Focus – Identifying residual cardiovascular risk: which are the best lipid biomarkers?
21 May 2021
In this report from the Copenhagen General Population Study, apolipoprotein B or non-high-density lipoprotein cholesterol (non-HDL-C) were preferred to low-density lipoprotein cholesterol (LDL-C) to better identify residual cardiovascular risk in statin-treated patients.
Johannesen CDL, Mortensen MB, Langsted A, Nordestgaard BG. Apolipoprotein B and non-HDL cholesterol better reflect residual risk than LDL cholesterol in statin-treated patients. J Am Coll Cardiol 2021;77:1439-50.
STUDY SUMMARY
| Objective: | To investigate which lipid markers best reflect residual cardiovascular risk in statin-treated patients: apolipoprotein (apo)B, non-high-density lipoprotein cholesterol (non-HDL-C) or low-density lipoprotein cholesterol (LDL-C). |
| Study design: | The Copenhagen General Population study is a prospective observational study. |
| Study population: | 13,015 statin-treated patients from the Copenhagen General Population Study with 8 years median follow-up. |
| Main study variables: | • All-cause mortality cases, identified from the Danish Civil Registration System and myocardial infarction (MI) cases, identified from the Danish Patient Registry. • Calculated non-HDL-C and measured apoB; LDL-C was calculated if triglycerides were <4.0 mmol/L or directly measured if above. |
| Methods: | Cox regression analysis was used to assess the association of apoB, non-HDL-C, and LDL-C with all-cause mortality or MI. Data were analysed by categories of concordant and discordant values defined by median values. |
RESULTS
Over a median follow-up of 8 years, 2,499 subjects died and 537 experienced an MI.
The median values for lipids were 92 mg/dL for apoB, 3.1 mmol/L (120 mg/dL) for non-HDL-C and 2.3 mmol/L (89 mg/dL) for LDL-C. Individually, high apoB or non-HDL-C levels were associated with increased risk for all-cause mortality and MI.
Compared with concordant values below the median (i.e., both low apoB and low LDL-C values), a high apoB (above the median) with a low LDL-C (below the median) value was associated with increased risk for all-cause mortality and MI. Furthermore, both high non-HDL-C and low LDL-C values were also associated with increased risk for both outcomes, compared with concordant low values (Table 1).
In contrast, a high LDL-C value with either a low apoB or low non-HDL-C value was not associated with increased risk of either all-cause mortality or MI (Table 1).
Table 1. Risk for outcomes: low concordant lipid values versus discordant values.
|
Hazard ratio (95% CI) |
|
|
All-cause mortality |
|
|
High apoB with low LDL-C |
1.21 (1.07 to 1.36) |
|
High non-HDL-C with low LDL-C |
1.18 (1.02 to 1.36) |
|
High LDL-C with low apoB |
0.86 (0.75-0.99) |
|
High LDL-C with low non-HDL-C |
0.97 (0.82-1.14) |
|
|
|
|
MI |
|
|
High apoB with low LDL-C |
1.49 (1.15 to 1.92) |
|
High non-HDL-C with low LDL-C |
1.78 (1.35 to 2.34) |
|
High LDL-C with low apoB |
0.94 (0.69-1.29) |
|
High LDL-C with low non-HDL-C |
0.97 (0.66-1.41) |
* Comparison to individuals with both directly measured and calculated remnant cholesterol <80th percentile for IHD and for MI; C cholesterol
High was defined as ≥80th percentile
Prediction of 10-year risk of MI was improved by adding directly measured or calculated remnant cholesterol to a model including the conventional risk factors. When using a cut point ≥80th percentile for directly measured or calculated remnant cholesterol, the net reclassification index was 4.7% (1.4–8.0%; p= 0.006) and 7.5% (3.5–11.5%; p< 0.001), respectively.
| Author conclusion: | High concentrations of both directly measured and calculated remnant cholesterol are associated with higher risk of IHD and MI. Furthermore, directly measured vs. calculated remnant cholesterol identifies 5% of overlooked individuals in the general population with cholesterol-rich, TG-poor remnants and 1.8-fold increased risk of MI. |
COMMENT
Remnant cholesterol, defined as the cholesterol contained in TG-rich lipoprotein remnants, which include chylomicron remnants, very low-density lipoproteins (VLDL), and intermediate-density lipoproteins (IDL), has attracted renewed focus with accumulating evidence supporting an association with cardiovascular disease. Indeed, the totality of evidence from observational studies and genetic analyses shows that elevated remnant cholesterol is a causal risk factor (1-4). Definitive proof is still required, however, from cardiovascular outcomes studies, such as PROMINENT (5).
