Reduction in Lp(a) With the PCSK9 Monoclonal Antibody Evolocumab
Editor's Note: Commentary based on Raal FJ, Giugliano RP, Sabatine MS, et al. Reduction in Lipoprotein(a) With PCSK9 Monoclonal Antibody Evolocumab (AMG 145): A Pooled Analysis of More Than 1,300 Patients in 4 Phase II Trials. J Am Coll Cardiol 2014;63:1278-88.
Lipoprotein(a) is a circulating LDL-like particle containing hepatically synthesized apo(a) covalently liked to apolipoprotein B.1 Increased circulating Lp(a) levels are linked with cardiovascular disease independent of other cardiovascular risk factors.2 This association persists in some, but not all, studies of participants treated with statin therapy. The biomarker has attracted increased attention related to ongoing translational work and genetic studies that suggest the Lp(a) link to cardiovascular disease is causal in nature. Limited therapeutic options to treat elevated Lp(a) are currently available beyond niacin, which is known to decrease Lp(a) by up to 40%.3
Proprotein convertase subtillisin/kexin type 9 (PCSK9) inhibitors are injectable compounds that decrease circulating LDL-cholesterol levels by inhibiting the intrahepatic degradation of LDL receptors.
Raal et. al present a pooled analysis of 1359 participants from four randomized controlled trials implementing 12-weeks of treatment with variable doses of AMG 145 (evolocumab), a human monoclonal antibody inhibitor of PCSK9. Studies were funded by Amgen (Thousand Oaks, CA). Individual study populations varied substantially, including 1. Primary hypercholesterolemia; 2. Statin-treated coronary disease; 3. Heterozygous familial hypercholesterolemia; 4. Statin-intolerant participants with hypercholesterolemia. The authors report the effect of AMG 145 on lipoprotein(a) levels, measured at baseline, after 12 weeks of therapy, and in follow-up in selected individuals using a well-validated assay.
As previously reported, AMG 145 led to substantial dose-dependent decreases in both LDL-C (40 – 59%) and apolipoprotein B (31 – 49%). Robust reductions in lipoprotein(a) were also noted, ranging from 14 to 30% across varying dosing regimens and time intervals. Percent reduction was similar across patient subgroups, including those with elevated baseline Lp(a), and slightly more pronounced in those using concomitant statin therapy. Percent reduction in LDL-Cholesterol was a moderate-strength predictor of Lp(a) reduction (Spearman r = 0.51). Lipoprotein(a) levels returned to baseline several weeks after therapy cessation in a subgroup of patients with available data.
Twelve weeks of therapy with the PCSK9 inhibitor AMG 145 leads to robust and reversible decreases in lipoprotein(a) levels largely independent of baseline patient demographics.
A large body of basic, translational, and genetic data supports PCSK9 inhibition as a viable therapeutic strategy in decreasing cardiovascular risk. The present analysis adds Lp(a) reduction to the efficacious impact of AMG 145 on circulating apolipoprotein B containing biomarkers. This finding is likely to be a class effect, with similar magnitude of reduction noted with another PCSK9 inhibitor SAR236553. The underlying mechanism of Lp(a) reduction is incompletely understood and is a major unanswered question in the field. Of note, statins also increase hepatic LDL-receptor density but have minimal impact on circulating Lp(a). Limited data suggests decreased availability of apolipoprotein B in individuals treated with PCSK9 inhibitors leads to decreased Lp(a) synthesis.
In addition to PCSK9 inhibition, multiple novel agents have been linked to Lp(a) reduction including the cholesteryl ester transfer protein inhibitor anacetrapib (31% reduction) and the antisense oligonucleotide targeting apolipoprotein B mipomersen (24% reduction).4-5 Because each of these agents is associated with substantial impact on other circulating lipid fractions, it will ultimately prove challenging to tease out whether any outcomes benefit is specifically related to Lp(a) reduction. An intervention that specifically targets Lp(a) would provide a definitive test of the "Lp(a) hypothesis" and is in early phase development.6
- Tsimikas S, Hall JL. Lipoprotein(a) as a potential causal genetic risk factor of cardiovascular disease: a rationale for increased efforts to understand its pathophysiology and develop targeted therapies. J Am Coll Cardiol 2012;60:716-21.
- Emerging Risk Factors Collaboration, Erqou S, Kaptoge S, et al. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA 2009;302:412-23.
- Carlson LA, Hamsten A, Asplund A. Pronounced lowering of serum levels of lipoprotein Lp(a) in hyperlipidaemic subjects treated with nicotinic acid. J Intern Med 1989;226:271-6.
- Stein EA, Mellis S, Yancopoulos GD, Stahl N, Logan D, Smith WB, Lisbon E, Gutierrez M, Webb C, Wu R, Du Y, Kranz T, Gasparino E, Swergold GD. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N Engl J Med 2012;366:1108-18.
- Akdim F, Visser ME, Tribble DL, Baker BF, Stroes ES, Yu R, Flaim JD, Su J, Stein EA, Kastelein JJ. Effect of mipomersen, an apolipoprotein B synthesis inhibitor, on low-density lipoprotein cholesterol in patients with familial hypercholesterolemia. Am J Cardiol 2010;105:1413-9.
- Merki E, Graham M, Taleb A, Leibundgut G, Yang X, Miller ER, Fu W, MullickAE,Lee R, Willeit P, Crooke RM, Witztum JL, Tsimikas S. Antisense oligonucleotide lowers plasma levels of apolipoprotein (a) and lipoprotein (a) in transgenic mice. J Am Coll Cardiol 2011;57:1611-21.
Keywords: Apolipoproteins A, Apolipoproteins B, Biomarkers, Cardiovascular Diseases, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Lipoprotein(a), Niacin
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