In the United States, atherosclerotic cardiovascular disease (ASCVD) accounts for 84.5% of cardiovascular deaths and 28% of all-cause mortality with a total cost estimated to be $315 billion in 2010.^1,2 Elevated low-density lipoprotein cholesterol (LDL-C) is a well-established causal factor for ASCVD and the main lipid value that clinicians use to make guideline-based decisions. Aggressive LDL-C lowering, both through the use of statin and certain non-statin therapies, reduces rates of major adverse cardiovascular events.³

The longstanding de facto standard for calculation of LDL-C is through the use of the Friedewald equation, where LDL-C is estimated as (total cholesterol) – (high-density lipoprotein cholesterol [HDL-C]) – (triglycerides/5) measured in mg/dL.⁴ The Friedewald equation was developed in just over 400 individuals with genetic dyslipidemia. Few of these individuals had low LDL-C levels in the modern high-risk treatment range (e.g., <70 mg/dL) as lipid-lowering therapies like statins, ezetimibe, and proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors did not yet exist. Friedewald and colleagues recognized the inaccuracy contained in simply dividing triglycerides by five, but it was viewed as a reasonable approach at the time since it is a relatively small part of the equation when LDL-C levels were not low.

The Friedewald equation takes a one-size-fits-all approach in assuming a fixed ratio between triglyceride levels and very low-density lipoprotein cholesterol (VLDL-C). This limits the utility of the Friedewald calculation, because of its underestimation of LDL-C in the setting of elevated triglycerides and low LDL-C.⁵ To address the inaccuracy of the Friedewald equation, a novel method for LDL-C calculation was developed at Johns Hopkins.⁶ This method uses an adjustable factor for the triglyceride:VLDL-C ratio based on the triglyceride and non-HDL concentrations to improve accuracy at low LDL-C concentrations.

In a recent study led by Seamus Whelton, the concordance between the Friedewald-estimated LDL-C and this novel method for LDL-C calculation was compared in the setting of LDL-C <70 mg/dL.⁷ Cross sectional analysis was performed in individuals from three sources: National Health and Nutrition Examination Survey (NHANES), Johns Hopkins Hospital, and Mayo Clinic. Data from 2,381 patients were analyzed. Individuals were considered concordant if LDL-C was <70 mg/dL by both the Friedewald and novel method and discordant if the LDL-C was <70 mg/dL by the Friedewald estimation and ≥70 mg/dL by the novel estimation.

The study found a discordance of 14-17% in NHANES participants, and 20% from both Johns Hopkins and Mayo Clinic patients. Among persons in the discordant group, nearly one quarter had LDL-C levels ≥80 mg/dL using the novel estimation. Furthermore, those in the discordant group had higher levels of non-HDL-C and apolipoprotein B (apoB) (p < 0.001), suggesting a higher atherogenic lipoprotein burden and an elevated ASCVD risk beyond merely a higher calculated LDL-C value.

There are several important clinical implications from these findings. According to the American College of Cardiology/American Heart Association Cholesterol treatment guidelines,⁸ in patients with diabetes mellitus and an ASCVD risk of ≥7.5%, an LDL-C ≥70 mg/dL can guide the determination of statin eligibility. Both the European Society of Cardiology and the National Lipid Association recommend treatment of hyperlipidemia to a goal LDL-C of <70 mg/dL in very high-risk individuals.^9,10 Therefore, if the estimation of LDL-C is inaccurate, patients who would benefit from intensification of lipid-lowering therapy may be falsely reassured as a significant percentage of adults with Friedewald LDL-C <70 mg/dL actually have significantly higher levels based on the novel estimation of LDL-C.

Lipid management has achieved additional success recently with the development and testing of monoclonal antibodies that inhibit PCSK9. In the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trial, evolucumab, when added to statin therapy lowered LDL-C levels by 59% and reduced the risk of major cardiovascular events by 15% over a median follow-up of 26 months.¹¹

The ongoing ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab trial is evaluating the use of alirocumab in addition to background high-dose statin therapy for reduction of cardiovascular events following acute coronary syndrome.¹² This trial is adjusting the dose of the agent based on LDL-C levels to maintain LDL-C within a pre-specified range of 25-50 mg/dL. Although beta quantification may be used for direct LDL-C assessment in selected patients in these trials, this is not scalable to clinical practice. Chemical direct LDL-C assays may be scalable, but are not well standardized and serious concerns about their accuracy have been raised.

Given the clinical implications of accurately estimating low LDL-C levels in the treatment of ASCVD and risk factor modification in high-risk patients, it becomes paramount that the level that is calculated and reported by the laboratory is in fact accurate. While additional investigation of the novel method of LDL-C estimation will certainly continue, it is important for clinical laboratories to respond to current best evidence.

It is clear that the Friedewald equation has marked limitation in its sustainability for modern clinical practice. Accordingly, clinicians may have to manually calculate the LDL-C on smartphones or internet calculators in order to get an accurate estimate, which is unnecessarily time consuming. Furthermore, it would involve extensive explanation by the clinicians to patients as to why the reported LDL-C on their laboratory results is inaccurate and likely underestimated. Modernizing LDL-C reporting by using the novel LDL-C equation developed at Johns Hopkins, as some major laboratories have already done, will streamline optimal care. Clinicians and patients should be provided with the opportunity to have the most accurate information possible in order to guide effective clinical decision-making and improve outcomes.

References

1. GBD 2013 Mortality and Causes of Death Collaborators. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2015;385:117-71.
2. Go AS, Mozaffarian D, Roger VL, et al. Executive summary: heart disease and stroke statistics--2014 update: a report from the American Heart Association. Circulation 2014;129:399-410.
3. Silverman MG, Ference BA, Im K, et al. Association between lowering LDL-C and cardiovascular risk reduction among different therapeutic interventions: a systematic review and meta-analysis. JAMA 2016;316:1289-97.
4. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972;18:499-502.
5. Meeusen JW, Snozek CL, Baumann NA, Jaffe AS, Saenger AK. Reliability of calculated low-density lipoprotein cholesterol. Am J Cardiol 2015;116:538-40.
6. 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;310:2061-8.
7. Whelton SP, Meeusen JW, Donato LJ, et al. Evaluating the athergenic burden of individuals with Friedewald-estimated low-density lipoprotein cholesterol <70 mg/dL compared with a novel low-density lipoprotein estimation method. J Clin Lipidol 2017;11:1065-72.
8. Stone NJ, Robinson JG, Lichtenstein AH, 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. J Am Coll Cardiol 2014;63:2889-934.
9. Catapano AL, Graham I, De Backer G, et al. 2016 ESC/EAS guidelines for the management of dyslipidaemias. Eur Heart J 2016;37:2999-3058.
10. Jacobson TA, Maki KC, Orringer CE, et al. National Lipid Association recommendations for patient-centered management fo dyslipidemia: part 2. J Clin Lipidol 2015;9:S1-122.
11. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clincial outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713-22.
12. Schwartz GG, Bessac L, Berdan LG, et al. Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: rationale and design of the ODYSSEY outcomes trial. Am Heart J 2014;168:682-9.

Keywords: Cholesterol, LDL, Cholesterol, VLDL, Apolipoproteins B, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Cholesterol, HDL, Risk Factors, Acute Coronary Syndrome, Triglycerides, Lipoproteins, VLDL, Antibodies, Monoclonal, Hyperlipidemias, Diabetes Mellitus, Proprotein Convertases, Subtilisins, Metabolic Syndrome, Dyslipidemias

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