2. Slide No 2June 18, 2013Date
What are insulin analogues?
• Structure of insulin is modified
• Pharmacokinetic properties modified to mimic
physiology
• Molecular pharmacology of human insulin
retained
3. Slide No 3June 18, 2013Date
Normal physiological profile of serum
insulin concentration
Kruszynska. Diabetologia 1987;30:16
Mealtime insulin excursions
Rapid rise; short duration
0800 1200 1600 2000 2400
0
10
20
30
40
50
0400
Time (h)
Seruminsulin(mU/L)
0800
Flat basal insulin profile
Breakfast Lunch Dinner
4. June 18, 2013 4
Limitations of conventional insulins
Profiles are
schematic
Intermediate-acting insulin
Soluble insulin
Sum of the added insulins
Physiological insulin profile
Seruminsulin
Time
5. Slide No 5June 18, 2013Date
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
Predictedplasmainsulin
concentrationprofile(mU/L)
6. Slide No 6June 18, 2013Date
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
7. 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
8. Slide No 8June 18, 2013Date
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
9. Slide No 9June 18, 2013Date
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
11. Slide No 11June 18, 2013Date
Insulin lispro
Glu
Thr
Lys
Thr
Tyr
Phe
Phe Gly Arg
Glu
Gly
Cys
Val
Leu
Tyr
Leu
Ala
Val
Leu
His
Ser
Gly
Cys
Leu
HisGlnAsnValPheB1
Asn Cys
Tyr
Asn
Glu
Leu
Gln
Tyr
Leu
Ser
CysIleSerThrCys
Cys
Gln
Ile
Gly
B28B30
Pro
Glu
Val
A21
A1
12. Slide No 12June 18, 2013Date
Insulin aspart
Glu
Thr
Lys
Thr
Tyr Phe
Phe Gly Arg
Glu
Gly
Cys
Val
Leu
Tyr
Leu
Ala
Val
Leu
His
Ser
Gly
Cys
Leu
HisGlnAsnValPheB1
Asn Cys
Tyr
Asn
Glu
Leu
Gln
Tyr
Leu
Ser
CysIleSerThrCys
Cys
Gln
Glu
Val
Ile
Gly
A21
A1
B28B30
Asp
Pro
Asp
13. Slide No 13June 18, 2013Date
Insulin glulisine
Glu
Thr
Lys
Thr
Tyr Phe
Phe Gly Arg
Glu
Gly
Cys
Val
Leu
Tyr
Leu
Ala
Val
Leu
His
Ser
Gly
Cys
Leu
HisGlnAsnValPheB1
Asn Cys
Tyr
Asn
Glu
Leu
Gln
Tyr
Leu
Ser
CysIleSerThrCys
Cys
Gln
Glu
Val
Ile
Gly
A21
A1
B29B30
Glu
Pro
Lys
B3
15. June 18, 2013 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
17. Slide No 17June 18, 2013Date
Strategies for protraction
Modification of isoelectric point: precipitation at pH 7.4
• Insulin glargine
Acylation with hydrophobic residues (and albumin binding)
• Insulin detemir
18. Slide No 18June 18, 2013Date
Insulin glargine
Glu
Thr
Lys
Thr
Tyr Phe
Phe Gly Arg
Glu
Gly
Cys
Val
Leu
Tyr
Leu
Ala
Val
Leu
His
Ser
Gly
Cys
Leu
HisGlnAsnValPheB1
Asn Cys
Tyr
Asn
Glu
Leu
Gln
Tyr
Leu
Ser
CysIleSerThrCys
Cys
Gln
Glu
Val
Ile
Gly
A21
A1
B30
Gly
Arg
Pro
Arg
+
19. Slide No 19June 18, 2013Date
Insulin
Insulin detemir
Thr
Glu
Lys
ValPhe
Asn
Glu
Leu
Gln
Tyr
Leu
SerCysIleSerCys
Cys
Gln
Glu
Val
Ile
Gly
Tyr
CysAsnLys
Pro
Thr
Tyr
Phe
Phe
ArgGly
Glu
Gly
Cys
Val
Leu
Tyr
Leu
Ala
Val
Leu
His
Ser
Gly
Cys
Asn Gln LeuHis
C14 fatty acid chain
(Myristic acid)
Thr
21. June 18, 2013 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
30. 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 chain
KK
N
H
O
OH
O NH
O
OH
O
Hexadecandioyl
L-γ-Glu
desB30 Insulin
LysB29Nε-hexadecandioyl-γ-Glu desB30 human insulinGludec de
TT
32. 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
33. 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
34. 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
35. HbA1c over time
IDeg Flexible/IGlar
Non-inferior
IDeg Flexible/IDeg Fixed
Non-inferior
0
FAS; LOCF
Comparisons: 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
36. Degludec medical communication
platform
Novel protraction mechanism
Ultra-long action (flat, stable & consistent)
Low rate
of hypos
(also at low FPG)
Flexible
dosing
Excellent
efficacy
Convenient
true OD
dosing
FlexTouch®
Up to 160U
Insulinsafety
37. Insulin degludec: summary III
Excellent improvement in HbA1c
Superior FPG reductionDegludecPlus
