Non–High-Density Lipoprotein Cholesterol and Guidelines for Cholesterol Lowering in Recent History

Stanley S. Levinson, PhD


Lab Med. 2020;51(1):14-23. 

In This Article


Non-HDLC has the advantage that it correlates most strongly with apo B, does not require fasting and, like apo B, identifies persons whose LDLC may be close to desirable levels but who are at increased risk because they exhibit sdLDL and remnant lipoproteins. This has become the most common type of lipidemia as obesity has become more rampant. Moreover, unlike apo B, it is derived from the routine lipid profile at no extra cost. One problem with using non-HDLC as a primary risk-assessment instrument is that most previous studies used LDLC as the eligibility criteria, which means if the studies are reexamined and non-HDLC is substituted for LDLC, the result would be statistically suspect because it would become a retrospective indicator.

I believe that the 2017 committee[3] should be commended for recommending non-HDLC as being equivalent to LDLC as a target because most clinical-outcome studies have targeted LDLC. In coming to this conclusion, the Committee considered more than RCT results but all of the evidence. This appraisal seems to have been confirmed by the results of recent studies in which PCSK9 inhibitor trials use LDLC and non-HDLC as thresholds for eligibility despite LDLC being below the eligibility cutoff, creating a prospective view.[43–45] Also, non-HDLC has been shown[45,46] to have a more robust relationship with ASCVD death (and all-cause mortality) than LDLC.

When triglycerides are elevated and the calculated cLDLC values are suspect, they can be compared against the non-HDLC values to assess accuracy, with the knowledge that there should be a 30 mg per dL difference between the 2 values. Concurrently, it is important to recognize that patients with metabolic syndrome and elevated triglycerides may exhibit borderline LDLC, but their non-HDLC may be elevated because they have increased numbers of sdLDL and remnants. According to the guidelines (Table 3), many of these patients can experience a 50% or greater drop in LDLC/non-HDLC. If the cLDLC and non-HDLC values are in disagreement, laboratory professionals should be able to consult with one another to determine how non-HDLC may be telling or, in rare instances, suggest measurement of dLDLC or apo B.

In November of 2018, the AHA and ACC released updated guidelines,[40] and concurrently, a document on risk-assessment tools to guide medical professionals in primary prevention.[47] A major focus of the risk-assessment article[47] was the addition of coronary-artery calcium measurement (CAC) in persons who might be at borderline risk but only if it is thought CAC measurement can provide sufficient information to modify the decision.

As previously, these guidelines pointed out that the main protein embedded in LDL and VLDL is apo B and like non-HDLC, apo B is a stronger indicator of atherogenicity than LDLC by itself.[40] The guidelines stated that in most cases, nonfasting specimens were sufficient for routine measurement of LDLC by calculation, which was a departure from previous guidelines, but if there was reason to suspect triglyceride interference, direct LDLC or apo B should be considered. However, these guidelines seemed to focus on LDLC, seemingly placing non-HDLC in a more subservient position. Nevertheless, these guidelines were described as an extension of the 2017 guidelines, with the goal of making the guidelines "shorter and enhancing user friendliness." Therefore, the guidelines did not appear to change the target values from those defined in Table 3. For this reason, clinical laboratories should include non-HDLC values and cutoffs in their reports.