How Pure EPA might be able to lower Triglyceride and not cause a rise of LDL...A new hypothesis..
At issue unlike Du's conclusion that a POSA would think it obvious to use EPA to lower Triglycerides because EPA would not increase LDL levels..ACTUALLY a POSA would think it obvious that EPA (like all other trig lowering therapies) would obviously increase LDL..Since DHA, Niacin, fibrates all increased the LDL levels.
More to the point..it was well understood why Trig lowering would increase LDL-C and this was substantiated by the Friedewald Equation...
The Friedewald Equation LDL = TC(total cholesterol)- HDL-C(high density lipoprotein cholesterol) -Trigs/5..
.The Friedwald Equation has proven its validity in a trial,of more than 30,000.measurements The Friedewald equation has been criticised for being inaccurate for very high trigs..But the reality is a these inaccuracies can be avoided by a simple correction of the Trigs/5 factor..
The importance of the Friedewald equation was well known before and during the MORI and KURA trials period. The simple arithmetic of this equation makes it perfectly obvious that if the TC and HDL-C remain constant then any lowering of the trigs must result in a higher level of LDL..And that would have been obvious to both Mori and Kura. So arguing a POSA would predict EPA would lower trigs and not raise LDL is factully incorrect..A POSA would think it obvious that if EPA lowers trigs it must also raise LDL..
And actually in addition to the Friedewald equation..The molecular activity which leads to the conversion of Trigs into LDL-C was understood..The Lipoprotein that transports trigs in the blood stream is VLDL..(very low density lipoprotein) and this protein is principally APO-b..Which is a protein which also transports LDL-C...
VLDL (being made of APO-b transports both trigs and cholesterol) Normally trigs are the biggest fraction..but if trigs are lowered by more than 50% in the VLDL protein packet..Then the VLDL is converted to LDL-C..So definitely a POSA at the time of Mori and Kura would have considered it obvious that trig lowering by any means, including EPA, would have to increase the LDL-C levels..And not what Du thinks..
To this day it remains a mystery of sorts as to why pure EPA alone can lower trigs and not increase harmful cholesterol..It is still not obvious.
My hypothesis is that this special effect of EPA is the result of EPA's special ability to lower Systemic Inflammation (SI). What is understood today is that trig levels reflect not so much dietary intake or liver production...But are regulated in a similar fashion to way blood sugar levels are...And that is by controlling the rate of removal. We are more familiar with the effects of insulin on controlling blood sugar..Insulin activity increases the removal of sugars (which are fuels like trigs) from the blood and stores them in the adipose tissue and we should not be surprised if trig use similar methods...The key here is that Systemic Inflammation (SI) elevation causes Insulin Resistance (IR) and IR weakens the ability of insulin to lower blood sugar and store it in the fat tissue. Triglyceries have their own brand of Insulin which is called Fatty Acid Synthase (FAS)..and its potency is like Insulin is diminished by high SI...
A plausable reason why EPA alone might be able to lower trigs and not raise LDL-C i due to the fact that EPA alone effects SI levels..This is not controversial..It is well known to scientists who study SI,,just not well known to cardiologists an lipidologists..EPA's effect might operate to remove trigs by FAS while other agents,,Fibrates, niacin, or DHA Which lacks the correct 3 dimmensional structure to interact with the eicosanoid cell membrane receptors that are the major controllers..of systemic Inflammation..EPA...By lowering SI could lower trigs the physiological way by increasing FAS activity and that might not increase LDL as much as the non physiological removals by other drugs..
If we, including epidemiologists, cardiologists and Diabetes specialists..recognized the similarities between trig control and diabetes..Then things might be understood a little better,,We should be thinking Trigabetes.
I do not envy Judge Du having to consider all these complicated issues in lipid and inflammatory and can understand how she came to the wrong conclusion..There is no way in 2000 or even ten years ago a POSA would have reached the conclusion that DU reached...
It would be like me that has a background in Engineering and clinical medicine would have troubled with the nuances in a complicated patent issue..
":>) JL
