Statin therapy increases PCSK9 and Lp(a) levels in patients at high CV risk
Effect of atorvastatin, cholesterol ester transfer protein inhibition, and diabetes mellitus on circulating proprotein subtilisin kexin type 9 and lipoprotein(a) levels in patients at high cardiovascular risk
Literature - Arsenault BJ, Petrides F, Tabet F, et al. - J Clin Lipidol 2018; 12: 130–136Background
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
In a sub-analysis of the ILLUMINATE study, in patients at high CV risk, PCSK9 and Lp(a) levels were dose-dependently increased by atorvastatin. The presence of T2DM was associated with higher PCSK9 levels and lower Lp(a) levels. Cholesterol ester transfer protein inhibition with torcetrapib slightly increased PCSK9 levels and decreased Lp(a) levels.
References
1. Dubuc G, Chamberland A, Wassef H, et al. Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis regulated convertase-1 implicated in familial hypercholesterolemia. Arterioscler Thromb Vasc Biol. 2004;24:1454–1459.
2. Awan Z, Seidah NG, Macfadyen JG, et al. Proprotein convertase subtilisin/kexin type 9 concentrations, and LDL cholesterol response: the JUPITER trial. Clin Chem. 2012;58:183–189.
3. Capoulade R, Chan KL, Yeang C, et al. Oxidized phospholipids, lipoprotein(a), and progression of calcific aortic valve stenosis. J Am Coll Cardiol. 2015;66:1236–1246.
4. Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med. 2007;357:2109–2122.
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