Near the beginning of the 21st century, pharmaceutical companies fell prey to the fallacy that “raising the good cholesterol” (HDL) must be a good idea, and multiple companies (whom I will not refer to by name just because they get weird about this stuff) attempted to raise HDL via CETP inhibition. (You can read more about CETP, which stands for Cholesteryl Ester Transfer Protein, in Chapter 5 of THIS BOOK).
Briefly, if you have less CETP activity, then those HDL particles won’t get fat and fluffy with triglycerides, and they won’t subsequently donate their cholesterol to ApoB-containing particles, so HDL-C will increase. And instances in which CETP activity was increased (ahem, insulin resistance) seemed to correlate with increased cardiovascular events, so the thought was that CETP inhibition would be a great way to complement LDL-C reduction for mitigating ASCVD risk.
The first attempt at this strategy was made by the same company who inadvertently restored the romantic zest in the lives of many couples with a failed blood-pressure drug (rhymes with Niagara). This first CETP inhibitor was called Torcetrapib and the trial was called ILLUMINATE; however, the light was permanently snuffed out for many people in this tragic trial and it was stopped early because people were dying. Unfortunately, some red flags were ignored in the pre-clinical phase of drug development and this drug had off-target effects on the renin-angiotensin-aldosterone system. This led to elevations in blood pressure and also messed up adrenal function; they would’ve been much better off just giving people more little blue pills.
Still bullish on the strategy of “raising HDL” in efforts to reduce heart attacks, 2 other drugs called Dalcetrapib and Evacetrapib were deployed and, although they didn’t hurt anyone, these trials were stopped early because they just weren’t effective. And then a fourth trial called REVEAL using an agent called Anacetrapib actually worked… sort of.
- REVEAL is still the largest lipid-lowering trial ever conducted, enrolling over 30,000 patients.
- Around the time of REVEAL, people were finally realizing that raising HDL cholesterol pharmacologically just isn’t any good; we just can’t ensure that these HDL particles will be functional by simply increasing their quantity. However, in looking at folks with genetic loss-of-function in the CETP gene, it was noted that CETP variants that not only raised HDL-C, but concurrently resulted in a lower LDL-C and ApoB, actually had about 16% less coronary events. This was consistent with other genetic variants such as HMGCR and PCSK9.
- In REVEAL, Anacetrapib actually reduced the incidence of major adverse cardiovascular events by 9%. However, people in that trial were enrolled with a baseline LDL-c of only 61 mg/dL…and the drug only lowered LDL-C 11 mg/dL. Although that fell in line with what was achieved in other trials with other therapies, it was considered underwhelming and further development was discontinued.
- Additionally, Anacetrapib remained in people’s fat cells interminably, which made the manufacturers skittish about continuing to pump a modestly effective drug into people’s ample supplies of adipose without knowing the long-term consequences.
So we’ve all given up on CETP inhibition, right? WRONG! There is a new CETP inhibitor called Obicetrapib (since Obi-wan-kenobi was awesome and also since Obi is the Swahili word for heart). This CETP inhibitor not only raises HDL-C (which we don’t think really matters), but also lowers LDL-C and ApoB much more than previous iterations. Additionally, there is a reduction in Lp(a) and there also seems to be less new-onset diabetes. So will the 5th time be the charm for CETP inhibition? That remains to be seen! But if successful, we believe it will be due to ApoB reduction and not manipulation of the “good cholesterol.”
