Clinical presentation. Novo Nordisk Clinical presentation of insulin detemir 1 Insulin detemir: Agenda Rationale: The need for a new basal insulin Pharmacology

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


Rationale: The need for a new basal insulin


The physiological insulin profile

Adapted from Polonsky et al. 1988


Basal-bolus therapy attempts torecreate the physiological insulin profile


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


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


NPH insulin Improved basal insulin

Pharmacokinetic limitations of subcutaneous exogenous basal insulin


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)


Variability in GIR profiles for 3 patients with type 1 diabetes following insulin glargine injection



The balance between control and tolerability: data from DCCT

New Engl J Med 1993;328:977


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


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


Pharmacology

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


Structure of insulin detemir


3-Dimensional structure of hexameric insulin

Human insulin Insulin detemir


Potential sites of protraction

In the subcutaneous depot

In the circulation

In the interstitial space

Subcutaneous

depot

Plasma compartment

Interstitial compartment


• 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


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


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


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)


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




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



D. Russell-Jones et al. Diabetologia 2002;45(Suppl. 2):A51

Clinical efficacy in type 1 and type 2

diabetes

Return to Agenda


9-point blood glucose profiles after 6 months’ therapy with once-daily insulin detemir or NPH insulin


Type 1 diabetes

*


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


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


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


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


Variability

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



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


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



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



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


Hypoglycaemia

Return to Agenda


Overall hypoglycaemic event rate by study

12 months

12 months

6 months 6 months


Nocturnal hypoglycaemic event rate by study in type 1 diabetes

12 months 12 months 6 months


Monthly rate of hypoglycaemic events in type 1 diabetes

P. Vague et al. Diabetes Care 2003;26(3):590-596


Risk of all nocturnal hypoglycaemic events in type 1 diabetes

I. De Leeuw et al. Diabetologia 2002;45(Suppl. 2):A257


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


Body weight

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


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


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


Weight change over 6 months in type 2 diabetes

Data from study 1336. (T. Haak et al. Diabetes 2003;52( Suppl.1):A120


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]*


Analogue versus human insulin-based basal-bolus therapy: 8-point blood glucose profiles

K. Hermansen et al. ADS/ADEA Annual Scientific Meeting: Abstract 510


Analogue versus human insulin-based basal-bolus therapy: HbA1c

Data from study 1374 (K. Hermansen et al. ADS/ADEA Annual Scientific Meeting: Abstract 510)


Analogue versus human insulin-based basal-bolus therapy: Hypoglycaemia

Data from study 1374 (K. Hermansen et al. ADS/ADEA Annual Scientific Meeting: Abstract 510)


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

Documents

Clinical presentation. Novo Nordisk Clinical presentation of insulin detemir 1 Insulin detemir: Agenda Rationale: The need for a new basal insulin Pharmacology