The most exciting heart disease drug isn't here yet
Why obicetrapib may be the most important drug on the horizon
The story of the CETP inhibitors1 is one of the most fascinating in medicine, and it’s still unfolding.
If you haven’t heard of this class of drugs, it’s because the story so far has mostly been a dud.
But a deeper dive into the CETP inhibitors is worthwhile for two reasons:
These drugs may totally change the way we prevent heart disease and dementia
Understanding the way this story almost ended over a decade ago is a cautionary tale about drawing conclusions about a subject when our understanding is superficial2
So I want to talk to you about the CETP inhibitors, in particular obicetrapib, which one of the most exciting drugs currently in development in any area of medicine.
The CETP inhibitors started out very promising - with a link between exceptional longevity and good health
Nir Barzilai is one of the world experts on the genetics of aging and chronic disease.
Almost 20 years ago, he published on the link between genetic variants in CETP leading to a long, disease free life.
It was an interesting observation - a natural mutation that leads to low LDL-cholesterol levels and high HDL-cholesterol.
Here’s a quote from the abstract of the paper, which suggests that a loss of function of CETP leads to better health and cognitive performance in addition to a long life:
Subjects with exceptional longevity and their offspring have significantly larger high-density lipoprotein (HDL) levels and particle sizes and low-density lipoprotein (LDL) levels that reflect on their health and cognitive function performance. A markedly higher frequency of a functional CETP variant that led to increased particle sizes of HDL and LDL and thus a better health performance is the first example of a phenotype and an associated genotype in humans with exceptional longevity.
Certainly a promising piece of observational data in favor of CETP inhibition.3
And it’s not just that low levels of CETP are good, but we also have data suggesting high levels are bad.
The rubber meets the road - the first CETP inhibitors fail in clinical trials
There were some huge failures in large clinical trials looking at CETP inhibitors.
Torcetrapib, developed by Pfizer, was tested in the ILLUMINATE trial. The drug did a fantastic job of raising HDL-cholesterol and lowering LDL-cholesterol levels.
Unfortunately, patients taking torcetrapib were more likely to die than patients taking a placebo:
The next drug that was studied in this class was dalcetrapib, tested in the dal-OUTCOMES trial.
Dalcetrapib raised HDL-cholesterol levels, but had a minimal impact on LDL-cholesterol, and didn’t change the risk of cardiovascular disease:
The same story could be seen with evacetrapib in the ACCELERATE trial.
The next trial in this story is REVEAL, looking at anacetrapib, which found an improvement in cardiovascular outcomes to the exact amount that would be predicted by the impact that the drug has on LDL-cholesterol levels:
You need to dig into the details of these trials to understand what’s going on
Part of the reason that the CETP inhibitors are so interesting is the way that knowing the top line results of the trial leaves you misinformed.
It’s not enough to read the abstract on these papers, you need to dig way deeper than that.
The fact that Merck went ahead with REVEAL after Pfizer’s ILLUMINATE catastrophe was pretty notable:
On a deep dive, what you’ll learn about these drugs is that there were different reasons why torcetrapib and dalcetrapib each failed.
Torcetrapib had an off target effect - it raised blood pressure by increasing aldosterone synthesis in the adrenal gland.
Of course it makes sense that a drug that raises blood pressure is going to be a problem for heart disease prevention.
Dalcetrapib was a bit different - while this drug raised HDL-cholesterol levels quite well, it had minimal impact on LDL-cholesterol.
And that’s why REVEAL was so important - it showed that the way that CETP interacts with cardiovascular risk is through LDL, not through HDL.
In many ways, the CETP story is what led to the discrediting of the HDL hypothesis and a large part of why most doctors think efforts to raise HDL-cholesterol are a waste of time.
So the newest CETP inhibitor on the block is by far the most exciting: obicetrapib
Obicetrapib has potential to be a game changer
Obicetrapib is a CETP inhibitor that has incredibly potent LDL-cholesterol lowering impact.
It has impressive LDL-C, apolipoprotein B, and Lp(a) lowering impact:
There is also some data that a successful CETP inhibitor won’t just impact heart disease risk:
CEPT inhibitors, including obicetrapib may reduce the risk of developing new onset diabetes4
Being born with a loss of function of CETP may reduce your risk of dying from sepsis
Lower levels of CETP may actually lead to lower blood pressure
The way that CETP may protect against Alzheimer’s disease in people at elevated risk
The theoretical promise for obicetrapib to be a drug that lowers the risk of heart disease and doesn’t come with a host of side effect is incredibly exciting.
And the possibility that it may also reduce the risk of developing those other conditions almost makes it sound too good to be true.
If it sounds like I’m ready to start prescribing this drug, don’t get ahead of yourself
Just because something sounds exciting, doesn’t mean that the actual data in real people is going to match up with the theoretical promise.
When we get data from the PREVAIL trail,5 I’ll start to get excited.
And even though there is promise that a better class of CETP inhibitors will help to reduce heart attacks without causing muscle aches or increasing the risk of diabetes, we need to wait for the outcomes data before starting to use these things.
The impact on cognitive function and Alzheimer’s prevention is another exciting set of experiments on the horizon.
But let’s not get ahead of ourselves. Anytime you’re studying a new molecule, there is potential for unplanned or unforeseen impact.
I’ve said this before, but the road to hell is paved with biologic plausibility.
CETP stands for cholesterol ester transfer protein. CETP is a protein that helps to move cholesterol from an HDL particle to an LDL particle. A CETP inhibitor thus raises HDL-cholesterol and lowers LDL-cholesterol.
When I was at the peak of Mount Stupid in my medical training, I was completely convinced that these drugs were useless and there was no point in further studying them.
Barzilai gave Grand Rounds at NYU when I was a chief resident, and I had the chance to walk him around for the morning and pepper him with questions. I remember him talking about how excited he was about the CETP inhibitors. Now keep in mind, this was 2016, so we already had results from ILLUMINATE and dal-OUTCOMES, which showed that torcetrapib and dalcetrapib were either failures or duds. It’s pretty interesting how that data didn’t reduce his enthusiasm for the potential of CETP inhibition.
The diabetes impact is thought to be due to the way that the way that CETP inhibition upregulates production of apolipoprotein A-1, which may remove cholesterol from pancreatic beta cells and augment insulin producing ability
The outcomes trial of obicetrapib that’s probably going to come out in 2026