I congratulate Porcellati et al. (1) for a long-awaited comparison of glargine and detemir pharmacodynamics. They clearly show that the duration of action for glargine (but not detemir) is greater than 24 h.
One of the major differences can be seen in the glucose infusion rate (GIR). At 12 h postinjection, glargine has higher area under the curve (AUC) GIR remaining (42 vs. 15%). The presence of GIR, a marker of insulin-mediated glucose disposal, proves the longer pharmacodynamic effect of glargine.
Even so, the report of the insulin activity profile is confusing. The authors state that they “modified the insulin activity profile formula by Radziuk et al.,” but the description is incomplete. The formula that they used has three components. The first component, the rate of insulin infusion, was not applicable after the first 2 h and remained zero. The second, plasma glucose concentration, always equaled 100% for glargine because the target was equal to achieved glucose. The third factor, the rate of GIR, changed from ∼1.5 mg · kg−1 · min−1 to 0.5 mg · kg−1 · min−1 at the end of the clamp. If this component was added to the second, how could the activity remain at 100%? For this to happen, the rate of GIR would have to equal zero at all times.
The importance of clarifying this point is that the figure showing glargine as having 100% insulin activity throughout the clamp may mislead the readers to think that glargine has a flat action profile. This is clearly not the case, and the author's discussion omits the following: 1) If glargine was studied under steady-state condition, why was there a 150% difference between the GIR in the first 6 compared with the last 6 h? 2) If the glucodynamic profile shows that the AUC GIR for glargine is 57 vs. 43% when comparing the first 12 h with the last 12 h (not quite half and half), was this difference magnified between the first to the last 6 h? 3) Based on the dawn phenomenon and experience with continuous subcutaneous insulin infusions, one expects a higher insulin requirement in early morning, manifested by a lower GIR. Why was the opposite found?
Based on this pharmacodynamic profile, the following practical questions deserve further study: 1) Do patients with type 1 diabetes and nocturnal hypoglycemia fare better with morning dosing? 2) Is titration based on fasting readings affected by the timing of glargine injection in type 1 diabetic subjects? 3) Does glargine have the same pharmacodynamics when used in type 2 diabetic subjects at high doses? Is the difference in the glucodynamic effect for the last 6 h, compared with the first 6 h, magnified?
Until these questions are answered, recognizing the imperfections of all available insulins will improve patient care, especially for those who fail the usual insulin titration algorithm.
