June 3, 2010

The Latest Avandia Outrage: A Shockingly Bad Study Promotes It for Prediabetes

The slimy weasels who profit from selling the dangerous drug Avandia don't give up easily. Though there is incontrovertible evidence that their drug causes heart failure in people who did not have it before starting the drug, as well as ostoporosis and an increased risk of heart attack, they keep sending the health media carefully doctored press releases touting new and marvelous features of their drug.

The latest is the claim that Avandia does a humdinger of a job at preventing diabetes, reducing it by two thirds. The study is a triumph of sleazy research technique, but because the drug reps will be hard at work "teaching" your doctor of this wonderful new feature of their dreadful drug, you need to understand what the study actually did and what it learned.

The study abstract can be found here:

Low-dose combination therapy with rosiglitazone and metformin to prevent type 2 diabetes mellitus (CANOE trial): a double-blind randomised controlled study. Prof Bernard Zinman. The Lancet. June 3, doi:10.1016/S0140-6736(10)60746-5

As you can see by looking at the title, this study combined Avandia with Metformin. Because we know that Metformin delays the diagnosis of Type 2 diabetes (by lowering blood sugar, not by correcting underlying flaws) you'd assume that any trial of metformin with another added drug would compare the combination with metformin alone.

But since the point of this study was to breath life into the decaying corpse of Avandia, that comparison was omitted. There are only two groups in this study, those on the Avandia metformin combo and those on a placebo.

Beyond that, the study involved only about 200 people, divided into two groups. This means that if one out of every two hundred people taking Avandia developed a severe or even fatal complication, the study group is too small to detect it. Since the problem with Avandia is that it has been shown in large studies to cause severe and sometimes fatal complications the study design used here is worthless and very clearly designed only to squeeze more profit out of GlaxoSmithKline's dangerous drug.

The next problem with the study is that it lasted only a median of 3.4 years. Why is this a problem? Because even if the study size had been big enough to make the severe side effects evident, the most serious of the Avandia side effects may take up to a decade to become evident. That is because Avandia works by transforming bone stem cells into baby fat cells into which glucose gets pushed. (That is why Avandia causes permanent weight gain.) This means that over time bones are weakened because they don't get new bone cells coming in to reinforce them. Eventually they start to crack and by then it is too late to fix the problem. But you won't see this effect over 4 years. So again, this study was designed to avoid highlighting a known damaging side effect of Avandia.

But setting aside the fact that it is impossible to know from this study whether Avandia is safe in this context, the actual finding of the study was another blow to Avandia's claims, and makes it crystal clear why there was no "metformin only" group included in the study--though you wouldn't know this from the press coverage.

The study claims,
70 (80%) patients in the treatment group regressed to normal glucose tolerance compared with 52 (53%) in the placebo group (p=0·0002).
Note that the study is reported as claiming that two thirds of those who took Avandia (with metformin, though the headlines miss that) did not progress to diabetes. But at the same time, more than one half of those who did not take any drug also reverted to normal blood sugar status. So in fact, the drug combo only kept an additional 27% of participants from being diagnosed with diabetic blood sugars.

Note that DPPT--a far more robust study of 3234 people with pre-diabetes found that Metformin alone decreased the progression to diabetes by 31% over an average of 2.8 years.

Reduction in the Incidence of Type 2 Diabetes with Lifestyle Intervention or Metformin:Diabetes Prevention Program Research Group NEJMVolume 346:393-403, February 7, 2002, Number 6

So there is basically no significant difference in effect between the use of metformin alone and metformin combined with dangerous drug Avandia even allowing for the extra couple months in the Avandia study.

All this seems to have eluded the peer reviewers who approved this study for publication.

Okay, that's bad enough, but there's one last point. The makers of Avandia promote it to doctors with the claim--unsupported by evidence--that members of the TZD drug class to which it belongs rejuvenate beta function. This study, like every other study of the subject finds that isn't true. The Lancet study states,
The change in β-cell function, as measured by the insulin secretion-sensitivity index-2, did not differ between groups (placebo −252·3, −382·2 to −58·0 vs rosiglitazone and metformin −221·8, −330·4 to −87·8; p=0·28)
So the improvement achieved in the drug group (most likely from taking the metformin) did not occur because the beta cells were functioning better, but only because blood sugar was lowered. Whether this was because the metformin blocked liver dumps, or because it promoted glucose uptake at the muscles by revving up AMP-Kinase, or because Avandia pushed excess glucose into brand new baby fat cells is unknown.

So that's the story that the folks at The Lancet somehow missed. And because they missed it, you can be sure some percentage of boneheaded doctors will read this new study and put patients who don't have diabetes on Avandia. After all, why prescribe an effective, safe, generic drug that can be bought for $4 a month--Metformin--when you can prescribe one that does nothing but harm and costs up to $100 a month? The answer has a lot to do with the subtle incentives drug companies still provide doctors, but that's the subject for another blog post.

