I’m a bit puzzled by all the excitement about Merck’s new drug, Anacetrapib (MK-0859), that’s said to lower risk for cardiovascular disease by lowering bad cholesterol. Earlier this week at the annual meeting of the American Heart Association, researchers presented promising findings on the drug, including results from the phase III DEFINE (Determining the EFficacy and Tolerability of CETP INhibition with AnacEtrapib) trial. The list of disclosures for that abstract is long and fairly shocking. On Wednesday, the results were published on-line in the NEJM.*
The new drug interests me, as an oncologist, because it’s an enzyme inhibitor – in some ways like many new and in-the-pipeline cancer treatments. Anacetrapib raises high-density lipoprotein (HDL, a.k.a. “good cholesterol”) and lowers low-density lipoprotein (LDL, a.k.a. “bad cholesterol”) by interfering with a cholesterol enzyme transfer protein (CETP). The experimental medication is a pill that, based on earlier safety studies, is taken at 100 mg by mouth, once daily. So it’s convenient enough.
In some respects, the results of this randomized, placebo-controlled large trial are knock-your-socks-off impressive: patients on the drug had, an average, a more-than doubling of their serum HDL levels, from 41 to 101 mg per deciliter.** At the same time, the HDL shift was just 40 to 46 for patients assigned to the placebo (control). Conversely, LDL levels went down dramatically in patients taking Anacetrapib, from 81 to 45 mg per deciliter on average, and the corresponding drop seen among the control patients was only 82 to 77. These numbers are really terrific, and the results highly significant from a statistical perspective. The study lasted for 76 weeks, i.e. well over a year, and the drug was very-well tolerated according to all published reports.
What’s wrong here? Well, it’s that we don’t know for sure how this new drug affects heart disease and other vascular conditions. In this study, the plasma cholesterol levels were monitored as surrogate markers for risk of atherosclerotic events, but these laboratory parameters are not the same thing as direct measures of disease. It is uncertain if this drug has any impact on mortality, or even on heart attacks, strokes or other clinical endpoints.
In my opinion, we need a lot more information about this new drug before we prescribe it to thousands or millions of people who have hyperlipidemia. Fortunately, as pointed out by Dr. Harlan Krumholz, writing for Forbes, Merck is “doing the right thing” by testing the drug in additional studies now, with clinical endpoints in mind. Still, his enthusiasm for what amount to very favorable blood testing seems extreme in light of the previous experience to which he refers with Pfizer’s torcetrapib, a drug of the same class that turned out to have significant side effects, and Merck’s previous marketing of Zetia.
According to the New York Times, John Boris, an analyst at Citigroup, wrote in a note to investors on Wednesday that the drug could potentially have sales of more than $1 billion a year. Dr. Steven Nissen, a sometimes cautious leader in the field, found the results encouraging, according to widely-cited comments such as those appearing in the Dow Jones Newswires.
In a few years, we’ll see what Merck finds out with the ongoing trials, and if the drug really helps reduce heart attacks and deaths in people with hyperlipidemia.
Meanwhile, since my cholesterol’s crept up, just a bit above 200, I’ve started eating oatmeal and quinoa more often. I take only skim milk in my cereal at breakfast, cut out most cheese and pizza, and enjoy ice cream but occasionally. I don’t wish to ingest any experimental enzyme inhibitors that aren’t essential in the life-saving sense.
The NIH offers tips for therapeutic lifestyle changes that can help reduce hyperlipidemia in many patients.
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**cholesterol units: milligrams per deciliter
I think you make a valuable point that more work and research is needed before pronouncing on this new drug. One of the problems is that, to be honest, most people reading just the headlines get excited about the idea of a “silver bullet” type of cure for anything. Whether it’s a new weight loss pill, or something like this, for cholesterol.
There does seem to be a danger that people will stop taking some responsibility for themselves if they think there’s a miracle cure out there. Your own example is a good counternote to that. You’ve noticed an increased chol. level and you’ve done something about it. The question then becomes “how many people would just pop a pill?”, if the magic pill was available.
My guess is that a lot of people would do that instead of taking some basic care of themselves. We can all be guilty of that, but really shouldn’t we be looking to medication as something of a last resort, not a first?
I am puzzled how you came to the conclusion that Dr. Krumholz had an extreme amount of enthusiasm for anacetrapib. In his blog post on the Forbes website that you reference, he clearly states that showing an effect on laboratory values — HDL and LDL, in this case — is not enough. I quote:
“The torcetrapib experience has had a great influence in this class of drugs … and perhaps is changing the perspective for a range of drugs that are intended to lower risk. Various recent studies have shown that what happens to patients is not always what we expect from changes in risk factors.
Merck is setting a good example by evaluating the drug in steps, carefully assessing its effect on patients, and not proceeding toward approval before testing the effect of the drug on patient outcomes in a large study. The question is not what the drug does to the lab tests — but what does it do to the risk of patients. The change in the lab test makes us hopeful — but cannot tell us what will happen to patients.”
Nowhere in Dr. Krumholz’s post do I see an extreme or inappropriate amount of enthusiasm for anacetrapib. In fact, it appears to me that the two of you are in agreement on the need to have evidence that the drug reduces the risk of cardiovascular endpoints and death before FDA approval.
Hi Marilyn,
I appreciate your comments here and on the ACP blog.
In general I agree with Dr. Krumholz, which is why his apparent enthusiasm for the new Merck drug, as suggested by the Forbes article, surprised me. Please note that this post is not intended as a rebuttal to his piece in particular, but to the general media blitz that surrounded the findings reported at the AHA meeting and which included references to his and other experts’ remarks and published commentary.
Torcetrapib is a very cautionary tale about surrogate biomarkers.