Clinical presentation. Novo Nordisk Clinical presentation of insulin detemir 1 Insulin detemir:...
-
Upload
archibald-kelly -
Category
Documents
-
view
219 -
download
1
Transcript of Clinical presentation. Novo Nordisk Clinical presentation of insulin detemir 1 Insulin detemir:...
Clinical presentation
2Novo Nordisk • Clinical presentation of insulin detemir •
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
3Novo Nordisk • Clinical presentation of insulin detemir •
Rationale: The need for a new basal insulin
4Novo Nordisk • Clinical presentation of insulin detemir •
The physiological insulin profile
Adapted from Polonsky et al. 1988
5Novo Nordisk • Clinical presentation of insulin detemir •
Basal-bolus therapy attempts torecreate the physiological insulin profile
6Novo 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
7Novo Nordisk • Clinical presentation of insulin detemir •
Therapeutic potential of intensive analogue-based insulin therapyAchievement 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
8Novo Nordisk • Clinical presentation of insulin detemir •
NPH insulin Improved basal insulin
Pharmacokinetic limitations of subcutaneous exogenous basal insulin
9Novo Nordisk • Clinical presentation of insulin detemir •
Variability in glucose infusion rate (GIR) profiles for 3 patients with type 1 diabetes following NPH injection
Data from study1450 (T. Heise et al. Diabetes 2003;52 (Suppl.1): A121)
10Novo Nordisk • Clinical presentation of insulin detemir •
Variability in GIR profiles for 3 patients with type 1 diabetes following insulin glargine injection
Data from study1450 (T. Heise et al. Diabetes 2003;52 (Suppl.1): A121)
11Novo Nordisk • Clinical presentation of insulin detemir •
The balance between control and tolerability: data from DCCT
New Engl J Med 1993;328:977
12Novo 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
13Novo Nordisk • Clinical presentation of insulin detemir •
Insulin receptor affinity
Metabolic
potency
IGF-I recepto
r affinity
IGF-IR/IRaffinity
Mitogenic potency
(Saos/B10 cells)
Human insulin
100 100 100 1 100
B10 Asp 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 11Adapted from P. Kurtzhals et al. Diabetes 2000;49:999
Receptor binding, metabolic and mitogenic potency of insulin analogues
14Novo Nordisk • Clinical presentation of insulin detemir •
Pharmacology
Return to Agenda
15Novo Nordisk • Clinical presentation of insulin detemir •
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
16Novo Nordisk • Clinical presentation of insulin detemir •
Structure of insulin detemir
17Novo Nordisk • Clinical presentation of insulin detemir •
3-Dimensional structure of hexameric insulin
Human insulin Insulin detemir
18Novo Nordisk • Clinical presentation of insulin detemir •
Potential sites of protraction
In the subcutaneous depot
In the circulation
In the interstitial space
Subcutaneous
depot
Plasma compartment
Interstitial compartment
19Novo Nordisk • Clinical presentation of insulin detemir •
• Self association (hexameric)
• Fatty acid side chains bind to albumin in injection depot
• Albumin binding in circulation
Protracted absorption
Insulin detemir Mode of protraction
‘Buffering’ effect and minor contribution to protraction
20Novo Nordisk • Clinical presentation of insulin detemir •
Albumin binding buffers against changes in absorption rate
DurationCalculated effect of a 60-minute doubling of absorption rate on the interstitial concentrations of NPH insulin and insulin detemir
0
75
125
150
175
0 60 120 240 360
Ab
sorp
tion
an
d r
ela
tive
ch
an
ge in
peri
ph
ery
(%
)
100
300180
200
225 Absorption rate from subcutaneous depot
Interstitial human insulin (muscle/fat)
