title: Insulin stacking versus therapeutic accumulation: understanding the differences.
abstract: OBJECTIVE
  The build-up in insulin levels following repeated injection of prandial insulin at close intervals--referred to as insulin stacking--can increase the risk of hypoglycemia. With the development of basal insulins with a half-life > 24 hours and a duration of action > 40 hours, clinicians may be concerned about stacking when these long-acting formulations are administered once daily. The objective of this review is to clarify the difference between inappropriate insulin stacking when shorter-acting insulin formulations are repeatedly used to correct hyperglycemia and the appropriate accumulation of long-acting insulin formulations dosed to steady-state pharmacokinetic (PK) profiles.
  
  
  METHODS
  Relevant literature on insulin stacking, glucose-clamp studies, and clinical studies of insulin, in conjunction with the clinical experience of the authors, were used to present an overview of insulin PK properties and the effects of appropriate and inappropriate dosing intervals on steady-state conditions and likely clinical outcomes.
  
  
  RESULTS
  Clinical studies confirm theoretical PK principles showing that unwanted insulin stacking (excessive concentrations) for basal insulin can be avoided by following recommended dosing and titration algorithms. Long-acting basal insulins need more time to reach steady state than shorter-acting basal insulins but then show reduced peak-trough fluctuations, translating into more consistent biologic action over a 24-hour period.
  
  
  CONCLUSIONS
  The unwanted stacking and consequent hypoglycemia that can occur when correctional doses of rapid-acting insulin are administered at close intervals does not occur when long-acting basal insulins are dosed in appropriate amounts and adjusted at appropriate time intervals (e.g., insulin stacking, insulin administration, diabetes, ultralong duration of action, hypoglycemia every three or more days), allowing for pharmacologic steady-state accumulation.
authors.affiliation: Profil, Neuss, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Heise
authors.affiliation: Miller School of Medicine, University of Miami, Miami, Florida.
authors.forename: Luigi F
authors.initials: LF
authors.lastname: Meneghini
mesh_terms: D006207:Half-Life; D006801:Humans; D007003:Hypoglycemia / Q000209:etiology; D007328:Insulin / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: D007328:Insulin