We were not able to normalize HbA1c values completely during triple therapy probably due to the fact that insulin action was not completely normalized by rosiglitazone and metformin, as stated by Davidson (1). Still, insulin-mediated glucose uptake was only 60% normal during triple therapy; however, a longer treatment period or a more potent insulin synthesizer may help in that respect. Another way to further reduce HbA1c values is to use a more aggressive algorithm, increasing the Novorapid dose further before meals. However, this may induce more hypoglycemic attacks during the day time. The South Danish Diabetes Study, a newly initiated 2-year follow-up study that includes 400 subjects, will hopefully answer this question.
Davidson (1) and Mikhail (2) focus on the different ways of monitoring blood glucose values when using the two approaches. They claim that a focus on the postprandial values in the triple therapy group compared with preprandrial values in the control group favors the triple therapy group. However, self-monitored glucose values showed that the preprandial values were identical in the triple therapy group and the control group. Hence, the adjustment of the insulin dosage would have been identical only if the preprandrial blood glucose values were also used in the triple therapy group (as in the control group). The curve for self-monitored glucose in the triple therapy group is flat (no postprandial rise in blood glucose values), with a geometric mean of ∼7 mmol/l, which is close to the findings in nondiabetic subjects. However, monitoring higher postprandial blood glucose values in the control group (NPH insulin alone) may have resulted in a further rise of the insulin dose, as proposed by Mikhail. We do not expect, however, to see a further effect of this on blood glucose values, since the 50% increase we already performed did not influence HbA1c values (3), but this postulate is still not tested. The last argument against the criticism raised is that we aimed for the same HbA1c values in both groups, which means that we did not rely on blood glucose values only. Thus, we cannot prove that monitoring the postprandial values in the control group also would have improved the glucose control in that group, but we showed that triple therapy was able to nearly normalize HbA1c values in type 2 diabetic patients, which has never been the case when using NPH insulin treatment alone.
We conclude that this trial confirms our hypothesis that the key to the treatment of type 2 diabetic patients is to control postprandial blood glucose values by reconstructing the insulin peaks after meals and by improving insulin action in skeletal muscle, fat, and liver cells. Triple therapy seems to be a safe and effective treatment of hyperglycemia in type 2 diabetic patients, but further studies, especially of a longer duration, are needed.
