Insulins and Insulin DeliveryInsulins and Insulin Delivery

Rob DyerRob Dyer

6 February 20096 February 2009

Case 1Case 1

37 year old man referred by GP. 37 year old man referred by GP. Type 1 diabetes for 18 years. HbA1c Type 1 diabetes for 18 years. HbA1c

consistently 9.0 – 10.5%consistently 9.0 – 10.5%Was on bd H Mixtard until 2002. Was on bd H Mixtard until 2002.

Transferred to Actrapid 20, 20, 20 and H Transferred to Actrapid 20, 20, 20 and H Insulatard 20 when in hospital in 2002.Insulatard 20 when in hospital in 2002.

‘‘Would he be a good candidate for Would he be a good candidate for Glargine?’Glargine?’

Miss RL – HbA1cMiss RL – HbA1c

4

6

8

10

12

14

16

18

HbA1c

Normal range

Target

Age 10Age 17

Glycaemic excursion and Glycaemic excursion and Premixed insulinPremixed insulin

Glucose Sensor Profile: 25-May-03

-5.0

0.0

5.0

10.0

15.0

20.0

12:00 AM 4:00 AM 8:00 AM 12:00 PM 4:00 PM 8:00 PM 12:00 AM

Time

Glu

cose

Co

nce

ntr

atio

n (

mm

ol/L

)

Meter Value

Paired Meter Value

Sensor Value

Insulin

Meal

Exercise

Other

DCCT Effect of intensive therapy on DCCT Effect of intensive therapy on complications and hypoglycaemiacomplications and hypoglycaemia

Intensive education, the Intensive education, the German experience.German experience.

1983 Muhlhauser et al (Michael Berger). 5 1983 Muhlhauser et al (Michael Berger). 5 day intensive educational programme for day intensive educational programme for patients with Type 1 diabetespatients with Type 1 diabetes

636 patients 636 patients

6 years of follow up6 years of follow up

Sustained improvement in HbA1c to 7.6%Sustained improvement in HbA1c to 7.6%

Reduced risk of hypoglycaemiaReduced risk of hypoglycaemiaRefs Refs Mulhauser I et al, Diabetologia 25;470-6, 1983Mulhauser I et al, Diabetologia 25;470-6, 1983

Bott S et al, Diabetologia 40:926-32, 1997Bott S et al, Diabetologia 40:926-32, 1997

Food ComparisonsFood Comparisons

How much carbohydrate?How much carbohydrate?

SALAD MEALSALAD MEAL

15g

Lettuce minimalCucumber "Tomatoes "Radish "Red Pepper "Cold chicken "Mayonnaise "Crisps 15g

Italian MealItalian Meal

Garlic Bread

Whole Pizza

Ice Cream

???g

Italian MealItalian Meal

Garlic Bread 70g

Whole Pizza 100g

Ice Cream 30g

200g

Mrs BS (3 months after course)Mrs BS (3 months after course)

Running marathonsRunning marathons

1 unit insulin: 12g CHO when inactive1 unit insulin: 12g CHO when inactive

1 unit insulin: 20g CHO when active1 unit insulin: 20g CHO when active

No nocturnal hyposNo nocturnal hypos

HbA1c 7.9% (9.5% before course)HbA1c 7.9% (9.5% before course)

Mrs BS (4)Mrs BS (4)

Insulin dose before courseInsulin dose before course

Lispro Lispro 8, 8, 88, 8, 8

Humulin IHumulin I 88 3232

Insulin dose after courseInsulin dose after course

LisproLispro 9 approx9 approx

Humulin I Humulin I 55 1414

Case 1 (contin)Case 1 (contin)

Has completed CHO counting course.Has completed CHO counting course.

HbA1c 8.9%HbA1c 8.9%

On Novorapid variable doses with mealsOn Novorapid variable doses with meals

H Insulatard at bedtime 22 unitsH Insulatard at bedtime 22 units

Prone to hypos if increases H Insulatard.Prone to hypos if increases H Insulatard.

What are the options?What are the options?

