modern insulin : an update
DESCRIPTION
Symposium on 17th June, 2013. Presented by Dr. Jobaida Naznin (MD Final part student), Endocrinology Department, BSMMUTRANSCRIPT
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MODERN INSULINAN UPDATE
Dr. Jobaida Naznin
MD Final part Student
Department of Endocrinology
BSMMU
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Slide No 2April 11, 2023Date
What are insulin analogues?
• Structure of insulin is modified
• Pharmacokinetic properties modified to mimic physiology
• Molecular pharmacology of human insulin retained
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Slide No 3April 11, 2023Date
Normal physiological profile of serum insulin concentration
Kruszynska. Diabetologia 1987;30:16
Mealtime insulin excursions
Rapid rise; short duration
0800 1200 1600 2000 24000
10
20
30
40
50
0400
Time (h)
Seru
m in
sulin
(m
U/L
)
0800
Flat basal insulin profile
Breakfast Lunch Dinner
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April 11, 2023 4
Limitations of conventional insulins
Profiles are schematic
Intermediate-acting insulin
Soluble insulin
Sum of the added insulins
Physiological insulin profile
Seru
m insu
lin
Time
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Slide No 5April 11, 2023Date
Attempts to recreate physiological insulin secretion with basal–bolus therapy
Profiles are schematic
60
50
40
30
20
10
0
6 222181410 6
Time of day
Rapid-acting insulin
Basal insulin
Total
Pre
dic
ted p
lasm
a insu
linco
nce
ntr
ati
on p
rofile
(m
U/L
)
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Slide No 6April 11, 2023Date
Properties of ideal analogues
Properties of an ideal mealtime (bolus) analogue:• Fast onset• Short duration of action• Predictability
Properties of an ideal basal analogue:• Long duration of action• Flat profile (no peak)• Predictability
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7
Factors determining insulin absorption rate
• Insulin preparation• Dose, concentration and
volume• Physical state (solution or
suspension)
• Injection site factors• Region of injection• Injection device• Depth of injection/
injection technique• Lipodystrophy• Insulin state
- self-association- precipitation
• Bloodflow changes, e.g. - temperature- exercise
• Metabolic state, e.g. - hypoglycaemia - ketoacidosis
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Slide No 8April 11, 2023Date
Dissociation of insulin after s.c. injection
Subcutaneous tissue
Molar concentration
Diffusion
Capillary membrane
10–3 10–4 10–5 10–8
Adapted from Brange. Diabetes Care 1990;13:923
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Slide No 9April 11, 2023Date
Currently available insulin analogues
Generic name Trade name Manufacturer
Rapid-acting analogues
Insulin aspart NovoRapid® Novo Nordisk
Insulin lispro Humalog® Eli Lilly
Insulin glulisine Apidra® sanofi aventis
Basal analogues
Insulin detemir Levemir® Novo Nordisk
Insulin glargine Lantus® sanofi aventis
Biphasic premixed analogues
Biphasic insulin aspart
NovoMix® Novo Nordisk
Biphasic insulin lispro
Humalog® Mix Eli Lilly
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Slide No 10April 11, 2023Date
Rapid-acting insulin analogues
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Slide No 11April 11, 2023Date
Insulin lispro
Glu
Thr
Lys
ThrTyr Phe Phe Gly Arg
GluGly
Cys
Val
Leu
Tyr
Leu
Ala
Val
Leu
His
Ser
GlyCysLeuHisGlnAsnValPheB1
Asn CysTyr
Asn
Glu
Leu
Gln
Tyr
LeuSerCysIleSerThrCys
Cys
Gln
Ile
Gly
B28B30Pro
Glu
Val
A21A1
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Slide No 12April 11, 2023Date
Insulin aspart
Glu
Thr
Lys
ThrTyr Phe Phe Gly Arg
GluGly
Cys
Val
Leu
Tyr
Leu
Ala
Val
Leu
His
Ser
GlyCysLeuHisGlnAsnValPheB1
Asn CysTyr
Asn
Glu
Leu
Gln
Tyr
LeuSerCysIleSerThrCys
Cys
Gln
Glu
Val
Ile
Gly
A21
A1
B28B30
AspPro
Asp
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Slide No 13April 11, 2023Date
Insulin glulisine
Glu
Thr
Lys
ThrTyr Phe Phe Gly Arg
GluGly
Cys
Val
Leu
Tyr
