A new study has drawn attention to inaccurate measurement of LDL-cholesterol levels in some patients with current assays, which could lead to incorrect therapeutic approaches.
The patient groups most affected are those with high levels of the lipoprotein Lp(a), in whom LDL-cholesterol levels are being overestimated in current laboratory tests, the authors say.
“Current laboratory assays all have the limitation that they cannot measure or report LDL cholesterol accurately. They are actually measuring the combination of LDL and Lp(a),” senior study author Sotirios Tsimikas, MD, University of California, San Diego, explained to this news organization.
Dr. Sotirios Tsimikos
“While this may not matter much in individuals with normal Lp(a) levels, in those with elevated Lp(a), the Lp(a) cholesterol may constitute a substantial proportion of the reported LDL cholesterol, and the actual LDL-cholesterol levels could be much lower that the value the lab is telling us,” he said.
Dr. Tsimikas gave the example of a patient with an LDL-cholesterol lab measurement of 75 mg/dL. “If that patient has an Lp(a) level of zero, then they do actually have an LDL level of 75. But as the Lp(a) increases, then the proportion of the result accounted for by LDL cholesterol decreases. So, if a patient with a measured LDL cholesterol of 75 has an Lp(a)-cholesterol level of 20, then their actual LDL level is 55.”
Dr. Tsimikas said it is important to know levels of both lipoproteins individually, so the correct therapeutic approach is used in situations where the Lp(a) cholesterol might be elevated.
“By understanding the actual values of LDL cholesterol and Lp(a) cholesterol, this will allow us to personalize the use of cholesterol-lowering medications and decide where to focus treatment. In the patient with a high level of Lp(a), their residual risk could be coming from Lp(a) cholesterol and less so from LDL cholesterol,” he added. “As we develop drugs to lower Lp(a), this patient might be better off on one of these rather than increasing efforts to lower LDL cholesterol, which might already be at goal.”
The study was published in the March 22 issue of the Journal of the American College of Cardiology.
Dr. Tsimikas noted that Lp(a) is now accepted as a genetic, independent, causal risk factor for cardiovascular disease, but current LDL-lowering drugs do not have much effect on Lp(a).
“Lp(a) can be lowered a little with niacin and PCSK9 inhibitors, but both have a quite a weak effect, and statins increase Lp(a). However, there are now multiple RNA-based therapeutics specifically targeting Lp(a) in clinical development,” he said.
At present, Lp(a) cholesterol has to be mathematically estimated, most commonly with the Dahlén formula, because of the lack of a validated, quantitative method to measure Lp(a) cholesterol, Dr. Tsimikas says.
For the current study, the researchers used a novel, quantitative, sensitive method to directly measure Lp(a) cholesterol, then applied this method to data from a recent study with the one of the new Lp(a)-lowering drugs in development – pelacarsen – which was conducted in patients with elevated Lp(a) levels.
Results showed that direct Lp(a)-cholesterol assessment, and subtracting this value from the laboratory LDL-cholesterol value, provides a more accurate reflection of the baseline and change in LDL cholesterol, the authors report. In the current study, corrected LDL cholesterol was 13 to 16 mg/dL lower than laboratory-reported LDL cholesterol.
Using the corrected LDL-cholesterol results, the study showed that pelacarsen significantly decreases Lp(a) cholesterol, with neutral to modest effects on LDL.
The study also suggests that the current method of calculating Lp(a) cholesterol, and then deriving a corrected LDL cholesterol – the Dahlén formula – is not accurate.
“The Dahlén formula relies on the assumption that Lp(a) cholesterol is universally a fixed 30% of Lp(a) mass, but this usually isn’t the case. The Dahlén formula needs to be discontinued. It can be highly inaccurate,” Dr. Tsimikas said.