Modern Insulin : An Update

MODERN INSULINAN UPDATE

Dr. Jobaida Naznin

MD Final part Student

Department of Endocrinology

BSMMU

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


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

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


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

)


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

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


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


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


Rapid-acting insulin analogues


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


Insulin aspart

Glu

Thr

Lys


GluGly

Cys

Val

Leu

Tyr

Leu

Ala

Val

Leu

His

Ser


Asn CysTyr

Asn

Glu

Leu

Gln

Tyr


Cys

Gln

Glu

Val

Ile

Gly

A21

A1

B28B30

AspPro

Asp


Insulin glulisine

Glu

Thr

Lys


GluGly

Cys

Val

Leu

Tyr

Leu

Ala

Val

Leu

His

Ser


Asn CysTyr

Asn

Glu

Leu

Gln

Tyr


Cys

Gln

Glu

Val

Ile

Gly

A21A1

B29B30

Glu

Pro

Lys

B3

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

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


Basal insulin analogues


Strategies for protraction

Modification of isoelectric point: precipitation at pH 7.4• Insulin glargine

Acylation with hydrophobic residues (and albumin binding)• Insulin detemir


Insulin glargine

Glu

Thr

Lys

ThrTyr Phe

Phe Gly ArgGlu

Gly

Cys

Val

Leu

Tyr

Leu

Ala

Val

Leu

His

Ser


Asn CysTyr

Asn

Glu

Leu

Gln

Tyr


Cys

Gln

Glu

Val

Ile

Gly

A21

A1 B30

Gly

ArgPro

Arg

+


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

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

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

April 11, 2023 22

Key benefits:

April 11, 2023 23

Levemir® gives you More


Biphasic premixed insulin analogues


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



NovoM

ix® 3

0

Rapid-acting insulin aspart

Pre

mix

ed

su

sp

en

sio

n

Intermediate-acting protamine-crystallised

insulin aspart



• 30% soluble aspart rapid absorption covers prandial insulin needs

• 70% protamine-crystallised aspart slower absorption addresses basal insulin needs

• Fewer injections


• 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

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

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

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

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

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

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

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

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

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


Thank You

Modern Insulin : An Update

Health & Medicine

Transcript of Modern Insulin : An Update