ARE INSULIN ANALOGUES ANY BETTER FOR THE

MANAGEMENT OF TYPE 1 DIABETES ?

DR COLIN JOHNSTON

WHHT

GOALS OF MANAGEMENT

• IMPROVED LIFE-EXPECTANCY

• REDUCED MORBIDITY/COMPLICATIONS

• IMPROVED QUALITY OF LIFE

INFLUENCES ON QUALITY OF LIFE

• FREEDOM FROM COMPLICATIONS

• FREEDOM FROM HYPOGLYCAEMIA

• KNOWLEDGE AND BEING ‘IN CONTROL’

INSULIN

• 1921 INSULIN INTRODUCED

• ANIMAL DERIVED

• 1947 NPH

• 1970s MC PORCINE

• 1980s HUMAN

• 1990s-now ANALOGUES

CLINICAL MANAGEMENT OF TYPE I DIABETES IN 1989• LIFE EXPECTENCY IMPROVED

• COMPLICATIONS STILL SEVERE

• MOST PATIENTS POORLY CONTROLLED

• MANY ON BD REGIMENS

• HUMAN INSULIN SAGA

NICE GUIDELINES/TARGETS

HbA1C 6.5-7.5%

24-hour plasma glucose and insulin profiles in healthy

individuals

Owens DR et al. Lancet 2001;358:739–746

©Elsevier Science. Reproduced with permission from Elsevier Science (The Lancet, 2001, Vol 358, pages 739–746).

NovoRapid®: more physiological insulin profile than soluble

human insulin

Lindholm et al. Diabetes Care 1999;22:801-5

Pla

sma insu

lin (

pm

ol/l)

Time (hours)

Insulin aspart, t = 0 min

Human insulin, t = 0 min

Human insulin, t = –30

min

(insulin dose 0.15 U/kg)

600

500

400

300

200

100

00 1 2 3 4 5 6

024

n = 22

24-hour plasma glucose and insulin profiles in healthy

individuals

Owens DR et al. Lancet 2001;358:739–746

©Elsevier Science. Reproduced with permission from Elsevier Science (The Lancet, 2001, Vol 358, pages 739–746).

Structure of 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

A21B28B30

AspPro

Asp

NovoRapid®: more physiological insulin profile than soluble

human insulin

Lindholm et al. Diabetes Care 1999;22:801-5

Pla

sma insu

lin (

pm

ol/l)

Time (hours)

Insulin aspart, t = 0 min

Human insulin, t = 0 min

Human insulin, t = –30

min

(insulin dose 0.15 U/kg)

600

500

400

300

200

100

00 1 2 3 4 5 6

024

n = 22

Self-monitored blood glucose profiles

European trial Insulin aspartHuman insulin

Blo

od g

luco

se (

mm

ol/l)

p < 0.001

p < 0.001

p < 0.01

p < 0.01

p < 0.01

6

7

8

9

10

11

12

0

Before and90 min afterbreakfast

Before and90 min afterlunch

Before and90 min afterdinner

Bedtime 2 a.m.

Home et al. Diabetic Med 2000;17:762-70

n = 1070

035

Prandial increment isthe mean increase in blood glucose from pre-meal to 90 min post-meal

European trial North American trial

Blo

od

glu

cose in

cre

men

t (m

mol/

l)

p < 0.001

0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

Insulin aspart

Human insulin

Postprandial blood glucose increment:

mean over the three meals at 6 months

Home et al. Diabetic Med 2000;17:762-70, Raskin et al. Diabetes Care 2000;23:583-8

p < 0.001

n = 1070

n = 884

035, 036

Basal-bolus dose optimisation study: protocol

Time (weeks)

Nine-point blood glucose profile

Blood sampling for HbA1c/dosing and adverse event assessment

Run-in

n = 213

n = 213

Insulin aspart + basal NPH insulin

Human insulin + basal NPH insulinScreening

12

–2 –1 0 1 2 3 4 5 6 7 8 9 10 11

Tamas et al. Diabetes Res Clin Pract 2001;54:105-14

065

**

**

Basal dose optimisation study: glycaemic control (2)

Insulin aspart Human insulin

Hb

A1

c (

%)

7.5

7.7

7.9

8.1

8.3

8.5

0

**p < 0.01

Tamas et al. Diabetes Res Clin Pract 2001;54:105-14

065

n = 426

Baseline12 weeks

NB: Broken

axis

Insulin aspart significantly reduces the rate of severe nocturnal hypoglycaemia

0

0.5

1

1.5

2

2.5

3

Totalevents

Nocturnalevents

Diurnalevents

Hyp

og

lycaem

ia e

ven

t ra

te(e

ven

ts p

er

pati

en

t-year)

