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Apidra®

 

When and how to add prandial insulin to basal insulin + OADs in Type 2 diabetes

 

As Type 2 diabetes progresses, addition of prandial insulin will be required after basal optimisation

  • 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)1
    • Unacceptably frequent or severe hypoglycaemia during basal insulin titration

Meal patterns vary among individuals with Type 2 diabetes

  • 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 would not be physiological

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 regimen

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* Basal insulin therapy considered optimised if FBG <6.1 mmol/L (<110 mg/dL) with average dose not exceeding 0.7 IU/kg

Traditional strategies to intensify insulin after basal optimisation

  • Basal bolus involves one injection of basal insulin plus prandial insulin injections at each meal:1
    • Perceived as the most physiological strategy - gold standard
    • But can prove difficult for patients to initiate and comply
  • Premixed insulins:
    • Perceived as convenient,1 with twice-daily injections versus four-times daily with basal bolus2
    • 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)

  • Combinations of 'basal' and 'prandial' insulin in a 'basal-bolus' insulin regimen are essential to maintain glycaemic control

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Limitations of regular human insulin (RHI) in a basal-bolus insulin regimen

  • 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 analogue,

Stable monomer

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LysB3 and GluB29 side chain interaction stabilises conformation

Molecular structure of insulin glulisine [rDNA origin]: Apidra®

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  • 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 stabilised with zinc.

Insulin uptake from subcutaneous tissue: Advantages of 'rapid-acting' insulin glulisine

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Components of rapid-acting insulins

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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 formation

  • 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 for Apidra®

  • 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

Absorption of insulin glulisine is twice as rapid as that of regular human insulin (RHI) in Type 1 diabetes

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Insulin glulisine: Earlier glucose disposal compared to regular human insulin (RHI)

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Key learning points: Apidra®

  • Provides rapid, early glucose disposal and shorter duration of action than RHI (However, at all doses, insulin glulisine was about twice as rapidly absorbed as RHI (INS-AUC0-2h: 3,792, 6,676, and 12,992 vs. 2,211, 3448, and 5,792 U.min.ml -1  ; P<0.05) and reached maximal serum concentrations in about one-half the time(INS-Tmax: 47,57, and 72 vs. 82, 104, and 119min; P<0.05)
  • Corresponding glucose disposition for insulin glulisine was twice as large within 2 h after injection than with RHI (GIR-AUC0-2h: 314,491, and 536 vs. 127,219, and 294 mg/kg; P<0.05) but was similar in extent on completion (GIR-AUCtotal: 499,1,090, and 1,476 vs. 416, 1,076, and 1,555 mg/kg; P=NS).
  • Provides better control of post-meal glucose excursions in obese Type 2 diabetes subjects

Key learning points: Type 2 diabetes and 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 regimen2

Initiation and adjustment of insulin regimens.

Insulin regimens should be designed taking lifestyle and meal schedule into account.

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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 diabetes, 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
    • Faster absorption, onset and shorter duration of action than RHI
    • Faster onset of action compared to insulin lispro, independent of BMI
  • Better glycaemic control in both Type 1 diabetes and Type 2 diabetes vs RHI
  • Flexible timing of injection: either pre- or post-meal

1.2.3 Study: Glargine Plus 1, 2 or 3 Doses of Glulisine

Subjects:

  • Insulin naïve (785 entered study, 343 randomised) with Type 2 diabetes (A1C ≥8.0%)

  • Receiving 2 or 3 OADs for ≥3 months (OADs continued except sulfonylurea)

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Davidson M et al. Endocr Pract 2011;Feb 16:1-9 (E-pub).

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A1C in all subjects (n=785) = 9.8 at run-in and 7.3 at randomisation

 

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References

Woerle H. Arch Intern Med 2004;164:1627-32.
Monnier L and Colette C. Diabetes Metab 2006;32 (1):7-13.
Adapted from Nathan D. et al. Diabetologia 2006;49:1711-21.
Rosenstock J. Clin Cornerstone 2001;4:50-64.
McCall A. In: Insulin Therapy. Leahy J, Cefalu W, eds. New York, NY: Marcel Dekker, Inc; 2002: p193-222.
Adapted from Kruszynska YT, et al. Diabetologia 1987;30:16-21.
Wittlin SD, et al. In: Leahy JL, Cefalu WT, eds. Insulin Therapy:2002:73-85.
1: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
Becker RH. Diabetes Technol Ther 2007;9:109-21.
INS-AUC= insulin infusion rate - area under the curve Becker RH, et al. Diabetes Care, published online August 3, 2007. Reproduced with permission.
GIR-AUC=glucose infusion rate - area under the curve Becker RH, et al. Diabetes Care, published online August 3, 2007.
Dailey G, et al. Diabetes Care 2004;27:2363-8
Johnson M, etal. ADA 2007. Abstract 2195-PO.
Davidson M et al. Endocr Pract 2011;Feb 16:1-9 (E-pub).
Riddle MC et al. Diabetes July 2011;60:A113;
Rosenstock J et al. Diabetes July 2011;60:A20.

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