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Lipoprotein(a) Reduction in Persons With Cardiovascular Disease
Study Questions:
Lipoprotein(a) [Lp(a)] levels are genetically determined and, when elevated, are a risk factor for cardiovascular disease (CVD) and aortic stenosis. What is the effect of the novel hepatocyte antisense oligonucleotide AKCEA-APO(a)-LRx [APO(a)-LRx] on Lp(a) in a dose-finding study?
Methods:
This randomized, double-blind, placebo-controlled, dose-ranging trial involved 286 patients with established CVD and screening Lp(a) levels of ≥60 mg/dl (150 nmol /L). Patients received APO(a)-LRx (20, 40, or 60 mg every 4 weeks; 20 mg every 2 weeks; or 20 mg every week), or saline placebo subcutaneously for 6-12 months. The Lp(a) level was measured with an isoform-independent assay with the primary endpoint percent change from baseline to month 6 of exposure.
Results:
Mean duration of treatment was 31.6 ± 11.5 weeks. About 60% were <65 years old and 30% were women. Roughly 85% were taking statins, 50% ezetimibe, and 20% a PCSK9 inhibitor. Median baseline Lp(a) levels in the six groups ranged from 205 to 247 nmol/L. Administration of APO(a)-LRx resulted in dose-dependent decreases in Lp(a), with mean percent decreases ranging from 35% at a dose of 20 mg every 4 weeks and 58% at 20 mg every 2 weeks, to 72% at 60 mg every 4 weeks, and 80% at 20 mg every week, as compared with 6% with placebo (P values for the comparison with placebo ranged from 0.003 to <0.001). There were no significant differences between any APO(a)-LRx dose and placebo with respect to platelet counts, liver and renal measures, or influenza-like symptoms. The most common adverse events were injection-site reactions.
Conclusions:
APO(a)-LRx reduced Lp(a) levels in a dose-dependent manner in patients with levels of ≥60 mg/dl (150 nmol/L) and established CVD.
Perspective:
Importantly, at the highest cumulative dose regimen, which was equivalent to 80 mg monthly, 98% of patients attained a lipoprotein(a) level of 50 mg/dl (125 nmol/L) or lower, a target value supported by European and US guidelines, and by empirical data from patients treated with statins. There was also a significant reduction of oxidized phospholipids on apo B and apo (a), which are proinflammatory components of Lp(a) linked to higher atherothrombotic risk. Clinical outcome trials are in progress, which should be particularly useful in familial hypercholesterolemia and persons with premature coronary artery disease in whom an elevated Lp(a) is the most common inherited lipid moiety.
Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Valvular Heart Disease, Atherosclerotic Disease (CAD/PAD), Advanced Lipid Testing, Lipid Metabolism, Nonstatins, Novel Agents, Primary Hyperlipidemia, Statins
Keywords: Aortic Valve Stenosis, Apolipoproteins A, Apolipoproteins B, Cardiovascular Diseases, Coronary Artery Disease, Dyslipidemias, Hepatocytes, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hyperlipoproteinemia Type II, Lipids, Lipoprotein(a), Oligonucleotides, Antisense, Phospholipids, Proprotein Convertases, Primary Prevention, Risk Factors
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