Poulsen et al. (1) recently demonstrated that triple therapy (metformin, rosiglitazone, and preprandial insulin aspart) lowered HbA1c levels much better than twice-daily NPH or MIX insulin in type 2 diabetic patients. They then claim that the reason for this improvement, compared with the patients treated with insulin alone, is the superiority of specifically treating the three pathophysiological components of type 2 diabetes (peripheral insulin resistance, hepatic insulin resistance, and impaired glucose-stimulated insulin secretion). Given the design of the study, this conclusion is suspect for two reasons.

First, the glycemic goals for the two groups were different. The goals for patients receiving only insulin were a preprandial value of 5–7 mmo1/l. The goal for patients receiving triple therapy was a postprandial value of 5–7 mmol/l. Achieving a postprandial goal of 5–7 mmol/l will necessarily lead to better control than achieving the same goal preprandially (since in the latter situation the postprandial glucose concentrations will obviously be higher).

Second, twice-daily NPH injections are a poor insulin regimen to achieve near euglycemia because there is no short- or rapid-acting insulin to blunt postprandial hyperglycemia. (The authors acknowledge this in their discussion.) How many of the eight patients in the control group were on twice-daily NPH insulin? Even the ones on MIX insulin (I assume this is a premixed insulin) are not on an optimal insulin regimen for achieving near euglycemia. One example illustrates this point. How does one adjust the MIX insulin dose in a patient whose preprandial glucose concentrations before supper are in the lower part of the goal range but whose preprandial lunch values exceed the goal range?

For both of these reasons one would expect higher postprandial glucose concentrations in the control group receiving only insulin (which is borne out in Fig. 2A) and consequently higher HbA1c levels. Hopefully these issues will not be ignored in subsequent long-term studies.

Poulsen MK, Henriksen JE, Hother-Nielsen O, Beck-Nielsen H: The combined effect of triple therapy with rosiglitazone, metformin, and insulin aspart in type 2 diabetic patients.
Diabetes Care