Therapeutic Lowering of Lipoprotein(a): A Role for Pharmacogenetics?

Abstract

See Article by Parish, Hopewell, and Hill et al We are on the cusp of having elevated plasma concentrations of lipoprotein(a) as a therapeutic target for cardiovascular disease (CVD). Recent large population studies and meta-analyses, genome-wide association studies, and Mendelian randomization studies have identified elevated lipoprotein(a) as an independent, causal risk factor for coronary heart disease and other atherothrombotic disorders.1 Elevated lipoprotein(a) is also emerging as a key risk factor for calcific aortic valve disease.2 Several therapeutic modalities capable of lowering lipoprotein(a) are in the marketplace or are in clinical trials.3 Yet, several obstacles remain. Most importantly, it has not been directly demonstrated that lowering lipoprotein(a) produces a clinical benefit, and to what extent lipoprotein(a) must be lowered to derive such a benefit. Beyond this, there remain fundamental unanswered questions on how lipoprotein(a) concentrations are established and the mechanisms underlying the lipoprotein(a)-lowering effects of current therapies. The article by Parish et al4 in this issue, describing a substudy of the Heart Protection Study 2–Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) randomized controlled trial of niacin/laropiprant, sheds interesting new light on the effect of niacin on lipoprotein(a) levels, while also crystallizing some key issues related to clinical management of lipoprotein(a) hyperlipoproteinemia. Lipoprotein(a) consists of a low-density lipoprotein (LDL)-like particle attached by a single disulfide bond to the unique glycoprotein apolipoprotein(a) (apo[a]). Apo(a) not only confers distinct structural and functional characteristics to lipoprotein(a) but also controls the rates of lipoprotein(a) synthesis and catabolism.5 The gene encoding apo(a), LPA , arose by duplication of the gene encoding plasminogen, and indeed apo(a) possesses domains homologous to kringle IV (KIV) and kringle V as well as the protease domain of plasminogen.6 Apo(a) lacks kringles I, II, and III that are found in plasminogen and instead …