are insulin analogues any better for the management of type 1 diabetes ? dr colin johnston whht
TRANSCRIPT
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ARE INSULIN ANALOGUES ANY BETTER FOR THE
MANAGEMENT OF TYPE 1 DIABETES ?
DR COLIN JOHNSTON
WHHT
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GOALS OF MANAGEMENT
• IMPROVED LIFE-EXPECTANCY
• REDUCED MORBIDITY/COMPLICATIONS
• IMPROVED QUALITY OF LIFE
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INFLUENCES ON QUALITY OF LIFE
• FREEDOM FROM COMPLICATIONS
• FREEDOM FROM HYPOGLYCAEMIA
• KNOWLEDGE AND BEING ‘IN CONTROL’
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INSULIN
• 1921 INSULIN INTRODUCED
• ANIMAL DERIVED
• 1947 NPH
• 1970s MC PORCINE
• 1980s HUMAN
• 1990s-now ANALOGUES
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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
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NICE GUIDELINES/TARGETS
HbA1C 6.5-7.5%
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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).
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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
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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).
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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
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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
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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
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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
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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
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**
**
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
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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
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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
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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
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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)
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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
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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
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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
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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)
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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)
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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
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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
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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
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NICE GUIDANCE TECH APRAISAL 53 DEC 2002
A TREATMENT OPTION FOR THOSE WITH TYPE 1 DIABETES
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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
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WHY CONTINUED POOR CONTROL
• CLINICAL EXPERIENCE
• VARIATION IN INSULIN ACTION
• SAFETY
• PEN DEVICE
• OTHERS
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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
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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
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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
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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
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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
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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
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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
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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
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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
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IMPROVED CONTROL IN TYPE 1 DIABETES
PROGRESS?• INSULIN TYPE
• INSULIN DELIVERY
• GLUCOSE MONITORING
• DIET (DAFNE)
• PSYCHOLOGY