Leu
Ala
Val
Leu
His
Ser
GlyCysLeuHisGlnAsnValPheB1
Asn CysTyr
Asn
Glu
Leu
Gln
Tyr
LeuSerCysIleSerThrCys
Cys
Gln
Glu
Val
Ile
Gly
A21A1
B29B30
Glu
Pro
Lys
B3
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April 11, 2023 14
Action profiles of insulin and rapid-acting insulin analogues
Onset (min) Peak (min) Duration (h)
Regular human insulin1
30–60 120–180 6–8
Insulin lispro 152 30–702 25
Insulin aspart 10–203 40–903 3–5
Insulin glulisine 204 555 3–5
1Oiknine. Drugs 2005;65:325–40
2Prescribing information, insulin lispro
3Prescribing information, insulin aspart
4Becker. Exp Clin Endocrinol Diabetes 2005;113:292–7
5Becker. Diabetes 2004;53(Suppl.2):A119
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April 11, 2023 15
Insulin aspart: safety issues
Insulin receptor affinity and mitogenicity
Mitogenic potency less than human insulin
Hypoglycaemia Incidence similar or lower than with human insulin
Hypoglycaemic awareness Physiological responses were preserved and equivalent for aspart compared with human insulin
Immunogenicity Transient increase in antibodies. No correlation with efficacy or safety
Adverse events Similar to soluble human insulin
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Slide No 16April 11, 2023Date
Basal insulin analogues
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Slide No 17April 11, 2023Date
Strategies for protraction
Modification of isoelectric point: precipitation at pH 7.4• Insulin glargine
Acylation with hydrophobic residues (and albumin binding)• Insulin detemir
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Slide No 18April 11, 2023Date
Insulin glargine
Glu
Thr
Lys
ThrTyr Phe
Phe Gly ArgGlu
Gly
Cys
Val
Leu
Tyr
Leu
Ala
Val
Leu
His
Ser
GlyCysLeuHisGlnAsnValPheB1
Asn CysTyr
Asn
Glu
Leu
Gln
Tyr
LeuSerCysIleSerThrCys
Cys
Gln
Glu
Val
Ile
Gly
A21
A1 B30
Gly
ArgPro
Arg
+
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Slide No 19April 11, 2023Date
InsulinInsulin detemir
Thr
Glu
Lys
ValPhe
Asn
Glu
Leu
Gln
Tyr
LeuSerCysIleSerCys
Cys
Gln
Glu
Val
Ile
GlyTyr
CysAsnLys
ProThr
TyrPhe Phe ArgGly
GluGly
Cys
Val
Leu
Tyr
Leu
Ala
Val
Leu
His
SerGly
Cys
Asn Gln LeuHis
C14 fatty acid chain
(Myristic acid)
Thr
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April 11, 2023 20
Action profiles of insulin and basal analogues
Onset (h) Peak (h) Duration (h)
NPH insulin1 1–2 5–7 13–18
Insulin glargine
1–21 No peak2 20–301
Insulin detemir3
1–23 No peak3 244
1Oiknine. Drugs 2005;65:325–40 3Prescribing information, insulin detemir
2Prescribing information, insulin glargine 4Heise. Diabetes Obes Metab 2007;9(8):648–59
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April 11, 2023 21
Insulin detemir: safety issues
Insulin receptor affinity and mitogenicity
Receptor affinity and mitogenic potency less than human insulin
Safety of albumin binding of insulin detemir
Insulin detemir has negligible impact on the binding capacity of the serum albumin pool
Hypoglycaemia Incidence of hypoglycaemia, especially nocturnal hypoglycaemia, generally lower than with human insulin
Immunogenicity No immunogenicity concerns
Adverse events Similar to NPH
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April 11, 2023 22
Key benefits:
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April 11, 2023 23
Levemir® gives you More
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Slide No 24April 11, 2023Date
Biphasic premixed insulin analogues
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Slide No 25April 11, 2023Date
Benefits of dual-release insulin replacement
1. Mimics physiological insulin release• Early release of rapid-acting insulin targets
postprandial glucose• Delayed release of intermediate-acting insulin fulfils
basal insulin requirement
2. Reduces hypoglycaemic risk
3. Improves HbA1c
4. Simplifies dosing• Option of postprandial dosing
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Slide No 26April 11, 2023Date
Biphasic premixed insulin analogues
NovoM
