A Summary of Dr. William T. Cefalu’s Editorial “Glycemic Targets and Cardiovascular Disease”
In this New England Journal of Medicine editorial from 2008, Dr. Cefalu provides an excellent review of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) and the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trials.
Those two trials investigated the same question: Does intensive glycemic control—working towards near normal levels of glycated hemoglobin—reduce the rate of cardiovascular events in diabetics?
However, as we know, the ACCORD and ADVANCE trials came to different answers on that question, and Dr. Cefalu summarizes the differences and implications well.
Difference 1: Rate of Reduction of HbA1c
In the ACCORD trial, patients who were in the intensive-therapy group (the group that had to be discontinued because of increased mortality) had a rapid rate of decline of the median HbA1c. There was an absolute decrease of 1.4% within 4 months.
However, in the ADVANCE trial, the absolute decrease was much lower: it was 0.5% at 6 months and 0.6% at 12 months.
It is not known if this difference is what caused the difference in cardiovascular outcomes; neither study was set up to address that particular question, and as Dr. Cefalu points out, that is an issue for future trials to address.
Difference 2: Strategies for Aggressive Pharmacological Intervention
The ACCORD trial had a higher rate of use of thiazolidinediones and insulin than the ADVANCE trial. More than 90% of patients in the intensive group of the ADVANCE trial used the sulfonylurea gliclazide.
This difference does not explain the differences in mortality, but it is still interesting to note.
Difference 3: Weight Gain
Patients in the ACCORD trial had a high mean weight gain than patients in the ADVANCE trial. The mean weight gain from baseline in ACCORD was 3.5 kg; in ADVANCE, it was .7 kg.
As Dr. Cefalu notes, this may be an important difference. Achieving tight glycemic control through an aggressive pharmacological strategy (as was done in ACCORD) is not the same as achieving tight control with lifestyle modification (as was done in ADVANCE).
Implications of ACCORD and ADVANCE
The most significant implication of these trials is that they both showed that targeting near normal HbA1c levels for high-risk type 2 diabetics does not have a beneficial effect on cardiovascular disease, a common complication of diabetes.
Dr. Cefalu writes that current recommendations are to create individualized goals for certain groups, such as high-risk type 2 diabetics. It’s suggested that an HbA1c level of 7% could be more appropriate for this population.