Clinical presentation
Insulin detemir: Agenda
•
•
•
•
•
•
•
Rationale: The need for a new basal insulin
Pharmacology
Clinical efficacy in type 1 and type 2 diabetes
Variability
Hypoglycaemia
Body weight
Summary
1
Novo Nordisk • Clinical presentation of insulin detemir •
Rationale: The need for a
new basal insulin
2
Novo Nordisk • Clinical presentation of insulin detemir •
The physiological insulin profile
3
Adapted from Polonsky et al. 1988
Novo Nordisk • Clinical presentation of insulin detemir •
Basal-bolus therapy attempts to
recreate the physiological insulin profile
4
Novo Nordisk • Clinical presentation of insulin detemir •
Insulin analogues: desired properties
• Meal-related analogues (e.g. insulin aspart)
designed to give:
• Rapid absorption
• Peak action coinciding with peak carbohydrate absorption
• Basal insulin analogue should provide:
• Slow and steady rate of absorption
• Protracted action
• Low within-subject variability in action
5
Novo Nordisk • Clinical presentation of insulin detemir •
Therapeutic potential of intensive
analogue-based insulin therapy
Achievement and maintenance of glycaemic targets:
• HbA1c
• Postprandial plasma glucose
• Fasting plasma glucose
• Low within-subject variability
• Reduced risk of hypoglycaemia
• Minimal weight gain
• Enhanced convenience and improved quality of life
6
Novo Nordisk • Clinical presentation of insulin detemir •
Pharmacokinetic limitations of
subcutaneous exogenous basal insulin
NPH insulin
7
Novo Nordisk • Clinical presentation of insulin detemir •
Improved basal
insulin
Variability in glucose infusion rate (GIR)
profiles for 3 patients with type 1
diabetes following NPH injection
8
Data from study1450 (T. Heise et al. Diabetes 2003;52 (Suppl.1): A121)
Novo Nordisk • Clinical presentation of insulin detemir •
Variability in GIR profiles for 3 patients
with type 1 diabetes following insulin
glargine injection
9
Data from study1450 (T. Heise et al. Diabetes 2003;52 (Suppl.1): A121)
Novo Nordisk • Clinical presentation of insulin detemir •
The balance between control
and tolerability: data from DCCT
10
New Engl J Med 1993;328:977
Novo Nordisk • Clinical presentation of insulin detemir •
Factors influencing insulin absorption
• Insulin preparation
• Dose, concentration and volume
• Physical status (solution or
suspension)
• Mechanism of protraction
• Self association
• Precipitation
• Albumin binding
• Injection site factors
• Region of injection
• Depth of injection
• Lipodystrophy
• Blood flow changes e.g.
temperature, exercise,
hypoglycaemia, ketoacidosis
11
Novo Nordisk • Clinical presentation of insulin detemir •
Receptor binding, metabolic and
mitogenic potency of insulin analogues
Insulin
receptor
affinity
Metabolic
potency
IGF-I
receptor
affinity
IGF-IR/IR
affinity
Mitogenic
potency
(Saos/B10 cells)
100
100
100
1
100
205 ± 20
207 ± 14
587 ± 50
2.9
975 ± 173
Insulin lispro
84 ± 6
82 ± 3
156 ± 16
0.9
66 ± 10
Insulin aspart
92 ± 6
101 ± 2
81 ± 9
1.9
58 ± 22
Insulin glargine
86 ± 3
60 ± 3
641 ± 51
7.5
783 ± 13
Insulin detemir
18 - 46
 27
16 ± 1
0.9
 11
Human insulin
B10 Asp
12
Adapted from P. Kurtzhals et al. Diabetes 2000;49:999
Novo Nordisk • Clinical presentation of insulin detemir •
Pharmacology
13
Novo Nordisk • Clinical presentation of insulin detemir •
Return to Agenda
Strategies for engineering
basal insulins
Modification of isoelectric point: precipitation at pH 7.4
• NovoSol Basal
• Insulin glargine
Strengthening of hexamer association, e.g.
• Co(III)-hexamer
Acylation with hydrophobic residues, e.g.
