Thursday, June 18, 2015

Real Truth in Labeling for the new statin replacement

The FDA is about to or just has approve a new cholesterol-fighting drug to supplement or replace statins.  But is it taking all the 'side effects' into account?  Should it?  The new substances (several pharmaceutical outfits apparently have them near to market) inhibit a different genetic pathway from what statins do and can be used to treat high cholesterol in those who can't handle statins, or for whom statins aren't lowering their LDL cholesterol, and may also actually be much more effective even for the current millions who take statins.

These drugs inhibit the action of a gene called PCSK9 and interfere with the liver's detection and response to LDL levels in the body; see the NYT story here from last week for more details about the drugs.  The excited news reports, at least, describe what are truly remarkable reductions in LDL levels without untoward side effects. If these facts stand up to larger or longer term trials and experience, it will be a major pharmaceutical more ways than one.

One immediate issue is the 'usage creep' that almost inevitably seems to follow the appearance of a new drug, and in this case one with fewer side effects and higher efficacy with regard to lowering the most dangerous type of circulating cholesterol (the 'bad', or LDL form). Recommended approval is for use in three groups of patients: those whose high LDL cholesterol can't be lowered sufficiently with statins, those at particularly high risk because of previous heart attack or diabetes and high LDL, and those with high levels of LDL who can't tolerate statins.

But if these agents are as effective as reports suggest, and with less or even no serious side effects, then even if they are initially approved or recommended for just these specific groups, usage will surely expand as the definition of who is 'at risk' expands. Perhaps people whose cholesterol is responding to statins but who don't like the side effects, or someone whose close relative has had heart disease but whose current LDL levels are not high will ask for this treatment as a preventive, or doctors will think 'off label' usage is absolutely proper, assuming no serious side effects. Hell, if the makers are extremely lucky, maybe it will turn out it even treats erectile dysfunction or male-pattern baldness! And then, what about extending to, say, younger ages or even simply to everyone, like putting vitamins in milk or iodine in salt?  This is what we mean by usage creep.

One might reasonably say that this is just what should be done.  Precedent might suggest that eventually we'll find that the agents are less effective than current tests suggest or have some serious long-term but as yet undiscovered downsides.  However, things that can't be known until the drug is used by millions of people for numbers of years.  Making decisions about usage is harder than one might think.

One reason for concern about usage creep is already being mentioned in the blaring news stories about the apparently genuinely major advantages of these compounds.  That is, the obvious issue of the financial mega-bonanza to be reaped by the pharmaceutical firms.  These drugs are going to be very expensive.  The money to be made is certain to encourage usage creep.  Could we expect otherwise?

But worse than just profiteering is that, even with Obamacare available so that presumably even the poor could have access to these beneficial drugs, putting the whole population, so to speak, on these pills for their whole lives, could bankrupt the health-care funding system that is already a heavy burden on society.  It's being suggested that these new pharmaceuticals could simply by themselves eat up any reasonable premium level for health care plans.

But there is another issue, and that relates to truth in advertising and the issue of side effects--and here we don't refer to incomplete data that may be leading to premature approval or anything like that.  Instead, it's more of a philosophical issue:  What does a list of side effects mean, in this case, and what would the whole truth actually be? What should the manufacturer or the FDA tell you so you would be truly better informed when you take the new drugs for the rest of your life, as so many are likely to do, across the developed world?

From the Sanofi website; Sanofi is one of the makers of these statin replacements

What the FDA and medical community doesn't list on the label
The FDA requires that known side effects of drugs be clearly stated on packaging or labeling material, and surely physicians will know about them.  Isn't that right?  It should be, but there is a sleeping tiger here, that apparently nobody has thought about or, if they have, that they've buried so deep you never will realize it.  In fact, there will be huge unstated negative side effects of these new drugs.  Indeed, shouldn't a proper labeling for these new medications include something like the following?:
"WARNING: Use of this product will greatly increase your risk of Alzheimer's Disease and other dementias, arthritis and other muscle and joint diseases, some forms of cancer, diminished vision and hearing, other degenerative disorders, and accidental death."
Of course such truth in labeling won't happen, and the reasons are subtle and if taken seriously would lead us, as a society, to think more deeply about the role of medicine in health, and of the meaning of health, in a real world in which life is finite.  There is no one who can provide 'the' answers to the problems that are raised, and indeed each person would, in principle, provide his/her own answers.

But at least, there should be a societal discussion.  The reason has to do with the concept of 'causation' and the demographic realities in a world of competing causes.  If these drugs lower LDL cholesterol anywhere nearly as much as they seem on present evidence to do, and if the association between LDL cholesterol and heart disease is as linear as is hoped, then that by itself will eliminate or greatly forestall the occurrence of fatal heart disease in those who take them.  But then what?

