I was walking through the hospital today and saw some big banners announcing “Diabetes Awareness Month,” which got me thinking about some recent and very interesting (in a head scratching kind of way) clinical trials.
Within the last year, there have been three major clinical trials reporting on the major cardiovascular benefits (prevention of heart attacks and strokes) of tight blood glucose control in type II diabetes (DMII). The three major clinical trials all have acronym names: ACCORD, ADVANCE (both published in the June 12, 2008 New England Journal of Medicine: http://content.nejm.org/content/vol358/issue24/index.shtml and VADT (not yet published) studies.
These studies compared patients who underwent tight, intensive control of blood glucose with patients who used “standard” methods of blood glucose control. Controlled glucose levels were defined by hemoglobin A1c levels, which is a measure of long-term (2 to 3 months) blood glucose control, of ~6.5 vs. ~7.5 to 8.5. These studies were based on the principle and long-believed idea that the major cardiovascular complications of diabetes (heart attack and stroke) are caused by non-physiologically high blood glucose levels.
In a surprise to everyone (literally), all three studies found no cardiovascular benefit to tight control of blood glucose. And in fact, one study–the ACCORD study–was stopped early due to increased death in patients with tight, intensive control of blood glucose! These results have shocked the entire field and forced physicians and scientists alike to stop and rethink their basic understanding of diabetes.
How could this be? Before you stop taking your insulin or glucose lowering medications or recommend the same to your patients, it is important to stop and consider the interpretations of these failed studies–this is exactly what the field of diabetes must do. In my opinion and many leaders in the field, these studies have uncovered a major flaw in clinical trials: the lack of consideration for the mechanisms through which drugs and interventions act.
These studies blindly believed that lower blood glucose would be better without considering pharmacologic mechanisms that were being used to lower blood glucose (e.g. insulin, and the various families of glucose-lowering drugs, all of which were used as needed on a patient by patient basis to meet the hemoglobin A1c targets). Type II diabetes is increasingly recognized as a state of deranged metabolism with selective insensitivity of some intracellular signaling pathways and over-activity of others–all in the setting of systemic inflammation. It is very likely that the addition of more drugs/insulin to lower the blood glucose–while achieving the sought after goal of maintaining more physiologic blood glucose–also causes greater stress on an already dysfunctional metabolic environment (e.g. through greater over-stimulation of already hyperactive signaling pathways).
Moreover, the level of metabolic disturbance in an individual is highly correlated to how clinically “sick” that person is–a factor that was not really considered in these studies. (Keep your ears open for possible reports that tighter glucose control may have a beneficial effect in prevention of major cardiovascular complications in sub-groups of those with type II diabetes!)
In the end, what do we take away from these studies? Well, not much in terms of prevention heart attack and stroke in type II diabetes with tight glucose control. For now, the recommendation is to continue to follow the treatment guidelines set by the American Diabetes Association:
More importantly though, these studies will hopefully inspire future clinical trials to be more careful in consideration of the molecular mechanisms that are used by therapeutic interventions in the setting of the pathophysiology of the disease being studied. I won’t get on my soapbox though–for now…
keywords: diabetes, type 2, insulin, blood glucose, cardiovascular complications, heart attack, stroke