Background

One of the central principles of atherosclerotic cardiovascular disease (ASCVD) risk reduction is the lowering of apolipoprotein B containing lipoproteins, including chylomicron remnants, very low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), low-density lipoproteins (LDL), and lipoprotein(a) (Lp[a]), which are major contributors to atherosclerosis formation and progression. Although ASCVD is very rare in youth, the process of atherosclerosis begins in childhood; therefore, focusing on prevention earlier in the life may lead to drastic reduction in ASCVD events during adulthood. Screening for dyslipidemia is an important and critical step to prevent ASCVD. A scientific statement from the National Lipid Association was recently published and reviewed clinical screening and testing of dyslipidemia.¹ Below is a summary and discussion of key aspects of this statement.

Screening for Hyperlipidemia

1. Starting Age for Screening
   
   It is currently recommended to screen pediatric patients with a non-fasting lipid profile once between the ages of 9-11 and again between the ages of 17-19. The United States (US) Preventive Services Task Force recommends screening adults for dyslipidemia between the ages of 20-35. After this, the recommended interval in patients without known ASCVD or dyslipidemia is uncertain. A lipid profile should be collected in a stable patient and not during an acute illness, during puberty, or during changes in chronic management. For instance, inflammatory conditions can rapidly increase triglyceride levels in the acute phase but may inhibit LDL production. Also, acute myocardial infarction can depress atherogenic lipid levels leading to the incorrect thought that dyslipidemia was not a risk factor.²
2. Fasting versus Non-Fasting Sample
   
   Traditional practice has been to instruct patients to fast at least 8 hours prior to blood lipid testing; however, the 2018 American Heart Association (AHA)/American College of Cardiology (ACC) Multisociety Cholesterol Guideline³ states that non-fasting total cholesterol and non-HDL cholesterol can be utilized to screen for dyslipidemia as these values are less affected by a non-fasting state. Fasting lipid testing should, however, be performed in patients who have high-risk values such as a non-HDL cholesterol of greater than 220 mg/dL or total cholesterol of greater than 200 mg/dL.
3. Methods to Calculate LDL-C
   
   The Friedewald formula has been used for calculating LDL cholesterol (LDL-C) since it was introduced in 1972 and then revalidated in 1990; however, for triglyceride levels ≥150 mg/dL there is a median underestimation of LDL-C of approximately 18 mg/dL. The Martin/Hopkins estimation of LDL-C, introduced and validated in 2013, demonstrated improved accuracy by 17% in LDL-C estimation for LDL-C levels <70 mg/dL and for triglyceride levels between 150 to 400 mg/dL. This method is now more commonly utilized and has been documented as a more accurate representation of LDL-C in multiple clinical trials, where the LDL-C outcomes were typically <70 mg/dL.⁴ When triglyceride levels are ≥400 mg/dL, however, a direct measurement of LDL-C is still recommended and better lifestyle habits plus pharmacotherapy are often urgently needed to reduce the triglycerides.

Advanced Lipoprotein Testing

Advanced lipoprotein testing can be helpful in patients who are at high ASCVD risk but have an LDL-C <70 mg/dL and in patients with borderline risk when decisions regarding the appropriateness of initiating statin therapy are less clear. Apolipoprotein B levels can provide more information on atherogenic particle concentrations. Although the 2018 AHA/ACC Multisociety Cholesterol Guideline classifies elevated apolipoprotein B levels as a risk factor for ASCVD, there are no current assays that have been standardized at this time. Small dense LDL-C is present in patients with insulin resistance and hypertriglyceridemia, and it has been seen that patients with an abundance of small dense LDL particles over larger LDL particles have an increased risk of ASCVD.⁵

Lp(a) is considered an independent risk factor for ASCVD yet is not routinely measured in clinically practice – likely due to the lack of an approved therapeutic agent.⁶ Lp(a) can be valuable in patients with a strong family history of ASCVD, patients who do not respond as expected to lipid-lowering therapies, or those who had an ASCVD event despite aggressive pharmacological therapy. Unfortunately, these assays are not well standardized primarily due to the variability in size of the Lp(a) particle. The sizes of these particles can vary as much as 26%. Due to this, multiple national experts and the National Lipid Association recommend measuring Lp(a) molality in nmol/L rather than mg/dL.⁶

Conclusion

Lipid testing is integral in identifying patients at risk for developing ASCVD or for having recurrent ASCVD events. Traditional methods and techniques are continuing to be refined as evidenced by the increased accuracy of the Martin/Hopkins method over the Friedewald formula. Also, advanced lipid testing is becoming more widely available, but these assays are not standardized and cross comparisons of advanced lipid assays are not well published at this time. Future research may lead to newer ways to estimate risk with our traditional assay as well as more standardization of newer, advanced lipid biomarkers.

References

1. Wilson PWF, Jacobson TA, Martin SS, et al. Lipid measurements in the management of cardiovascular diseases: practical recommendations: a scientific statement from the National Lipid Association Writing Group. J Clin Lipidol 2021;Sep 24:[Epub ahead of print].
2. Nordestgaard BG, Langsted A, Mora S, et al. Fasting is not routinely required for determination of a lipid profile: clinical and laboratory implications including flagging at desirable concentration cut-points-a joint consensus statement from the European Atherosclerosis Society and European Federation of Clinical Chemistry and Laboratory Medicine. Eur Heart J 2016;37:1944-58.
3. 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 2019;73:3168-3209.
4. Martin SS, Giugliano RP, Murphy SA, et al. Comparison of low-density lipoprotein cholesterol assessment by Martin/Hopkins estimation, Friedewald estimation, and preparative ultracentrifugation: insights from the FOURIER Trial. JAMA Cardiol 2018;3:749-53.
5. Hirayama S, Miida T. Small dense LDL: an emerging risk factor for cardiovascular disease. Clin Chim Acta 2012;414:215-24.
6. Wilson DP, Jacobson TA, Jones PH, et al. Use of lipoprotein(a) in clinical practice: a biomarker whose time has come. A scientific statement from the National Lipid Association. J Clin Lipidol 2019;13:374-92.

Clinical Topics: Cardiovascular Care Team, Diabetes and Cardiometabolic Disease, Dyslipidemia, Advanced Lipid Testing, Hypertriglyceridemia, Lipid Metabolism, Nonstatins, Novel Agents, Statins

Keywords: Cholesterol, LDL, Chylomicron Remnants, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Lipoproteins, IDL, Hyperlipidemias, Triglycerides, Lipoprotein(a), Lipoproteins, VLDL, American Heart Association, Insulin Resistance, Cardiovascular Diseases, Acute Disease, Atherosclerosis, Dyslipidemias, Cholesterol, Hypertriglyceridemia, Risk Factors, Myocardial Infarction, Biomarkers, Risk Reduction Behavior, Life Style, Reference Standards, Apolipoproteins

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