Lipoprotein(a), PCSK9 Inhibition, and Cardiovascular Risk

Abstract

Background: Lipoprotein(a) [Lp(a)] may play a causal role in atherosclerosis. Proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors have been shown to significantly reduce plasma Lp(a) concentration. However, the relationship between Lp(a) levels, PCSK9 inhibition and cardiovascular (CV) risk reduction remains undefined. Methods: Lp(a) was measured in 25,096 patients in FOURIER, a randomized trial of evolocumab versus placebo in patients with established atherosclerotic CV disease (median follow-up 2.2 years). Cox models were used to assess the independent prognostic value of Lp(a) and the efficacy of evolocumab for coronary risk reduction by baseline Lp(a) concentration. Results: The median [IQR] baseline Lp(a) concentration was 37[13-165] nmol/L. In the placebo arm, patients with baseline Lp(a) in the highest quartile had a higher risk of coronary heart disease (CHD) death, MI or urgent revascularization (UR) (adjusted HR Q4:Q1 1.22, 95% CI 1.01-1.48) independent of LDL-C. At 48 weeks, evolocumab significantly reduced Lp(a) by a median [IQR] of 26.9% [6.2-46.7%]. The percent change in Lp(a) and LDL-C at 48 weeks in evolocumab patients was moderately positively correlated (r=0.37, 95% CI 0.36-0.39, Pmedian, and by 7% (HR 0.93, 0.80-1.08; P interaction=0.07) in those ≤median. Coupled with the higher baseline risk, the absolute risk reductions and NNT_3y were 2.49% and 40 vs. 0.95% and 105, respectively. Conclusions: Lp(a) is associated with the risk of CV events in patients with established CV disease irrespective of LDL-C. Evolocumab significantly reduced Lp(a) levels, and patients with higher baseline Lp(a) levels experienced greater absolute reductions in Lp(a) and tended to derive greater coronary benefit from PCSK9 inhibition. Clinical Trial Registration: URL: https://clinicaltrials.gov Unique Identifier: NCT01764633