Interstitial detemir (muscle/fat)
Data on file: Novo Nordisk
21Novo Nordisk • Clinical presentation of insulin detemir •
Safety of albumin binding (1)
• Plasma concentration of HSA ~600 x 10-6 M
• FFA binding sites/HSA molecule at least 8
• Plasma concentration of FFA ~300 x 10-6 M
• Insulin detemir conc. at therapeutic dose <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
22Novo 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
P. Kurtzhals et al. Journal of Pharmaceutical Sciences 1997;86(12)
23Novo Nordisk • Clinical presentation of insulin detemir •
Pharmacodynamic profile of insulin detemir - subjects with type 1 diabetesPharmacodynamic 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
Adapted from T. Pieber et al. Diabetes 2002;51(Suppl. 2):A53
Insulin detemir 0.2 U/kg
Insulin detemir 0.3 U/kg
Insulin detemir 0.4 U/kg
24Novo 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
Data from study1450 (T. Heise et al. Diabetes 2003;52 (Suppl.1): A121)
25Novo Nordisk • Clinical presentation of insulin detemir •
D. Russell-Jones et al. Diabetologia 2002;45(Suppl. 2):A51
Clinical efficacy in type 1 and type 2
diabetes
Return to Agenda
26Novo Nordisk • Clinical presentation of insulin detemir •
9-point blood glucose profiles after 6 months’ therapy with once-daily insulin detemir or NPH insulin
D. Russell-Jones et al. Diabetologia 2002;45(Suppl. 2):A51
Type 1 diabetes
*
27Novo Nordisk • Clinical presentation of insulin detemir •
FPG at baseline and after 16 weeksin subjects with type 1 diabetes
Data from 1448 study (P. Home et al. Diabetes 2003;52(Suppl. 1):A122)
p = 0.004
28Novo Nordisk • Clinical presentation of insulin detemir •
Glycaemia results
Baseline HbA1c = 8.60%
Insulin detemirq 12 hour
Insulin detemi
ram + bed
NPHinsulinam + bed
p-value
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
29Novo Nordisk • Clinical presentation of insulin detemir •
Insulin detemir consistently achieves lower FPG values than NPH insulinInsulin detemir NPH insulin DifferenceTrial N mmol/l
endpointN mmol/l
endpointInsulin 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†
–1.1 p < 0.0001
*Study in type 2 diabetes † Meta-analysis of trials 1181, 1205, 1335, 1447, 1448
30Novo Nordisk • Clinical presentation of insulin detemir •
HbA1c: Meta-analysis of phase 3 trials in type 1 diabetes
Insulin detemir (a)
NPH insulin (b)
Difference (a-b) after 4–6 months
N Mean (SE) N Mean (SE) Mean, p
983 8.30% (0.01%)
485 8.41% (0.11%)
–0.11% p < 0.05
Endpoint data from three trials (1335, 1447, 1448) comparing insulin detemir with NPH insulin in basal-bolus therapy
31Novo Nordisk • Clinical presentation of insulin detemir •
Variability
Return to Agenda
32Novo Nordisk • Clinical presentation of insulin detemir •
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
Data from study1450 (T. Heise et al. Diabetes 2003;52 (Suppl.1): A121)
33Novo Nordisk • Clinical presentation of insulin detemir •
Reproducibility: Probability ranges for blood glucose lowering effect of repeated injections
95% probability ranges for individual pharmacodynamic responses relative to the mean
T. Heise et al. Diabetes 2003;52(Suppl.1):A121
Avera
ge G
IR o
ver
24
hours
34Novo Nordisk • Clinical presentation of insulin detemir •
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% 2.7% 6.5%
Implications of within-subject pharmacodynamic variability
Data from study1450 (T. Heise et al. Diabetes 2003;52 (Suppl.1): A121)
35Novo Nordisk • Clinical presentation of insulin detemir •
3
2
1
Mea
n fl
uctu
atio
n fr
om in
divi
dual
aver
age
bloo
d gl
ucos
e (m
mol
/L)
0
–1
–26 14 18 22 6210
Time (hours)
Insulin detemir
NPH insulin
Daytime Nocturnal
