Merck kills off new cholesterol-lowering drug
I have just come across a very interesting item entitled:
“Check the Obits: Lipid Research Died Last Week” (1).
It is published by a mainstream medical magazine “Medpage Today”. The article was in response to the decision by Merck, one of the major pharmaceutical companies that it would not pursue the approval of anacetrapib for clinical use. The entire programme for commercialization of the drug was scrapped. The article has been written by Milton Parker MD, who acts as a consultant for Big Pharm and presumably therefore represents some of the thinking in the industry.
The background is that the drug lowers LDL cholesterol and nearly doubles HDL cholesterol. It was tested in a trial of 30,449 patients who were already taking a statin and were followed for an average of 4.1 years. The results showed those patients treated with anacetrapib had a lower risk of the composite of coronary death, myocardial infarction or coronary revascularization (P=0.004). The drug was well tolerated and there were no important safety issues. Anacetrapib is given as a single oral tablet once daily. There are no injections.
The business perspective
The question posed by the author is:
“Why would a company abandon a drug that was safe, effective and easy to use and improved cardiovascular outcomes?”
His primary explanation is that after many halcyon years when sales of statins boomed, the field of lipid lowering drugs is in sharp decline for the following reasons:
• Many people simply hated statins. Some developed side effects, but many viewed statins as a symbol of medical disempowerment. If taking a statin became more important than watching your diet or taking natural supplements, then you no longer had personal control of your health. This bred resentment in many people.
• A new class of drugs emerged to be added to statins — the PCSK9 inhibitors. Statins were given orally, were cheap and reduced the risk of cardiovascular events by 30-40% (depending on the analysis). Although the PCSK9 inhibitors had a dramatic effect on LDL cholesterol, but they reduced cardiovascular risk by only 15%. Furthermore, they were really expensive and required periodic injections. Payers objected to their price, and the drugs languished. The most recent trial with bococizumab yielded disappointing results, and the sponsor never sought approval.
• Another class of lipid lowering drugs was introduced — the CETP inhibitors. They were effective modulators of a high-risk lipid profile. But several large-scale trials produced disappointing results. Torcetrapib harmed people; two other agents yielded no benefits.
Then came the trial with anacetrapib, and amazingly, the drug worked. It reduced cardiovascular risk — but by only 9%.
The author reasons that despite the advantages of the drug, the benefit was so small the company would not be able to charge enough for the business venture to be successful. This is a particularly revealing comment as I think his assessment of the reduction in risk of cardiovascular events is somewhat inflated. Nevertheless it is still regarded as “small”. It is also interesting to contrast this view with the picture presented by the pharmaceutical companies in the promotion of statins to the medical profession and to the general public.
Decline of lipid research
It is fascinating to have what is essentially an “inside” view of cholesterol-lowering, which has been the one of the predominant strategies of the medical professions to tackle heart disease. In the USA, the National Cholesterol Education Program devotes huge resources to what is effectively cholesterol-lowering. Over the years the target levels for blood cholesterol have been progressively reduced so that the point has now been reached where the majority of people aged 50 years or more are encouraged to go on statins. It is highly significant that despite this Dr. Parker concludes that:
“Billions of dollars have been spent to make everyone’s lipid profile look good. But I fear that we have now reached the point of diminishing returns.”
In other words, the bonanza is over, time to move on to something else.
The full story
I find it very interesting that from the limited perspective of this commentator, he maintains that the emphasis on lipids is coming to an end. The reality is that there are other powerful reasons that support his conclusion, which he does not mention.
The primary one is that the “cholesterol theory” simply does not stand up to examination. In my view, the only result I wish to know, is the effect on all-cause mortality (ACM). It really is not much comfort to reduce your chances of dying from heart disease if your risks of dying from another cause is increased so that there is no impact on your life expectancy. Furthermore, the diagnosis of heart disease is somewhat arbitrary, which means that the data cannot be regarded as objective.
When the focus is on ACM we get some very interesting results. The ultimate test is monitor the total cholesterol levels in blood (TC) of a large number of people over a long period so that the deaths of a substantial proportion can be recorded. This precisely what has been done in the Norwegian HUNT 2 study. I have shown the details in this blog (2).
The most important finding is that for both men and women, the highest ACM was in those with the TC levels below 5.0 mmol/L. What this means is that those who comply with the official guidelines in countries such as the UK or the USA have the HIGHEST death rates or shortest life expectancy.
In men, there was no increase in the ACM with raised TC. Those with a TC level between 5.0 and 5.9 mmol/L had the lowest death rate, which was 23% lower than those with a TC below 5.0 mmol/L. At higher values, the rate increased again.
For women the pattern is different. The higher the TC, the lower the risk of dying from all causes. Compared with those with a TC below 5.0 mmol/L, those with the highest TC levels were 28% less likely to die from all causes.
Clearly these results drive a coach and horses through the case for lowering TC. Yet in practice there are an enormous number of individuals desperately concerned because their TC is “too high” and are only too ready to accept the advice of their doctor to go on statins. While it is a fact that statins do have some limited benefit for middle-aged men with heart problems, it almost certain that this is NOT because the TC has been lowered and is probably due an effect on inflammation.
There are indications that the pharmaceutical industry is losing interest in cholesterol-lowering for hard-nosed commercial reasons. It will be very interesting to see how the medical profession as a whole reacts. It would be very good news if the big push to lower TC in patients was abandoned and the focus shifted to aspects of lifestyle that are so much more effective and less costly.