ix® 3
0
Rapid-acting insulin aspart
Pre
mix
ed
su
sp
en
sio
n
Intermediate-acting protamine-crystallised
insulin aspart
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Slide No 27April 11, 2023Date
Biphasic premixed insulin analogues
• 30% soluble aspart rapid absorption covers prandial insulin needs
• 70% protamine-crystallised aspart slower absorption addresses basal insulin needs
• Fewer injections
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Slide No 28April 11, 2023Date
• Mean prandial glucose increment lower in NovoMix® 30 group (p < 0.0001)
• Patients receiving NPH monotherapy benefit from switching to NovoMix® 30 (bid)
NovoMix® 30 offers better glycaemic control than NPH
Christiansen JS et al. Diabetes, Obesity & Metabolism 2003;5(6):445-452
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Ad
van
cem
en
ts
Animal insulin preparations
Recombinant human insulin
Rapid-acting insulin
analogues
Basal insulin
analogues
New-generationinsulin analogues/
combination insulins
Isolation of insulin
(Banting & Best)
Time1922
1977
Biphasicinsulin
Degludec
DegludecPlus
1990s
2000s
Advancing insulin therapyTowards a new stage in the evolving story of insulin therapy
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Unique molecular engineering:degludec molecular structure
s
s
s
FF VV NN QQ HH LL CC GG SS HH LL VV EE AA LL YY LL VV CC GG EE RR GG FF FF YY TT PP
GG II VV EE QQ CC TT SS II CC SS LL YY QQ LL EE NN YY CC NNCC
s
s s
A chain
B chainKK
NH
O
OH
O NH
O
OH
OHexadecandioyl
L--Glu
desB30 Insulin
LysB29Nε-hexadecandioyl-γ-Glu desB30 human insulinGludec de
TT
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Hexamer(36 kDa)
Dimer Monomer(6 kDa) Blood vessel
Ce
ll
Engineering insulin analogues
Di-Hexamer(72 kDa)
Multi-Hexamer(>5000 kDa)
Rapid actingLong acting
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Insulin degludec: summary I
• The protraction mechanism of insulin degludec involves:
• Multi-hexamer formation upon injection
• Slow and stable release of monomers
• This property is critically dependent on the spacer and side chain used
• This design is expected to provide ultra-long and flat PK/PD profiles
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Insulin degludec has a flat and stable insulin action
Nosek et al. IDF 2011:P-1452 NN1250-1987; Diabetologia 2011;54(suppl. 1):S429 (1055-P); Diabetes 2011;60(suppl. 1A):LB14.
T2DM, N=49, 26h EG clamp on days 6 and 12, 120 min PK sampling
Insulin-treated Type 2 diabetes (n=49) 0.4, 0.6, 0.8 U/kg once daily for 6 days
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Insulin degludec: summary II
• In Steady State: Input = Output
• For insulin degludec: Steady state level is reached in 2–3 days
• Insulin degludec provides an ultra long duration of action that leads to a flat and smooth pharmacokinetic and pharmacodynamic profile
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HbA1c over time
IDeg Flexible/IGlar Non-inferior
IDeg Flexible/IDeg FixedNon-inferior
0
FAS; LOCFComparisons: Estimates adjusted for multiple covariates
IDeg Flexible (n=229)
IDeg Fixed (n=228)
IGlar (n=230)
NN1250-3668; IDeg Flexible vs IDeg Fixed and IGlar in T2. Submitted for ADA 2011
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Degludec medical communication platform
Novel protraction mechanism
Ultra-long action (flat, stable & consistent)
Low rateof hypos
(also at low FPG)
Flexibledosing
Excellentefficacy
Convenienttrue ODdosing
FlexTouch®
Up to 160U
Insu
lin s
afe
ty
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Insulin degludec: summary III
Excellent improvement in HbA1c
Superior FPG reductionDegludecPlus
Achieveglycaemic control
Efficacy
Less hypoglycaemia
Reduction of up to 36% in nocturnal hypoglycaemia DegludecPlus
Avoid hypos Safety
Dosing flexibility: administration any time on any dayDegludecPlus
Flexibility Convenience
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Slide No 38April 11, 2023Date
Thank You