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

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.

Meta-analysis

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)

• In the statin-vs.-placebo trials, significantly elevated Lp(a) levels following statin therapy vs. placebo were seen in the MIRACL (mean change: 8.5% vs. -0.4%, P<0.001) and ASTRONOMER (19.6% vs. -0.7%, P<0.001) trials, whereas no significant increase in Lp(a) was seen in children with FH (2.3% vs. 12.6%, P=0.081).
• In PROVE-IT, atorvastatin resulted in a significantly higher increase in Lp(a) levels, compared to pravastatin (24.2% vs. 11.6%, P<0.001), whereas no significant effect was seen in REVERSAL (18.7% vs. 20.4%, P=0.080) and in VISION (-6.4% vs. -1.3%, P=0.70).
• In the statin-vs.-placebo group, the OR for the number of patients with increased Lp(a) levels was 1.55 (95%CI: 1.33-1.80, P<0.0001) in the statin group, compared to the placebo group.
• In the statin-vs.-statin group, the OR for the number of patients with increased Lp(a) levels was 1.16 (95%CI: 0.99-1.37, P=0.0681) in the atorvastatin 80 mg group, compared to the pravastatin 40 mg group.
• In concordance with the primary analyses, the pooled analyses showed significantly greater increases in Lp(a) levels with statins vs. placebo and with atorvastatin vs. pravastatin.

Statins and individual changes in Lp(a)

• A waterfall plot showed both increased and decreased Lp(a) levels in the statin (absolute changes in Lp(a) ranging from -68.3 mg/dL to +101.3 mg/dL) and placebo group (from -68.0 mg/dL to +104.4 mg/dL), but overall more patients treated with statins had elevated Lp(a) levels compared to those in the placebo group.
• Decreased Lp(a) levels were seen in about 52.5% of those treated with placebo and in 38.8% in the statin group. Lp(a) levels were increased in 47.5% in the placebo group and in 61.2% of those assigned to statins.

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

• Treatment with atorvastatin 5 µM for 24 hours resulted in 1.7-fold higher LDLR and 1.5-fold higher PCSK9 mRNA levels, compared with untreated cells.
• Atorvastatin 10 µM for 12 and 24 hours resulted in significantly, 1.6- and 1.9-fold higher LDLR expression, respectively, and 2- and 4-fold higher PCSK9 mRNA levels, respectively. Compared to untreated control cells, treatment with atorvastatin 10 µM for 24 hours significantly increased LPA expression by 1.5-fold, but at a delay compared to LDLR and PCSK9 expression.
• Both the absolute amount of apo(a) protein expression and secretion relative to cellular protein, and the relative amount normalized to no treatment with atorvastatin were significantly elevated with increasing doses of atorvastatin.

Conclusion

References

Find this article online at Eur Heart J