Review ArticleInsulin Stacking Versus Therapeutic Accumulation: Understanding the Differences
Section snippets
INTRODUCTION
Excessive accumulation of insulin in the circulation, often referred to as “stacking,” is typically discussed in conjunction with the administration of rapid-acting insulin to correct hyperglycemia. Hirsch 1., 2. described stacking as “the practice of providing correctional doses of insulin before a prior dose of prandial insulin (or the peak action of neutral protamine Hagedorn, [NPH]) has had its full effect,” whereas Bequette (3), in the context of continuous subcutaneous insulin infusion,
GOALS OF BASAL INSULIN THERAPY
The goal of basal insulin replacement therapy is to reproduce the physiologic 24-hour secretion of insulin that occurs naturally via continuous small pulses from pancreatic beta-cells, keeping glucose levels stable in the fasting state. Intermediate-acting basal insulins, such as NPH, do not reproduce the endogenous (physiologic) glucose-lowering effect needed for proper basal insulin replacement due to substantial (and unwanted) peaks in biologic activity and insufficient duration of biologic
INSULIN PHARMACOKINETICS
Addressing clinical concerns about insulin accumulation when duration of action exceeds 24 hours requires clarification of how basal insulin is absorbed and eliminated and how it reaches a stable, steady state following repeated once-daily dosing. The gold standard for obtaining data describing insulin absorption, elimination, and plasma concentration over time (i.e., PK) and the glucose-lowering effect (i.e., PD) is the glucose-clamp study 14., 15., 24., 32.. In these studies, fasted subjects
STEADY STATE AND HALF-LIVES OF BASAL INSULINS
The steady-state principles described above have been demonstrated in a PK/PD study in people with type 1 diabetes using the long-acting basal insulin analog, insulin detemir (25). In a glucose clamp study involving 25 subjects, insulin detemir was dosed twice daily over 7 to 14 days (mean daily dose, 0.36 ± 0.11 U/kg). PK levels increased from zero to a mean maximum level of 2,217 ± 960 pmol/L after the second injection on the first treatment day (25). Thereafter, however, there was no
CONCLUSION
Steady-state accumulation is a normal part of the PK process that enables a long-acting insulin to reach a stable, steady-state condition with subsequently minimal fluctuation in insulin levels, and therefore, glucose-lowering activity. This should not be confused with the potentially dangerous acute overaccumulation (stacking) that occurs when a corrective dose of rapid-acting insulin is administered to correct hyperglycemia before the previous dose has been eliminated. Basal insulins with an
DISCLOSURE
Dr. Luigi F. Meneghini is a consultant for Novo Nordisk and Sanofi-Aventis and is on advisory boards for Novo Nordisk and Halozyme. He receives research support from Pfizer, MannKind, Boehringer Ingelheim, and Sanofi-Aventis. Dr. Tim Heise’s institution received research support from Astellas, Bayer, Becton-Dickinson, Biocon, Biodel, Boehringer Ingelheim, GlaxoSmithKline, Roche, Johnson & Johnson, Eli Lilly, Novo Nordisk, Prosidion, Sanofi-Aventis, and SkyePharma. Dr. Heise is on the advisory
ACKNOWLEDGMENT
We thank Gabrielle Parker and Gary Patronek for editing and writing assistance, supported by Novo Nordisk.
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