Modern Insulins:

Evolution for Better Glycemic

Control
Topics to discuss…

• Physiological Insulin Profile

• Available Human Insulins
• Limitation of Human Insulins
• Modern Insulins: Do they answer the limitations?
• Available Modern Insulins
– Rapid-acting
– Long-acting
– Premixed
• Summary
Insulin

First hormone to be
• Discovered-oldest hypoglycemic agent
• Introduced in clinical practice
• Structurally characterized
• Synthesized – chemically
• Biosynthesized – by rDNA technology

‘one of the most extensively studied

proteins’
 Insulin

The Most Powerful Agent We Have

to Control Glucose
 30th July 1921
Experiments in Toronto
University

F Banting, surgeon
C Best, medical college
student

Banting & Best- extracted

insulin from dog & proved that
it controls symptoms of
diabetes in dogs – 1921

Banting & Macleod-

Nobel Prize for Medicine
& Physiology in 1923
 Milestones In Development 0f
Insulin

• 1921 – Discovery of insulin. Following which Eli Lilly and Novo Nordisk start
industrial production.

• 1936 – First long-acting insulin (PZI), 1946-NPH, 1953-IZS

• 1960s – First neutral soluble insulin; pre-mixed preparations

• 1973 – Monocomponent insulin, new standard in purity, by Novo

• 1981 - Semi-synthetic human insulin produced

• 1987 – Human insulin (recombinant DNA-Novo)

• 1996 – First insulin analogue

Types of insulin

• Based on SPECIES of origin: Bovine, Porcine & Human

• Based PURITY: Early preparations, Highly purified &

Monocomponent

• Based on ACTION profile: Short, Intermediate, Long-acting;

Mixed

• Based on STRENGTH of preparation: 40 i.u./ml & 100 i.u. /ml

 Targets for Glycemic Control*

• ADA Target A1c < 7.0%

• Eur IDF and AACE Targets A1c < 6.5%
• Normal A1c < 6.0%
• Realistic Target --- Lowest A1c possible
without unacceptable adverse effects

*DCCT-referenced assays- Normal Range 4-6%

So, Why Modern Insulins ?
"In using insulin it would of course
be ideal if it could be supplied so as
to imitate the natural process"

Macleod and Campbell 1925

(co-discoverers of insulin with Banting and Best)
 Insulin Analogues
-Rationale (1)

Limitations of conventional soluble human insulin

• Inability of s.c. injected soluble insulin to mimic the
physiological pattern
 Delayed onset of action (30-60 min after injection) i.e.
should be injected 30-60 min prior to a meal
 Prolonged duration of action (6-8 hrs after injection)
• Inadequate insulin when in need
• Insulin when not needed
• Fitting lifestyle - No
 Insulin Analogues
-Rationale (2)

• Postprandial glucose
– Due to variable absorption soluble human
insulin does not limit postprandial glucose
excursions effectively, which could be an
important clinical failing
Contribution of Fasting & Post-Prandial
Glycemia to A1C in T2DM

Fasting Post-Prandial

100

80
Contribution (%)

60

40

20

0
< 7.3 7.3-8.4 8.5-9.2 9.3-10.2 >10.2
A1C (%) quintiles
Monnier L et al. Diabetes Care 2003;26:881
The shortcomings of conventional
Actrapid

• Physiological insulin profile:

basal component
meal-related peaks

• Human Actrapid fails to match

normal insulin peak

Fails to match the physiology

 Insulin Analogues
-Rationale (3)

• Variability of human insulin Action

– Leads to UNPREDICTABILITY in Insulin Action

• PREDICTABILITY in insulin action means :

To get a blood glucose control which is least variable (or fluctuating)
from day to day With the same insulin dose
 CGMS plots for one patient on three
successive days of once-daily NPH insulin
Day 1 Day 2 Day 3
20.0
Glucose concentration (mmol/l)

15.0

10.0

Blood Glucose level is highly Variable with same insulin

5.0
in the same patient Due to UNPREDICTABLE insulin action

0.0

CGMS : Continuous Glucose Monitoring System

-5.0
12:00 am 4:00 am 8:00 am 12:00 pm 4:00 pm 8:00 pm 12:00 am

Time
Data from David Russel-Jones,2000
Variability : So what ?

