Yet another piece of bad news showed up--without mainstream coverage--in the health news this week. A long term study of Actos discovered that there is a clear dose and time-related increase in bladder cancer among those who take it. As MedPage Today reports:An interim analysis of data from the study, which includes more than 193,000 patients with type 2 diabetes, revealed no statistically significant increase in bladder cancer among pioglitazone users compared with nonusers (hazard ratio 1.2, 95% CI 0.9 to 1.5), but "the risk of bladder cancer increased with increasing dose and duration of [pioglitazone] use, reaching statistical significance after 24 months of exposure.Of concern to all of us should be the way that the company that makes the drug attempts to wave off this latest of many findings that show how their drug ruins lives. Takeda's spokesweasel claims, "the data did not reach statistical significance for the primary endpoint of increased risk of bladder cancer." What this means is that even though the data shows a very strong relationship between bladder cancer and their drug when a larger dose is taken for 2 years, the relationship disappears when you add into your statistical pool all the people who took it for a shorter time period or at low doses.If you can't see the problem with this argument, I worry about you. Apparently the renegade doctors who earn huge salaries hyping drug company products have decided a drug is only dangerous if it kills large numbers of those who take it, not just a measurable number of those who take it at commonly prescribed dosage levels for several years. But that's not what I'm blogging about here. What I'm blogging about is why so many of the new drugs have such terrible side effects and why we only learn about them ten to fifteen years after the drug is on the market.The reason is this. Today's newer generation of drugs target specific genes and cell receptors. The TZD drugs, Actos and Avandia, target the PPAR-gamma transcription factor which regulates genes that affect how lipids are stored. No one questions that they do this, or that in a significant number of patients (but by no means all who take them) they lower blood sugar.The problem is that PPAR-gamma regulates genes involved in a bunch of other processes in the body, too--processes that have nothing to do with blood sugar control. PPAR-gamma, for example, transforms the bone stem cells that should turn into new bone into new fat cells. This is why after a decade on the drug many people start experiencing broken bones in their arms and legs (the areas where PPAR-gamma is most active) and why once bones begin to break there is no cure. A decade of rebuilding has been subverted and the weakened structure of the bone cannot be fixed.And this points to the huge problem with the drug regulation process. There is no requirement--none, zilch--that a company applying for permission to market a new drug investigate what OTHER physiological processes are affected by the drugs's mechanism. All the drug company has to show is that it achieves what they are selling it to do. In the case of Actos and Avandia, that means causing a very modest drop in A1c--about .5%. If course, if a drug undergoing the approval process does something that is severely damaging right away, the problem will show up during the approval testing. If lots of people's skin peels off, or lots of people have strokes, a drug won't usually get approved. But most of the unintended consequences of the way new drugs work are more subtle and don't cause dramatic events during the first year or two that a person takes them. Many of these life-ruining side effects happen so slowly they don't show up for five to ten years--and then it takes a lot of work to link the side effect to the drug. Many of these side effects are never linked. Doctors expect to see people with cancer in their practices and don't connect the cancers with a drug the person has taken for a decade. They expect to see heart attacks in people with diabetes and don't know that more people are having heart attacks than expected and that this is because of some drug they prescribed four years before.It is only when the side effect is odd that anyone notices at all. If young people with no sign of heart disease suddenly develop heart failure as happens with both Avandia and Actos, a few doctors notice and report this to the FDA. (Many of course, don't.) If people start breaking arms and legs--an odd pattern for osteoporosis--as happens with both Avandia and Actos, a few more doctors notice. But the fact that a few doctors notice and report doesn't mean that other doctors hear about these side effects since they get all their "drug education" from drug company sales reps, those pretty young ladies who used to be college cheerleaders who show up at the office bringing such welcome take out lunches. And the FDA will not pull a drug from the market when evidence of these more subtle side effects emerges either. It takes years to kill a dangerous drug--years during which the company that sells it continues to rake in its billions. Cancer is a particularly troubling side effect of newer drugs, because the public believes, erroneously, that the drug approval process keeps cancer producing drugs off the market.This turns out not to be true. Though drug testing eliminates drugs that cause cells to become cancerous in a test tube over a few weeks or which cause malignancies over the short life spans of rodents, it cannot identify drugs that change how the body fights cancers in ways that allow slow developing human cancers to gain traction.That is why evidence a that a drug is raising the incidence of cancer rarely appears until a drug is almost at the end of its 14 year patent period. It has taken more than 12 years to notice the link between bladder cancer and Actos. It took nine years after its approval for anyone to notice the signal suggesting that Diovan raises cancer incidence by about 8%.And that's why it won't be until another nine years or more that the public will learn that any drug that inhibits DPP-4 is turning off an immune system mechanism essential to fighting melanoma, prostate cancer, ovarian cancer and lung cancer. Details HERE.)Even when the link between a drug and a serious, even fatal, side effect finally made clear by large population studies don't expect the drug to be taken off the market. There will be panels and hearings and FDA deliberations, but if the history of Avandia is anything to go by, the drug will still be selling at your local pharmacy five years after its clear what its real dangers are. Because these secondary effects don't kill everyone who takes the drug, or 50% of them or even 10%, the drug company spokesweasels will argue, as the Takeda one does above that unless it is damaging everyone who takes it, it's still a good drug. They will also claim--though there is not a scintilla of evidence to support this claim, that the drug is saving many other lives which balance out the ones we know it is taking. The only oral diabetes drug for which there is conclusive evidence that that it prevents deaths is Metformin, which has been on the market (in Europe) since the 1950s. And not so incidentally, Metformin is the only oral diabetes drug that has not been linked conclusively with causing a fatal side effect. Though it was long thought that it might, rarely, cause lactic acidosis, that has been disproved. We now now that the incidence of lactic acidosis in those taking metformin is identical to its incidence among those not taking it.But there is no evidence that the expensive newer diabetes drugs do anything but lower blood sugar very slightly--much less than dietary changes and exercise can do. There is no evidence any of these newer drugs are saving lives. And because when the drug companies go looking for this evidence, they keep finding the opposite--it was that kind of study that stopped the profits rolling in from Avandia--don't expect to see such studies funded in the future. Is there any way to detect these life-ruining side effects before several million people have taken the drug? A very good place to start would be to require that drug companies investigate the effect of a new drug on all the known expressions of the gene, transcription factor, protease or other physiological component it is known to impact. This information is widely available. There are databases online that link to all the research about every gene for example. A reasonable person should be able to read through these studies and determine which impacts might cause harm. Then those effects could be investigated as part of the approval process. Doing this would have given us the answer we need about whether inhibiting DPP-4, a protease known to fight cancers, raises the incidence of the DPP-4 sensitive cancers--research that researchers say should be done, but that has not been done. Drug companies will tell you this is too expensive and that such regulations would mean no more wonder drugs. But when wonder drugs are clearly killing tens of thousands of people who would otherwise have lived, you have to ask yourself how wonderful they really are. We went to war over an attack that killed less than 3,000 people. But we let drug companies sell products that may be killing tens of thousands unnecessarily. Even though there is good evidence that the drug companies know their products are causing unnecessary deaths and hiding this evidence so they can continue to rake in their billions. Isn't it time this changed?
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