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When and how to addAs T2DM progresses, addition of prandial insulin will be required after basal optimisation1,2
  • The need for prandial insulin despite optimal titration of basal insulin is indicated by:
    • FBG at or close to target 5–7 mmol/l (90–126 mg/dl) but HbA1c ≥7%.
    • FBG controlled but PPBG consistently high (>8.8 mmol/l, >160 mg/dl).
    • Unacceptably frequent or severe hypoglycaemia during basal insulin titration.
Meal patterns vary among individuals with T2DM
    • Few people eat three consistent meals with limited extra snacks.
    • Many people eat one main meal.
    • Meal patterns vary from day to day.
    • Differences in physiology define blood glucose response to meals.

Therefore, the same inflexible insulin regimens applied to all individuals are often ineffective. Basal Plus strategy: a logical stepwise strategy to basal–bolus
  • Add one injection of prandial insulin , starting with the main meal.
  • Determine the main meal.
  • 'Fix postprandial hyperglycaemia'.
  • Use a flexible approach.
  • Further prandial injections can be added, progressing towards basal–bolus therapy.
Guidance for initiation and adjustment of Basal/Basal Plus regimen3
Traditional strategies to intensify insulin after basal optimisation4,5
  • Basal bolus involves one injection of basal insulin plus prandial insulin injections at each meal:
    • Perceived as the most physiological strategy – gold standard
    • But can prove difficult for patients to initiate and comply
  • Premixed insulins:
    • Perceived as convenient1 with twice-daily injections versus four-times daily with basal bolus
    • But not flexible because the fixed ratio of basal to prandial insulin requires fixed mealtimes.
Replacement insulin therapy should mimic endogenous insulin profile in type 1 Diabetes Mellitus (T1DM) and insulin-treated type 2 diabetes mellitus (T2DM)6
  • Combinations of ‘basal’ and ‘prandial’ insulin in a ‘basal–bolus’ insulin regimen are essential to maintain glycaemic control
Limitations of regular human insulin (RHI) in a basal–bolus insulin regimen7
  • Slow onset of action
  • Requires administration 30–45 minutes before a meal
  • Mismatch between injection and postprandial peak
  • Risk of interprandial hypoglycaemia
APIDRA® (insulin glulisine): A novel ‘rapid-acting’ insulin analogue Glulisine: a short-acting insulin analogues: more stable monomer and less fibril formation

