ACCORD and ADVANCE again

Several months ago, I wrote about two diabetes trials: ACCORD and ADVANCE. Both studies involved people who have both type 2 diabetes and high risk of cardiovascular disease, but they came to opposite conclusions about whether tight control of blood glucose was harmful in these patients.

ACCORD surprised experts when it was announced that patients in the tight-control part of the study (aiming for A1C below 6.0) had more deaths than patients in the standard-treatment group (aiming for A1C between 7 and 7.9). This unexpected finding generated a lively discussion amongst endocrinologists: were the problems in the intensive group actually due to hypoglycemia, and if not, to what? There was no answer at the time, but it was expected that when more information from the study was available, it might answer the questions.

The following week, another study, ADVANCE, released the results of an interim analysis of their patients. In this study, researchers found the reverse: the results from an interim analysis did not show evidence of an increased risk of death among those patients receiving intensive treatment to lower blood glucose. Again, it was anticipated that further results would be available soon.

Well, additional information has now become available. The New England Journal of Medicine has just published two articles:
Effects of Intensive Glucose Lowering in Type 2 Diabetes (the ACCORD results) and
Intensive Blood Glucose Control and Vascular Outcomes in Patients with Type 2 Diabetes (the ADVANCE results).

So, what's new? Sadly, not much to help clarify whatever resulted in the disparate results announced previously.

The ACCORD authors state "Our findings indicate that a comprehensive, customized, therapeutic strategy targeting glycated hemoglobin [A1C] levels below 6.0% increased the rate of death from any cause after a mean of 3.5 years, as compared with a strategy targeting levels of 7.0 to 7.9% in patients with a median glycated hemoglobin level of 8.1% and either previous cardiovascular events or multiple cardiovascular risk factors."

They speculate that "the higher rate of death in the intensive-therapy group may be related to factors associated with the various strategies. These factors include but are not limited to differences in the achieved glycated hemoglobin level of 6.4% in the intensive-therapy group, as compared with 7.5% in the standard-therapy group; in the magnitude of the reduction in glycated hemoglobin levels in the two study groups; in the speed of the reduction in glycated hemoglobin levels, with reductions of approximately 1.4% in the intensive-therapy group and 0.6% in the standard-therapy group within the first 4 months after randomization; in changes in drug regimens and in the rate of hypoglycemia; in adverse effects due to an undetected interaction of the various drug classes used at high doses; or in some combination of these or many other possibilities, perhaps in combination with the clinical characteristics of the patients in the study." In other words, they don't know what caused the excess number of deaths.