The Role of Modern Premixed Analogues in Clinical Practice

Raef M. Botros

Professor of Medicine

Ain Shams University

Facts & Figures about Diabetes

• 285 Million Diabetic patients 2010• 439 Million Diabetic patients 2030• 70% of diabetics live in developing

countries• 3.8 Million deaths per year• 1 Million amputations per year• 2.5 Million cases of retinopathy

per year

Source: IDF Diabetes Atlas 2010 - WHO

Presentation overview

• Does strict glycaemic control matter?

• Why and when should insulin be initiated?

• Psychological barriers for Insulin initiation

• Targets for glycaemic control

• Contribution of FPG & PPG to overall glycaemic control

• Biphasic Insulin Aspart 30: Superior glycaemic control & Safety profile

• Biphasic Insulin Aspart 30: improved convenience

• Conclusion

Improving control reduces risks oflong-term complications

Every 1% drop in HbA1c can reduce long-term diabetes complications

43%

Lower extremity amputation or fatal peripheral

vascular disease

37%

Microvascular disease

19%

Cataract extraction

14%

Myocardial infarction

16%

Heart failure

12%

Stroke

UKPDS: Stratton et al. BMJ 2000;32:405–12

HbA1c & Microvascular ComplicationsR

ela

tive R

isk

Retinopathy

Nephropathy

Neuropathy

Microalbuminuria

HbA1c (%)

15

13

11

9

7

5

3

1

6 7 8 9 10 11 12

Skyler JS. Endocrinol Metab Clin. 1996;25:243–254.

Poor glycaemic control leads toLong-term complications…

Diabetic nephropathy

Proliferativediabetic retinopathy

Atherosclerosis

Diabetic foot

Sections through an arterySections through an artery

Beta

-cell

fun

ctio

n (

%)

Years from diagnosis

50% beta-cells declined at time of diagnosis

0

50

100

75

25

Diagnosis

­12 8 0 4 8 12

The beginning of the beta-cell loss was estimated by extrapolation back to 100% function and the lack of significant insulin secretion by extrapolation forward.IGT=impaired glucose tolerance.Modified from Lebovitz HE. Diabetes Reviews. 1999;7:139-153.

Why is insulin initiation inevitable?

-4

Type 2 diabetes is a progressive disease

Glycaemic control deteriorates over time in type2 diabetic patients

Media

n H

bA

1c

(%

)

Years from randomisation

Recommended target ≤ 6.5†

2 4 6 8 100

GlibenclamideChlorpropamideMetformin

6

7

8

9

0

5

4

3

2

1

†Diabetes UK guidelinesUK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854–65

Typical range of HbA1c in people without diabetes

Patients on SU + Metformin with HbA1c > 8%

44%

68%79% 85%

0%

20%

40%

60%

80%

100%

First year Second year Third year Fourth year

Years­after­addition­of­SU­to­MET

Patients­with­A1c­>­8%

Not only OAD Mono-therapy fails but also Combination OADs fail too

Cook et al. Diabetes Care 2005; 28:995-1000

2220 patients with T2DM treated with SU+MET were studied in a retrospective analysis of electronic medical records from U.K.

Insulin use is often delayed, despite poor glycaemic control1,2

1­OAD

2­OADs

3­OADs

Diet

­2.9 years­­­­­ 4.7 years 2.5 years 2.7 years

Mean H

bA

1c a

t la

st

vis

it (%

)

8

9

10

8.8%

9.4% 9.1%

1Novo Nordisk. Type 2 Diabetes Market Research. 2Roper Starch US Study, 2000.

OAD, oral antidiabetic drug

Insulin use is often delayed, despite it is the most effective anti diabetic agent

Nathan DM. N Engl J Med. 2007;356:437-40.