LysB3 and GluB29 side chain interaction stabilizes conformation

Molecular structure of insulin glulisine [rDNA origin]: Apidra®
  • Impeded hexamer formation by LysB3.
  • Impaired but not blocked self-assembly due to GluB29.
  • Enhanced monomer stability due to a dipol bridge between GluB29 and GlyA1 replacement.
Thus insulin glulisine exists in solution in mono-dimer equilibrium without the need to be stabilized with zinc.
Insulin uptake from subcutaneous tissue: Advantages of ‘rapid-acting’ insulin glulisine8,9
Components of rapid-acting insulins
Component Function   Qualitative composition  
    Human insulin     Insulin glulisine
Insulin or insulin analogue Active ingredient 100 U/mL     100 U/mL
Metacresol Preservative +     +
Phenol Preservative -     -
Trometamol Buffering agent -     +
Disodium hydrogen phosphate Buffering agent -     -
Sodium chloride Tonicity agent -     +
Glycerol (85%) Tonicity agent +     -
Zinc Complexing agent +     -
Polysorbate 20 Stabilising agent -     +
Sodium hydroxide Alkalising agent +     +
Hydrochloric acid Acidifying agent +     +
Water for injection Solvent +     +
From human insulin, insulin lispro, insulin aspart and insulin glulisine summary product characteristics (SmPCs).
Glulisine is formulated with polysorbate 20 to reduce the unfolding monomers and prevent against fibril formation10
  • Polysorbate 20 is a dispersing agent preventing precipitation of insulin hexamer to form fibrils (1,2,3).
  • Polysorbate 20 is added to glulisine to enhance physical stability without reducing equilibria between monomer and dimer.
Key points: Apidra®11
  • A novel molecular structure with two amino acid substitutions.
  • A unique zinc-free formulation.
  • Added polysorbate 20 enhances stability and prevents fibril formation.
Pharmacokinetic and pharmacodynamic characteristics of Apidra® (insulin glulisine)
  • vs regular human insulin.
  • vs insulin lispro fibril formation.
Absorption of insulin glulisine is twice as rapid as that of regular human insulin (RHI) in T1DM12
Insulin glulisine: Earlier glucose disposal compared to regular human insulin (RHI)12
Key learning points: Apidra®
  • Provides rapid, early glucose disposal and shorter duration of action than RHI.
  • Maintains more rapid onset of action in lean to obese non-diabetic subjects.
  • Provides better control of post-meal glucose excursions in obese T2DM subjects.
Key learning points: T2DM & Apidra®
  • Better glycaemic control (HbA1c & PPBG) than RHI with NPH as basal insulin1.
  • The majority of subjects can achieve HbA1c < 7.0% with Lantus® plus Apidra® in a basal–bolus regimen.
Initiation and adjustment of insulin regimens.
  • Insulin regimens should be designed taking lifestyle and meal schedule into account.
Timing of prandial insulin injections
  • For the most effective control of PPG excursions, Apidra® should be administered immediately before meals.
  • However, as demonstrated in the 12-week study in subjects with Type 1 DM, effective prandial glucose control can be achieved with Apidra® even when it is administered immediately after a meal.
Appropriate dosing of Apidra®
  • Dose titration according to self-monitored blood glucose values at 2 hours after a meal, with a target of at least < 180 mg/dL.
  • Target sought avoiding hypoglycaemia.
  • Exercise following meals may necessitate a reduction in dose to avoid hypoglycaemia.
Summary: Apidra® – a novel ‘rapid-acting’ insulin analogue
  • The unique molecular structure provides faster absorption and onset of action, plus stability without the need for zinc.
  • Advantageous pharmacokinetic/pharmacodynamic profile.
    • More rapid absorption, onset and shorter duration of action than RHI.
    • More rapid onset of action compared to insulin lispro, independent of BMI.
  • Better glycaemic control in both T1DM and T2DM vs RHI.
  • Flexible timing of injection: either pre- or post-meal.
  • Tendency to fewer catheter occlusions and fewer unexplained hyperglycaemic episodes in pumps.
1.2.3 Study: Glargine plus 1, 2 or 3 doses of glulisine15
  • Insulin naïve (785 entered study, 343 randomized) with type 2 diabetes (A1C ≥8.0%).
  • Receiving 2 or 3 OHAs for ≥3 months (OHAs continued except sulfonylurea).

1.2.3 Study: Glargine plus 1, 2 or 3 doses of glulisine15
1.2.3 Study: Glargine plus 1, 2 or 3 doses of glulisine15
1. Woerle H. Arch Intern Med 2004;164:1627–32.
2. Monnier L and Colette C. Diabetes Metab 2006;32 (1):7-13.
3. Nathan D. et al. Diabetologia 2006;49:1711-21.
4. Rosenstock J. Clin Cornerstone 2001;4:50–64.
5. McCall A. In: Insulin Therapy. Leahy J, Cefalu W, eds. New York, NY: Marcel Dekker, Inc; 2002: p193-222.
6. Kruszynska YT, et al. Diabetologia 1987;30:16–21.
7. Wittlin SD, et al. In: Leahy JL, Cefalu WT, eds. Insulin Therapy:2002:73–85.
8. Brange J, et al. Diabetes Care 1990:13;923–54.
9. Becker RH. Diabetes Technol Ther 2007;9:109–21.
10. R. Becker; Diabetes Technology & Therapeutics Volume 9, Number 1, 20072: J.Brange, Journal of Pharmaceutical Sciences 1997; 86 (7); 517-525;3: J.DongJ.Mol. Biol 2003, 330:431-442; 4:RG Strickley, Pharmaceutical Research, 21,201-230, 2004
11. Becker RH. Diabetes Technol Ther 2007;9:109–21.
12. Becker RH, et al. Diabetes Care, published online August 3, 2007.
13. Dailey G, et al. Diabetes Care 2004;27:2363–8.
14. Johnson M, et al. ADA 2007. Abstract 2195-PO. 15. Davidson M et al. Endocr Pract 2011;Feb 16:1-9 (E-pub).


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