Unfortunately, even doctors who are gun shy about Avandia still believe that its evil twin Actos is safe. It isn't. Actos also causes heart failure and works by changing bone baby cells into baby fat cells causing permanent weight gain and, long term, damaged and broken bones. Actos may not cause heart attack, but that information won't mean much if you develop heart failure, which over time is just as fatal. It's also worth noting both drugs raise the risk of retinal edema which means that if you are particularly unlucky, both Avandia and Actos can seriously damage your vision.

Bottom line: If you have pre-diabetes can't get your blood sugar back to normal by cutting carbs (which has been proven far more effective than any drug) stick with metformin. It's safe, it works, and its side effects include things like weight loss and a lower incidence of cancer.


Chris Kresser said...

Excellent work, as always.

The negligence and malfeasance of researchers never ceases to amaze me. I know they are smart people, and they must be very well aware that omitting a metformin-only group in a trial like this makes it virtually meaningless in determining Avandia's effect. Yet they do it anyways.

When we're talking about side effects like death, that's just inexcusable. How can they sleep at night?

Scott said...

And people wondered why I fought the FDA on enabling salespeople from promoting off-label uses for drugs! But the real concern is why so many doctors might consider this info. to promote Avandia for purposes other than which the drug was actually approved -- that practice needs to be legislated out of existence, as the FDA cannot be relied upon to be judicious in enforcement -- regardless of my admiration for the steps the new leadership has taken to fix the broken Fatal, err Food and Drug Administration.

pjnoir said...

Scribbling on a pad is far easier than doing any real doctoring & if Avandia can twist the other arm as they write, then only we, the patients are the losers.

dmoak said...


Most diabetes oral meds have side effects, many very serious. Do you know of any side effects of taking metformin other than the possible nerve damage due to depletion of vitamin B?

Jenny said...

I have documented the evidence about Metformin side effects here:


It has a very long track record, and it turns out that lactic acidosis is not any more common among people who take metformin than among those who do not.

Vitamin B-12 deficiency can sometimes arise with very long term use. Your doctor should test for this from time to time, but it is not terribly common and if you test it can be remediated without causing problems.

Outside of that, the main problems are with the gastrointestinal tract. They usually go away, and taking the extended release form (ER or XR) solves that for many people.

People with liver or significant kidney disease are not supposed to take it.

Helen said...

Thank you as always for helping guide us through the morass of diabetes treatments. If anyone suggests Avandia to me, I'll run for the hills.

dmoak said...

Thanks, Jenny

I've been eating a very low carb diet for a about 18 months. In a very short period of time, Metformin seemed to have no effect on my blood sugars. Eventually I came off it (for about the last year). My recent labs revealed an unexpected A1c of 6.6 so we decided to get back on the Metformin. Now it is working better than it ever has. My doctor thinks that the time off is making my body respond better, but anticipates that the effect will be short-lived. We'll see

Jenny said...


That's a high A1c for someone eating low carb. Have you had your insulin or c-peptide tested to make sure you don't have LADA (slow autoimmune diabetes?) If an LC diet doesn't knock blood sugars down to normal you have to wonder if something is keeping the beta cells from secreting properly.

Metformin will have an impact even on people with LADA because it stops liver dumps.

Helen said...
This comment has been removed by the author.
Jenny said...


Metformin should be effective in a week or two.

Let's keep our discussion on this blog post on the topic of the post from here on in.

Helen said...

Sorry to get off-topic. BTW, I can't thank you enough for your book, web site, and blog. Your work is an invaluable resource.

Jim Purdy said...

"Shockingly Bad"
"slimy weasels"
"sleazy research"
"dreadful drug"
"decaying corpse of Avandia"
"study design used here is worthless"
"dangerous drug"
"boneheaded doctors"
"evil twin Actos"

Jenny, so you really, really like Avandia? LOL!

Jim Purdy
The 50 Best Health Blogs

Michael said...

New member here, and what a great job you did of seeing through the haze and showing us what this study really says.
Thank you.

dmoak said...


I have had insulin and c-peptide tested and they were OK. I should mention that I have been type II for 25 years and that I was on Metformin most of that time. For a year on low carb, my numbers showed steady improvement (A1c as low as 5.6). It was just this one lab that jumped up so high. Since adding the Metformin back (and continuing very low carb) my numbers have been great. Fasting in the range of 85-95 most days. Average levels at or around 100 most days. so I'm pleased with the effect Metformin is making.

Boz said...

The only thing Avandia did for me was leave with nasty scars on my lower legs from water blisters. What a disaster that crap is. But, when a doctor consults his or hers PDA when proscribing a treatment, it's no wonder this is what we get. Learn, baby, learn is the only way we can get ahead of the blood sugar game.

Michael Barker said...

Once again Jenny, thanks for the great job.

The one thing I wish to note, is how can such poor studies be continually published? This isn't the first one like this you have noted and probably not the last. Now I find myself reading journals with the same attitude that I have when listening to telephone solicitations.