Short acting analoguesShort acting analogues

Are more convenient to take than standard Are more convenient to take than standard soluble insulinsoluble insulin

Give better post-prandial glycaemic controlGive better post-prandial glycaemic control

Probably do not result in better HbA1cProbably do not result in better HbA1c

May reduce hypoglycaemiaMay reduce hypoglycaemia

1530 Levemir® vs. NPH in treat-to-1530 Levemir® vs. NPH in treat-to-target trial: Hypoglycaemiatarget trial: Hypoglycaemia

Hypoglycaemia

Hermansen K, et al., Diabetologia 2004;47(Supplement 1):A273

Within-patient variability with NPH insulinWithin-patient variability with NPH insulin

Selected clamp profiles on 4 identical study days for 8 out of 17 subjects on NPH who completed the study

The CV for all 17 patients on NPH who completed the study was 68%

Heise, T. et al., Diabetes, 2004; Vol. 53: 1614-1620Data on file: InsDet 09 2004

Within-patient variability with LevemirWithin-patient variability with Levemir®®

Selected clamp profiles on 4 identical study days for 8 out of 18 subjects on Levemir® who completed the study

The CV for all 18 patients on Levemir® who completed the study was 27%

Heise, T. et al., Diabetes, 2004; Vol. 53: 1614-1620Data on file: InsDet 09 2004

6

7

8

9

10

11

12

1 2 3

HbA1c (%)

Post-

Baseline Post-CSIIPost-TIFA

Changes in HbA1c during transfer to Pump therapy (CSII)

Individual patients

Torbay CSII First 11 patientsTorbay CSII First 11 patients

5

6

7

8

9

10

11

12

13

14

6months

12month

18month

2 years 3 years 4 years

8.4

9.6

8.3

8

8.1

11.9

7.4

6.5

7.5

7.7

9.3

Other benefits of CSIIOther benefits of CSII

Reduction in hypoglycaemiaReduction in hypoglycaemiaReduction of post-prandial glucose excursionReduction of post-prandial glucose excursionReduction in Hba1c (in the majority)Reduction in Hba1c (in the majority)Easier to manage illnessEasier to manage illnessManagement of ‘dawn phenomenon’Management of ‘dawn phenomenon’

Less swings in blood glucose levelsLess swings in blood glucose levelsImproved QOL.Improved QOL.Feeling in controlFeeling in control‘‘Patient power’Patient power’

Primary Care Insulin InitiationPrimary Care Insulin Initiation

A practice is just starting out on insulin A practice is just starting out on insulin initiation in Type 2 diabetes.initiation in Type 2 diabetes.

The staff find it confusing that there are so The staff find it confusing that there are so many insulins.many insulins.

They ask you to advise them on a limited They ask you to advise them on a limited range to make life simpler as they are range to make life simpler as they are starting out.starting out.

What would you advise?What would you advise?

4T Baseline Characteristics4T Baseline CharacteristicsBiphasic Prandial Basal

N=235 N=239 N=234

Age (years) 61.7 ±8.9 61.6 ±10.5 61.9±10.0Diabetes duration (years)* 9 (6-2) 9 (6-4) 9 (6-12)

Body weight (kg) 86.9 ±16.8 84.9 ±14.4 85.5 ±16.3Body mass index (kg/m2) 30.2 ±4.8 29.6 ±4.5 29.7 ±4.6

HbA1c (%) 8.6 ±0.8 8.6 ±0.8 8.4 ±0.8Fasting plasma glucose (mmol/l) 9.7 ±2.8 9.6 ±2.7 9.5 ±2.6

LDL cholesterol (mmol/l) 2.5 ±0.7 2.4 ±0.7 2.3 ±0.7HDL cholesterol (mmol/l) 1.0 ±0.3 1.0 ±0.2 1.0 ±0.3Triglycerides (mmol/l)* 1.6 (1.2-2.1) 1.5 (1.2-2.3) 1.5 (1.1-2.2)

No significant differences between groups *interquartile range

N Engl J Med 2007; 357: 1716-30

RandomisationRandomisation

* Intensify to a combinationinsulin regimen in year one if unacceptable hyperglycaemia

708T2DM

on dual OAD

Add biphasic insulintwice a day

Add prandial insulinthree times a dayR

Year 1Comparison of three

single insulin regimens,added to OADs*

Add basal insulinonce (or twice) daily

Add prandial insulinat midday

Add basal insulinbefore bed

Years 2 and 3If HbA1c >6.5%, stop

sulfonylurea and add a second insulin formulation

Add prandial insulinthree times a day

N Engl J Med 2007; 357: 1716-30

Insulin Dose AdjustmentsInsulin Dose Adjustments

Morning injection of basal insulin 34% (n=79) of patients randomised to pre-bedtime

basal insulin required, per protocol, an additional morning injection by one year