• “ I took the same insulin

and the same meal, but
woke up in the night with
an RBS of 45 mg/dl”
• “ Some days, I get ‘hypo’
at 6pm and have to eat
something”
• “ Doctor, I hate snacking
as I become fat, but what Doctor, meri sugar kyon
to do about the low sugars badalti rehti hain?
?”
Variability : So what ?
• “ I took the same insulin
and the same meal, but
woke up in the night with
an RBS of 25 mg/dl”
• “ Some days, I get ‘hypo’
at 6pm and have to eat
something”
• “ Doctor, I hate snacking
as I become fat, but what Doctor, meri sugar kyon
to do about the low sugars
?”
badalti rehti hain?
Patients’ experience

Unpredictable BG
Hypoglycaemia

DEMOTIVATION
Periods of poor
control
Suspicion

Inability to titrate

Can we have a more

predictable insulin?
Shortcomings of human insulin

• Physiological insulin
profile: basal component
meal-related peaks
Period of unwanted
hyperglycemia Period of unwanted
hypoglycemia

• Mixtard fails to re-

create the physiological
insulin profile
Human
Human Insulin
Insulin in
in the
the
subcutaneous
subcutaneous space
space

(Brange J et al. Diabetes Care 1990;13:923)

Modern Insulins: Definition

• Modified or ‘Modern insulins’ or Newer Insulins

• Molecules
– differ by one or a few amino acids from
primary structure of insulin
• Developed
– to provide more physiologic replacement after
s.c injection than human insulin
• Made possible by the advent of Biotechnology-
rDNA technology
• Provide more optimal time-action profiles
Engineering insulin analogues

s s A-chain
A1 A21

s s
s s B-chain

B1 B30

Light blue: residues preserved in naturally occurring insulins

Red: residues involved in receptor binding

Kaarsholm & Ludvigsen. Receptor 1995;5:1-8.

Safety of Modern Insulins
IGF-1 R
IGF-1 : IR
affinity Mitogenic potency
(Saos/B10 cells)
Human insulin = 100 1 = 100
Insulin X10 587 ± 50 2.9
975 ± 173
Insulin aspart 81 ± 9 0.9 58 ± 22
Insulin lispro 156 ± 16 1.9 66 ± 10
Insulin glargine 641 ± 51 7.5 783 ± 13
Insulin detemir 16 ± 1 0.9 ~ 11

Kurtzhals P, et al. Diabetes 2000; 49: 999

Modern Insulins: Addressing the
limitations with human insulins
• Mimics the physiological insulin secretion

• Better time-action profile than human insulins

• Have more predictable action

• Superior PPG reduction  more cardiovascular benefits

• More safety  less hypoglycaemia

• Less undesired weight gain

• Meal-time flexibility  can be taken just before/after food

• Convenient to use  available in simple-to-use pens with painless needles

Modern Insulins: Classification

Rapid-acting Insulin aspart (NovoRapid)

Insulin lispro
Insulin glulisine

Long-acting Insulin detemir (Levemir)

Insulin glargine

Premix Biphasic Insulin Aspart (NovoMix 30)

Lispro Mix 25
Rapid-Acting Modern Insulins
NovoRapid (Insulin Aspart)

Pro

Phe Gly Arg

Asp Tyr Phe
Glu
Thr Gly
B20
Asp Cys
Lys B28
B30 Thr A21 Asn Cys
Tyr
Val
Leu
A1 Gly Asn
Tyr
Ile Glu
Leu
Val Leu
Glu Ala
Gln
Glu
Gln Tyr
Val
Cys Leu
Cys Ser
Thr Ser Ile Cys Leu
His
Ser
Gly
Leu Cys
B1 Phe Val Asn Gln His
 NovoRapid vs Actrapid

Better Pharmacokinetics

Human ActrapidTM NovoRapidTM

Onset of action 30-60 minutes 10-15 minutes

Duration of action 6-8 hours 3-5 hours

NovoRapidTM has a faster onset , earlier peak and
sharp return to baseline
Twice as Rapid onset &
as High peak
Doubleblind, cross-over, single dose study in healthy volunteers,
n=24

(mU/l) (pmol/l)
500 50 min/ 400
pmol/l NovoRapid ®

7
Serum insulin

5 400 Human Actrapid ®

(0.2 U/kg)
5 300 100 min/ 200
pmol/l
0
200
2
5 100

0 0
-60 0 60 120 180 240 300 360 420 480 540 600
Time (minutes)

(Heinemann L et al. Diabetes Med 1996;13:683)

 Mealtime Flexibility
Just Before / After Food…

15 HI(–15min)
Plasma glucose (mmol/l)

14 HI(0min)
NovoRapid®(0min)
13 NovoRapid®(+15min)
12 n = 20
11

10

0
-30 0 30 60 90 120 150 180 210 240 270

Test meal Brunner et al. Diabet Med. 2000 May;17(5):371-5.

