New joint Initiative on Quantifying Atherogenic Lipoproteins

The last decade has seen a revolution in the management of low-density lipoprotein cholesterol (LDL-C), the guideline-recommended primary lipid target for preventing cardiovascular disease (CVD).1,2 In parallel, there has also been escalation in the rates of obesity and type 2 diabetes mellitus, typically characterized by elevated levels of triglycerides (a marker of triglyceride-rich lipoproteins and their remnants), with or without low plasma high-density lipoprotein cholesterol (HDL-C), and often referred to as ‘atherogenic dyslipidemia.’3 In addition, lipoprotein(a) [Lp(a)], a causal risk factor for CVD, has gained new prominence, driven by recognition that 20-25% of a Caucasian general population have elevated Lp(a) levels (this may differ in other ethnic groups).4 Both atherogenic dyslipidemia and elevated Lp(a) have been shown to be contributors to lipid-related residual cardiovascular risk that persists in individuals with well controlled LDL-C levels.5-8

The above scenario poses some key questions for clinicians (Box 1). 

Box 1. Key questions about atherogenic lipoproteins
• Is LDL-C still the main biomarker? And if so, how reliable is LDL-C measurement?

• Are there better biomarkers for patients with elevated triglycerides?

• Are non-HDL-C or apoB replacement or ‘add-on’ tests to LDL-C?

•Which is the ‘best choice’ atherogenic lipoprotein test?

• Can patient follow-up be simplified with the use of a single biomarker?

To address these concerns, a Joint Consensus Initiative from the European Atherosclerosis Society and European Federation of Clinical Chemistry and Laboratory Medicine appraised the evidence and provided recommendations to optimize measurement of atherogenic lipoproteins for cardiovascular risk assessment and clinical management.9 Key findings are discussed here.

Is LDL-C the best biomarker?

LDL-C determination, whether by assays which measure the cholesterol content of LDL particles or calculated, is a key component of cardiovascular risk assessment. Yet, in the era of attainable very low LDL-C levels is this still the case? Furthermore, from the analytical perspective, is LDL-C measurement still reliable at very low LDL-C levels? It has to be borne in mind that variability between different tests for LDL-C is not negligible, and can be exacerbated if testing is performed by different laboratories using different methods or if a laboratory changes the method. This effect may be magnified at low LDL-C levels with implications for clinical decision making.

It is important to recognize that LDL-C also contains the cholesterol from Lp(a), which may represent a substantial proportion in individuals with high Lp(a) levels (>50 mg/dl), possibly leading to overestimation of measured or calculated LDL-C. Such a scenario may explain a poor response to statin treatment in some patients; increasing the statin dose is unlikely to be helpful. With potent LDL-C lowering agents, the attained ‘true’ LDL-C (i.e. after correction for the cholesterol contained in Lp(a)) may be as low as 0.3 mmol/L, which may be relevant for individuals with extreme hyperlipoprotein(a)-emia.

An increasing prevalence of hypertriglyceridemia associated with obesity also poses specific issues. It is underappreciated that in such individuals, LDL-C measurement may not reflect the atherogenicity associated with the higher proportion of small dense LDL particles carrying more atherogenic apolipoprotein (apo) B, the major protein component of LDL.10  Thus, LDL-C measurement may be less predictive of cardiovascular risk. Additionally, discordance between LDL-C measurements and “true” values, as defined by the reference method,11 may be more of an issue in the setting of mixed dyslipidemia,12  with implications for classification of cardiovascular risk. For example, in a pooled analysis of high-risk individuals with elevated triglycerides, more than one-third with triglycerides 1.7–2.3 mmol/L (150 to 199 mg/dL) and over half with values of 2.3– 4.5 mmol/L (200 to 399 mg/dL) were classified as being below LDL-C goal (<1.8 mmoL/l) although the ‘true’ LDL-C level was higher.13

Despite these concerns, this Joint Consensus Initiative concluded that LDL-C remains the primary target of lipid-lowering therapy.

Key recommendations are summarized in Box 2

Box 2. Consensus recommendations about LDL-C
• LDL-C is the primary target of lipid-lowering therapy

• LDL-C measurement or calculation is acceptable in individuals with normal triglycerides. While
nonspecificity errors may confound measurement in individuals with elevated triglycerides (>2.0 mmol/L) or at low LDL-C levels, this error may be less than between-method or between laboratory errors.