Adherence to dose adjustment suggestions (±10%) Biphasic 89.7% Prandial 80.4% Basal 90.2%

N Engl J Med 2007; 357: 1716-30

Primary Outcome: HbAPrimary Outcome: HbA1c1c at One Year at One Year

— Biphasic— Prandial— Basal

Mean ±SD at 1 year (%)7.3±0.9

Baseline to 1 year (%)-1.3±1.1

7.2±0.9, p=0.08 vs. biphasic7.6±1.0, p<0.001 vs. biphasic or prandial -0.8±1.0

-1.4±1.0

Months since randomisation

Gly

cate

d ha

emog

lobi

n (%

)

P<0.001

N Engl J Med 2007; 357: 1716-30

Glucose Profiles Before & After Starting InsulinGlucose Profiles Before & After Starting Insulin

— Biphasic— Prandial— Basal

Change in FPG (mmol/l))-2.5±3.1

Change in PPG (mmol/l)-3.8±3.5

-1.3±2.7-3.3±2.9 -2.6±3.0

-4.6±3.0p<0.001 vs. biphasicp<0.001 vs. biphasic or prandial

0

— At baseline

Hypoglycaemia (≥ Grade 2) at One YearHypoglycaemia (≥ Grade 2) at One Year

Months since randomisation

Pro

port

ion

with

eve

nts

(%)

P=0.001

— Biphasic— Prandial— Basal

Mean at 1 year (events/patient/year) 5.712.0, p<0.002 vs. biphasic 2.3, p=0.01 vs. biphasic, p<0.001 vs.prandial

N Engl J Med 2007; 357: 1716-30

Biphasic analogue insulins vs Biphasic analogue insulins vs standard biphasic insulinstandard biphasic insulin

Are more convenient to takeAre more convenient to take

May give better post-prandial controlMay give better post-prandial control

Probably don’t result in better HbA1cProbably don’t result in better HbA1c

Probably cause less hypoglycaemia than Probably cause less hypoglycaemia than standard biphasic insulinsstandard biphasic insulins

‘‘Convenience insulins’Convenience insulins’

Good devicesGood devices

Conclusions – Conclusions –

In 518 patients with type 2 diabetes, once daily In 518 patients with type 2 diabetes, once daily bedtime insulin glargine is as effective as once or bedtime insulin glargine is as effective as once or twice daily NPH in improving and maintaining twice daily NPH in improving and maintaining glycemic control.glycemic control.

Conclusions – Conclusions –

In 518 patients with type 2 diabetes, once daily bedtime In 518 patients with type 2 diabetes, once daily bedtime insulin glargine is as effective as once or twice daily insulin glargine is as effective as once or twice daily NPH in improving and maintaining glycemic control.NPH in improving and maintaining glycemic control.

ButBut

All patients were taking multiple injection therapyAll patients were taking multiple injection therapy

Raskin P, Rojas P, Hu P et al. Comparison of twice-daily biphasic insulin aspart 70/30 (NovoLog Mix® 70/30) with once-daily insulin glargine in patients with type 2 DM on

oral antidiabetic agents. Diabetes Care 2005; 28; 260-5.

1530 Levemir® vs. NPH insulin 1530 Levemir® vs. NPH insulin Treat-to-target trial: WeightTreat-to-target trial: Weight

p<0.001

Hermansen K, et al., Diabetologia 2004;47(Supplement 1):A273

Baseline BMI

35

36

34

39

55

37

42

50

69

76

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

-0.5

Mean w

eig

ht

chan

ge (

kg)

25 >25-27 >27-29 >29-31 >31

Insulin detemir

NPH insulin

1530 Hermansen: Change in weight by 1530 Hermansen: Change in weight by baseline BMIbaseline BMI

K. Hermansen et al. EASD 2005

Type 1 effect of improved HbA1cType 1 effect of improved HbA1c

HbAHbA1c1c cross-sectional, median values

06

7

8

9

0 3 6 9 12 15

HbA

1c (%

)

Years from randomisation

Conventional

Intensive

6.2% upper limit of normal range

0.0

0.2

0.4

0.6

0 3 6 9 12 15

Prop

ortio

n of

pat

ient

s w

ith e

vent

s

Years from randomisation

Conventional (411)

Intensive (951)

Metformin (342)

Any diabetes related endpointAny diabetes related endpoint

M v Ip=0.0034

overweight patients

M v C p=0.0023