Effects of mipomersen, an apolipoprotein B100 antisense, on lipoprotein (a) metabolism in healthy subjects
Elevated lipoprotein (a) [Lp(a)] levels increase the risk for CVD. Novel treatments that decrease LDL cholesterol (LDL-C) have also shown promise for reducing Lp(a) levels. Mipomersen, an antisense oligonucleotide that inhibits apoB synthesis, is approved for the treatment of homozygous familial hyp...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2018-12-01
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| Series: | Journal of Lipid Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S002222752034164X |
| _version_ | 1819293990618398720 |
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| author | Renu Nandakumar Anastasiya Matveyenko Tiffany Thomas Marianna Pavlyha Colleen Ngai Stephen Holleran Rajasekhar Ramakrishnan Henry N. Ginsberg Wahida Karmally Santica M. Marcovina Gissette Reyes-Soffer |
| author_facet | Renu Nandakumar Anastasiya Matveyenko Tiffany Thomas Marianna Pavlyha Colleen Ngai Stephen Holleran Rajasekhar Ramakrishnan Henry N. Ginsberg Wahida Karmally Santica M. Marcovina Gissette Reyes-Soffer |
| author_sort | Renu Nandakumar |
| collection | DOAJ |
| description | Elevated lipoprotein (a) [Lp(a)] levels increase the risk for CVD. Novel treatments that decrease LDL cholesterol (LDL-C) have also shown promise for reducing Lp(a) levels. Mipomersen, an antisense oligonucleotide that inhibits apoB synthesis, is approved for the treatment of homozygous familial hypercholesterolemia. It decreases plasma levels of LDL-C by 25% to 39% and lowers levels of Lp(a) by 21% to 39%. We examined the mechanisms for Lp(a) lowering during mipomersen treatment. We enrolled 14 healthy volunteers who received weekly placebo injections for 3 weeks followed by weekly injections of mipomersen for 7 weeks. Stable isotope kinetic studies were performed using deuterated leucine at the end of the placebo and mipomersen treatment periods. The fractional catabolic rate (FCR) of Lp(a) was determined from the enrichment of a leucine-containing peptide specific to apo(a) by LC/MS. The production rate (PR) of Lp(a) was calculated from the product of Lp(a) FCR and Lp(a) concentration (converted to pool size). In a diverse population, mipomersen reduced plasma Lp(a) levels by 21%. In the overall study group, mipomersen treatment resulted in a 27% increase in the FCR of Lp(a) with no significant change in PR. However, there was heterogeneity in the response to mipomersen therapy, and changes in both FCRs and PRs affected the degree of change in Lp(a) concentrations. Mipomersen treatment decreases Lp(a) plasma levels mainly by increasing the FCR of Lp(a), although changes in Lp(a) PR were significant predictors of reductions in Lp(a) levels in some subjects. |
| first_indexed | 2024-12-24T04:19:12Z |
| format | Article |
| id | doaj.art-20eac1f990a7469cb9064ec8c18f8aab |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-12-24T04:19:12Z |
| publishDate | 2018-12-01 |
| publisher | Elsevier |
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| series | Journal of Lipid Research |
| spelling | doaj.art-20eac1f990a7469cb9064ec8c18f8aab2022-12-21T17:15:52ZengElsevierJournal of Lipid Research0022-22752018-12-01591223972402Effects of mipomersen, an apolipoprotein B100 antisense, on lipoprotein (a) metabolism in healthy subjectsRenu Nandakumar0Anastasiya Matveyenko1Tiffany Thomas2Marianna Pavlyha3Colleen Ngai4Stephen Holleran5Rajasekhar Ramakrishnan6Henry N. Ginsberg7Wahida Karmally8Santica M. Marcovina9Gissette Reyes-Soffer10Columbia University College of Physicians and Surgeons, New York, NYColumbia University College of Physicians and Surgeons, New York, NYColumbia University College of Physicians and Surgeons, New York, NYColumbia University College of Physicians and Surgeons, New York, NYColumbia University College of Physicians and Surgeons, New York, NYColumbia University College of Physicians and Surgeons, New York, NYColumbia University College of Physicians and Surgeons, New York, NYColumbia University College of Physicians and Surgeons, New York, NYColumbia University College of Physicians and Surgeons, New York, NYNorthwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington, Seattle, WATo whom correspondence should be addressed.; Columbia University College of Physicians and Surgeons, New York, NYElevated lipoprotein (a) [Lp(a)] levels increase the risk for CVD. Novel treatments that decrease LDL cholesterol (LDL-C) have also shown promise for reducing Lp(a) levels. Mipomersen, an antisense oligonucleotide that inhibits apoB synthesis, is approved for the treatment of homozygous familial hypercholesterolemia. It decreases plasma levels of LDL-C by 25% to 39% and lowers levels of Lp(a) by 21% to 39%. We examined the mechanisms for Lp(a) lowering during mipomersen treatment. We enrolled 14 healthy volunteers who received weekly placebo injections for 3 weeks followed by weekly injections of mipomersen for 7 weeks. Stable isotope kinetic studies were performed using deuterated leucine at the end of the placebo and mipomersen treatment periods. The fractional catabolic rate (FCR) of Lp(a) was determined from the enrichment of a leucine-containing peptide specific to apo(a) by LC/MS. The production rate (PR) of Lp(a) was calculated from the product of Lp(a) FCR and Lp(a) concentration (converted to pool size). In a diverse population, mipomersen reduced plasma Lp(a) levels by 21%. In the overall study group, mipomersen treatment resulted in a 27% increase in the FCR of Lp(a) with no significant change in PR. However, there was heterogeneity in the response to mipomersen therapy, and changes in both FCRs and PRs affected the degree of change in Lp(a) concentrations. Mipomersen treatment decreases Lp(a) plasma levels mainly by increasing the FCR of Lp(a), although changes in Lp(a) PR were significant predictors of reductions in Lp(a) levels in some subjects.http://www.sciencedirect.com/science/article/pii/S002222752034164Xfractional clearance rateproduction rateapoB antisense treatment |
| spellingShingle | Renu Nandakumar Anastasiya Matveyenko Tiffany Thomas Marianna Pavlyha Colleen Ngai Stephen Holleran Rajasekhar Ramakrishnan Henry N. Ginsberg Wahida Karmally Santica M. Marcovina Gissette Reyes-Soffer Effects of mipomersen, an apolipoprotein B100 antisense, on lipoprotein (a) metabolism in healthy subjects Journal of Lipid Research fractional clearance rate production rate apoB antisense treatment |
| title | Effects of mipomersen, an apolipoprotein B100 antisense, on lipoprotein (a) metabolism in healthy subjects |
| title_full | Effects of mipomersen, an apolipoprotein B100 antisense, on lipoprotein (a) metabolism in healthy subjects |
| title_fullStr | Effects of mipomersen, an apolipoprotein B100 antisense, on lipoprotein (a) metabolism in healthy subjects |
| title_full_unstemmed | Effects of mipomersen, an apolipoprotein B100 antisense, on lipoprotein (a) metabolism in healthy subjects |
| title_short | Effects of mipomersen, an apolipoprotein B100 antisense, on lipoprotein (a) metabolism in healthy subjects |
| title_sort | effects of mipomersen an apolipoprotein b100 antisense on lipoprotein a metabolism in healthy subjects |
| topic | fractional clearance rate production rate apoB antisense treatment |
| url | http://www.sciencedirect.com/science/article/pii/S002222752034164X |
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