FDA, in 2008, did something that many people thought was preposterous. They began requiring companies to prove that diabetes drugs they developed did not kill people. Actually, to be more specific, they required the companies to prove that the risk of dying on the drug was not more than 1.8X higher than not being on the drug.

This caused an uproar. To prove such a ridiculous thing, some companies howled, would require 10,000 patients or more. Maybe 20,000 patients. (I should note here that the big companies were not complaining, just the small ones–I will post abour regulatory capture in a future blog). Some small biotechs that were developing diabetes drugs, like Phenomix, went under. (Biotech companies going out of business is extraordinarily rare, but this is one example.)

Does that sound crazy to you? That FDA would require diabetes drugs, which are supposed to make people healthier, to not kill people?

Or to put it another way, should drug companies be allowed to sell diabetes drugs even if it doubled the probability of death?

Yeah, I didn’t think so. FDA seems completely sane in this case, don’t you think?

The problem is this. You need 15,000 patients in your outcome study only if your drug doesn’t work. If your drug doesn’t save any lives, then you have to show equivalence to placebo. Equivalence trials are larger trials.

But if your drug actually does save lives, then you can run a smaller trial. Very small trial if your drug works really well.

The root cause of this whole problem is that most diabetes drugs don’t save lives. Many of them increase, rather than decrease, mortality. Yup, you heard that right. Even insulin, which is a life-saving drug when used correctly in the right patients,  increases mortality when used in the wrong patients.  In the ACCORD study (a study which is verboten to mention to any card-carrying endocrinologist) tightly controlling Type II diabetes with insulin was proven to increase the risk of death by 22%. P-value was <0.001. The study caused a flurry of hand waving to explain away the results–nay arm flapping, and the arms are still flapping away. Kind of hard to explain away the results of a 10,000 patient study.

Here is one article that gives an overview of the diabetes drug controversy. It’s a bit rabid, to be frank, but nothing in the article is factually inaccurate. The issue is that very few drugs for diabetes has been proven to be good for you (at least in terms of lowering mortality, and sometimes even in lowering other sequelae of diabetes).

But how could that be? Isn’t diabetes bad for you? Isn’t high sugar bad for you?

Well, those are two separate questions, because diabetes isn’t just high sugar. Treating diabetes is probably a good thing, but it’s not clear lowering sugar is enough. High sugar may or may not be why you get renal failure, eye problems, and other problems. All we know is that when someone has high blood sugar for a long time, they also seem to develop these other problems.

But is it the high sugar, or is it something else that’s the cause. Maybe high blood sugar is just the first symptom of the disease, kind of like a cough you develop when you’re starting get a cold. The cough doesn’t cause the cold, it’s a symptom-an epiphenomenon. A virus causes the cold. So is high blood sugar like the cough or is it like the virus?

In many ways, high blood sugar resembles the cough. Except at very high levels, which is very unusual, high blood sugar is relatively asymptomatic. It’s not like someone with a blood sugar of 180 feels pain or is incapacitated. Often they don’t even know, which is why we need an instrument to measure it.

More importantly, if high blood sugar was what caused the renal failure, eye problems, and increased mortality, then every drug that lowered blood sugar should benefit patients. Not all do, which means that blood sugar is not driving all the problems with diabetes, or at least that it’s not the only thing driving the problems.

So that makes sense, right? But then the other question that immediately comes up is, “OK, it makes sense that drugs that lower blood sugar doesn’t always work because sugar may not be the cause of diabetes. But why would those drugs make people worse instead?”

Why is it that so many diabetes drugs increase mortality?

Here, I must pause. This is not unique to diabetes. Many drug candidates that are developed to treat diseases have the opposite of intended effect. They often worsen the exact disease they’re trying to treat. Beta agonists is a perfect example. These are the bronchodilators that asthma patients use. The long-acting inhalers increase mortality in asthma patients.

The most likely reason is that you’re revving up the body’s natural homeostasis system. Here is what may be happening: the body is trying to get blood sugar levels up for some reason. You keeping on lowering the sugar and the body just revs up the disease state to get the blood sugar level to where it wants it to go. The result is that you make the underlying disease worse. It’s like wounding the bear without killing it–just making things worse.

