21 July 2011
A class of their own?
A recent article about a possible new lipid-modifying drug has raised several important issues. Here are some of the relevant remarks from an article in the Daily Telegraph:
“early trials of (the) drug, called torcetrapib, showed that, when given in conjunction with a statin to lower levels of bad cholesterol, levels of good cholesterol (HDL) rose by 67%. Those given the statin alone saw no such change.”
“However . . . this trial was stopped because (it) resulted in more cardiovascular problems and deaths.”
“these negative effects were the result of torcetrpib alone, and not the entire class of drugs.”
“Two other drugs from the same class, called dalcetrapib and anacetrapib, are being developed.”
These statements point up several important points.
I am always a little wary of drugs which only work well in combination with another. This is not to say that combination therapy itself is not a good idea. At the Primary Care Training Centre we have been advocating this in the field of cardiovascular disease prevention for many years in order to improve patient adherence to therapy.
However, the problem with HDL is an interesting one and low levels of this lipoprotein seem as harmful as high levels of, say, LDL. This is why we refer to dyslipidaemia rather than hyperlipidaemia.
At this point, it is instructive to look at what researchers call “outcome measures”. These are the measures by which researchers measure the success or otherwise of a treatment. There are two sorts:
1. Endpoint outcome measures
These are what might be called the bottom line and, in cardiovascular terms are usually death or a major cardiovascular event such as heart attack of stroke.
2. Interim outcome measures
These are interesting in that measures are used which are known to be associated with a high risk of end point outcomes. Lowering of blood pressure and improved lipid levels are examples which are also sometimes called surrogate outcome measures.
As you will note from torcetrapib, unfortunately it does not follow that because an interim outcome measure is improved that endpoint outcomes are also improved. This was also the catch that saw the demise of rosiglitazone. Similarly, reducing blood glucose levels in a person with diabetes does not translate into a reduction of macrovascular disease as it does with microvascular disease.
There’s another snag. If a drug causes serious side effects, then manufacturers of similar drugs do their best to argue that this is an effect of the individual drug and not of all similar drugs.
The term you will see used is “class effect”. For instance, all drugs belonging to the class of Non-Steroidal Anti-inflammatory Drugs (NSAID) carry a risk of gastrointestinal haemorrhage. On the other hand, of the class of drugs known as glitazones, only troglitazones adversely affected liver function. Other drugs in the same class do not do this.
Obviously if a drug has beneficial effects, then potential manufacturers of similar drugs (“me-too drugs”) will attempt to show that the beneficial effect is a class effect.
So, torcetrapib unfortunately inceased the risk of cardiovascular disease but the investigators are hoping that this is an individual and not a class effect and that dalcetrapib and anacetrapib will not have a similar effect.
“A spokesman for the British Heart Foundation said that it was too early to comment on whether dalcetrapib and anacetrib would make suitable candidates for drugs.” This is a masterful understatement. It takes a long time and large samples to identify significant improvements in cardiovascular risk.
Bottom line (including two “IF’s”)
IF dalcetrapib and anacetrapib increase HDL
IF cardiovascular disease risk is improved
THEN there may be a place for these drugs.
Even Olympic athletes can only hold their breath for a maximum of a few minutes and this won’t be long enough to sort out the IF’s.