Heller et al. Diabetic Medicine 2004, in press 066

IAsp

HI

n = 155

72% risk reduction with IAsp

Differences between DTSQ scores for insulin aspart and HI groups from

baseline to 3 and 6 months10 8 6 4 2 0 5

Favours insulin aspart

Favours human insulin

3 months

6 months

Preference-weightedtreatment satisfaction

Preference-weightedtreatment satisfaction

Total DTSQ score

Total DTSQ score

Data are mean differences in unadjusted changes in DTSQ scores and 95% CI

Bott et al. Diabet Med. 2003 Aug;20(8):626-34. 035 QoL

Conclusions

• Patients considered insulin aspart treatment to be more flexible and convenient compared with HI

• Overall treatment satisfaction improved with insulin aspart treatment

• Insulin aspart improved QoL regarding diet restrictions compared with HI

• Modest benefits in glycaemic control

Bott et al. Diabetic Medicine 2003;20:626-634

035 QoL

Limitations of protracted-acting insulin formulations – peak in insulin

levels (1)

Porcellati F et al. Diabetologia 2001;44(Suppl 1):A208 (Abstract 799) (Adapted from poster)

Patients with Type 1 diabetesStudy duration 4 weeks (+ 15-day run-in period)n=29 (subset shown)

Primary structure of insulin glargine (Lantus®)

NH2

COOHNH2

COOH

S

S S

S

S

A21[Gly]

B-chain

A-chain

S

B31[Arg]B32[Arg]

Rosskamp R, Park G. Diabetes Care 1999;22(Suppl 2):B109–B113

Retardation principle of insulin glargine (Lantus®)

Acidic solution injected (pH 4)

Precipitation in tissue (pH 7.4)

Slow dissolution of free hexamers from precipitatedinsulin glargine (Lantus®)

Delayed absorption,protracted action

Clear solutionpH 4

pH 7.4

Precipitation

Dissolution

Hexamer Dimers Monomers

Capillary membrane

Insulin in blood

10-3 M 10-5 M 10-8 M

Heinemann L et al. Diabetes Care 2000;23:644–649

Pharmacokinetics of insulin glargine (Lantus®) – flat insulin profile with no

pronounced peaks (1)

Porcellati F et al. Diabetologia 2001;44(Suppl 1):A208 (Abstract 799) (Adapted from poster)

Patients with Type 1 diabetesStudy duration 4 weeks (+ 15-day run-in period)n=29

Pharmacodynamics of insulin glargine (Lantus®) – flat activity profile with

no pronounced peaks (1)

Patients with Type 1 diabetesStudy duration 4 weeks (+ 15-day run-in period)n=29

Porcellati F et al. Diabetologia 2001;44(Suppl 1):A208 (Abstract 799) (Adapted from poster)

Less intrasubject variability with insulin glargine (Lantus®) vs NPH

insulin (1)

Patients with Type 1 diabetes *p <0.05 vs CSII and insulin glargineStudy duration 4 weeks (+ 15-day run-in period)n=29

Porcellati F et al. Diabetologia 2001;44(Suppl 1):A208 (Abstract 799) (Adapted from poster)

Significantly lower FPG and HbA1c with insulin glargine (Lantus®) vs NPH

insulin

Pieber TR et al. Diabetes Care 2000;23:157–162

*p=0.0005 and **p=0.03 vs insulin glargine (Lantus®) treatment groups combinedStudy duration 4 weeksn=333

Only the insulin glargine [30] formulation is marketed

Significantly lower FPG with less hypoglycaemia, with insulin glargine

(Lantus®) vs NPH insulin

Ratner RE et al. Diabetes Care 2000;23:639–643

*p <0.03; **p<0.02Study duration 28 weeks; n=534

Hypoglycaemia

Benefits of insulin glargine (Lantus®) in Type 1 diabetes

• Lower FBG level achieved with insulin glargine (Lantus®) versus NPH insulin in combination with either regular human insulin or insulin lispro

• Equivalent reduction in HbA1c compared with NPH insulin

• Efficacy associated with a lower risk of hypoglycaemia, especially nocturnal and/or severe episodes

NICE GUIDANCE TECH APRAISAL 53 DEC 2002

A TREATMENT OPTION FOR THOSE WITH TYPE 1 DIABETES

AUDIT OF GLARGINE AT HH/SACH

• 56 SUBJECTS (8 NOT FOLLOWED, )

• 41/48 HBAIC FELL FROM 8.6% TO 8.1% AT 6 MONTHS

• 40 CONTACTABLE , 29 REDUCED HYPOGLYCAEMIA, 11 NO CHANGE

• 26 IMPROVED QUALITY OF LIFE 14 NO CHANGE

WHY CONTINUED POOR CONTROL

• CLINICAL EXPERIENCE

• VARIATION IN INSULIN ACTION

• SAFETY

• PEN DEVICE

• OTHERS

LysB29(N-tetradecanoyl)des(B30)human insulin

Thr

Glu

Lys

ValPhe

Glu

Leu

Gln

Tyr

LeuSerCysIleSerCys

Gln

Glu

Val

Ile

GlyTyr

CysAsnLys

ProThr

TyrPhe Phe ArgGly

GluGly

Cys

Val

Leu

Tyr

Leu

Ala

Val

Leu

His

SerGly

Cys

Asn Gln LeuHisB1

A21

A1

B29

C14 fatty acid chain

(Myristic acid)