If people live much longer as a result, they will inevitably get the sorts of diseases that could be included in an empirically correct labeling!  If you don't get heart disease, it is simply obvious that you will get something else, and it is likely to be slower and more progressive than the quick end to life that heart attacks can be.  Note that our warning list did not include some causes, like kidney failure, diabetes, and the like that could be stalled or avoided by lowering LDL cholesterol--so we are being quite conservative here.

The problem is that of what are known as competing causes, and we've written about it before.  It is inevitable that you will die of something.  If not heart disease, something else.  One might say, well, OK, but at least I'll have more years of life before that something-else gets me. This is likely to be true to some extent, but there are two cautions.

First, people with heart disease often have other health issues because by and large heart diseases gets people at older age, and they are more likely to have less healthy lifestyles.  That includes more risky conditions than high cholesterol.  So, these other causes may be lurking just around the corner, so the removal of heart disease may mean that the gain in years might not be very much!

Secondly, other disorders that those saved from heart attacks will eventually get, if they don't have them already, are ones with gradual onset: you become more and more affected over time.  Mental deficiencies, joint and mobility problems, vision and hearing, are clear examples.  And the nature of accelerating risk is that if you slow it down you defer the onset of serious-level symptoms but you also stretch out the decay process at the end: you have more years with more and more serious symptoms before your body finally conks out.

What is 'cause'?
Are we just playing word games here?  Is it accurate to suggest that the new drugs will 'cause' dementia?  Surely the chemical doesn't mess with neurons!  Let's assume that's true and that no such direct molecular effect is ever found. Then the effect of the medication is related to the occurrence of these other traits, but not in a directly causal way.

This raises questions about causation.  It is more than simply saying that correlation is not the same as causation, because while the active mechanisms responsible for, say, Alzheimer's or joint disease, are not affected by the LDL-reducing drugs, they open the way for the former to act because the person lives longer.  Correlations such as the brand of car you drive being associated with some forms of disease arise because both may be the result of income levels and associated dietary habits. The dietary habits, not the type of car, are causes of interest.

But in the case of competing causes of disease, reduction of one is a sort of mechanistic effect, not just a spurious cause.  If a mechanism is changed in a way that allows a different mechanism to proceed for longer times, this is part of the overall mechanism of the related traits.  The chronic late-onset diseases most of us in the rich world die of now are directly the result of so successfully controlling infectious diseases, our previous killers. One definition of cause is that if you remove it, the effect changes, in this case the protective effect, relative to cancer, of dying of a heart attack.

And what if widespread use of these new drugs puts serious pressure on the health care system, so that some treatments will have to be deferred or denied to more people than presently?  Is that so unlikely?  And is that then not a cause of deteriorating health?

And what if it worked miracles and the relative fraction of our population (and the world's population) of wearing-out old people substantially increased?  That puts all sorts of pressures and pinches on everyone else, indeed, even on the normal living needs of the increased elderly segment.

Causation is not so simple and straightforward a notion.

So, what is 'health care'?
The new LDL reducers raise many deep, and deeply important questions.  The point here is to be realistic about disease in our society and have an open consideration of how to deal with the kinds of game-changing environmental or behavioral aspects of our society, and their long shadow of implications.

In a very serious sense, even if indirectly, the new LDL-lowering agents might have disastrous effects for countless numbers of people.  It's a discussion we should be having.  The news media should be leading the way, to force that on the scientists and health system.

Indeed, these issues should force us to consider what, exactly, we even mean by 'medical care' and 'health care'.  How do they relate to each other, and to the idea of 'public health'?

We think these are real, complex, disturbing, serious truths that have no one answer, and that affect individuals as well as society.  This is not a matter of complaining about science, policy or even drug company profits.  It is about profound issues in human life, that should be discussed openly and fully, because they affect everyone's future.


Kirk Maxey said...

The field of therapeutic lipid lowering drugs is complex. PCSK9 inhibitors owe their existence to the discovery of human genetic null mutants for the PCSK9 gene, who had dramatically lower plasma LDL levels and rates of atherosclerosis. However, these new drugs do not lower PCSK9 activity by this mechanism. The APO-A1 Milano 'super-HDL' mutation was also first discovered in humans, but these subjects had such low levels of HDL that their physicians were at first shocked at what looked like a huge CVD risk factor. The Darwinian history of both sets of mutations is rather cautionary. Neither has shown any significant positive selection advantage, and both remain very rare mutations. And attempts to boost HDL levels and activity (See The Failure of Torcetrapib) resulted in higher CVD mortality and the failure of the whole class of CETP inhibitors as drugs.

