Transcript Insulin detemir
Clinical presentation
Insulin detemir: Agenda
Rationale: The need for a new basal insulin
Clinical efficacy in type 1 and type 2 diabetes
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: • • HbA 1c 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 Improved basal insulin 7 Novo Nordisk • Clinical presentation of insulin detemir •
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 Human insulin Insulin receptor affinity
100
Metabolic potency
100
IGF-I receptor affinity
100
IGF-IR/IR affinity
1
Mitogenic potency (Saos/B10 cells)
100 2.9
975 ± 173
B10 Asp Insulin lispro Insulin aspart
205 ± 20 207 ± 14 587 ± 50 84 ± 6 92 ± 6
Insulin glargine Insulin detemir
86 ± 3
18 - 46
82 ± 3 101 ± 2 60 ± 3
27
156 ± 16 81 ± 9 641 ± 51
16 ± 1
0.9
1.9
7.5
0.9
66 ± 10 58 ± 22 783 ± 13
11
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 •
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 Insulin detemir 16 Novo Nordisk • Clinical presentation of 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 Protracted absorption ‘Buffering’ effect and minor contribution to protraction 18 Novo Nordisk • Clinical presentation of insulin detemir •
Albumin binding buffers against changes in absorption rate 225 200 175 150 125 100 Absorption rate from subcutaneous depot Interstitial human insulin (muscle/fat) Interstitial detemir (muscle/fat) 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 Duration of action (hr) GIR max Pharmacodynamic parameters for insulin detemir and NPH Insulin detemir (mg/kg/min) 0.2 U/kg 12 1.1
0.4 U/kg 20 1.7
NPH 0.3 IU/kg 13 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 •
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 HbA 1C (%) Office FPG (mM) Insulin detemir
q 12 hour
7.75 9.75
Home FBG (mM)
8.28
Insulin detemir
am + bed
7.78 8.94
NPH insulin
am + bed
7.94
11.24
p
-value
= 0.08
< 0.001
8.26
9.05
= 0.005
Baseline HbA 1c = 8.60% 27 Novo Nordisk • Clinical presentation of insulin detemir •
Insulin detemir consistently achieves lower FPG values than NPH insulin
Trial 1335 1447 1448 Insulin detemir N 453 252 261 1336* 309 mmol/l endpoint 10.6
9.5
9.3
9.7
N 230 125 119 152 NPH insulin mmol/l endpoint 11.7
11.1
11.2
9.6
Difference Insulin detemir – NPH mmol/l (95% CI) –1.2 (–1.8, –0.5) –1.6 (–2.5, –0.8) –1.9 (–2.8, –1.0) 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 28 Novo Nordisk • Clinical presentation of insulin detemir •
HbA 1c : Meta-analysis of phase 3 trials in type 1 diabetes
N Insulin detemir (a) Mean (SE) 983 8.30% (0.01%) N 485 NPH insulin (b) Mean (SE) 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 •
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
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% 2.7% 6.5% 33 Data from study1450 (T. Heise
et al
.
Diabetes
2003;52 (Suppl.1): A121) Novo Nordisk • Clinical presentation of insulin detemir •
Mean fluctuation from average blood glucose level across the day in monitored type 1 patients
Daytime Nocturnal –1 –2 3 2 1 0 6 10 14 18 Time (hours) 22 2 6 Insulin detemir NPH insulin 34 D. Russell-Jones
et al. Diabetologia
2002;45(Suppl. 2):A51 Novo Nordisk • Clinical presentation of insulin detemir •
Within-subject variability of self-monitored pre-breakfast glucose concentrations
Trial 1335 1447 1448 1336 * 1374** Insulin detemir Mean (mmol/l)
SD
7.6
7.9
8.2
7.5
7.8
2.8
2.6
2.9
1.3
2.6
*Type 2 diabetes **Analogue vs. HI 35 Novo Nordisk • Clinical presentation of insulin detemir • NPH insulin Mean (mmol/l)
SD
8.4
8.2
9.0
7.6
8.3
3.6
3.1
3.5
1.4
3.0
p (SD)
< 0.001
< 0.001
< 0.001
< 0.05
< 0.0001
Hypoglycaemia
36 Novo Nordisk • Clinical presentation of insulin detemir •
Overall hypoglycaemic event rate by study 12 months 12 months 6 months 6 months
37 Novo Nordisk • Clinical presentation of insulin detemir •
Nocturnal hypoglycaemic event rate by study in type 1 diabetes 12 months 12 months 6 months
38 Novo Nordisk • Clinical presentation of insulin detemir •
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
Relative risk
HbA 1c adjusted Insulin aspart as bolus * Human soluble insulin as bolus *
(ID/NPH)
0.79
0.79
95% CI
0.66–0.94
0.67–0.93
P
0.009
0.006
Type 2 diabetes
Relative risk (ID/NPH)
95% CI
P
HbA 1c 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 41 Data on file: Novo Nordisk Novo Nordisk • Clinical presentation of insulin detemir •
Body weight
42 Novo 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 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 10.0
7.5
5.0
2.5
0 0 Intensive (Insulin) Conventional 3 6 9 12 Years from randomisation 15
UKPDS Group (33).
Lancet
1998;352:837-853 Novo Nordisk • Clinical presentation of insulin detemir •
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 between group difference at end of trials Trial ID 1181 1243 1205 1316 1335 1447 1448 1336 1374 Insulin detemir N Mean 209 76.1
132 76.3
278 71.2
209 71.3
460 76.3
253 76.2
263 75.1
314 85.8
285 73.0
NPH insulin N Mean 206 76.3
118 77.2
136 71.7
96 72.7
234 76.5
122 75.3
122 76.4
155 91.0
283 74.1
Difference: Insulin detemir – NPH [95% C.I.] –1.12 [–1.68, –0.56]* –1.58 [–2.61, –0.56]* –1.01 [–1.57, –0.45]* –1.44 [–2.19, –0.68]* –0.61 [–1.05, –0.17]* –0.95 [–1.46, –0.44]* –0.73 [–1.26, –0.21]* –0.77 [–1.41, –0.13]* –1.01 [–1.37, –0. 66]*
48 Novo Nordisk • Clinical presentation of insulin detemir •
Analogue versus human insulin-based basal bolus 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: HbA 1c
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 •