 Superior Postprandial
blood glucose Reduction
Type 1 diabetes p < 0.001 p < 0.001

Mean values
1.8
after 6 months
1.6
Blood glucose increment

1.4 NovoRapid®
Human insulin
1.2
(mmol/l)

1.0
Prandial increment is the
0.8 mean increase in blood
glucose from pre-meal to
0.6 90 min post-meal

0.4

0.2

0
European trial North American trial
n = 1070 n = 884
Home et al. Diabetic Med 2000;17:762-70
Raskin et al. Diabetes Care 2000;23:583-8
Less risk of hypoglycemia

Double-blind, crossover comparison in

T1DM on basal-bolus, duration 4 months, n = 155
Episodes per patient per year

1.4 NovoRapid ®
1.2 Human Actrapid ®
1
0.8 **
0.6 *
72%
0.4
*** p <
0.2 0.005
0
Total Nocturnal 24:00 –
6:00
4 months
Heller et al. Diabetes 2001;50(2):A137
Modern Insulin of choice in
special situations
• Approved in children above 2 years

• Safe for use in patients with Liver & Kidney

dysfunction

• Preferred for use in Insulin pumps

• Ideal for managing hyperglycaemic emergencies

Only Modern Insulin approved in
Pregnancy by EMEA & FDA after RCTs

• Pettit et al. Diabetes Care 2003

– NovoRapid safe & effective as human insulin
• 3 studies from 65th ADA, 2005 NovoRapid got EU
– US study (Jovanovic et al.) approval
– Indian study: Seshaiah et al. for use in pregnancy on
31st July 2006 & FDA on
– Ireland study (Kinsley et al) 7th feB 2007
• 2 Studies from 66th ADA, 2006
– Multicentric study (Hod M et al). Published Am J
Obstet Gynecol. 2007 Sep 29; [Epub ahead of
print]
– Multicentric study (Mathiesen et al). Published
Diabetes Care.2007;30 (4):771-776.
 Long-Acting Modern Insulins

Glargine 21

30

Detemir

29
 Design of Insulin detemir -Levemir

LysB29(N-tetradecanoyl)des(threonine)human insulin
C1
4f
a
(M tty a
yri
sti cid ch
ca
cid ain Phe Phe Gly Arg
) Tyr Glu
Thr Gly
Pro Cys
Lys
Thr Val
Lys
B29 A21 Asn Cys
Tyr Leu
A1 Gly Asn Tyr
Ile Glu Leu
Val Leu Ala
Glu Glu
Gln
Gln
Tyr Val
Cys Leu Leu
Cys Thr Ser Ile Cys Ser
His
Ser
Gly
Cys
Leu
B1 Phe Val Asn Gln His

Des-threonine myristic(mir) acid

 Levemir vs Glargine
Similar time action profile
Randomized, double-blind, parallel trial; 27 insulin-treated male
subjects with T2DM. Levemir shows significantly less within-subject
variability than Glargine

Presented at ADA 2006. Klein D et al. Diabetes 2006; June (Suppl):A494

Levemir: more predictable than
glargine & NPH
Glucose infusion rates

NPH Glar Det

Heise T et al. Diabetes June 2004;53:1614-1620

 Levemir vs. insulin glargine

p < 0.05
Insulin detemir + IAsp
7 Insulin glargine + IAsp
6 p < 0.05
5 0.4

4
Episodes per subject-ye 0.3
Episodes per subject-year
3
0.2
2
1 0.1

0 0

Nocturnal Hypoglycemia Major episodes

72% lesser major hypoglycemic events

32% lesser nocturnal hypoglycemic events

Pieber et al Diabetologia 2005;48(Suppl. 1):A92

Less undesired weight gain

n = patient numbers in each BMI category

3.5 Insulin detemir
36 37
Mean weight change (kg)

39 NPH insulin
3.0 50
76

2.5 35

2.0 34

1.5
55
1.0 69
42
0.5

0.0
≤ 25 >25-27 >27-29 >29-31 >31
-0.5
Baseline BMI

K. Hermansen et al. Diabetes 2005;54(suppl 1):A67

Levemir once daily

• with OADs for type 2 diabetes

• with NovoRapid as basal-bolus therapy for both

type 1 & 2 diabetes
Premixed modern insulin

• Biphasic Insulin Aspart (NovoMix 30)

• Lispro Mix 25
Biphasic insulin aspart 30

70% protaminated 30% soluble, rapid-

insulin aspart, which acting insulin aspart
is intermediate-acting

NovoMix® 30
NovoMix® 30- pharmacokinetics

Healthy Volunteers
Serum insulin (mU/L)

35
NovoMix® 30
25 Human Insulin 30/70 Premix

15

5
0
4 8 12 16 20 24

Injection Time (hour)

Weyer, Diabetes Care 1997;10:1612-1614
Meal-time flexibility
Just before/After food…

After preprandial injection (63.0 ± 28.9 U)

240
Mean plasma glucose (mg/dl)

After postprandial injection (64.6 ± 29.2 U)