In the face of such complexity, I would much prefer to see the FDA completely ban advertising of hypolipidemic drugs, and perhaps all prescription pharmaceuticals. The endless spiels of contraindications and side effects, interspersed with positive and glowing people doing stilted and scripted "happy things" is an absolute pox on the face of humanity. How exactly are we supposed to interpret a happy middle-aged couple planting flowers with the voice over, " may have swelling of the face and lips, internal bleeding, and may die of tuberculosis or a fungal infection."

Ken Weiss said...

Absolutely. I would go much farther, as I think even a minor response should be to ban entirely advertising by docs, pharmas, clinics, hospitals, lawyers, etc. industries that prey on those desperate for solutions to life's problems. We did fine as a society before those floodgates (or is the proper term sewers?) were opened

David J. Littleboy said...

Just a couple of comments here. Healthcare in the US is expensive for a variety of reasons, but many of them are political. It's illegal for the government to negotiate with big pharma over drug prices. That's a purely political decision. We don't have to be that stupid. So if second generation statins really are something everyone should be taking, big pharma can be paid for the patents, told to take a hike, and the drugs manufactured as generics.

Second, you must be really young, a long way from retirement, and not know very many old folks. It looks to me that for most folks, what old age looks like is a long period with most abilities intact, and very rapid decline afterwards. There was a review article (in your field, if memory serves) in Science by a bloke who was 100 when he wrote it. His obituary was in one of the next two issues. I play in a couple of jazz bands here in Tokyo: in both, most of the players are over 80. The amateurs are a bit rough around the edges but are having fun and the pros are still making gorgeous music. So what the world looks like to this about-to-retire 63-year old, is that I'll be able do all sorts of fun stuff that I haven't had time for while working. And what that means is that anything that puts off the next problem is really appreciated. If something lets me off the hook for heart attacks in my 60s, I'm real happy about dying from prostate cancer in my 80s. The idea that there's a down side _for the patient_ to something that helps a problem they are having now makes no sense. It's really cutesy and stupid, but it really is true that the only thing worse than getting old is not getting old.

Also, the US has this thing about worrying about retirees busting the bank. That also doesn't have to be a problem. The US will never have as high a ratio of retirees to working age blokes as Japan does now. Japan is managing OK, for now, with a tad over 4 retirees to each 10 working age blokes. In the US it's currently a tad under 2 for each 10 now, projected to be a tad under 4 for each 10 in 2060. Japan will be 7 for each 10 in 2060. (Interestingly, Germany and Italy are similar to Japan in this.)

Now, it may turn out that second-generation statins aren't all that wonderful. That is, after all, what happened to the first-generation ones (there was a bloke with a kewl TED talk and a book, but he was wrong). But that's a question that needs a careful, scientific answer.

Ken Weiss said...

I am, in fact 73, and retired though I stay active. Fortunately, I'm still healthy. But not everyone. I spent much of my career in research on aging and its demographic implications. We see the world from different perspectives, I guess we see the world differently, and neither will be around to gauge how accurate our projections are. That some smokers live to 100, or some in privilege see through rosy glasses is not evidence that the whole world is like that, and of course, the same who see differently and think they understand the objective facts. Time will tell.

Jackie said...

The newer drugs hold promise only because the massive business of mainstream medicine says so. Not because the real non-medical industry-crafted scientific data support it.

Some of the biggest problems with statins (e.g., increased risk of cancer, arterial calcification, pancreatitis, diabetes) are exactly the result of lowering 'bad' LDL cholesterol by blocking its production, leading to physiological events like an increase in inflammation, a higher risk of infections, the lowering of steroid hormone production, etc. (The various ways statins - and a cholesterol-lowering popular diet pill advertised by Dr. Oz - manifest their adverse effects, such as in diabetes, are rather thoroughly explained in the scholarly report at ). These new "advanced" drugs do all of that too. Therefore, the use of these new "advanced" drugs is equally irresponsible.

But like with statins, here too the huge medical business claims these drugs reduce the risk of death, that they are safe as this corrupt cartel has done with statin drugs (just look at the propaganda put out by the Mayo clinic on statin drugs: "the risk of life-threatening side effects from statins is very low") when statins, in actual fact, increase mortality and morbidity, including deaths from cancer (see above report). Statins have almost no real benefit in the very vast majority of users. It's a "scientific" scam.

And because of such medical propaganda, few people are aware that the medical claims of benefits of statins are mostly based on flawed and fraudulent "scientific" studies conducted by people with vested interests. Expect the very same here with these new drugs, positioned to become new blockbuster wares for corporate medicine.

Ken Weiss said...

These are strong statements that I don't know enough to judge, but if true they reinforce the problem of conflict of interest. Drug companies either believe to must for business reasons say, that their products are safe and effective. Government and the media have a responsibility to keep things honest. On the other hand a real problem is that truth is complex and elusive and, given environmental and behavioral change, truths about risks also change.

Ken Weiss said...

I meant pharmas must actually believe or must _for_ business reasons say they do