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Monday, February 11, 2008

More crumbling dogma ? -this time lower and lower blood sugar is better

How many evening diner,CMEoid sessions included the chant, "treat to goal,treat to goal" in regard to blood sugar. As with LDl cholesterol-the goal just kept getting lower and lower.

The DPPT study seemed to provide very good evidence that the microvascular complications of type 1 diabetes could be significantly mitigated by "good"control of blood sugar.Later a follow up report from that landmark trial also provided some reasonable evidence that perhaps macrovascular disease could also be decreased.

There has been the hope that we could accomplish the same thing with the complications of type 2 diabetes by a similar surge of intensive treatment aimed at bringing about near normoglycemia. Would that life and disease and managing disease were so simple.

The UKPDS trial was-and to date is the only large trial with more or less the medications that are now used-that tried to examine whether tighter control of blood glucose would do for the type 2 diabetic patients what the DPPT trial showed that it did for type 1 patients.

The DPPT was a fairly simple trial. There were patients with a disease that seemed fairly homogenous and has relatively straightforward pathophysiology , i.e insulin lack from the get go and the treatment intervention was simply more insulin. On the other hand, the UKPDS trial involved several treatment arms and greater heterogeneity of comorbid conditions in the subjects as well as more variation in the the tempo of the various pathophysiological disturbances and the pathophysiology of type 2 is much more complex than in type 1.

With trials with more complicated conditions and multiple treatment arms there is greater likelihood of chance and confounding and various biases clouding the results. Clouded results or not the UKPDS became a major element in the argument to treat to lower blood glucose value in type 2 diabetes. The results of the UKPDS were not earth moving but were encouraging. There was some decrease in blood vessel disease on retinal exam and some decrease in the rate of progression of urinary protein leak but no change in renal failure or blindness or clinical manifestations of macrovascular disease. The benefit in terms of reduction of retinal microvascular and perhaps renal disease was arguably balanced by an almost four fold increase in serious hypoglycemia episodes ( 0.6% per year versus 2.3%). The former effect was emphasized and the later effect was not in the 2002 position paper from the American diabetes Association from which a lot of the enthusiasm for tight control arose. A somewhat less optimistic assessment of the UKPDS trial is offered here by Dr. Roy Poses and fits more with my ever increasingly cynical nature.

Now fast forward to the ACCORD trial . Here is the announcement of the cancellation of the intensive treatment arm of this large randomized trial. This was supposed to be the trial that would answer-among other questions- the question "can we decrease the macrovascular events associated with type 2 diabetes with intensive blood glucose control ?" Here the treatment goal was a HbA1C of less than 6 %, i.e. basically normal.

However,there were more overall deaths in the intensive treatment arm than in the standard treatment arm. Of those intensively treated about 1/2 had hemoglobin A1C values of less than 6.4 while in the standard treatment arm 1/2 had value less than 7.5. The mortality increase was certainly not what the investigators likely expected.The overall death rate was reported as 20% higher but there were actually fewer heart attacks in the intensive treatment arm but of those there was a higher mortality. So what is happening to cause increase mortality? The NIH announced their analysis so far has not determined what factor(s) are to blame.

Is this simply a matter of getting the glucose too low? Maybe, but an early report from the trial claimed that the excess mortality was not related to hypoglycemia although there were expectedly more hypoglycemia episodes in the intensive treatment group. Also the NIH reports the analysis so indicates no link to the use of any particular medication ,e.g. rosiglitazone.

Dr RW suggested that excessive insulin use may really be the culprit though not necessarily by precipitating hypoglycemia episodes but by fueling weight gain and the metabolic syndrome and insulin resistance. Other suggestions have been made,see here for references, including the stress placed on patients to achieve a difficult therapeutic goal and the theory that too rapid decrease in blood glucose might have played a role.

Dr. Steven Pinker has written extensively and eloquently about the human mind's mysterious and marvelous workings and has discussed how the human mind can see events in different frames. I'll bet that we be seeing the results of this trial (so far we have only a snippet of the results) spun this way and that. But deaths are not a surrogate measure and the major observation of more deaths with intensive treatment may well shift the momentum of diabetic treatment from "lower is better" to "well maybe not too low" and maybe " not necessarily the same target for everyone". A number of doctor bribe programs (A.K.A. pay for performance ) are keyed to hemoglobin A1C levels .Will we see those third party payers whose interests are claimed to be in improving quality of care quickly revise their guidelines?

Physicians want better treatments for their patients and they want results of promising treatments to be true. That desire to do good for their patients coupled with big pharma funded hype often aided by a shinny veneer pasted on by academic and other thought leaders can really energize therapeutic exuberance that may have a much less robust evidentiary base that we were lead to believe.Treating to a goal or treating the numbers can make clinical life seem simpler, sometimes too simple.

First, we find out that maybe we were giving to much EPO, and then maybe lower LDL per se is not better and now more insulin may be too much of a good thing (haven't we known that for a long time?). It is a good thing we quasi- codified all or some of those things into guidelines and pay-for-compliance programs otherwise we might not have had a chance to use them before we decided there weren't really a great idea after all. I remember as house officers we used to talk about the patient dying but the electrolytes were in balance.


Roy M. Poses MD said...

Great post!
Actually, our post on the ACCORD results is here:

james gaulte said...

I am going to have to practice on getting my links right.
sorry and thanks for the correct link.