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Saturday, June 07, 2008


Today both the ACCORD and ADVANCE trials, and some editorials related to them, were published in the new England Journal of Medicine. They were massive studies covering thousands of subjects over long periods. The newspapers today are already trumpeting the news. News like this in the New York Times:
Tight Rein on Blood Sugar Has No Heart Benefits

I'm very disappointed by these studies. Not so much for the conclusions they drew, but for the ones that I believe they missed.

You can read them in full on the links. I've only had time for a very quick glance. I hope someone can show me where I'm wrong and point out where the valid conclusions are from these massive studies.

Effects of Intensive Glucose Lowering in Type 2 Diabetes The Action to Control Cardiovascular Risk in Diabetes Study Group

Intensive Blood Glucose Control and Vascular Outcomes in Patients with Type 2 Diabetes The ADVANCE Collaborative Group

New England Journal of Medicine Editorial
Intensive Glycemic Control in the ACCORD and ADVANCE Trials

New England Journal of Medicine Editorial
Glycemic Targets and Cardiovascular Disease

That second editorial is the better of the two in my opinion, and makes this point:
"In the ACCORD trial, patients in the intensive-therapy group who did not have a history of a cardiovascular event or whose baseline glycated hemoglobin level was below 8% had significantly fewer fatal and nonfatal cardiovascular events than did patients at higher risk. These findings suggest that intensive therapy was beneficial at least in this subgroup. Whether achieving glycemic targets below 7% will be beneficial to the vast majority of patients with type 2 diabetes and a low risk of cardiovascular disease remains another unanswered question."

This is a section from the first NEJM editorial, which didn't actually compare the two trials so much as attempt to make a conglomerate sense out of them. Judging by the snippet I include at the foot of one of their conclusions, I believe they failed.

"Two studies in this issue of the Journal — the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial7 (ClinicalTrials.gov number, NCT00000620) and the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) trial8 — sought to determine the effect of the lowering of glucose to near-normal levels on cardiovascular risk. Although the ACCORD and ADVANCE trials both compared intensive and standard glucose-lowering targets in type 2 diabetes, the trials differed substantially (Table 1). Most patients in both studies received drugs from a variety of classes, with or without insulin. However, in the ACCORD study, there were no restrictions on glucose-lowering treatments to reach glycemic targets, whereas in the ADVANCE study, all patients in the intensive-control group were required to receive the sulfonylurea gliclazide (modified release) at initiation. Thiazolidinedione treatment was infrequent during the ADVANCE ."
And they note:
"Neither study appears to have emphasized lifestyle or dietary modification."

In other words, both studies ignored that as a means of lowering A1c to their respective targets or even of assisting the meds. I know from past discussions that ACCORD educated subjects in "adhering to" the standard low-fat high-carb dogma. My brief skim of both papers indicates that there were two major differences; ADVANCE covered a wider range of nationalities, and thus lifestyles, and both studies intensively used drugs, but different drugs. However, that was a very quick skim so I would be very interested in hearing opinions from others more analytical or more qualified than I.

And the NEJM analysis conclusions? In part:
"The most appropriate target for glycated hemoglobin should remain 7%, though lower individualized targets may be appropriate when the focus is primary prevention of macrovascular disease. When glycated hemoglobin values under 7% are the goal, clinicians will need to balance the incremental benefit of a reduction in microvascular events with the increased rates of adverse events; these patients may benefit from consultation with a specialist.


These studies could have achieved so much and they actually achieved so little. Worse than that, the scientists are missing a point that to me is blindingly obvious, and using that misunderstanding to reinforce an incorrect conclusion.The conclusion that jumps out at me from just this cursory analysis of both papers is that attempting to use medications to drive down type 2 diabetes glycemic levels without individually reviewing the appropriateness of the present dietary guidelines for each patient has inherent dangers clearly shown in ACCORD and shown to a lesser degree in ADVANCE.

Cheers, Alan

1 comment:

Robert Miles said...

For at least some of the studies I've seen more recently, the scientists at least mention that they used piling on the medicines as the only method they researched. Instead, it was those who rewrote it for the public who blindly assumed that it was the only possible method.