Physicians' Academy for Cardiovascular Education

Elevated Lp(a) levels and apo(a) production in response to statins

Statin therapy increases lipoprotein(a) levels

Literature - Tsimikas S, Gordts PLSM, Nora C et al. - Eur Heart J 2019; doi:10.1093/eurheartj/ehz310

Introduction and methods

Despite statin therapy, participants of clinical trials show significant residual CV risk, with more events occurring while patients are on statins than events prevented by statins. This might be due to the fact that statins do not optimally reduce all atherogenic lipoproteins, such as lipoprotein(a) (Lp[a]). Lp(a) is a genetic, independent, and likely causal risk factor for CVD [1,2]. This observed causal association is strongest in not only primary care populations, but also in patients on statins in high risk primary and secondary settings [3-6].

Results on the effect of statins on plasma Lp(a) levels are mixed. As early as in 1989, lovastatin has been shown to cause a dose-dependent increase in Lp(a) levels [7] and a recent meta-analysis demonstrated a mean 11% increase in Lp(a) with statins [8], whereas other studies did not find a significant increase in Lp(a). This is due to various study limitations. For instance, studies use different assay methodologies to measure Lp(a), studies are small and diverse, Lp(a) levels can vary 1000-fold requiring large datasets, and individual-level patient data are missing. This study therefore performed an individual-participant-data meta-analysis of 6 statin trials, using a single well-established Lp(a) method to investigate the change in Lp(a) in response to statin therapy. Also, a cell culture study was performed to gain insight into potential underlying mechanisms of elevated Lp(a) levels following statin treatment.


For this meta-analysis (n=5256), data of individuals treated with placebo were pooled and data of those on statins were analyzed both pooled and individually. Statin treatment in the trials included atorvastatin 10 mg/day or 80 mg/day, pravastatin 40 mg/day, rosuvastatin 40mg/day, or pitavastatin 2 mg/day. Three statin-vs.-placebo (MIRACLE, children with familial hypercholesterolemia (FH), and ASTRONOMER) and three statin-vs.-statin trials (PROVE-IT, VISION, REVERSAL) were included, with different available timepoints for on-treatment Lp(a) measurements and varying type of patients. The primary analysis was based on log-transformed data, because Lp(a) values were non-normally distributed. For pooled analysis, log-transformed data were back-transformed to geometric means. Placebo-vs.-statin and statin-vs.-statin trials were analyzed separately, using log-transformed data that were back-transformed to geometric means.

Cell culture study

In the cell culture study, the human hepatoma cell line HepG2 was treated with 5 or 10 µM atorvastatin for 12 or 24 hours. Expression of the LDLR, PCSK9, and LPA genes was evaluated.

Main results

Statins and relative and absolute changes in Lp(a)

Statins and individual changes in Lp(a)

Effect of statins on LPA expression and apo(a) production in human hepatoma cell culture


This study, consisting of a well-powered meta-analysis and cell culture study showed significant elevations in Lp(a) levels upon treatment with statins, as well as increased apo(a) production. This suggests that Lp(a) measurements might be considered both before and after first initiation of statin treatment. It might be that the adverse effects of increased Lp(a) levels play a role in the residual risk in subjects on statins and should therefore be further investigated.


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Find this article online at Eur Heart J

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