Achieve
glycaemic
control
Efficacy
Less hypoglycaemia
Reduction of up to 36% in
nocturnal hypoglycaemiaDegludecPlus
Avoid
hypos Safety
Dosing flexibility: administration
any time on any dayDegludecPlus
Flexibility Convenience
The physiological insulin profile comprises a basal component with meal-related peaks References Kruszynska. Diabetologia 1987;30:16
The pharmacokinetics of injected insulin do not match the physiological secretion profile. Bolus insulins (e.g. soluble human insulin) are absorbed too slowly and their effect lasts too long Basal insulins (e.g. NPH, lente insulin) are absorbed too quickly, their profile is not flat enough, and absorption rates are variable As a result, there is a risk of hypoglycaemia, and it is difficult to refine treatment
Basal–bolus therapy attempts to mimic the physiological insulin profile. The theory is that a rapidly-absorbed insulin preparation will have a rapid onset and short duration of action and thereby mimic the prandial insulin response if taken before meals, while a longer-acting preparation with protracted absorption will substitute the basal insulin output In practice, however, available preparations of human insulin are poorly able to reproduce such a profile. Soluble human insulins are absorbed with too protracted an action to accurately recreate the prandial insulin response, while basal products such as NPH insulin poorly recreate the low constant and consistent profile of overnight insulin secretion
Among these factors, self-association is one that is related to the properties of the insulin molecule. Insulin analogues were developed on the principle of changing the rate of association/dissociation
Human regular insulin tends to associate into dimers and hexamers. However, monomers are the form recognised by the insulin receptor The rapid-acting analogues were developed to dissociate more rapidly after s.c. injection The b asal analogues, on the other hand, were designed to be absorbed at a protracted, steady absorption rate References Figure adapted from Adapted from Brange. Diabetes Care 1990;13:923
Three types of insulin analogues are currently available, as shown Some of these analogues have slightly different names in the USA: NovoRapid ® is NovoLog ® , and NovoMix ® is NovoLog ® Mix
In lispro, the two amino acids at positions 28 and 29 of the insulin B chain have been transposed. This change disrupts the strength of the bond between monomer units in the insulin dimer
In aspart, the proline residue at position B28 has been replaced with an asparagine residue. As with lispro, this change disrupts the strength of the bond between monomer units in the insulin dimer
In glulisine, residues at positions B3 and B29 have been replaced as shown
Typical action profiles for human insulin and the rapid-acting analogues are shown. These values are from studies in healthy volunteers or patients with type 1 diabetes, as available The values quoted in different references may vary somewhat according to the conditions of the study. Nevertheless, it is clear that the analogues reach a peak concentration faster than human insulin, and that their activity is also of shorter duration References Oiknine . Drugs 2005;65:325 – 40 Prescribing information, Insulin lispro. Available at: www.emea.europa.eu/humandocs/PDFs/EPAR/Novorapid/H-088-PI-en.pdf. Accessed 18 February 2008 Prescribing information, Insulin aspart. Available at: www.emea.europa.eu/humandocs/PDFs/EPAR/Novorapid/H-258-PI-en.pdf. Accessed 18 February 2008 Becker . Exp Clin Endocrinol Diabetes 2005;113:292 – 297 Becker . Diabetes 2004;53(Suppl. 2):A119
