K INDER K RANKENHAUS AUF DER B ULT für Kinder und Jugendliche Akademisches Lehrkrankenhaus...

KINDERKRANKENHAUS AUF DER BULT für Kinder und Jugendliche

Akademisches Lehrkrankenhaus

Intensive Outpatient Treatment of Intensive Outpatient Treatment of Children with DiabetesChildren with Diabetes

Thomas Danne, Diabetes-Zentrum für Kinder und Jugendliche

Kinderkrankenhaus auf der Bult, Hannover

Biannual Conference of the Barbara Davis Center for Childhood DiabetesJuly 12 – 16, 2008 Keystone Colorado



Hannover

This is Hannover, Germany



In „good“ centers a good HbA1c is present in patients with short and long diabetes duration

mean HbA1c of patients with a diabetes duration below 3 years8 9 10 11

7

8

9

10

11

me

an

HbA

1c

of p

atie

nts

with

ad

iab

ete

s d

ura

tion

abo

ve 3

ye

ars

7

19951995 R=0.83 p<0.001 R=0.83 p<0.00119981998 R=0.77 p<0.001 R=0.77 p<0.001

Danne et al. (2001) Diabetes Care



0 5 10 150

0,2

0,4

0,6

0,8

1

14.4

HbA1c (3-12mo) < 7.5%(n=112)

12.4

HbA1c (3-12mo) > 7.5%(n=109)

p<0.03

diabetes duration (years)

pro

ba

bili

ty fo

rre

ma

inin

g fr

ee

of r

etin

opa

thy

Mean HbA1c during the first year (3 to 12 months) Mean HbA1c during the first year (3 to 12 months) of DM and later development of background retinopathyof DM and later development of background retinopathy

Berlin Retinopathy Study



•Health policy and reimbursement•Treatment targets•Insulin therapy•Team and education•Networking

What factors play a role for Succesful Intensive Outpatient Management of

Children with Diabetes?



Health policy – the German situation

Demonstration in Berlin, March 13, 2008



No added value of insulin analogs?• On February 21st, 2008 the German GBA

(health policy group) has recommended no further reimbursement for rapid acting analogues in Germany

• A previous Health Technology Assessment by the IQWiG Institute found no added value compared to regular human insulin in type 1 diabetes

• Unless the German Health Ministry decides not to pass this bill in April modern insulins will not be reimbursed as long as they remain 20-30% more expensive than human insulin

How did this happen ?



How many studies were included in the IQWiG report ?

How many comments were dealt with for the finalIQWiG-report?

Of 400 submitted comments to the preliminary report only 17 were presented at the expert hearing and 37 comments were mentioned in the final report

According to work plan classified as not relevant 1255 (not analysed in full text (abstract only))

Acording to workplan judgedas not relevant29 (analyzed full text)

To

tal

sear

ch:

110

2 p

ub

lic

atio

ns

302 duplicates

1293 39 9

9 study duration not sufficient2 wrong primary endpoints

12 no RCT2 no predefined targeted intervention2 no relevant taget criteria1 not in predfined language of publication1 no full publication available

2 Aspart1 Glulisin6 Lispro

baseline

used in IQWiG report



Institution MDI CSII Children and Adolescents

IQWIG 2007 9 6 6

Cochrane 2006 15 7 5

CCOHTA 2006 28 7 8

NICE 2004 23 8 7

How many studies were included in the Cochrane-Analysis, the Canadian HTA (CCOHTA) and the English Guideline (NICE) compared to the IQWiG-final report ?

http://www.cochrane.org/

Canadian Coordinating Office for Health Technology Assessment (CCOHTA) http://dev.ccohta.ca/ final draft July, 2006

English National Institute for Health and Clinical Excellence NICE: http://www.nice.org.uk/page.aspx?o=CG015



Source: Calculated on the base of data of SAP BW/ IMS® Health, pharmacy and clinical market, MAT November 2006(Basis: sale in millions of units)

Percentage of Humaninsulin/animal insulin andmodern insulin in the segment of short acting insulins

46%59%

23% 19% 22%14% 19%

9%

54%41%

77% 81% 78%86% 82%

91%

0%

20%

40%

60%

80%

100%

Europe D NL F A UK CH S

Human insulin/ animal insulin modern insulin

In the European perspective Germany has a particular low percentage of insulin analogues: are

we saving money or slowing advances in therapy ?



