Replies to post #174993 on Amarin Corp Plc (AMRN)

[jessellivermore]

bogatie....

Exceptional post...very scientific and hopefully the company and the cards read this post...

I would like to add the possibility that the LDL-C increase in the placebo arm, over and above that seen in the active arm, might actually be the result of a LDL-C lowering effect by EPA in the active arm...This has not been ruled out..Lowering VLDL levels in most cases does result in higher LDL=C levels. This is seen in fibrates, niacin and DHA/EP mixes (Lovaza for example)...This LDL-C increase resulted in a CRL from the FDA in Lovaza's case...

THe important news in 2010 (MARINE) and later ANCHOR was that trig lowering (VLDL lowering) by pure EPA did not result in significant increases in LDL-C...

My conceptualization of the metabolism of lipids and simple sugars is that systemic inflammation levels are extremely important in terms of how the body metabolizes them..,Principally determining blood levels by controlling the rate of removal of these "fuels" from the blood stream..The currently best understood (by clinicians) is the effect of insulin on blood sugar...Elevated systemic inflammation results in insulin resistance (IR) in which the sugar lowering activity of insulin is reduced and the blood sugar increases...We see the same effect in trigs...Except FAS is the enzyme instead of insulin, but elevated systemic inflammation lowers the trig reducing effect of FAS and the trigs go up...In both cases the higher blood levels are not so much the result of higher intake via diet or liver production..but rather result from the diminished activity of the enzymes that remove these fuels from the blood stream...I would predict that a similar mechanism exists for LDL-C.

So what increasing EPA does (along with other actions) is to decrease systemic inflammation by increasing the EPA/AA ratio which effects all body cells with the exception of RBCs...By altering the competitive inhibition on COX,LOX and PPAR cell membrane and nuclear membrane receptors...Higher EPA levels increase the activity of these fuel removing enzymes and that lowers the blood levels...

In this specific case this would produce an LDL-C lowering effect in the active arm when compared to the placebo arm which might be incorrectly interpreted as a LDL-C increase in the placebo arm....

":>) JL