All the rapid-acting analogues have undergone studies to establish their safety with respect to the aspects shown, but we will focus on aspart Insulin aspart has been shown to be safe in the following special populations: patients with hepatic or renal impairment, obese patients, children and adolescents, pregnant women. These will be covered in more detail in Session 9 References Mitogenic potency Kurtzhals P . Diabetes 2000;49:999 – 1005 Hypoglycaemic awareness Frier. Diabet Metab Res Rev 2000;16:262 – 268 Immunogenicity Lindholm . Diabetes Care 2002;25:876 – 882 Adverse events Prescribing information, Novo Nordisk
When insulin is injected into subcutaneous tissue, it forms a depot. It must then pass through capillary walls into the circulation, and from there must pass back through capillary walls to reach the interstitial fluid of the target tissues. Thus, the route to the receptor involves passage through three compartments, giving three potential sites of protraction One strategy has been to modify the isoelectric point such that the insulin is liquid upon injection (when in a suitable medium), but crystallises into a slowly-absorbed precipitate depot in the neutral pH of the subcutaneous environment. This method has been used with some success with insulin glargine, which has a very protracted action, but variability may still be a problem – perhaps as a result of physical differences in the nature of precipitation from one injection to another Another strategy has been to acylate fatty acid residues to the insulin molecule, enabling the resulting analogue to bind to albumin. This approach was used in the development of insulin detemir
Amino acid changes in glargine shift its isoelectric point (pH 5.4 → 6.7). It is presented in an acidic solution (pH 4.0) and forms a microprecipitate in neutral subcutis The result is slow dissolution and absorption, but precipitation and the subsequent dissolution are unpredictable processes
Insulin detemir has a C14 fatty acid attached to a Lys residue at B29. The fatty-acid side chains enable insulin detemir to bind to albumin. This is possible in all three compartments between injection and receptor interaction – in the s.c. depot, in the circulation and in the interstitium of the target tissue itself. Thus, there are three potential sites where protraction of action could take place The acylation with myristic acid stabilises hexamers, allows dihexamerisation, and allows albumin binding Absorption is slow due to prolonged self-association and albumin binding at the injection site Dynamic, reversible plasma albumin binding ‘buffers’ changes in the absorption rate
Glargine and detemir both have a longer duration of action than NPH. References Oiknine . Drugs 2005;65:325 – 40 Prescribing information, Insulin glargine. Available at: www.emea.europa.eu/humandocs/PDFs/EPAR/Lantus/H-284-PI-en.pdf. Accessed 18 February 2008 Prescribing information, Insulin detemir. Available at: www.emea.europa.eu/humandocs/PDFs/EPAR/levemir/H-528-PI-en.pdf. Accessed 18 February 2008 Heise. Diabetes Obes Metab 2007;9(8):648 – 59
Safety issues have been investigated for detemir as shown, and no cause for clinical concern has been noted Special populations: small studies have suggested that neither hepatic nor renal impairment affect the pharmacokinetics of detemir in a clinically significant way. Detemir has been shown to be effective and tolerable in children and adolescents. Detemir has not been studied in pregnant women. These issues will be covered more fully in Session 10
