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EAS 2017 April 25: Keynote Lecture: A salutary lesson from kinetic studies

26 April 2017   (0 Comments)
Posted by: Charlotta Johansson
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There was much anticipation of the Keynote Lecture by Professor Henry Ginsberg, the Irving Professor of Medicine and Director Emeritus of the Irving Institute for Clinical and Translational Research at Columbia University Medical Center, New York, USA. Aside from his unique expertise in lipoprotein research, Professor Ginsberg has made a major contribution to the success of the EAS, as Co-Chair of the EAS Consensus Panel with Professor John Chapman. 

In recognition of his contribution to the Society, Professor Ginsberg was awarded the Richard J. Havel Keynote Lecture. EAS President Professor Lale Tokgözoğlu and co-collaborators Professor John Chapman and Professor Gerald Watts warmly congratulate Professor Ginsberg.

During his lecture, Professor Ginsberg showed how studying the kinetics of novel agents, specifically the PCSK9 inhibitor alirocumab, the cholesteryl ester transfer protein anacetrapib and the apolipoprotein (apo) B antisense agent mipomersen, has provided critical insights about the efficiency of their removal from the circulation.

The kinetics of alirocumab was a clear case of expected findings. In this study, alirocumab kinetics were consistent with the known mechanism of action of PCSK9 inhibition, showing that the reduction in LDL cholesterol with this agent was due to increased fractional clearance of LDL apoB, as well as reduced production of intermediate-density lipoprotein (IDL), by direct removal of IDL, thereby reducing the conversion of IDL to LDL, in normal individuals. Doubling in the fractional catabolic rate of LDL effectively meant that alirocumab doubled the number of LDL receptors on the cell surface.

However, not all findings are so simple.  Kinetic studies of the effect of anacetrapib raised a conundrum. While anacetrapib lowered LDL cholesterol and apoB, this was shown to be due to an increase in the LDL apoB fractional catabolic rate, which was a surprise given mechanistic understandings. It is, however, possible that diverting cholesteryl ester to the liver via the action of scavenger receptor B1 may contribute to upregulation of the LDL receptor.

And, finally, study of the kinetics of mipomersen produced completely unexpected results, with no reduction in either very low density lipoprotein (VLDL) apoB or triglyceride secretion. In addition, reduced production of IDL reduced production of LDL, and there was increased fractional clearance of LDL, leading to 40% reduction in LDL. While the finding that the LDL fractional catabolic rate was increased during mipomersen treatment is inexplicable, Professor Ginsberg proposed that apoB synthesis could be a target for reducing plasma apoB-lipoprotein levels depending on the status of lipid content, although this hypothesis requires further study.

Professor Ginsberg concluded his lecture on a philosophical note. ‘The EAS truly represents a United Nations of Scientists, with researchers from across the globe attending this Congress. Long may this commitment to education, research and advocacy across the globe continue.’   

References for the studies discussed by Professor Ginsberg:

Reyes-Soffer G, Pavlyha M, Ngai C, Thomas T, Holleran S, Ramakrishnan R, Karmally W, Nandakumar R, Fontanez N, Obunike J, Marcovina SM, Lichtenstein AH, Matthan NR, Matta J, Maroccia M, Becue F, Poitiers F, Swanson B, Cowan L, Sasiela WJ, Surks HK, Ginsberg HN. Effects of PCSK9 Inhibition with alirocumab on lipoprotein metabolism in healthy humans. Circulation 2017;135:352-62.

Millar JS, Reyes-Soffer G, Jumes P, Dunbar RL, deGoma EM, Baer AL, Karmally W, Donovan DS, Rafeek H, Pollan L, Tohyama J, Johnson-Levonas AO, Wagner JA, Holleran S, Obunike J, Liu Y, Ramakrishnan R, Lassman ME, Gutstein DE, Ginsberg HN, Rader DJ. Anacetrapib lowers LDL by increasing ApoB clearance in mildly hypercholesterolemic subjects. J Clin Invest 2015;125:2510-22.

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