Assessing lipid-related cardiovascular risk: which assays to use?

Routine lipid monitoring studies LDL cholesterol (LDL-C) (the bad cholesterol that infiltrates the artery wall), non-HDL cholesterol (non-HDL-C), Apoprotein B (Apo B) and sometimes a marker of inflammation: C-reactive protein (CRP).
Lipoprotein (a): Lp(a) has already been mentioned, and the question is whether these "classic" routine lipid parameters can replace its measurement for cardiovascular risk assessment?
A number of authors [1] have recently addressed this important question, all the more so as an elevated Lp(a) level, found in one in five people, is a genetic risk factor for cardiovascular disease (CVD), whether atherosclerosis or aortic valve narrowing.
Lipoprotein(a) consists of an LDL-type particle with apolipoprotein B linked to another element, apolipoprotein(a).
Many international guidelines now recommend a single lipoprotein(a) assay, but these recommendations are not applied in practice, in the "mistaken" belief that the risk of CVD is already taken into account by the 3 elements mentioned.
However, lipoprotein(a) confers a CVD risk six times higher than LDL cholesterol.
Furthermore, it has been suggested that the cardiovascular risk associated with high lipoprotein(a) levels is partly linked to mild inflammation.
It was therefore useful to quantify the respective contribution of each element to the onset of CVD.
This study was carried out on over 70,000 men and 45,000 women from Copenhagen and a British database.
Information on CVD included cardiac death, myocardial infarction or coronary artery intervention, ischemic stroke or lower limb artery disease.
The use or non-use of statins at the start of follow-up was taken into account. Genetic abnormalities of LDL cholesterol and/or lipoprotein(a) were not taken into account.
Among these people aged around 60, 53% of whom were women (for once...), 7,155 and 32,292 developed CVD and 1,521 and 6,864 a stroke during a follow-up period of a dozen years.
In patients not receiving statins at baseline, stroke rates in both groups (the 2 sources of people) were explained respectively for 19% and 13% by LDL-C, 22% and 15% by non-HDL-C, 14% and 16% by apoprotein B, and 0.2% and 1.1% by CRP.
In statin users, values were logically lower for all components: LDL-C, non-HDL-C and apoB explained a lower percentage risk in statin-treated people than in those not receiving statins. This is not surprising, as these measures are not as reliable predictors of cardiovascular risk in statin-treated people.
In people with elevated lipoprotein (a): more than 0.3 g/l, compared with all included individuals, the risks explained by LDL-C, non-HDL-C, apoB and CRP were generally similar or slightly higher.
In this study of 528,790 individuals from two general population cohorts, the fraction of CVD and stroke risk explained by LDL-C, non-HDL-C, apoB or CRP measurements in statin-treated and statin-untreated individuals was minimal to negligible, and this analysis serves to underline the impossibility of relying on other laboratory measurements to meaningfully assess lipoprotein(a)-related risk.
The strengths of this study include the fact that it is based on a general population, with data from large cohorts, long follow-up and a minimal number of people lost to follow-up.
These results show that other laboratory measures cannot replace lipoprotein(a) in clinical practice for the accurate assessment of CVD and stroke risk.
Consequently, lipoprotein(a) levels should be measured once in a lifetime in all individuals, as already advocated by numerous recommendations and consensus statements worldwide. It therefore appears that an elevated lipoprotein(a) level, generally defined as between 0.3 and 0.5 g/l, should be a therapeutic target, rather than focusing on other lipid parameters.
However, a high lipoprotein(a) level will only be a valid therapeutic target once ongoing studies have confirmed that lowering Lp(a) significantly reduces the risk of CVD.
In conclusion, what is the main finding?
The fraction of CVD risk explained by the measurement of LDL cholesterol, non-HDL-C cholesterol, Apoprotein B or CRP in statin-treated and non-statin-treated patients is minimal, if not negligible.
Lipoprotein(a) measurement is necessary in all individuals for a precise assessment of a given individual's cardiovascular risk, with consequences for the therapeutic decisions to be implemented.

Reference:
Thomas P.E. et al: Lipoprotein(a) cardiovascular risk explained by LDL cholesterol, non-HDL cholesterol, ApoB, or hsCRP is minimal :
J Am Coll Cardiol 2025 Mar 19: S0735-1097(25)00484-X.