• Insulin detemir
14
Novo Nordisk • Clinical presentation of insulin detemir •
Structure of insulin detemir
15
Novo Nordisk • Clinical presentation of insulin detemir •
3-Dimensional structure of
hexameric insulin
Human insulin
16
Novo Nordisk • Clinical presentation of insulin detemir •
Insulin detemir
Potential sites of protraction
In the subcutaneous depot
In the circulation
In the interstitial space
17
Novo Nordisk • Clinical presentation of insulin detemir •
Insulin detemir
Mode of protraction
• Self association (hexameric)
• Fatty acid side chains bind to
albumin in injection depot
• Albumin binding in circulation
18
Novo Nordisk • Clinical presentation of insulin detemir •
Protracted
absorption
‘Buffering’ effect and
minor contribution to
protraction
Albumin binding buffers against
changes in absorption rate
Absorption rate
from subcutaneous depot
Absorption and relative
change in periphery (%)
225
200
Interstitial human insulin (muscle/fat)
175
150
Interstitial detemir (muscle/fat)
125
100
75
0
0
60
120
180
240
300
360
Duration
Calculated effect of a 60-minute doubling of absorption rate on
the interstitial concentrations of NPH insulin and insulin detemir
19
Data on file: Novo Nordisk
Novo Nordisk • Clinical presentation of insulin detemir •
Safety of albumin binding (1)
• Plasma concentration of HSA
• FFA binding sites/HSA molecule
• Plasma concentration of FFA
• Insulin detemir conc. at
therapeutic dose
~600 x 10-6 M
at least 8
~300 x 10-6 M
<0.01 x 10-6 M
• Therefore, insulin detemir occupies only a minute
fraction of available albumin binding sites
HSA: human serum albumin
FFA: free fatty acid
20
Novo Nordisk • Clinical presentation of insulin detemir •
Safety of albumin binding (2)
No drug–drug interactions observed in in vitro studies
with drugs at clinically relevant concentrations.
Compounds investigated:
• FFA (C8 FA, C12 FA, C16 FA)
• phenylbutazone, warfarin
• ibuprofen, diazepam
• Sulphonylureas (tolbutamide, glibenclamide)
• aspirin, valproate
21
P. Kurtzhals et al. Journal of Pharmaceutical Sciences 1997;86(12)
Novo Nordisk • Clinical presentation of insulin detemir •
Pharmacodynamic profile of insulin
detemir - subjects with type 1 diabetes
Pharmacodynamic parameters for insulin detemir and NPH
Insulin detemir
NPH
0.2 U/kg
0.4 U/kg
0.3 IU/kg
Duration of action (hr)
12
20
13
GIRmax (mg/kg/min)
1.1
1.7
1.6
Insulin detemir 0.2 U/kg
Insulin detemir 0.3 U/kg
Insulin detemir 0.4 U/kg
22
Adapted from T. Pieber et al. Diabetes 2002;51(Suppl. 2):A53
Novo Nordisk • Clinical presentation of insulin detemir •
Variability in time-action profile
of basal insulins
GIR profiles following four non-consecutive injections of identical doses
(0.4U/kg, thigh) in three patients
23
Data from study1450 (T. Heise et al. Diabetes 2003;52 (Suppl.1): A121)
Novo Nordisk • Clinical presentation of insulin detemir •
Clinical efficacy in
type 1 and type 2 diabetes
24
D. Russell-Jones et al. Diabetologia 2002;45(Suppl. 2):A51
Novo Nordisk • Clinical presentation of insulin detemir •
Return to Agenda
9-point blood glucose profiles after 6
months’ therapy with once-daily insulin
detemir or NPH insulin
Type 1 diabetes
*
25
D. Russell-Jones et al. Diabetologia 2002;45(Suppl. 2):A51
Novo Nordisk • Clinical presentation of insulin detemir •
FPG at baseline and after 16 weeks
in subjects with type 1 diabetes
p = 0.004
26
Data from 1448 study (P. Home et al. Diabetes 2003;52(Suppl. 1):A122)
Novo Nordisk • Clinical presentation of insulin detemir •
Glycaemia results
Insulin
detemir
Insulin
detemir
NPH
insulin
q 12 hour
am + bed
am + bed
HbA1C (%)
7.75
7.78
7.94
= 0.08
