Another new cholesterol-lowering drug is licensed despite no evidence of benefits for health

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I was reading here that there’s a new cholesterol-lowering drug in the pipeline. The Food and Drugs Administration in the US has approved the injectable agent mipomersen for the treatment of ‘homozygous familial hypercholesterolaemia – a genetic cause of raised cholesterol levels associated with cardiovascular disease developing early in life. Mipomersen has been shown to reduce low density lipoprotein (LDL) levels by about a quarter. The hope is that this will help reduce the risk of individuals suffering premature death from, most likely, heart attack.

I’ve used the word ‘hope’ in the preceding sentence but, in reality, the FDA panel that has ratified mipomersen has no idea whether it has health benefits or not. That’s because the studies used to assess this drug were not large enough in scope to detect change in ‘clinical endpoints’ such as risk of heart attack or death. In other words, the licensing of this drug has been on the basis of its impact on ‘surrogate endpoints’ (in this case, cholesterol levels), rather than clinical endpoints (the thing that really matters).

And I’m not splitting hairs either, as we already have examples in the not-too distant past of drugs that promised a lot in terms of their impact on cholesterol, but failed to deliver in terms of actual health. For example, the drug ezetimibe is a proven cholesterol-lowerer, yet not one single study to dates demonstrates it has benefits in terms of clinical endpoints. Also, the drug torcetrapib looked at one time to be a new hero of cholesterol management, until appropriately designed studies found it was killing people (it’s since been dropped).

But the principle that something that benefits cholesterol does not necessarily benefit health does seem to have been somewhat lost on the FDA. And worse still, it seems the panel may have put their faith in cholesterol modification above some quite troubling data. Here you can read how the FDA’s own review of mipomersen revealed a number of concerns about this drug. Here’s an excerpt from the article:

Serious adverse events of cardiac disorders occurred in 3.8% (10/261) of patients in the mipomersen group compared with 3.1% (4/129) in the placebo group. The reviewers concluded that “the possibility that mipomersen therapy increases the risk for cardiovascular events cannot be excluded.”

Other concerns were raised by the finding that mipomersen increased the levels of ‘liver enzymes’ and increased the amount of fat in the liver (both signs of damage to the liver). Here’s another except:

The FDA reviewers said they did not know whether long-term use of mipomersen could cause irreversible liver damage, but warned that patients could be at risk for cirrhosis and liver-related death if the observed liver changes progressed.

And perhaps worse still, there’s even concern that mipomersen might have cancer-inducing potential:

According to the review, during clinical testing neoplasms, both benign and malignant, were detected in 3.1% (23/749) of patients who received mipomersen compared with 0.9% (2/221) of patients who received placebo. However, the FDA clinical reviewer noted that there was a diversity of malignant neoplasms and that two out of nine mipomersen patients who developed a malignancy had been on mipomersen for less than a month, “making it highly unlikely that mipomersen played a role.” The review concluded that ”there are several confounding factors that make it difficult to conclude that mipomersen is playing a dominant role in this cancer imbalance.”

Forgive me, but personally I detect a hint of ‘sweeping the issue under the carpet’ here. The same thing, by the way, happened with ezetimibe, which has been shown to increase the risk of death from cancer, an effect which researchers put down to chance (even though the effect was statistically significant and therefore highly unlikely to be due to chance). See here for more about this.

The FDA panel’s vote on mipomersen was relatively close (9 v 6), so at least some members of the panel had their doubts. It is said that the severe nature of homozygous familial hypercholesterolaemia was a major determining factor in swaying the vote. That’s laudable, perhaps, but I don’t think it excuses the fact that this drug has been licensed despite an absence of data that it benefits health, as well as the presence of data which points very much in the opposite direction.

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