Thr

Cys

Asn

Insulin detemir – amino acid structure

Insulin detemir – albumin binding • the myristic acid

attached to position B29 of the insulin detemir molecule binds to albumin

• >5 distinct free fatty acid binding sites are available per albumin molecule5

5) Curry et al., Nature Structural Biology,1998; Vol. 5: 827-835

Adapted from 10) Pieber et al. Diabetes, 2002;51 (Suppl. 2): A53

GIR

(m

g/k

g/m

in)

5.0

4.0

3.0

2.0

1.0

0

Insulin detemir, 0.4 U/kg

0 2 4 6 8 10 12

Time since insulin injection (hours)

14 16 18 20 22 24

Time-action profile of insulin detemir

• Insulin detemir provides a smooth and protracted pharmacodynamic profile10

• The duration of action of insulin detemir is up to 24 hours depending on dose10

Detemir significantly reduces within patient variability vs. glargine and

NPH

1. Heise, T. et al., Diabetes, 2003; Vol. 52 (Suppl. 1): A121

6848

27

0

10

20

30

40

50

60

70

80

Insulin detemir Insulin glargine NPH

-44%

p < 0.001

-60%

GIR

-AU

C 0

-24h

Co-e

fficie

nt

of

vari

ati

on

(%

)

CV = Co-efficient of variation = (Standard deviation / Mean) x 100 expressed as percentage

• 24-hour clamp study • 54 subjects• 0.4 U/kg

Medinfo/Det/0147 April 2004

Insulin detemir - long-term safety12

IGF-1 receptor affinity (%)

Mitogenic potency (%)

Human insulin 100% 100%

Insulin aspart 81 ± 9 58 ± 22

Insulin lispro 156 ± 16 66 ± 10

Insulin glargine

641 ± 51 783 ± 132

Insulin detemir

16 ± 1 ~11

Adapted from: 12) Kurtzhals P. et al., Diabetes 2000; Vol. 49: 999-1005

Study designtype 164 sites in 15 countriesRandomized 1:1

Screening

Insulin Detemiram+bed + meal aspart (n = 298)

NPHam+bed + meal HSI (n = 297)

2 weeks

Randomization

18 weeks

1374

Titration target: European Diabetes Policy Group

(5.7-7.3 mmol/L fasting and pre-prandial; 8.5-10.1 mmol/L post-prandial)

8.Hermansen et al Diabetes UK abstract 2004

Medinfo/Det/0147 April 2004

Results of HbA1CInsulin

Detemir-aspart

NPH-HSI DifferenceDet.asp-NPH.HSI

p-value [95% CI]

HbA1c (%) 7.88 (0.047)

8.11 (0.047)

-0.221 0.0004[-0.344;

-0.099]

Non-inferiority criterion: Upper confidence limit of difference <0.4% (absolute)Superiority criterion: Non-inferiority met and upper confidence limit of

difference <0% (absolute)

1374

Medinfo/Det/0147 April 2004

8.Hermansen et al Diabetes UK abstract 20049. Data on File 1374

Hypoglycaemia• Detemir reduced the risk of all hypoglycaemic

episodes by 22% vs. NPH• Detemir reduced the risk of nocturnal

hypoglycaemic episodes by 34% vs. NPH

3. Vague, P. et al., Diabetes Care, 2003; Vol. 26, No. 3: 590-596

Medinfo/Det/0147 April 2004

p = 0.002

Insulin detemir

NPH insulin

p = 0.003

p < 0.001

Ch

an

ges in

bod

y w

eig

ht

(Kg

)

-0.5

0

0.5

1.0

1.5

StandlRussell-Jones Leeuw, de

6 month studies 12 month studies

Vague

p = 0.001

0.3

1.4

0.7

0.4

0.2

1.2

0.1

No weight gain (in type 1’s)

6) Russell-Jones, D. et Al Diabetologia 2002;45(Suppl. 2):A147 3) Vague, P. et al., Diabetes Care, 2003; Vol. 26, No. 3: 590-596 4) Standl, E. et al., Diabetes, 2002; Vol. 51 (Suppl. 2): A115 5) De Leeuw, I. et al., Diabetologia 2002;45(Suppl. 2):A257

0.2

Medinfo/Det/0147 April 2004

IMPROVED CONTROL IN TYPE 1 DIABETES

PROGRESS?• INSULIN TYPE

• INSULIN DELIVERY

• GLUCOSE MONITORING

• DIET (DAFNE)

• PSYCHOLOGY