Office FPG (mM)
9.75
8.94
11.24
< 0.001
Home FBG (mM)
8.28
8.26
9.05
= 0.005
p-value
Baseline HbA1c = 8.60%
27
Novo Nordisk • Clinical presentation of insulin detemir •
Insulin detemir consistently achieves
lower FPG values than NPH insulin
Insulin detemir
Trial
NPH insulin
Difference
N
mmol/l
endpoint
N
mmol/l
endpoint
Insulin detemir – NPH
mmol/l (95% CI)
1335
453
10.6
230
11.7
–1.2 (–1.8, –0.5)
1447
252
9.5
125
11.1
–1.6 (–2.5, –0.8)
1448
261
9.3
119
11.2
–1.9 (–2.8, –1.0)
1336* 309
9.7
152
9.6
0.1 (–0.4, 0.5)
Meta-analysis of five 4- and 6-month trials
in type 1 diabetes†
*Study in type 2 diabetes
† Meta-analysis
28
Novo Nordisk • Clinical presentation of insulin detemir •
–1.1 p < 0.0001
of trials 1181, 1205, 1335, 1447, 1448
HbA1c: Meta-analysis of phase 3 trials in
type 1 diabetes
Insulin detemir
(a)
NPH insulin
(b)
N
Mean (SE)
N
Mean (SE)
983
8.30%
(0.01%)
485
8.41%
(0.11%)
Difference (a-b)
after 4–6 months
Mean, p
–0.11%
p < 0.05
Endpoint data from three trials (1335, 1447, 1448) comparing
insulin detemir with NPH insulin in basal-bolus therapy
29
Novo Nordisk • Clinical presentation of insulin detemir •
Variability
30
Novo Nordisk • Clinical presentation of insulin detemir •
Return to Agenda
Variability in time-action profile
of basal insulins
Glucose infusion rate profiles following four non-consecutive injections
of identical doses (0.4U/kg, thigh) in three patients
31
Data from study1450 (T. Heise et al. Diabetes 2003;52 (Suppl.1): A121)
Novo Nordisk • Clinical presentation of insulin detemir •
Reproducibility: Probability ranges for
blood glucose lowering effect of
repeated injections
Average GIR over 24 hours
95% probability ranges for individual
pharmacodynamic responses
relative to the mean
32
T. Heise et al. Diabetes 2003;52(Suppl.1):A121
Novo Nordisk • Clinical presentation of insulin detemir •
Implications of within-subject
pharmacodynamic variability
Insulin detemir Insulin glargine
NPH insulin
The subject’s risk of experiencing less than half their mean
overall insulin effect (hyperglycaemic risk)
0.5%
7.5%
15.5%
The subject’s risk of experiencing more than twice their mean
maximal insulin effect (hypoglycaemic risk)
0.1%
33
2.7%
Data from study1450 (T. Heise et al. Diabetes 2003;52 (Suppl.1): A121)
Novo Nordisk • Clinical presentation of insulin detemir •
6.5%
Mean fluctuation from individual
average blood glucose (mmol/L)
Mean fluctuation from average blood
glucose level across the day in
monitored type 1 patients
Daytime
Nocturnal
3
2
1
0
–1
–2
6
10
14
18
Time (hours)
34
Insulin detemir
NPH insulin
D. Russell-Jones et al. Diabetologia 2002;45(Suppl. 2):A51
Novo Nordisk • Clinical presentation of insulin detemir •
22
2
6
Within-subject variability of
self-monitored pre-breakfast glucose
concentrations
Insulin detemir
Trial
Mean (mmol/l) SD
NPH insulin
Mean (mmol/l) SD
p (SD)
1335
7.6
2.8
8.4
3.6
< 0.001
1447
7.9
2.6
8.2
3.1
< 0.001
1448
8.2
2.9
9.0
3.5
< 0.001
1336*
7.5
1.3
7.6
1.4
< 0.05
1374**
7.8
2.6
8.3
3.0
< 0.0001
*Type 2 diabetes
**Analogue vs. HI
35
Novo Nordisk • Clinical presentation of insulin detemir •
Hypoglycaemia
36
Novo Nordisk • Clinical presentation of insulin detemir •
Return to Agenda
Overall hypoglycaemic event rate
by study
12 months
12 months
37
Novo Nordisk • Clinical presentation of insulin detemir •
6 months
6 months
Nocturnal hypoglycaemic event rate
by study in type 1 diabetes
12 months
38
Novo Nordisk • Clinical presentation of insulin detemir •
12 months
6 months
Monthly rate of hypoglycaemic events
in type 1 diabetes
39
P. Vague et al. Diabetes Care 2003;26(3):590-596
