Diabetes lowers Lp(a) but raises PCSK9, and CETP inhibition with torcetrapib cuts Lp(a) by 11.1%, a clinical trial analysis (J Clin Lipidol 2018)

Original title: 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

J Clin Lipidol · 12 October 2017 · 7

Arsenault BJ, Petrides F, Tabet F, Bao W, Hovingh GK, Boekholdt SM, Ramin-Mangata S, Meilhac O, DeMicco D, Rye KA, Waters DD, Kastelein JJP et al.

This analysis of the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events trial measured PCSK9 and Lp(a) in patients with coronary heart disease and/or type 2 diabetes (T2D), titrated on atorvastatin (10-80 mg/day) then randomised to add the CETP inhibitor torcetrapib or placebo. At baseline, both PCSK9 and Lp(a) rose dose-dependently with atorvastatin dose; patients with T2D had higher PCSK9 (357 vs 338 ng/mL, P=.0012) but lower Lp(a) (28 vs 32 mg/dL, P=.0005) than those without. Torcetrapib significantly increased PCSK9 (+13.1 ng/mL, +3.7%, P=.005) and significantly decreased Lp(a) (-3.4 mg/dL, -11.1%, P<.0001), while placebo changed neither (PCSK9 +2.6 ng/mL, +0.7%, P=.39; Lp(a) +0.3 mg/dL, +0.1%, P=.92). The findings show atorvastatin dose-dependently raises both PCSK9 and Lp(a), T2D shifts the two in opposite directions, and CETP inhibition with torcetrapib modestly raises PCSK9 while lowering Lp(a) by about 11.1%.

Original abstract

Background: Proprotein subtilisin kexin type 9 (PCSK9) and lipoprotein (a) [Lp(a)] levels are causative risk factors for coronary heart disease.

Objectives: The objective of the study was to determine the impact of lipid-lowering treatments on circulating PCSK9 and Lp(a).

Methods: We measured PCSK9 and Lp(a) levels in plasma samples from Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events trial patients with coronary heart disease and/or type II diabetes (T2D) mellitus. Patients received atorvastatin, which was titrated (10, 20, 40, or 80 mg/d) to achieve low-density lipoprotein cholesterol levels <100 mg/dL (baseline) and were subsequently randomized either to atorvastatin + torcetrapib, a cholesterol ester transfer protein inhibitor, or to atorvastatin + placebo.

Results: At baseline, both plasma PCSK9 and Lp(a) were dose-dependently increased with increasing atorvastatin doses. Compared with patients without T2D, those with T2D had higher PCSK9 (357 ± 123 vs 338 ± 115 ng/mL, P = .0012) and lower Lp(a) levels (28 ± 32 vs 32 ± 33 mg/dL, P = .0005). Plasma PCSK9 levels significantly increased in patients treated with torcetrapib (+13.1 ± 125.3 ng/mL [+3.7%], P = .005), but not in patients treated with placebo (+2.6 ± 127.9 ng/mL [+0.7%], P = .39). Plasma Lp(a) levels significantly decreased in patients treated with torcetrapib (-3.4 ± 10.7 mg/dL [-11.1%], P < .0001), but not in patients treated with placebo (+0.3 ± 9.4 mg/dL [+0.1%], P = .92).

Conclusion: In patients at high cardiovascular disease risk, PCSK9 and Lp(a) are positively and dose-dependently correlated with atorvastatin dosage, whereas the presence of T2D is associated with higher PCSK9 but lower Lp(a) levels. Cholesterol ester transfer protein inhibition with torcetrapib slightly increases PCSK9 levels and decreases Lp(a) levels.

Summary written by lp-a.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.