Wednesday, February 13, 2008

Science by Press Release? More Evidence of Commercial Control of Research

The best way to do this post is in 3 parts.

Part One: Recently the ACCORD study of tight control of Type II diabetes was stopped prematurely, due to the unexpected result of excess risk of death in the group with tighter control:

I was contacted by a reporter to comment, and I gave the poor guy an earful about how the lack of benefit of tight control in preventing vascular complications of Type II diabetes had been amply proven in the past, so that at least the lack-of-benefit part, if not the actual added-harm part, was no surprise. (And it was very odd that the so-called national experts on diabetes, when interviewed by the media, acted like it was.) The major study to show the lack of benefit of tight control for preventing major diabetes complications was the United Kingdom Prospective Diabetes Study (UKPDS) which followed a large group of diabetic patients (Type II, remember) for 10 years and is probably the largest-scale study of Type II diabetes outcomes that will be done in my lifetime, at any rate.

Part Two: The intrepid reporter e-mailed me earlier today to ask whether I had altered my opinion, in light of a press release he had received from these folks:

The George Institute for International Health. You've heard of them, right? They're right up there with Harvard and Johns Hopkins and NIH and Mayo Clinic as one of the great centers for medical research, right? (Well, maybe not.) They happen to be located in Australia.

Anyway, the press release was not on their website when I just checked (I am guessing it will appear in the next day or so), so basically what it says is that thse guys are doing a study called ADVANCE, involving 11,140 diabetics, to test the effects of tight control of both blood pressure and blood sugar. The blood pressure results (which show a slight reduction in complications with tighter control, no surprise there) were published in Lancet, September 14, 2007. The tight blood sugar control part of the study is nearly complete.

What the George Institute wanted us to know right away, via the press release, is that their data safety and monitoring board for ADVANCE had snooped into the data (as they are supposed to), even though the study is not yet complete, and that they were very pleased to report that ADVANCE has not found what ACCORD did-- that is, there was no excess risk of cardiovascular complications in the tight control group.

Part Three: This is the e-mail message I sent back to the reporter, with my comments on all the above:

If a group of scientists (#1) are doing a study, and another scientific study (#2) is published that shows certain results, and the scientists doing study #1 are quite sure that their study will show different results, it is in my experience extremely unusual that group #1 would send out a press release to announce this. Rather, it would be the usual practice to wait until the results of #1 had received the usual scientific peer review, and been accepted for journal publication, before any publicity would go out.
Sending out press releases fast and furious, on the other hand, is SOP for companies trying to sell drugs.
I looked on the George Institute website and it appears that they are heavily funded by drug companies. (Just how much is not clear from their financial statement as they do not break their funding sources down by commercial vs. non-commercial.)
I note that the drugs being used in the ADVANCE study are all, apparently, new, brand name drugs that are probably "me too" drugs that closely resemble in their actions older, generic drugs that are considerably cheaper and whose side effects are much better elaborated. A study that looks at new, expensive brand-name drugs in preference to more widely used drugs is often a commercially funded study designed primarily to push the new drugs.
All those things will make me view the results of ADVANCE with considerable suspicion, once we actually know what the results are.
Now, let me take the press release at face value. ACCORD showed basically two things, 1) that tight glucose control was of no benefit to diabetics, and 2) that tight glucose control could actually have caused harm. So far as I know, #2 is a new result, and could easily be a statistical fluke. One danger of stopping a study early is that a statistical fluke could be responsible for your finding, and only by carrying on the study longer would you find out that it was a fluke and not real. (Now, I have to add a qualification here. One known risk of trying too aggressively to lower blood sugar is to cause excess cases of low blood sugar (hypoglycemia), which can be damaging to one's health. So it would not be unexpected that hypoglycemia appeared as a downside in any study that aimed at aggressively tight glucose control. I did not mention this initially because based on what we know so far of ACCORD, it was not clear that hypoglycemia was the means by which the adverse results apparently occurred.)
On the other hand, when I told you at first that one could have predicted the results of ACCORD based on the previous experience of the UKPDS trial, I was referring to #1, that is, the lack of benefit of tight control. I find it interesting therefore that the ADVANCE press release makes no claim whatever that they found benefit-- merely that they did not find harm. If indeed the ADVANCE group is heavily drug company funded, the SOP would be to do their best to spin whatever data they get, to make it seem as if there is a significant benefit to tight control using their expensive, preferred drugs, even if there is not. Sorry if that sounds cynical but it is just what we have recently seen in the ENHANCE trial of lowering cholesterol, and other previous occasions too numerous to list here.
ADVANCE has also showed, so far, according to the press release, that lowering blood pressure in diabetics helps reduce the risk of complications. This is old news and fully predictable by UKPDS. The favorable result also could have been achieved with old, generic drugs and would not require expensive brand-name drugs.


