Drug company kills off another cholesterol-modifying drug

I rarely meet someone who has not heard of cholesterol and does not believe it to be a largely dangerous substance. And increasing number of people seem to be aware of the conventional wisdom regarding the different forms of cholesterol, specifically low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C). Actually, these names are a bit misleading, as these particles are not cholesterol (though they do contain cholesterol). But, anyway, the conventional wisdom is that LDL-C dumps cholesterol on the inside of our arteries while HDL-C clears cholesterol. As a result, LDL-C and HDL-C are often dubbed ‘bad-’ and ‘good-’ cholesterol.

The most commonly prescribed cholesterol drugs are known as statins, and their main mechanism of action is to lower LDL-C levels. However, other types of cholesterol-modifying drugs exist, including a relatively new class known as cholesterylester transfer protein inhibitors (CEPT inhibitors), which the conversion of supposedly healthy HDL-C into supposedly unhealthy LDL-C. If you believe the conventional wisdom on cholesterol (I don’t), then this should translate into benefits for health with regard cardiovascular disease (e.g. heart disease and stroke).

All this theory is meaningless, however. The only important thing is not the effect drugs (or anything else) have on cholesterol levels, it’s the impact they have on health. Some years back the drug company Pfizer spent in the region of $800 million developing a CEPT inhibitor by the name of torcetrapib. It had ‘positive’ effects on LDL-C and HDL-C levels, but also turned out to kill people. Pfizer promptly and quite rightly ceased development of the drug.

The crashing failure of torcetrapib has not stopped other drug companies seeking to find a commercially viable CEPT inhibitor of their own. More recently, drug company Roche invested in the development of a drug known as dalcetrapib. However, in the middle of this year Roche abandoned plans for further development, and a recently-published study shows us why [1].

In this study, published in the New England Journal of Medicine, almost 16,000 patients who had suffered from ‘acute coronary syndrome’ (e.g. angina or heart attack) were treated with dalcetrapib or placebo for an average of about two and a half years.

These are just the sort of patients one would expect to benefit most from an intervention because, as a group, they would generally be at high risk of future problems. Also, the number of subjects here is huge, and therefore more than big enough to detect any real benefit the drug may have.

The researchers assessed the effects of dalcetrapib using a ‘composite endpoint’ – which essentially means lumping several outcomes together. The composite outcome included death from heart disease, non-fatal heart attack, ischemic stroke (strokes due to blockage of blood vessels rather than bleeding), unstable angina (angina that can come on at rest), and cardiac arrest with resuscitation. The use of composite endpoints ups the odds that a ‘statistically significant’ benefit for a drug will be found (compared to when only one single outcome is chosen).

Biochemical analysis revealed that dalcetrapib did, as expected, have considerable HDL-boosting effect. But the study showed that this drug had no benefits for health at all.

Another interesting thing about the study was that dalcetrapib was found to increase markers of inflammation – a process which is believed to play a key part on the development of heart disease and stroke.

This study was originally designed to run for longer but was terminated early once these results were in. Early termination of studies is known to generally inflate the benefits of drugs and downplay their risks. Who knows what may have happened if they’d continued.

Of course you’re unlikely to hear about the dalcetrapib study because it wasn’t announced with the blaze of publicity usually afforded to more ‘positive’ studies about cholesterol-reducing drugs. But this is often the way with cholesterol-related research in particular: positive results are spun in a way which gives medication seeming miraculous properties, while negative results and inconvenient truths are swept under the carpet.


1. Schwartz GG, et al. Effects of Dalcetrapib in Patients with a Recent Acute Coronary Syndrome. N Engl J Med 29 November 2012 (epub)

5 Responses to Drug company kills off another cholesterol-modifying drug

  1. Kris Gunnars 14 December 2012 at 4:38 pm #

    When you’re trying to establish whether a patient is at risk of heart disease, what biomarkers and criteria do you use?

    From what I’ve read, Triglycerides:HDL ratio (of course, in context with weight and overall health) is a good indicator of insulin resistance, metabolic syndrome and subsequent risk of complications like heart disease and diabetes.

  2. Chris 14 December 2012 at 9:04 pm #

    positive results are spun in a way which gives medication seeming miraculous properties, while negative results and inconvenient truths are swept under the carpet.

    Yes, whenever the popular media report striking benefits of some new wonder drug you can bet they are quoting a reduction in relative risk. There is striking link between cause and effect here (as applies to me at any rate) for such headlines immediately invoke a strong feeling of nausea. Negative trials seem in turn to be causally linked to amnesia in others.

  3. Robert Ferrari 15 December 2012 at 2:31 am #

    Very informative and just a bit scary.

  4. PhilT 15 December 2012 at 6:11 pm #

    Killed OFF, shirley ?

  5. Lorna 15 December 2012 at 11:10 pm #

    Yet more research that does not find its way into the media and therefore into public debate. Wonder if this (and other abandoned studies) are included into meta-analyses? Silly question!!! Recently came across a DVD called ‘Statin nation’, produced by an independent film producer. It very clearly (in approx 15 mins) tells us about the background to the ‘faulty’ research over many decades and the various claims made in the cholesterol debate. Highly recommended! http://www.statinnation.net

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