if TG were between 200 and 399 mg/dL.

Besides inaccuracy in patients with hypertriglyceridemia, other limitations of the FF include inaccuracy in those with very low levels of TG6 and LDL7, in patients with type III hyperlipidemia, in patients with renal and liver diseases, and those with diabetes mellitus and other metabolic conditions. Additionally, the FF cannot be used in non-fasting samples as it does not consider the lower cholesterol triglyceride ratio characteristic of post-prandial chylomicrons. Measurements of LDL-C are further complicated by the fact that the cholesterol content of this particle is changed in response to the triglyceride content of all plasma lipoproteins. The particle content of cholesterol can vary by four-fold or more and therefore the particle number and apoB value is often very different from the blood LDL concentration as measured by the cholesterol value.9-10

The non-HDL-C allows adding the contribution of very low density lipoprotein (VLDL) remnants in fasting blood and this compensates for the loss of cholesterol from LDL through action of the cholesterol ester transfer protein (CETP) activity. Thus, non-HDL-C is a closer correlate of apoB. Recent reviews have established the superiority of these markers over LDL-C in predicting CVD risk in epidemiological studies10 and in randomized trials of patients on statin treatment.11 In terms of clinical practice, the National Lipid Association regards non-HDL-C as the superior treatment target for modification12, but the American Heart Association reports no additional mortality benefit to further treat non-HDL-C levels once an LDL-C goal is reached.13 However, this is a comment on the general population and does not address the special needs of those with high triglycerides and low HDL-C.


  1. Benner JS, Tierce JC, Ballantyne CM, et al. Follow-up lipid tests and physician visits are associated with improved adherence to statin therapy. Pharmacoeconomics. 2004;22 Suppl 3:13-23.
  2. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of the 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). JAMA. 2001;285: 2486–97.
  3. Stein EA. Measuring LDL cholesterol: for old and new calculations, is there an optimal formula? Chin Chem. 2014;60: 1466–68.
  4. Martin SS, Blaha MJ, Elshazly MB, et al. Friedewald-estimated versus directly measured low-density lipoprotein cholesterol and treatment implications. J Am Coll Cardiol. 2013;62:732–739.
  5. Martin SS, Blaha MJ, Elshazly MB, et al. Comparison of a novel method vs the Friedewald equation for estimating low-density lipoprotein cholesterol levels from the standard lipid profile. JAMA. 2013;310:2061–2068.
  6. Ahmadi SA, Boroumand MA, Gohari-Moghaddam K, Tajik P, Dibaj SM. The impact of low serum triglyceride on LDL-cholesterol estimation. Archives of Iranian Medicine. 2008.11;3:318-321.
  7. Scharnagl H Nauck M, Wieland H, Marz W. The friedewald formula underestimates LDL cholesterol at low concentrations. Clinical Chemistry and Laboratory Medicine. 2001. 39;5:426-431.
  8. Cromwell WC, Otvos JD, Keyes MJ, Pencina MJ, Sullivan L, Vasan RS, et al. LDL particle number and risk of future cardiovascular disease in the Framingham Offspring Study — implications for LDL management. J Clin Lipidol. 2007;1:583–92.
  9. Hattori Y, Suzuki M, Tsushima M, Yoshida M, Tokunaga Y,Wang Y, et al. Development of approximate formula for LDL-chol, LDL-apo B and LDL-chol/LDL-apo B as indices of hyperapobetalipoproteinemia and small dense LDL. Atherosclerosis. 1998;138:289–99.
  10. Sniderman AD, Williams K, Contois JH, Monroe HM, McQueen MJ, de Graaf J, et al. A meta-analysis of low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B as markers of cardiovascular risk. Circ Cardiovasc Qual Outcomes. 2011;4:337–45.
  11. Contois JH, McConnell JP, Sethi AA, Csako G, Devaraj S, Hoefner DM, et al. Apolipoprotein B and cardiovascular disease risk: position statement from the AACC Lipoproteins and Vascular Diseases Division Working Group on Best Practices. Clin Chem. 2009;55:407–19.
  12. Jacobson TA, Ito MK, Maki KC, Orringer CE, Bays HE, Jones PH, et al. National Lipid Association Recommendations for Patient-Centered Management of Dyslipidemia: Part 1 – Full Report. J Clin Lipidol. 2015. 9;2:129-169.
  13. Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, 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.

CME Information

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