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J Clin Lipidol. 2018 Jan - Feb;12(1):122-129.e2. doi: 10.1016/j.jacl.2017.10.024. Epub 2017 Nov 2.

Temporal variability in lipoprotein(a) levels in patients enrolled in the placebo arms of IONIS-APO(a)Rx and IONIS-APO(a)-LRx antisense oligonucleotide clinical trials.

Author information

1
University of Washington, Seattle, WA, USA.
2
Department of Medicine, Ionis Pharmaceuticals, Carlsbad, CA, USA.
3
Department of Medicine, University of California San Diego, La Jolla, CA, USA.
4
Department of Medicine, Ionis Pharmaceuticals, Carlsbad, CA, USA; Department of Medicine, University of California San Diego, La Jolla, CA, USA. Electronic address: stsimikas@ucsd.edu.

Abstract

BACKGROUND:

Lipoprotein(a) [Lp(a)] levels are primarily genetically determined, but their natural variability is not well known.

OBJECTIVE:

The aim of the study was to evaluate the short-term temporal variability in Lp(a) in 3 placebo groups from the IONIS-APO(a)Rx and IONIS-APO(a)-LRx trials.

METHODS:

The placebo groups comprised 3 studies: Study 1 with 10 subjects with any Lp(a) concentration; Study 2 with 13 subjects with Lp(a) ≥75 nmol/L (∼30 mg/dL); and Study 3 with 29 patients with Lp(a) ≥125 nmol/L (≥∼50 mg/dL). Lp(a) was measured in serial blood samples (range 7-12 samples up to 190 days of follow-up) and analyzed as absolute change and mean percent change from baseline. Outliers were defined as having a > ±25% difference in Lp(a) from baseline at any future time point.

RESULTS:

No significant temporal differences in mean absolute Lp(a) levels were present in any group. However, among individuals, the mean change in absolute Lp(a) levels at any time point ranged from -16.2 to +7.0 nmol/L in Study 1, -15.8 to +9.8 nmol/L in Study 2, and -60.2 to +16.6 nmol/L in Study 3. The mean percent change from baseline ranged from -9.4% to +21.6% for Study 1, -13.1% to 2.8% for Study 2, and -12.1% to +4.9% in Study 3. A total of 21 of 52 subjects (40.4%) were outliers, with 13 (62%) >25% up and 8 (38%) >25% down. Significant variability was also noted in other lipid parameters, but no outliers were noted with serum albumin.

CONCLUSION:

In subjects randomized to placebo in Lp(a) lowering trials, modest intra-individual temporal variability of mean Lp(a) levels was present. Significant number of subjects had > ±25% variation in Lp(a) in at least 1 time point. Although Lp(a) levels are primarily genetically determined, further study is required to define additional factors mediating short-term variability.

KEYWORDS:

Antisense oligonucleotides; Cardiovascular events; Genetics; Isoforms; Lipoprotein(a); Single-nucleotide polymorphisms; Therapy

PMID:
29174389
DOI:
10.1016/j.jacl.2017.10.024

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