Now don’t get me wrong. Metformin is a great drug. It saves lives. And there is one drug, bromocriptine, that is quite impressive in lowering mortality in people.

The story of bromocriptine is quite… unorthodox. So hold onto your hats:

The theory behind bromocriptine is a theory of diabetes. Some scientist believe that diabetes is not a degenerative disease. They believe that it is a misprogramming of the body. You see, the hallmarks of diabetes/metabolic syndrome like increase in glucose, fat storage, and high choleterol, resemble the natural physiological changes that mammals undergo when we prepare for winter. The effects are particularly pronounced in hibernating animals. Squirrels turn into little tubs of butter before winter. Bears’ cholesterol levels shoot up into stratospheric ranges. Even people tend to gain weight and undergo natural metabolic changes when winter rolls around.

What triggers this?

One theory is that certain chemicals, like fructose, serve as a trigger to the body. Fructose is found in fruit, generally plentiful in the fall, so the theory goes. It’s an odd chemical, and the body reacts very strangely to it. And not in a good strange way, in a bad strange way. Humans have a mutation in our uricase gene that makes us extremely vulnerable to the fructose-induced hibernation mode.

The other trigger may be shortening of the days. And the theory is that with artificial light, we have wreaked havoc with the seasonal tracking system in our brain, and our bodies are thinking that we’re constantly about to go into winter. (We all have these proteins calle cryptochromes that detect blue light and control the circadian rhythm. I’ll talk about that in a different post.)

So the folks who developed bromocriptine, brand named Cycloset, decided to use the drug to reprogram the brain into thinking that it was summer. So they did the clinical trials, and they showed that it worked. It reduced glucose. So they submitted the data to the FDA. And as the first drug of its class, the FDA convened an Advisory Committee to review the data.

Then all hell broke loose.

The idea behind the drug was so… radical. It ran completely against the grain of orthodox thinking on diabetes. The Committee was baffled. They didn’t know what to do. So here is what they did:

They required an outcome trial. They wanted the company to show that the drug actually made the patients do better, not just lower glucose. I’m certain they never thought the drug would show an outcome benefit.

But here’s the thing. This was before the FDA imposed the outcome requirement on diabetes drugs. Years before. So, because of idealogical prejudice against an unorthodox theory of diabetes, the opinion leaders required an outcome study. Fact ran into ideology and ideology won. Diabetes drugs were being approved left and right without outcome data, sometime in face of data suggesting they were worsening outcome. Except this one.

So the sponsor ran an outcome study. And the results were jaw-dropping. Cycloset reduced cardiovascular event by over 50%. It met statistical significance with only 1,791 patients. How was the study so small? Because the drug worked so darn well.

I’m sorry to say that Cycloset didn’t do too well in the market, partly because doctors don’t really believe the theory and partly because of some side effects. Do I believe the theory? I think it may be correct, but we probably need more data. But I will say that it is certainly the most convincing theory I’ve seen so far. In fact, I don’t think there is any alternate plausible theory right now so it’s either that theory or nothing.

If the theory is correct, the implication is very important. As I posted previously, degenerative diseases, where the body parts wear out over time, are much more difficult to treat than programmed diseases. If diabetes is not a degenerative disease but rather a biological switch that’s stuck in the wrong position, it would be a cause for celebration.

Same thing with heart disease. Heart disease and diabetes are really considered to be the same disease, so if we can switch off diabetes, we may be able to switch off progression of heart disease.

And the most exciting possibility? Alzheimer’s disease. Alzheimers disease is looking more and more like an extension of metabolic syndrome, which means that it may be just a late manifestation of the same disease as diabetes and heart disease. This is why some scientists are now calling Alzheimer’s disease Type 3 Diabetes. I’ll also post more on this later, but the take-away is that if the logic chain I’ve laid out is correct–and it may or may not be (though like everyone else, I tend to favor theories I want to believe in)–then we should be able to prevent Alzheimer’s disease, or in people who already have it, stop it in its tracks.

Of course, as always, do not change your medicines without talking to your doctor. Do what your doctor says to do.