Mipomersen, an Antisense Oligonucleotide to Apolipoprotein B-100, Reduces Lipoprotein(a) in Various Populations With Hypercholesterolemia. Issue 3 (March 2015)

• Record Type: Journal Article
• Authors: Santos, Raul D.; Raal, Frederick J.; Catapano, Alberico L.; Witztum, Joseph L.; Steinhagen-Thiessen, Elisabeth; Tsimikas, Sotirios
• Is Part Of: Arteriosclerosis, thrombosis, and vascular biology. Volume 35:Issue 3(2015)
• Publication Date: 2015-03
• Subjects: Arteriosclerosis -- Periodicals; Thrombosis -- Periodicals; Blood-vessels -- Pathophysiology -- Periodicals; Electronic journals; 616.13
• DOI: 10.1161/ATVBAHA.114.304549
• Languages: English
• ISSNs: 1079-5642

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <title>Objective—</title> <p>Lp(a) is an independent, causal, genetic risk factor for cardiovascular disease and aortic stenosis. Current pharmacological lipid-lowering therapies do not optimally lower Lp(a), particularly in patients with familial hypercholesterolemia (FH).</p> </sec> <sec> <title>Approach and Results—</title> <p>In 4 phase III trials, 382 patients on maximally tolerated lipid-lowering therapy were randomized 2:1 to weekly subcutaneous mipomersen 200 mg (n=256) or placebo (n=126) for 26 weeks. Populations included homozygous FH, heterozygous FH with concomitant coronary artery disease (CAD), severe hypercholesterolemia, and hypercholesterolemia at high risk for CAD. Lp(a) was measured 8× between baseline and week 28 inclusive. Of the 382 patients, 57% and 44% had baseline Lp(a) levels >30 and >50 mg/dL, respectively. In the pooled analysis, the mean percent decrease (median, interquartile range in Lp(a) at 28 weeks was significantly greater in the mipomersen group compared with placebo (−26.4 [−42.8, −5.4] versus −0.0 [−10.7, 15.3]; <italic>P</italic><0.001). In the mipomersen group in patients with Lp(a) levels >30 or >50 mg/dL, attainment of Lp(a) values ⩽30 or ⩽50 mg/dL was most frequent in homozygous FH and severe hypercholesterolemia patients. In the combined groups, modest correlations were present between percent change in apolipoprotein B-100 and Lp(a) (<italic>r</italic>=0.43; <italic>P</italic><0.001) and low-density lipoprotein cholesterol and Lp(a) (<italic>r</italic>=0.36; <italic>P</italic><0.001) plasma levels.</p> </sec> <sec> <title>Conclusions—</title> <p>Mipomersen consistently and effectively reduced Lp(a) levels in patients with a variety of lipid abnormalities and cardiovascular risk. Modest correlations were present between apolipoprotein B-100 and Lp(a) lowering but the mechanistic relevance mediating Lp(a) reduction is currently unknown.</p> </sec> </abstract>