Premixed insulin analogues contain just one rapid-acting insulin analogue, together with enough protamine to crystallise a certain proportion For example, NovoMix ® 30 is a modern premixed insulin analogue, but contains just one insulin: insulin aspart. NovoMix ® 30 contains enough protamine to crystallise 70% of the insulin aspart, leaving 30% soluble aspart Similarly, Humalog ® Mix 25 contains insulin lispro in a formulation in which 25% is soluble lispro and 75% is protaminated The soluble rapid-acting insulin analogue and intermediate-acting, protamine-crystallised insulin analogue in premixes allow the targeting of poor postprandial glycaemic control and fasting blood glucose, respectively
In NovoMix ® 30, rapid-acting, soluble, insulin aspart is absorbed more quickly than soluble human insulin, thus, unit-for-unit, reaching a higher plasma insulin concentration in a shorter time. This soluble aspart covers prandial insulin needs The 70% protamine-crystallised aspart is absorbed more slowly and has a similar duration of action to NPH . It thus addresses basal insulin needs Premixed analogues can be injected once-, twice- or three-times-daily. They can offer patients the possibility of fewer injections compared with basal-bolus therapy. In some situations this is particularly advantageous (e.g. for young schoolchildren who may require adult help to inject) NovoMix ® 30 will be covered in more detail in Session 11
Manuscript submitted BIAsp 1069 NPH monotherapy = once- or twice-daily NPH. The study did not distinguish between patients taking NPH either once a day or twice a day.
The insulin degludec molecule retains the human insulin (HI) amino acid sequence except for the deletion of ThrB30 and the addition of a 16-carbon fatty di-acid chain attached to LysB29 via a glutamic acid spacer (linker). The primary structure is designed to allow the formation of soluble multi-hexamer assemblies upon subcutaneous injection, to give an ultra-long peak-less PK profile. The degludec molecule differs from human insulin in that the amino acid residue threonine in position B30 has been omitted and the ε-amino group of lysine in position B29 has been coupled to a C16 fatty di-acid (hexadecanedioic acid) via a spacer of glutamic acid (chemical name: LysB29Nε-hexadecandioyl-γ-Glu desB30 human insulin).
In this double-blind, two-period, crossover trial, we investigated the dose-response relationship of three doses of IDeg (0.4, 0.6, and 0.8 U/kg) at steady state (SS) in people with type 2 diabetes. Participants (insulin-treated people with type 2 diabetes without concomitant oral anti-diabetic agents, n=49; mean age, 58.7 years; BMI, 29.6 kg/m²; A1C, 7.6%; duration of diabetes, 14.1 years) were given IDeg once daily for 6 days, with a washout period of 13–21 days between treatments. Following dosing on Day 6, subjects underwent a euglycemic glucose clamp (Biostator; clamp blood glucose level: 90 mg/dL). Pharmacokinetic samples were taken up to 120 h after the last injection of IDeg. For all dose levels, mean 24 h glucose infusion rate (GIR) profiles were flat and stable (Figure 1). Total glucose-lowering effect (AUCGIR,total,SS) increased linearly with increasing dose. Over 24 h, the glucose-lowering effect of IDeg was evenly distributed between the first and second 12 h for all 3 dose levels (AUCGIR,0-12h,SS / AUCGIR,total,SS = 0.5). The blood glucose levels of all participants stayed very close to the clamp level until the end of the experiment (mean blood glucose levels in the last 10min of a 24-h dosing interval were 90–92 mg/dL for all IDeg doses). The terminal half-life estimated across the three dose levels after the last dose was 25.1 h. IDeg was well tolerated and no safety concerns were identified. In conclusion, IDeg has a flat and stable blood glucose-lowering effect, and a duration of action beyond 24 h in people with type 2 diabetes
Data are LOCF ± SEM Please note that due to regulatory requirements the statistics shown are model-based (using LS means) to account for possible confounding factors.