Statin therapy increases PCSK9 and Lp(a) levels in patients at high CV risk

Background

Statins reduce low-density lipoprotein cholesterol (LDL-c) levels, increase the expression of proprotein subtilisin kexin type 9 (PCSK9) levels, and may increase lipoprotein a (Lp(a)) levels [1-3]. In this sub-analysis of the ILLUMINATE (Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events) study, the impact of different doses of statins on circulating PCSK9 and Lp(a) levels was evaluated in patients at high CV risk, with or without type 2 diabetes (T2DM), and with or without the addition of a cholesterol ester transfer protein (CETP).

The ILLUMINATE trial included 15,067 individuals, aged 45-75 years, with a history of myocardial infarction, stroke, acute coronary syndrome, unstable angina, peripheral vascular disease, or cardiac revascularization within 30 days to 5 years before screening [4]. During a run-in period of 4-10 weeks, patients received atorvastatin, which was titrated as appropriate at 2-week intervals to achieve LDL-c levels <100 mg/dL. Patients who met the LDL-c target were randomly assigned to receive either atorvastatin plus 60 mg of torcetrapib or atorvastatin plus placebo [4].

For this analysis, 594 patients receiving torcetrapib and atorvastatin were matched in a 1:2 ratio to 1,151 patients receiving placebo and atorvastatin. Plasma PCSK9 and Lp(a) levels were measured at baseline (after the run-in period) and 3 months after randomization.

Main results

At baseline:

• Plasma PCSK9 and Lp(a) levels were dose-dependently increased with increasing atorvastatin doses.
• Compared with patients without T2DM, those with T2DM had higher PCSK9 (357 ± 123 vs 338 ± 115 ng/mL; P=0.0012) and lower Lp(a) levels (28 ± 32 vs 32 ± 33 mg/dL; P=0.0005).
• Regardless of T2DM status, higher atorvastatin doses were associated with higher PCSK9 levels and with higher Lp(a) levels.

After 3 months of treatment:

• Plasma PCSK9 levels significantly increased in patients treated with torcetrapib (+13.1 ± 125.3 ng/mL; +3.7%; P=0.005), but not in patients treated with placebo (+2.6 ± 127.9 ng/mL; +0.7%; P=0.39).
• Increases in PCSK9 levels with torcetrapib were statistically significant in patients with T2DM only.
• Plasma Lp(a) levels significantly decreased in patients treated with torcetrapib (-3.4 ± 10.7 mg/dL; -11.1%; P <0.0001), but not in patients treated with placebo (+0.3 ± 9.4 mg/dL; +0.1%; P=0.92).

Conclusion

References

Find this article online at J Clin Lipidol 2018