On the topic of HDL-C.
The science in this area has been complex and still evolving to say the least.
The earlier 'relationship" between HDL-C and CV risk appeared to have orginated from Framingham.
Researchers at the time acknowledged that HDL-C and TG were invariably inversely related and "incorrectly" attributed the increase in CV risk to low HDL-C rather than the elevated TG .
TG were frequently dismissed by KOLs as a CV risk factor and HDL-C was hailed as important second to LDL-C.
I recall delivering a lecture on Lipids to a group of Physicians in Denver several years ago and the typical question on HDL-C arose during Q&A session.. At that time I had just read about the exciting data on Apo-A1 Milano, where in a small town in Italy a family tree of very low HDL-C often in the teens had the unexpected observation of increased longevity and DECREASE in CV risk. I shared this data with the audience and how Cedars Sinai was exploring this further by injecting this Apo-A1 variant to subjects with atherosclerotic plaques and demonstrating significant plaque regression. Without even conducting a CV outcomes trial, the small Biotech Esperion which had developed this Apo-A1 variant in the laboratory, was purchased by Pfizer.
This was my first exposure to the science demonstrating that it was not the quantity but rather the quality ( functionality ) of HDL-c that was the key in the HDL-C space.
However, many lipidologists at the time were still focused on raising the amount of HDL-C.
CETP inhibitors were the next big wave with regard to HDL-C.
BPs such as Merck, PFE, Lilly, Roche, devoted large $ in R&D towards CETP inhibitor research realizing that these agents could raise HDL-C by >100%. The "potential" for such elevation in HDL-C was considered by the experts to be huge at the time.
Then the CETP CV Outcome trials (CVOT) followed one after another with each one failing in turn.
These included PFE, Lilly, Roche and Merck.
Merck was perhaps the only BP publishing favorable CVE with their CETP inhibitor but soon thereafter announced that the Co was not going to move forward with NDA to the FDA and that marked the end of the CETP chapter.
Articles in the media that followed essentially summarized the great expectations of CETP inhibitors ending with greater disappointments. I recall titles such as "Blockbuster that wasn't", "Trials and tribulations of CETPs" etc etc.
It was very clear that BP had poured huge $ on the HDL-C hypothesis.
Subsequent trials of Fibrates and Niacin as add ons to Statins failed repeatedly in their CVOTs.
The FDA reviewed the risks vs benefits of Fibrates or Niacin as add on to Statins and redacted the indication of Fibrates or Niacin as add on to Statins in reducing CVE.
More recently elegant genetic research by Dr Amit Khera, a rising star in preventative Cardiology out of Harvard, demonstrated that LDL-C and TG independently correlated almost equally with CV risk while HDL-C had zero correlation.
Dr Khera explained that population studies on HDL-C and CV risk were confounded by the inverse relationship of HDL-C and TG, and scientists 'selected" HDL-C over TG. The genetic studies were able to study this lipid particles independently.
This was perhaps the "nail in the coffin " for the focus on HDL-C quantitatively.
More recent research in this area has been focusing on functionality of HDL-C, and this is still a very complex evolving area.
While it is a fact that V is associated with a decrease in HDL-C, the clinical relevance of this, if any, is still unknown.
Preston Mason has also demonstrated interesting effects of EPA on HDL functionality.
We are all aware of the amazing RRR in R-IT and the Total events to be reported at ACC, as mentioned by AVII, may be even more breathtaking.
The history of add on to Statins has been a very challenging and difficult road for scientists and BP.
The modest 6% RRR with Ezetimibe add on with no CV mortality benefit and the 15% RRR with PCSK9s with no CV benefit has left BP thirsting for some glimmer of hope to address the disease which contributes to the highest mortality risk in the USA - CVD.
With this history over the past three decades, with billions of $ spent by BP searching for something beyond Statins, Amarin comes a small Biotech comes up with such amazing results with R-It.
To state that BP, like huge whales, after spending billions on R&D on coming short, must be salivating at the R-It results, may be an understatement of the decade or of the century.
JL. BB, VBru, AVII have all probably touched on the significance of these findings.
Clinicians on this board may appreciate what this means for the health and lives of the at risk patients.
The magnitude of the implications of this science has still not sunk in.
Perhaps, ACC March 18, may be another wake up call for some.
This is unchartered seas, and for those of us on this journey, 'buckle up" may be the thing to do!
