Premixed insulin dosing in actual practice

Premixed insulin dosing in actual practice

Anas Bahnassi PhD RPh

The Community Pharmacist’s Role in Diabetes Management 4

Conventional premixed insulin formulations

Insulin Onset of action

Peaks Duration

Humalog mix 75/25 or 50/50

Lispro + N

30 minutes

2 to 4 hours

22 to 24 hours

Humulin mix 70/30 or 50/50 R +N

Novolog mix 70/30

Aspart + N

Novolin mix 70/30

R+N 11/15/2013

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Step 3:Give 2 parts in the morning and 1 part in the evening

Morning=20U Evening=10 U

Premixed insulin dosing

Step1:First calculate the total daily starting requirement of insulin

2

Weight Body For a 60kg patient total daily dose =30 units

Step 2:Then divide this dose into 3 equal parts 10+10+10

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Premixed insulin dosing

Step1:First calculate the total daily starting requirement of insulin

2

Weight Body For a 60kg patient total daily dose =30 units

Another approach is to provide 50% of the dose In the morning and 50% at bedtime Other doses of 55:45 to 60:40 where morning doses exceed evening doses are preferable

Jung, C. H., et al. Diabetic Medicine (2013). 11/15/2013

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Dose titration

If the patients is using, 1-10 units………….….+/- 1 unit 11-20 units……………+/- 2 units 21-30 units……………+/- 3 units 31-40 units……………+/- 4 units…………………..

You can increase or decrease the dose of pre-mixed insulin by 10 %

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Advantages of premixed insulin

• Easy to administer for the physician

• Easy to fill and inject by the patient

• Provides both basal and bolus coverage with fewer number of injections.

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Disadvantages of premixed insulin

• No dose flexibility

• Increasing or decreasing the dose of one component if the premix will result in corresponding change to the other component.

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160

140

120

100

80

60

40

20

0

Insu

lin (m

U/m

L)

0800 1200 1600 2000 2400 0400

IGT

Type 2 diabetes

Twice-daily split mixed regimen

Nocturnal hypoglycemia

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160

140

120

100

80

60

40

20

0

Insu

lin (m

U/m

L)

0800 1200 1600 2000 2400 0400

IGT

Type 2 diabetes

Three-times-daily split mixed regimen

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The dual-release insulin concept

• Physiological insulin profile:

- meal-related peak

- basal component

• Rapid-acting insulin

analogue together with

a basal insulin analogue

provide physiological insulin

replacement

• Premix analogues mimic

physiological insulin secretion

Physiological insulin profile

Protamine crystallised insulin aspart

Rapid insulin analogue

Premix analogue

Profiles are schematic 11/15/2013

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Human vs. Analogue insulin mix

Weyer C, et al. Diabetes Care 1997;10:1612–1614

Glu

cose

infu

sio

n r

ate

(m

g/k

g/m

in) 12

8

6

4

2

0

10

0 240 480 720 960 1200 1400

Premixed human insulin

Humalog mix 30%

Dose = 0.3 U/kg n = 24 healthy volunteers

Time (min)

Faster onset of rapid-acting part and similar duration of the basal component compared with premixed human insulin

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Boehm B, et al. Diabet Med 2002;19:393–399

*

Blo

od

glu

cose

(m

mo

l/l)

*

0 Pre-

10

12

Post-

8

6

*

*

Lunch

Pre- Post-

Breakfast

Pre- Post-

Dinner

Bedtime 02.00 h

Premixed analogue insulin

Premixed human insulin

* p < 0.05

n = 294 type 1 and type 2 patients

Improved postprandial blood glucose after 3 months

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0

0.5

1

1.5

2

2.5

3

Analogue Premix human insulin Premix

Me

an p

ran

dia

l glu

cose

in

cre

me

nt

(mm

ol/

l) p < 0.02

(n = 128) (n = 141)

Boehm B, et al. Diabet Med 2002;19:393–399

Post-prandial blood glucose

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Boehm B, et al. Eur J Int Med 2004;15:496–502

Major hypoglycaemia episodes

0

2

4

6

8

10

12

1st year 2nd year Year of study

Pat

ien

ts w

ith

at

leas

t o

ne

maj

or

ep

iso

de

(%)

p = NS

p = 0.04

3

events

11

events

8

events

n = 125 type 2 diabetes patients

Human insulin Premix

Premixed Analogue

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Nocturnal hypoglycemia

McNally P, et al. Diabetologia 2004;47(Suppl 1):A327

CB

GM

R

ead

ings

<3

.5 m

mo

l/l (

%)

