How should low-density lipoprotein cholesterol concentration be determined?

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Original Research

How should low-density lipoprotein cholesterol concentration be determined?

J Fam Pract. 2002 November;51(11):972-975

By

Fred H. Faas, MD

The National Cholesterol Education Program Adult Treatment Panel III Report (NCEP-ATP III) has identified low-density lipoprotein cholesterol (LDLC) as the primary target of therapy and has recommended using the Friedewald calculated LDL-C (C-LDL-C). The present study compared a direct LDL-C (D-LDL-C) method with the C-LDL-C and determined the possible impact on treatment decisions. C-LDL-C and D-LDL-C were compared in 464 consecutive patients. The D-LDL-C was 18% higher than the C-LDL-C at 100 mg/dL, an important level for medical decision making. This can result in inappropriate drug therapy (usually overtreatment) if the NCEP-ATP III treatment guidelines are followed with the D-LDL-C rather than the C-LDL-C. The C-LDL-C is preferred because this assay has been used in clinical trials documenting the benefits of cholesterol-lowering therapy.

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References

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KEY POINTS FOR CLINICIANS

The C-LDL-C remains the method of choice for LDL-C determination.
The D-LDL-C has not been adequately standardized and was not used in the clinical trials which were the basis for the current NCEP-ATP III recommendations.
Some D-LDL-C assays may give significantly different results from those of the C-LDL-C.
Some D-LDL-C assays do not perform well in hypertriglyceridemia, the very situation for which they are advocated.
Use of the D-LDL-C increases cost without evidence of benefit.

The National Cholesterol Education Program Adult Treatment Panel III Report (NCEP-ATP III) has identified low-density lipoprotein cholesterol (LDL-C) as the primary target of therapy.^1,2The Friedewald calculated LDL-C (C-LDL-C) is the preferred method^2,3and is calculated with the following equation:

LDL-C =TC – HDL-C – TG/5

where TC is total cholesterol concentration, HDL-C is high-density lipoprotein cholesterol concentration, and TG is triglyceride concentration. The complete NCEP-ATP III report has indicated that methods to directly measure LDL-C (D-LDL-C) in the non-fasting state have been developed and will grow in use but require careful quality control.²Our VA hospital clinical laboratory is 1 of 10 hospitals in the South Central VA Health Care Network that routinely reports D-LDL-C rather than C-LDL-C levels to clinicians. Telephone calls to 4 other research and clinical laboratories found that all are using D-LDL-C to some extent.

D-LDL-C assays correlate variably with C-LDL-C measurements used in research studies.^4-17The purported advantages of such measurements are that fasting is not required and that D-LDL-C may be determined in patients with serum triglyceride levels greater than 400 mg/dL when the C-HDL-C and are less reliable. However, clinical trials demonstrating benefit of lowering LDL-C with drug therapy used the C-LDL-C.^18-22Only the recently reported Heart Protection Study used a non-fasting D-LDL-C.²³Thus, it is important in practicing evidence-based medicine to demonstrate that the D-LDL-C measurements are comparable to those of the C-LDL-C. The present study determined how the D-LDL-C correlated with C-LDL-C and how such a correlation would affect treatment decisions based on the NCEP-ATP III guidelines.

Methods

Data from all patients with a lipid panel during a single week were analyzed. Patients with triglyceride levels above 1000 mg/dL were excluded. Thirty-four patients with triglyceride levels between 400 and 1000 mg/dL were analyzed separately. A C-LDL-C was determined and compared with the D-LDL-C in all 464 patients. Total cholesterol, triglyceride, and HDL-C measurements were done with an autoanalyzer. D-LDL-C was measured with Sigma Diagnostics EZ LDL Cholesterol, procedure 358 (Sigma, St. Louis, MO). Linear regression was performed using Microsoft Excel (Microsoft Corporation, Redmond, WA).

Results

The samples in this study represented the expected distribution of LDL-C concentrations seen in a clinical practice of predominantly male veterans. Of the 464 patient samples with triglyceride levels below 400 mg/dL, the mean C-LDL-C was 123 mg/dL. Twenty-eight percent had a C-LDL-C below 100 mg/dL, 32% had a C-LDL-C of 100 to 129.9 mg/dL, 24% had a C-LDL-C of 130 to 159.9 mg/dL, 12% had a C-LDL-C of 160 to 189.9 mg/dL, and 4% had a C-LDL-C above 190 mg/dL.

The Figure shows the correlation between the C-LDL-C and D-LDL-C in all patients with triglyceride levels below 400 mg/dL. Although there is a strong correlation between the C-LDL-C and D-LDL-C (r = .86), the regression line does not go through 0. A C-LDL-C of 100 mg/dL or lower is the NCEP-ATP III goal for patients with known coronary heart disease (CHD) and other clinical forms of atherosclerotic disease, diabetes, or multiple risk factors that confer a 10-year risk for CHD greater than 20%.¹At this cutoff for C-LDL-C, the D-LDL-C derived from the regression line is 118 mg/dL. At a C-LDL-C of 160 mg/dL, the 2 values are comparable; at a C-LDL-C of 190 mg/dL, the D-LDL-C is slightly lower at 182 mg/dL. This is demonstrated graphically in the Figure by a dashed line indicating a perfect correlation between the 2 methods. The Figure also displays vertical and horizontal lines through an LDL-C of 100 mg/dL, the level above which drug therapy is likely to be started or increased in patients with CHD or CHD risk equivalents. This partition illustrates those patients who would require treatment when using the 100 mg/dL treatment goal by the C-LDL-C, the D-LDLC, neither, or both. This is also shown in the (Table, which shows the number of patients who would be treated with the LDL-C cutoffs for treatment recommended by NCEP-ATP III. At an LDL cutoff of 100 mg/dL, 60 patients (13% of total) would be treated with the D-LDL-C and not the C-LDL-C, whereas only 2 patients (<1%) would be treated with the C-LDL-C and not with the D-LDL-C. The results are similar when using a 130 mg/dL cutoff for treatment. Thus, treatment decisions based on the D-LDL-C results in many patients being treated who would not have been treated when using the C-LDL-C.