Holman et al. report that there was a significant difference in the number of deaths from cardiovascular causes among patients in the three study groups in the 4-T study. Of 14 deaths from cardiovascular causes, 4 were in the biphasic group, 9 in the prandial group, and 1 in the basal group (P=0.002). This result is of particular interest in light of the findings of the ACCORD trial,1 in which there was increased cardiovascular mortality in the intensive-therapy group (target glycated hemoglobin level, <6%) than the standard-therapy group (target glycated hemoglobin level, 7.0 to 7.9%). In the ACCORD trial, the proportions of patients who received prandial insulin regimens and who had severe hypoglycemia were higher in the intensive-therapy group than in the standard-therapy group. Because patients in the ACCORD trial were randomly assigned to a therapeutic strategy rather than a specific treatment regimen, it was not possible to establish whether the increased cardiovascular mortality was related to specific drugs or drug combinations (e.g., prandial insulin and rosiglitazone), the sequelae of hypoglycemia, or other factors associated with intensive therapy. We believe that the results regarding the rate of death from cardiovascular causes in the 4-T study merit further attention and scientific discussion.