220
n = 93
200 type 2 diabetes
180 patients

160

140

120

100
-15 60 120 180 240
Time (minutes)

Warren ML, et al. Diabetes Res Clin Pract 2004;66:23–29

 INITIATE Trial
Study Design
N = 233 T2DM patients
Continue OAD* + glargine 10-12u at HS

A1C > 8% (insulin naïve)

OAD failures on MET ≥ 1000 mg/d Continue OAD* +
Biphasic Aspart 70/30 5-6u
BID
4 wk run-in & 28 wks of treatment
with insulin adjustments titration

Target FPG: < 110 mg/dL

* Secretagogues and carbohydrate inhibitors discontinued; rosiglitazone
switched to pioglitazone 30 mg/d
Raskin P, et al. Diabetes Care 2005;28:260-265
INITIATE Trial
Primary Endpoint (A1C)

P = 0.478 Biphasic Aspart 70/30

11 Glargine
9.7 9.8
10
P = 0.001
9
A1C (%)

8 7.4
6.9
7
6
5
Baseline 28-weeks
Raskin P, et al. Diabetes Care 2005;28:260-265
 INITIATE Trial
Achieving A1C Goal
70
Biphasic Aspart 70/30
60 Glargine
% Reaching Goals

50
P = 0.0002
40
P = 0.036
30

20

10

0
ADA: A1C < 7% AACE: A1C < 6.5%
Baseline A1C was 9.7% for Biphasic Aspart 70/30 & 9.8% for
Glargine
Raskin P, et al. Diabetes Care 2005;28:260-265
 INITIATE Trial
8-point BG Profiles
350

300
Blood Glucose (mg/dL)

250 Baseline

Biphasic
200
* *
Aspart
Glargine
150
+ * *
Week 28
100
BB B90 BL L90 BD D90 Bed 3am

∗ Biphasic Aspart 70/30 lower BG vs glargine P < 0.05

+ Glargine lower BG vs Biphasic Aspart 70/30, P < 0.05

Raskin P, et al. Diabetes Care 2005;28:260-265

 INITIATE Trial
Additional Outcomes
Weight Gain in kilograms All Hypoglycemia (median)
P = 0.001 P = 0.03
6 5.4 10 9.4
9
5
Weight Change (kg)

Events/patient/year
4 7
3.5 5.6
6
3 5
4
2
3
1 2
1
0 0
Biphasic Aspart 70/30
Glargine
Raskin P, et al. Diabetes Care 2005;28:260-265
The 1 – 2 – 3 Study
using Biphasic Insulin Aspart 30/70
Phase 1
Pre-dinner x 16 wk End
A1C ≤ 6.5% of
QD Start with 12 U at dinner
Study

If A1C > 6.5%, go to BID, d/c secretagogues

Phase 2
Pre-breakfast & dinner x 16 wk End
BID Add 3 U at breakfast if FPG ≤ 110 A1C ≤ 6.5% of
Add 6 U at breakfast if FPG > 110 Study

If A1C>6.5%, go to TID
Phase 3
TID x 16 wk
TID Add 3 U at lunch

Titrate according to schedule every 3 days.

N = 100 Type 2 DM ≥ 12 months with A1C ≥ 7.5 ≤ 10%, ≥ 2 OADs or ≥ 1 OAD plus
basal insulin OD (max 6 0U).
Jain R, et al. Diabetes. 2005 ;54(suppl 1):A69
1-2-3: Cumulative proportion of
patients achieving targets
1. Start with NovoMix 30,
once a day

41% reached Target

2. Add a second NovoMix 30

dose if needed

77% on
70%
41% on target
target
3. Add a third NovoMix 30
(HbA1c ≤ 7.0%)
dose if needed

Garber et al. Diabetes Obes Metab 2006;8:58–66

 The 1 – 2 – 3 Study
Achievement of A1c Targets

A1C ≤ 6.5% A1C < 7.0%

100
87.8
100
78.4
80
77.0
80
66.2
% of 60
Patients 60 45.9
40
40
28.4

20 20

0 QD BID TID 0 BID TID

QD

Jain R, et al. Diabetes. 2005;54(suppl 1): A69.

 Switching to Modern Insulins
from other insulins
From < 30 U premixed or basal insulin:

Transfer units 1:1, titrate according to titration schedule

From > 30 U premixed or basal insulin

From a once-daily regimen

Transfer units 1:1, titrate according to titration schedule

From a twice-daily regimen

Transfer units 1:1, titrate according to titration schedule

Christiansen et al. Diab Obes Metab 2003;5:445-452

McSorley et al. Clin Ther 2002;24:530-539
 Insulin Analogs

Fulfilling the Promise of Recombinant DNA

Technology:
Better Basal
Better Bolus
Better Premix
Better Glucose control
Thank you