Unless you’ve been living on another planet during the last couple of days, you couldn’t miss the headlines about the failure of Pfizer’s cholesterol drug, torcetrapib. The headlines about the failure of this drug’s clinical trials have appeared on the front page of almost every newspaper in the country. They read something like this:
“A promising blockbuster cholesterol drug goes bust.”
The subtitle, in smaller type, stated
“Researchers and doctors are stunned.”
So what’s the real story?
First, you have to understand cholesterol transport—that means a bit of biochemistry
Cholesterol and triglycerides (fats) are transported from the liver to peripheral tissues (heart muscle, skeletal muscle, fat tissue) in particles that are called VLDL or very low-density lipoproteins. VLDL particles are triglyceride-rich. That means they have a lot more triglycerides in them than cholesterol.
VLDL particles in the circulation bump into membranes of the cells of peripheral tissues and disgorge their triglyceride content into those cells. This action requires the action of an enzyme, LPL or lipoprotein lipase. Once the triglycerides are inside the cells, they are used as a source of energy (muscle and heart cells) or they are stored as a future source of energy (fat cells).
When HDL particles (high-density lipoprotein or “good” cholesterol) bump into VLDL, they transfer cholesterol into the VLDL particles via the action of another enzyme, CETP or cholesteryl ester transfer protein. If HDL particles don’t meet up with VLDL, they transport the cholesterol to the liver where it is eliminated from the body via the bile acids.
This is a two-part process:
- Release of triglycerides into peripheral tissues
- Acquisition of cholesterol from HDL
These two processes together transform VLDL into the infamous LDL or low-density lipoprotein.
LDL has a very high ratio of cholesterol to triglycerides. As a high cholesterol particle, LDL plays a key role in clogging arteries with cholesterol-laden plaques. That is why LDL is known as “bad” cholesterol.
A key point, with respect to the Pfizer drug, is that the enzyme CETP is critical in the transformation of VLDL to LDL. The obvious conclusion would be, then, if you inhibit CETP, you should end up with more HDL cholesterol (“good”) and less LDL cholesterol (“bad”).
If the idea is so good, how could the results be so bad?
Several pharmaceutical companies embarked on the development of drugs that inhibit CETP in the hopes that they could end up with a very attractive product that would simultaneously increase HDL (“good”) cholesterol and lower LDL (“bad”) cholesterol. The drug that is the most advanced in development is Pfizer’s torcetrapib. Unfortunately, early analysis of the ongoing clinical trial to test the drug in humans has shown an increased risk of mortality from, believe it or not, cardiac events, such as heart attacks. This is the opposite of the anticipated (and hoped for) outcome.
The negative results from this clinical trial that made the headlines had the following design:
- 15,000 patients were enrolled.
- Half of these patients received Lipitor alone. Lipitor is a widely prescribed “statin” drug that lowers LDL.
- The other half received Lipitor plus torcetrapib.
There were 82 deaths in the Lipitor-torcetrapib group and only 52 deaths in the Lipitor only group.
So, what does this mean?
Of course, every loss of life is tragic, notwithstanding the fact that the participants in the trial were all volunteers who gave informed consent. But there is another aspect that left a great impression: The enormity of the scientific and financial undertaking (frankly, a financial gamble).
Just consider the facts:
- The drug was discovered by Pfizer in 1992. It took 14 years to get to this stage, and fail!
- To satisfy the statistical requirements of clinical trials, 15,000 patients were enrolled. This is an enormous number by any measure.
- The company spent $800 million on the development of this drug. What a gamble!
This is an aspect of the pharmaceutical industry that we rarely consider; if they didn’t take these incredible risks, we would still be treating heart disease, or cancer, or infections or any other affliction known to man the way our ancestors did in the 19th century and earlier.
Enough of these political musings. What could have gone wrong with the trial?
It’s the biology, stupid
There are several possibilities to explain what caused the higher mortality:
- The problem is inherent in the drug itself, not in the concept of inhibiting CETP. Several drugs that are designed to inhibit CETP are now in early development stages, so time will tell.
- In early trials of the drug, it was noted that there was a rise in systolic blood pressure, an average of 1-3 mm Hg. High blood pressure can be a significant co-morbidity factor in patients suffering from heart disease. However, this rise is so minimal that I doubt it could account for the significant rise in mortality.
- We simply don’t know the biology of HDL other than its role in cholesterol transport. Are all HDL particles the same? There is some evidence that there are different species of HDL particles. Are we raising a putative “bad” HDL particle rather than the “good” one? Does HDL have different effects on different tissues? For instance, could it be that unlike HDL’s beneficial effects on blood vessels, at high levels, it may have a bad effect on the heart itself? All of this is unknown.
So what’s a patient to do?
First, don’t worry. Let’s not forget that the present therapy for elevated blood cholesterol is highly effective. Lipitor belongs to a class of drugs called statins. These drugs reduce the levels of LDL, the bad cholesterol, and this is highly beneficial even without elevating the level of HDL.
If you insist on elevating your HDL levels, there are several things you could do.
- Take niacin. We don’t really know how it works, and it causes annoying flushing in many people who take it. But the bottom line is that it does elevate HDL, albeit only moderately.
- Aerobic exercise. Among its many benefits is an elevation of HDL levels. So walking, running, swimming, biking, they all beat taking drugs.
My favorite is to drink a couple of alcoholic beverages per day. I like to drink 2 glasses of wine with dinner, usually red, so that I get the added benefit of a bit of resveratrol. This will result in a rise in HDL level. If you choose to follow my example, don’t overdo it—more alcohol (even if it is red wine) is not better. If you consume more than a couple of drinks a day, the bad effects of alcohol (like liver damage) start to kick in and negate its beneficial effects.