Novo Nordisk • Clinical presentation of insulin detemir •
Risk of all nocturnal hypoglycaemic
events in type 1 diabetes
40
I. De Leeuw et al. Diabetologia 2002;45(Suppl. 2):A257
Novo Nordisk • Clinical presentation of insulin detemir •
Relative risk for all hypoglycaemic
events: Insulin detemir vs. NPH insulin
Type 1 diabetes
HbA1c adjusted
Relative risk
(ID/NPH)
95% CI
Insulin aspart
as bolus*
0.79
0.66–0.94
0.009
Human soluble
insulin as bolus*
0.79
0.67–0.93
0.006
Type 2 diabetes
HbA1c adjusted
P
Relative risk
Insulin aspart
as bolus
(ID/NPH)
95% CI
0.92
0.48–1.77
P
0.810
*Meta-analyses of trials comparing insulin detemir with NPH insulin
in type 1 diabetes
41
Data on file: Novo Nordisk
Novo Nordisk • Clinical presentation of insulin detemir •
Body weight
42
Novo Nordisk • Clinical presentation of insulin detemir •
Return to Agenda
Weight gain with insulin therapy
• Seen in both type 1 and type 2 diabetes
• May worsen underlying defect in type 2 diabetes
• Barrier to starting insulin therapy in type 2 diabetes
• May decrease compliance with insulin regimens
• May lower self-esteem
43
Novo Nordisk • Clinical presentation of insulin detemir •
Weight gain in type 1 diabetes:
DCCT data
Initial 12 months
44
DCCT. Diabetes Care 1988;11:567-73 and Purnell et al. JAMA 1998;280:140-46
Novo Nordisk • Clinical presentation of insulin detemir •
Quartile of weight gain at
mean follow up, 6.1 years
Weight change in comparative trials in
type 1 diabetes
45
Novo Nordisk • Clinical presentation of insulin detemir •
Weight gain in type 2 diabetes:
UKPDS data
Change in weight (kg)
10.0
7.5
Intensive (Insulin)
5.0
2.5
Conventional
0
0
3
6
9
12
Years from randomisation
UKPDS Group (33). Lancet 1998;352:837-853
Novo Nordisk • Clinical presentation of insulin detemir •
15
Weight change over
6 months in type 2 diabetes
47
Data from study 1336. (T. Haak et al. Diabetes 2003;52( Suppl.1):A120
Novo Nordisk • Clinical presentation of insulin detemir •
Mean body weight (kg) and betweengroup difference at end of trials
Trial ID
Insulin detemir
NPH insulin
Difference:
Insulin detemir – NPH
[95% C.I.]
N
Mean
N
Mean
1181
209
76.1
206
76.3
–1.12
[–1.68, –0.56]*
1243
132
76.3
118
77.2
–1.58
[–2.61, –0.56]*
1205
278
71.2
136
71.7
–1.01
[–1.57, –0.45]*
1316
209
71.3
96
72.7
–1.44
[–2.19, –0.68]*
1335
460
76.3
234
76.5
–0.61
[–1.05, –0.17]*
1447
253
76.2
122
75.3
–0.95
[–1.46, –0.44]*
1448
263
75.1
122
76.4
–0.73
[–1.26, –0.21]*
1336
314
85.8
155
91.0
–0.77
[–1.41, –0.13]*
1374
285
73.0
283
74.1
–1.01
[–1.37, –0. 66]*
48
Novo Nordisk • Clinical presentation of insulin detemir •
Analogue versus human insulin-based basalbolus therapy: 8-point blood glucose profiles
49
K. Hermansen et al. ADS/ADEA Annual Scientific Meeting: Abstract 510
Novo Nordisk • Clinical presentation of insulin detemir •
Analogue versus human insulin-based
basal-bolus therapy: HbA1c
50
Data from study 1374 (K. Hermansen et al. ADS/ADEA Annual Scientific Meeting: Abstract 510)
Novo Nordisk • Clinical presentation of insulin detemir •
Analogue versus human insulin-based
basal-bolus therapy: Hypoglycaemia
51
Data from study 1374 (K. Hermansen et al. ADS/ADEA Annual Scientific Meeting: Abstract 510)
Novo Nordisk • Clinical presentation of insulin detemir •
Summary
Insulin detemir provides:
• A protracted and reproducible time-action profile
• Lower FPG than NPH insulin
• Reduced variability in comparison to NPH insulin and
insulin glargine
• A risk reduction for nocturnal hypoglycaemia
compared with NPH insulin
• A reduced risk of weight gain compared with NPH
insulin
52
Novo Nordisk • Clinical presentation of insulin detemir •
Return to Agenda