Anonymous said...

Re: the George Institute, the ADVANCE trial and the extent of drug company funding, there is an interview with an ADVANCE study author here which asserts an independance from industry in terms of conduct and publication:

Norman Swan: We should just do a declaration here; this is a drug company funded study?

Stephen MacMahon: The primary sponsor for the study was Servier Laboratories who are the manufacturers of the drugs that we studied but it was also funded by the Australian National Health and Medical Research Council.

Norman Swan: And the degree of independence from the drug company?

Stephen MacMahon: 100%, this study was initiated by us, conducted by us, reported by us, independently of all sponsors.

That still doesn't explain the choice of expensive drugs though. Would hydrochlorothiazide have done as well as indapamide?

And I agree that the positive results of blood pressure lowering in the BP arm of ADVANCE seemed predictable and not really "new news". Except perhaps that even those without high BP seemed to benefit from treatment - but at the expense of quite a high number needed to treat.

I suspect that encouraging diabetic patients without hypertension to take a combination antihypertensive pill would be a hard sell - especially on top of all the other medications they may be on.

Red Sphynx said...

UKPDS...showed the lack of benefit of tight control for preventing major diabetes complications.

Well, sort of. UKPDS showed the weakness of feeding diabetics large amounts of carbs, then trying to control the glucose roller coaster with massive amounts of meds. ACCORD added to this knowlege—showing that if you add fibrate and statins to the mix, things don't get any better. (Surprise!)

There is another model. Some of us eat small amounts of carbs and use small amounts of meds. This achieves much tighter control than was reached in UKPDS or the DCCT or ACCORD. Like A1c down below 5.5%, often below 5.0%.

Howard Brody said...

I appreciate Red Sphynx's post. I cannot comment on the evidence in favor of the low carb-low med regimen described without doing more research. The simple point I would make here is that, if this regimen is indeed effective, it shows that it matters HOW one goes about lowering blood sugar--that certain lifestyle changes, for example, work much better than just throwing meds at the problem. I think that is the lesson of all the studies so far, that the mere lowering of blood glucose by whatever means is NOT reliably correlated with good outcomes in Type II diabetes.

Anonymous said...

Here is a whole list of diabetics staying in control by using carbohydrate restriction to some degree.

Just throwing more insulin at a problem of too much insulin doesn't even sound like a good idea.

Carbohydrate restriction improves the features of Metabolic Syndrome. Metabolic Syndrome may be defined by the response to carbohydrate restriction

Conference Coverage: Nutrition and Metabolic Aspects of Carbohydrate Restriction -- 2006 Nutrition and Metabolism Scientific Sessions

Low-carbohydrate diet in type 2 diabetes. Stable improvement of bodyweight and glycemic control during 22 months follow-up

Low-carbohydrate nutrition and metabolism

Low carbohydrate diets improve atherogenic dyslipidemia even in the absence of weight loss

Effects of a carbohydrate-restricted diet on emerging plasma markers for cardiovascular disease

Low-Carb Diets Combat Metabolic Syndrome

Association of Hemoglobin A1c with Cardiovascular Disease and Mortality in Adults: The European Prospective Investigation into Cancer in Norfolk

Glycemic Control and Coronary Heart Disease Risk in Persons With and Without Diabetes

Red Sphynx said...

Howard Brody,

Do you have a clinical practice? Do you treat diabetics?

Adam Becker Sr

Howard Brody said...

Per Red Sphinx's query above, I am not currently engaged in clinical practice. I practiced as a family physician for 26 years, ceasing practice in 2006. I took care of a great many diabetic patients during that time.