Day time (06.00 to midnight)

Night time (midnight to 06.00)

Human insulin mix 30

Analog mix 30

n = 160 type 2 diabetes patients

p = 0.067

p = 0.02

19%

2.9

6.3

3.3

7.8

0

1

2

3

4

5

6

7

8

9

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Warren ML, et al. Diabetes Res Clin Pract 2004;66:23–29

Efficacy or safety of pre- or post-meal dosing of Analogue mix 30

After preprandial injection (63.0 ± 28.9 U)

After postprandial injection (64.6 ± 29.2 U)

Mea

n p

lasm

a gl

uco

se (

mg

/dl)

-15 60 120 180 240

120

100

140

160

180

200

220

240

n = 93 type 2 diabetes patients

Time (minutes)

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

Blo

od

glu

cose

exc

urs

ion

0–

5 h

(m

mo

l/l/

h)

p < 0.05

–10%

p < 0.001

–17%

0

13

14

15

16

17

18

19

20

21

Lispro Mix 25TM Aspart Mix® 30 Premixed human insulin

n = 61 type 2 diabetes patients

Mean injection dose 0.4 U/kg

Glucose excursions

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Luzio S, et al. Diabetes 2004;53(Suppl. 2):A136

Aspart Mix 30 or glargine

Aspart Mix 30

0

50

100

150

200

250

300

350

400

-1 4 9 14 19 24

Time (h)

Pla

sma

insu

lin (

pM

) NovoMix® 30

Glargine

PI AUC0-24 h; p < 0.01

n = 12 type 2 diabetes patients

Total daily injection dose 0.5 U/kg

AUC of premixed aspart insulin vs. long acting glargine insulin

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Once-daily analong mix effect on blood glucose over 24 hours

• Once-daily phase of the 1-2-3 Study

Blo

od

Glu

cose

(m

mo

l/l)

Lunch

Baseline

Analog mix OD (16 weeks)

4

14

Before After Bed time

3am Breakfast

Before After Before After

Dinner

6

8

10

12

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Once-daily analogue mix effect on HbA1c in type 2 diabetes

Suwanwalaikorn Diabetologia 2004;48(suppl 1):A308. Lund et al Diabetes 2005;56(suppl 1):A126. Kilo et al J Diabetes Complications 2003;17(6):307-13. Garber et al Diab Obes Metab 2005, in press

Re

du

ctio

n in

Hb

A1

c(%

)

-2

-1.5

-1

-0.5

0

n=71

n=46 n=100 n=120

8.6% 9.5% 8.2% 8.6%

(11 weeks)

(12 weeks)

(12 weeks) (16 weeks)

Baseline values

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The 1-2-3 study: Investigating Asprat Mix OD, BID and TID

Pre-dinner x 16 week Start with 12 U at dinner

HbA1c≤ 6.5% OD

Phase 1 End of

Study

If HbA1c> 6.5%, go to BID, d/c secretagogues

Pre-breakfast & dinner x 16 week Add 3 U at breakfast and titrate

BID

Phase 2 End of

Study

HbA1c≤ 6.5%

If HbA1C> 6.5%, go to TID

TID x 16 week Add 3 U at lunch and titrate TID

Phase 3

Titrate according to schedule every 3 days n = 100 type 2 DM 12 months with HbA1c 7.5 10%, 2 OADs or 1 OAD plus basal insulin OD (max 60 U) G

arb

er A

, et

al.

Dia

bet

es, O

bes

ity

an

d M

eta

bo

lism

20

06

;8(1

):5

8-6

6

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Sum-up

• Analogue Premixed insulin BID vs. glargine OD – 34% higher glucose lowering effect in equal daily dose

clamp (Luzio et al)

– 50% more patients reach HbA1c targets (Raskin et al)

– reduces PPG (Raskin et al)

– comparable FPG reduction (Raskin et al)

– equal risk of major hypoglycaemia and more minor hypoglycaemia (Kann et al)

• Analogue Premixed insulin vs. premixed human insulin 30/70 – improves postprandial blood glucose (Boehm et al 2002)

– reduces risk of hypoglycaemia (Boehm et al 2004, McNally et al)

– dosing immediately before or after meal (Warren et al)

– reduces triglycerides (Schmoelzer et al)

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The Community Pharmacist’s Role in Diabetes Management CE program for pharmacists

[email protected]

http://www.twitter.com/abpharm

http://www.facebook.com/pharmaprof

http://www.linkedin.com/in/abahnassi

Anas Bahnassi PhD CDM CDE