The availability of new assays for direct measurement of remnant cholesterol underlines the need to test whether the association of calculated remnant cholesterol with cardiovascular risk also applies to directly measured remnant cholesterol. Furthermore, there is also the need to investigate whether inclusion of directly measured remnant cholesterol adds to cardiovascular risk estimation.
The current study tested both questions. First, the researchers showed that directly measured elevated remnant cholesterol is also associated with increased cardiovascular risk, similar to that reported for calculated remnant cholesterol. Second, they showed that compared with calculated remnant cholesterol, directly measured remnant cholesterol identifies a further 5% of the general population with high remnant cholesterol and correspondingly high risk for MI, and therefore adds value to risk prediction scores.
The findings are pertinent to the PROMINENT study with pemafibrate, which has incorporated use of directly measured remnant cholesterol in the study methodology. Results from this study will provide a true test whether lowering directly measured remnant cholesterol reduces cardiovascular risk in statin-treated diabetic patients with atherogenic dyslipidemia.
| Authors’ conclusion: | In statin-treated patients, elevated apoB and non-HDL-C, but not LDL-C, are associated with residual risk of all-cause mortality and myocardial infarction. Discordance analysis demonstrates that apoB is a more accurate marker of all-cause mortality risk in statin-treated patients than LDL-C or non-HDL-C. ApoB is also a more accurate marker of risk of myocardial infarction than LDL cholesterol. |
COMMENT
The results of this study indicate that LDL-C may not be the best lipid marker for identifying residual cardiovascular risk in statin-treated patients. Instead, the authors propose either the use of either apoB or non-HDL-C as preferred biomarkers for this risk. This approach is also supported by expert consensus, which considered non-LDL lipoproteins (non-HDL-C, apoB, remnant cholesterol and lipoprotein(a)) as potential biomarkers of residual cardiovascular risk (1). Based on findings from this appraisal, non-HDL-C was proposed to better reflect the residual risk associated with atherogenic dyslipidemia, characterized by elevated triglycerides with or without low HDL-C, common in high-risk patients at LDL-C goal. Moreover, lipid guidelines recommend either apoB or non-HDL-C as secondary lipid targets, especially among individuals with cardiometabolic disease who may not necessarily have elevated LDL-C levels, due in particular to small and dense LDL (2).
The current study suggested that apoB may be the preferred marker. Such an approach makes sense, given current understanding of the integral role of apoB-containing lipoproteins in atherosclerosis. Each of these lipoproteins contains one molecule of apoB. Thus, apoB is likely to provide a more accurate estimate of residual atherogenic risk than other guideline-recommended lipid targets (3).
There is a possible misconception from this study that LDL-C may no longer be relevant in the context of residual risk. This relates to the finding from discordance analysis that a high LDL-C value with either a low apoB or low non-HDL-C value was not associated with increased risk of either all-cause mortality or MI in statin-treated patients. It should be emphasized, however, that LDL-C remains the primary lipid target for intervention to prevent cardiovascular events. Individuals with high LDL-C levels should receive intensified therapy, preferably combination therapy, to manage their LDL-related risk (2,4).
| References | 1. Averna M, Stroes E; lipid alterations beyond LDL expert working group. How to assess and manage cardiovascular risk associated with lipid alterations beyond LDL. Atheroscler Suppl 2017;26:16-24. 2. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J 2020;41:111-88. 3. Sniderman AD, Thanassoulis G, Glavinovic T, et al. Apolipoprotein B particles and cardiovascular disease: a narrative review. JAMA Cardiol 2019;4:1287-95. 4. Packard CJ, Chapman MJ, Sibartie M, et al. Intensive low-density lipoprotein cholesterol lowering in cardiovascular disease prevention: opportunities and challenges. Heart 2021; https://heart.bmj.com/content/early/2021/03/31/heartjnl-2020-318760 |
| Key words | residual cardiovascular risk; apolipoprotein B; non-HDL cholesterol; lipid marker |