12

Patient­Concerns:1. Anxiety about pain and proper injection technique

2. Fear of hypoglycaemia

3. Perceived restriction in lifestyle

4. Social embarrassment with pre-meal injections

5. Concern that disease has progressed to a serious level

Hunt et al. Diabetes Care 20(3):292, 1997

Psychological Barriers for insulin initiation

Patient­Concerns: Continue6.Timing of pre-meal injections 7.Sense of failure

8.Need for careful blood glucose monitoring

9.Concern that insulin will cause weight gain

Hunt et al. Diabetes Care 20(3):292, 1997

Psychological Barriers for insulin initiation

Physician Concerns:

1. Time requirement for teaching insulin therapy

2. Increased risk of severe hypoglycaemia

3. Worsened insulin resistance

4. Concern that insulin will cause weight gain

Hunt et al. Diabetes Care 20(3):292, 1997

Psychological Barriers for insulin initiation

ADA1 ACE/IDF2

HbA1c­(%) <7.0 6.5

Fasting/preprandial

90-130­mg/dl5.0-7.2­mmol/l­

<100­mg/dl<5.6­mmol/l

2-hour­postprandial

<180­mg/dl<10.0­mmol/l

<135­mg/dl<7.5­mmol/l

Targets for glycaemic control

For Optimal Management Should We Target……

FPG The basal

glucose level

PPGThe peak glucose level

HbA1cThe long-term average glucose level

Relative contributions of PPG and FPG to diurnal hyperglycaemia

Monnier et al. Diabetes Care 2003;26:881–5

0

10

20

30

40

50

60

70

80

90

100

<7.3 7.3–8.4 8.5–9.2 9.3–10.2 >10.2

HbA1c quintiles

Rela

tive c

ontr

ibuti

on

of

PPG

and

FPG

to d

iurn

al hyperg

lyca

em

ia (

%) Postprandial

glucose (PPG)

Fasting plasma glucose (FPG)

70%

FPG increases with worsening diabetes

30%

Treatment should cover meal times glucose peaks

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

NovoMix30 (Biphasic insulin aspart) What is Insulin aspart?

Absorption: human insulin vs. Insulin aspart

Insulin aspart

Insulinconcentr ation (M)

Absorption

Monomer

Capillary membrane

T-typehexamer

Dimer

R-typehexamer

10–3

10–4

10–6

10–8

Human insulin

This is purely schematic to illustrate absorption of molecules

Dual-release insulin concept: BHI 30

• Physiological insulin profile:basal componentmeal-related peaks

Physiological insulin profile

Hyperglycaemia

Hypoglycaemia

• Biphasic Human Insulin fails to re-create the physiological insulin profile

BHI 30

Jacobsen L et al. Eur J Clin Pharm 2000;56:399–403

Rationale for NovoMix 30 faster onset, more effective control and lower risk of hypoglycaemia

• Physiological insulin profile:basal componentmeal-related peaks

Physiological insulin profile

Protamine crystallised insulin aspart

• Rapid-acting insulin analogues together with a basal insulin provide physiological insulin replacement

Soluble insulin aspart• NovoMix® 30 replace both meal-related and basal insulin

NovoMix® 30

(30%)

(70%)

• Better PPG control

• Lower risk of hypoglycemia

Jacobsen L et al. Eur J Clin Pharm 2000;56:399–403

Improved Glycaemic control with NovoMix 30 Once or twice-daily

Garber­study­(1-2-3)

• Aim: To assess whether addition of NovoMix30 could achieve AACE, IDF and ADA guidelines in type 2 diabetic patients failed on OADs

• Method: – 100 patients had diabetes > 12 months – Using 2 OADs or at least one OAD plus once-daily basal

insulin – HbA1c level is between (7.5% and <10%) and the

average is 8.6%

Garber et al. Diabetes Obes Metab 2006;8(1):58-66

HbA1c reduction with NovoMix 30 Once- & twice-daily

Garber et al. Diabetes Obes Metab 2006;8(1):58-66

HbA1c

Conclusion:This trial demonstrates that initiation of NovoMix30 to type 2 patients poorly controlled on OAD was an effective­treatment­approach

HbA1c reduction using NovoMix 30 in 6 international studies

INITIATE EuroMix ACTION PREFER 1-2-3 IMPROVETM

9.7%

6.9%

9.2%

7.5%

8.1%

6.5%

8.4%

7.2%

6.5

7.0

7.5

8.0

8.5

9.0

9.5

10.0

8.6%

7.2%

HbA

1c (%

)

