Diabetes Care
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Diabetes Care 31:e17 2008
DOI: 10.2337/dc07-2234
© 2008 by the American Diabetes Association
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Online Letters: Comments and Responses

Comparison of Pharmacokinetics and Dynamics of the Long-Acting Insulin Analogs Glargine and Detemir at Steady State in Type 1 Diabetes: a Double-Blind, Randomized, Crossover Study

Response to Banarer

Francesca Porcellati, MD, Paolo Rossetti, MD, Geremia B. Bolli, MD and Carmine G. Fanelli, MD

From the Department of Internal Medicine, Section of Internal Medicine, Endocrinology and Metabolism, University of Perugia, Perugia, Italy

Address correspondence to Prof. Geremia B. Bolli, Department of Internal Medicine, Endocrinology and Metabolism, University of Perugia, Via E. Dal Pozzo 06126 Perugia, Italy. E-mail: gbolli{at}unipg.it

We thank Dr. Banarer (1) for his appreciation of our work (2) and for the opportunity to discuss his criticism.

The formula we used to describe the insulin activity profile was constructed to emphasize the ability of a basal insulin preparation to maintain plasma glucose at the target value during fasting, which is the clinical target of a basal insulin preparation. Accordingly, the second variable of the formula, plasma glucose concentration, was given greater power. The impact of the glucose infusion rate (GIR) variable was deliberately minimized by adjusting minute-by-minute GIR for the total GIR. We do not believe that our figure misleads readers, since glargine maintains plasma glucose concentration constant at the target throughout our study; rather, this information simplifies the interpretation of sometimes complicated pharmacokinetics and pharmacodynamics of clamp studies.

We would like to respond to Dr. Banarer on a point-by-point basis: 1–2) Even under steady-state condition, there is variability in GIR during clamp studies. In addition, plasma free fatty acid increments during the last part of the study, due to prolonged fasting along with initial waning of insulin action, may result in reduced GIR. 3) Based on our study, it is not possible to derive information about the dawn phenomenon because several confounding variables (insulin dose, insulin kinetics changing over time, role of substrates, omission of the evening meal, and prolonged fasting) come into play.

With regard to morning dosing, we agree that it is an option when nocturnal hypoglycemia limits titration of basal insulin injected in the evening; however, we favor evening dosing because of steady-state activity at waking-up time. Concerning titration, while it is likely that titration of glargine may be affected by the time of injection, this was not the aim of our clamp study. Finally, with regard to type 2 diabetes, we are aware of only one study in which 0.8 and 1.6 units/kg were administered during 24-h clamp studies performed by using the biostator (3).

We agree with Dr. Banarer's final considerations. However, we believe that our formula of insulin activity may be useful to interpret pharmacokinetic and pharmacodynamic clamp data of a given insulin preparation by taking into account not only GIR, which is the pharmacodynamic marker, but also the more clinically relevant information given by plasma glucose and its deviations from the target value.

References

  1. Banarer S: Comparison of pharmacokinetics and dynamics of the long-acting insulin analogs glargine and detemir at steady state in type 1 diabetes: a double-blind, randomized, crossover study (Letter). Diabetes Care 31:e16, 2008. DOI: 10.2337/dc07-2062[Free Full Text]
  2. Porcellati F, Rossetti P, Busciantella NR, Marzotti S, Lucidi P, Luzio S, Owens DR, Bolli GB, Fanelli CG: Comparison of pharmacokinetics and dynamics of the long-acting insulin analogs glargine and detemir at steady state in type 1 diabetes: a double-blind, randomized, crossover study. Diabetes Care 30:2447–2452, 2007[Abstract/Free Full Text]
  3. Klein O, Lynge J, Endahl L, Damholt B, Nosek L, Heise T: Albumin-bound basal insulin analogues (insulin detemir and NN344): comparable time-action profiles but less variability than insulin glargine in type 2 diabetes. Diabetes Obes Metab 9:290–299, 2007[Medline]

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This Article
Right arrow Extract Freely available
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Right arrow Articles by Porcellati, F.
Right arrow Articles by Fanelli, C. G.
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PubMed
Right arrow Articles by Porcellati, F.
Right arrow Articles by Fanelli, C. G.
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