• LDL-C levels should be reported with the test method used. Follow-up from baseline to on- treatment measurements should ideally be performed with the same method (and preferably in the same laboratory)

• Values near the therapeutic decision cutpoints should ideally be confirmed by repeated measurement(s) using the same method and then averaged.

• Lp(a)-corrected LDL-C should be assessed at least once in patients with suspected or known high

• Lp(a), or if the patient shows a poor response to LDL-lowering therapy

Yet even with achievement of very low LDL-C levels, the risk of cardiovascular events is not eliminated, as illustrated by the FOURIER trial (median on-treatment LDL-C 0.78 mmol/L or 30 mg/dL).14 This residual cardiovascular risk may be attributable to a number of other biomarkers, both lipid and non-lipid; the CANTOS trial clearly illustrated the benefit of targeting residual inflammatory risk in high-risk patients with very well controlled LDL-C levels.15  With such a scenario, should other lipid tests, beyond LDL-C, be performed?

Non-high-density lipoprotein cholesterol (HDL-C) and apoB are guideline-recommended secondary lipid targets.1,2  By definition, non-HDL-C is calculated as [total cholesterol – HDL-C] and thus takes account of the cholesterol in all atherogenic particles, i.e., LDL, very low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), chylomicron remnants, and Lp(a).  Non-HDL-C therefore provides more comprehensive risk estimation than LDL-C in patients with elevated triglycerides as it includes remnant cholesterol, and is a useful alternative to calculated LDL-C when the Friedewald equation is invalid. 

While errors in direct HDL-C measurement may affect the calculation of non-HDL-C, there is better concordance with CVD risk than with LDL-C (either calculated or measured) in individuals with elevated triglycerides.16 There are also practical advantages with the use of non-HDL-C, as it can be determined under nonfasting conditions, at no additional expense above conventional lipid testing.

ApoB measurement is also accessible. In fasting samples, >90% of circulating apoB is apoB100, the main isoform which is synthesized in hepatocytes and found in VLDL, IDL, LDL, and Lp(a). Measurement of apoB does not require fasting, is standardized and easily automated. As biological variability is low, repeated measurement of apoB in each patient may be more reliable than calculated non-HDL-C.  

Evidence from meta-analyses suggests that all three biomarkers – LDL-C, non-HDL-C and apoB – are generally comparable for risk assessment.17-19 

Key recommendations about non-HDL-C and apoB are summarized in Box 3

Box 3. Consensus recommendations about Non-HDL-C and ApoB
• Non-HDL-C and apoB tests are more accurate than LDL-C (either measureed or calculated), especially under conditions of hypertriglyceridemia, nonfasting, or at low LDL-C concentration.

• In contrast to LDL-C, non-HDL-C includes remnant cholesterol.

• The addition of non-HDL-C or apoB to LDL-C has the potential to improve risk prediction, by identifying ‘hidden’ CVD risk and for judging the adequacy of therapy.

Non-HDL-C is recommended as an add-on test for all lipid profiles

Is there a “best choice” for lipoprotein testing?

Current guidelines recommend measurement of total cholesterol, triglycerides, HDL-C, and LDL-C as the primary approach for dyslipidemia diagnosis and CVD risk categorization.1,2 Yet, the continued use of LDL-C for follow-up is contentious, with recognition of the high residual cardiovascular risk that persists in high risk patients below goal (LDL-C <1.8 mmol/L).  The use of either non-HDL-C or apoB, which measure all atherogenic lipoproteins, has been advocated to simplify lipid testing. Non-HDL-C may represent the best choice, when considering cost. There remain, however, outstanding issues, notably errors in direct HDL-C measurement in dyslipidemic samples, variability between assays and the fact that current risk cutpoints and treatment targets have not been validated for routine clinical application. 

Outstanding questions

Lipoprotein management remains a very focused effort and requires an individualized approach for each patient. This Joint Consensus Initiative has appraised the evidence to provide recommendations for optimizing the quantification of atherogenic lipoproteins for cardiovascular risk management. The Initiative recognizes the limitations of LDL-C measurement in hypertriglyceridemic patients, and suggests complementary use of LDL-C, non-HDL-C and apoB. Uncertainties remain regarding the preferred secondary marker – non-HDL-C or apoB? To improve understanding of the concept of ‘atherogenic lipoproteins’ among clinicians, non‑HDL-C may be preferred. Whether patient follow-up could be simplified with the use of a single biomarker, or multimarker panels, to improve assessment of dyslipidemia-related residual risk is still a point for discussion. 


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