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.