9.4%

7.1%

HbA1c

1- McSorley PT et al. Clin Ther 2002;24(4):530–539­

2- Kann PH et al. Insulin Therapy in Type 2 Diabetes ... Exp Clin Endocrinol Diabetes 2006; 114: 527–532

3- Diabetes, Obesity and Metabolism, 2008

4- Garber et al. Diabetes Obes Metab 2006;8(1):58-66

5-The American Journal of Medicine (2009) 122, 1043-1049

6- P.Valensi ,2009 Int J Clin Pract

*1

*3

*2

*4

*5

*6

Boehm B et al. Diabet Med 2002;19(5):393–399

Significantly lower prandial glucose

increment with NovoMix® 30

0

0.5

1

1.5

2

2.5

3

BiAsp 30 BHI 30

Mean p

randia

l glu

cose

in

crem

ent

(mm

ol/l)

p < 0.02 between treatment groups

(n = 128) (n = 141)

29%reduction

PPG

Reduced glucose excursionsvs. Lispro Mix25TM and BHI 30

p < 0.05

–10%

p < 0.001

–17%

0

13

14

15

16

17

18

19

20

21

Lispro Mix 25TM NovoMix® 30 BHI 30

Blo

od

glu

cose

exc

urs

ion

0– 5

h (m

mo

l/l h

)

Hermansen K et al. Diabetes Care 2002;25:883–888

PPG

FPG reduction using NovoMix 30 in 6 international studies

14.0

INITIATE EuroMix ACTION PREFER 1-2-3 IMPROVETM

11.011.0

9.6

0

6

7

8

9

10

11

12

FPG

(mm

ol/L)

9.2

6.4

13

14

7.1

8.6

7.2

8.1

10.9

6.6

0

100

150

200

250

FPG

(mg/d

L)

FPG

1- McSorley PT et al. Clin Ther 2002;24(4):530–539­

2- Kann PH et al. Insulin Therapy in Type 2 Diabetes ... Exp Clin Endocrinol Diabetes 2006; 114: 527–532

3- Diabetes, Obesity and Metabolism, 2008

4- Garber et al. Diabetes Obes Metab 2006;8(1):58-66

5-The American Journal of Medicine (2009) 122, 1043-1049

6- P.Valensi ,2009 Int J Clin Pract

*5

*2

*1

*3

*4

*6

Reduced major hypoglycaemia after 3 months

Nu

mb

er o

f h

ypo

gly

caem

ic e

pis

od

es

0

5

10

15

20

25

30

35

40

45

NovoMix® 30 BHI 30

42 events

20 events

52% relative risk reduction

Boehm B et al. Diabet Med 2002;19(5):393–399

(n = 138) (n = 153)

Warren ML et al. Diabetes Res Clin Pract 2004;66(1):23-29

After­preprandial­injection

After­postprandial­injection

Mean p

lasm

a g

luco

se (

mg/d

l)

-15 60 120 180 240Time (minutes)

Blood glucose levels did not differ between injection times

37-41%­lower­injection­force­than­KwikPen®

Next Generation FlexPen®

APROM ID: 1062Created: October 2009

Next Generation FlexPen® has lower injection force

than SoloSTAR® and KwikPen®

With NovoFine® 32G Tip needleMean injection force of Next Generation FlexPen®, SoloSTAR® and KwikPen® at three different injection speeds

15-22%­lower­injection­force­than­SoloSTAR®

Asakura et al. Evaluation of injection force of three insulin delivery pens. Expert Opin Pharmacother 2009;10:1389-1393

How to start NovoMix30

Simple intensification with the same insulin in the same device

NovoMix 30 core data sheet June 2008

Conclusion:

Strong relation exists between A1C reduction and reduction of

microvascular complications

Glycaemic control deteriorates over time in type2 patients

using OADs

Insulin use is often delayed, despite poor glycaemic control `

NovoMix® 30 FlexPen® provides superior glycaemic control

& significant reduction in major hypoglycemia

NovoMix® 30 FlexPen® offers convenient mealtime flexibility

THANK YOU