Mean fluctuation from average blood glucose level across the day in monitored type 1 patients
D. Russell-Jones et al. Diabetologia 2002;45(Suppl. 2):A51
36Novo Nordisk • Clinical presentation of insulin detemir •
Within-subject variability of self-monitored pre-breakfast glucose concentrations
Insulin detemir NPH insulin
Trial Mean (mmol/l) SD 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
37Novo Nordisk • Clinical presentation of insulin detemir •
Hypoglycaemia
Return to Agenda
38Novo Nordisk • Clinical presentation of insulin detemir •
Overall hypoglycaemic event rate by study
12 months
12 months
6 months 6 months
39Novo Nordisk • Clinical presentation of insulin detemir •
Nocturnal hypoglycaemic event rate by study in type 1 diabetes
12 months 12 months 6 months
40Novo Nordisk • Clinical presentation of insulin detemir •
Monthly rate of hypoglycaemic events in type 1 diabetes
P. Vague et al. Diabetes Care 2003;26(3):590-596
41Novo Nordisk • Clinical presentation of insulin detemir •
Risk of all nocturnal hypoglycaemic events in type 1 diabetes
I. De Leeuw et al. Diabetologia 2002;45(Suppl. 2):A257
42Novo Nordisk • Clinical presentation of insulin detemir •
Relative risk for all hypoglycaemic events: Insulin detemir vs. NPH insulin
Data on file: Novo Nordisk
Type 1 diabetes Relative risk
(ID/NPH) 95% CI P
HbA1c adjusted 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 Relative risk
(ID/NPH) 95% CI P
HbA1c adjusted Insulin aspart as bolus
0.92 0.48–1.77 0.810
*Meta-analyses of trials comparing insulin detemir with NPH insulin in type 1 diabetes
43Novo Nordisk • Clinical presentation of insulin detemir •
Body weight
Return to Agenda
44Novo Nordisk • Clinical presentation of insulin detemir •
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
45Novo Nordisk • Clinical presentation of insulin detemir •
Weight gain in type 1 diabetes: DCCT data
DCCT. Diabetes Care 1988;11:567-73 and Purnell et al. JAMA 1998;280:140-46
Initial 12 months Quartile of weight gain at mean follow up, 6.1
years
46Novo Nordisk • Clinical presentation of insulin detemir •
Weight change in comparative trials in type 1 diabetes
Novo Nordisk • Clinical presentation of insulin detemir •
Ch
an
ge in
weig
ht
(kg
)
0 3 6 9 12 15
0
2.5
5.0
7.5 Intensive (Insulin)
Conventional
Years from randomisation
10.0
Weight gain in type 2 diabetes: UKPDS data
UKPDS Group (33). Lancet 1998;352:837-853
48Novo Nordisk • Clinical presentation of insulin detemir •
Weight change over 6 months in type 2 diabetes
Data from study 1336. (T. Haak et al. Diabetes 2003;52( Suppl.1):A120
49Novo Nordisk • Clinical presentation of insulin detemir •
Mean body weight (kg) and between- group difference at end of trials
Trial ID Insulin detemir
N Mean
NPH insulin
N Mean
Difference: Insulin detemir –
NPH [95% C.I.]
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]*
50Novo Nordisk • Clinical presentation of insulin detemir •
Analogue versus human insulin-based basal-bolus therapy: 8-point blood glucose profiles
K. Hermansen et al. ADS/ADEA Annual Scientific Meeting: Abstract 510
51Novo Nordisk • Clinical presentation of insulin detemir •
Analogue versus human insulin-based basal-bolus therapy: HbA1c
Data from study 1374 (K. Hermansen et al. ADS/ADEA Annual Scientific Meeting: Abstract 510)
52Novo Nordisk • Clinical presentation of insulin detemir •
Analogue versus human insulin-based basal-bolus therapy: Hypoglycaemia
Data from study 1374 (K. Hermansen et al. ADS/ADEA Annual Scientific Meeting: Abstract 510)
53Novo Nordisk • Clinical presentation of insulin detemir •
SummaryInsulin 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
Return to Agenda