What is the best insulin therapy for children ?



Higher HbA1 in Adolescents with Premixed Insulin

8.1±0.1339CSII

8.2±0.0926Basal Bolus

8.2±0.268Thrice daily

7.9±0,1*296Twice daily Free Mix

8.6±0.1+160Twice daily Pre Mix

8.2±0.1309Regimen Miscellaneous

HbA1c (Mean± SEM)

NDifferent Insulin regimens in 2098 adolescents (11 to 18ys) (mean age 14.5 years, diabetes duration 6 years)

De Beaufort et al. (2007): Continuing Stability of Center Differences in Pediatric Diabetes Care: Do Advances in Diabetes treatment Improve the Outcome ? Diabetes Care 30: 2245-50

P<0.0001

P<0.0001



Regular Insulin and Short Acting Insulin can be used alternatively depending on the meal plan

0.00 6.00 12.00 18.00 22.00

0.00 6.00 12.00 18.00 22.00

Regular-Insulin

NPH-Insulin / longacting analog

Rapid acting analog

Meal

school

no school



840 adolescents with type 1 diabetes (49,8 %female) from 7 German pediatric diabetes centers representing 72 % of their patients aged 11 to 18 years age: 14,6 ± 2,0 yearsdiabetes duration: 5,9 ± 2,0 years

Center-adjusted HbA1c in the German MAD-Trial and Basal insulin

121214229271N =

Type of Basalinsulin

CSIISemilenteNPHGlargin

Ad

just

ed

Hb

A1c

(%

)

16

14

12

10

8

6

4

2

730

422

413484155

182274

457

356

903041173364336657123648

430492803447833

260202

342590341229

450616124

7,79139Mean HbA1c 7,72135 7,79120 7,63123

no significant mean differences

26%Semilente

27%NPH

32%Glargin15% CSII

Diabetes 53; Suppl.1 (2004)



MAD-Study: HbA1c with same method (Metrika)MAD-Study: HbA1c with same method (Metrika)

HBA1C METRIKA

13,0012,50

12,0011,50

11,0010,50

10,009,50

9,008,50

8,007,50

7,006,50

6,005,50

5,00

Fre

quen

cy

160

140

120

100

80

60

40

20

0

Mean = 7,79 1,49 %

N = 835

7596937218385231N =

Centre7654321

HB

A1C

ME

TR

IKA

14

12

10

8

6

4

831

803

833

709

590

616

522

571

342

341457450447

310276241302

304

236

260

96117220901821134866

229

124

202

All Patients By centre

Significant difference between centres p<0.001MAD-Study– Danne, Lange et. al



6,5

6,7

6,9

7,1

7,3

7,5

7,7

7,9

8,1

8,3

8,5

Center # 1/2 Center # 3/4/5 Center # 6/7

0

0,2

0,4

0,6

0,8

1

1,2

1,4

1,6

1,8

2

HbA1c (%) Prandial/Basal-Ratio

good, average, poor center - HbA1c (%)

Prandial/Basal-Ratio

High Percentage of Basal Insulin =High Percentage of Basal Insulin = Poor HbA1c ?Poor HbA1c ?



Daily insulin requirement

Insulin dose

(U/kgBW/day)

Children 0,8 – 1,0

Adolescents 1,2 – 0,8

Adults 0,6 – 0,7

Basal insulin requirement 0,3 – 0,40



Prerequisite for Basal-Bolus: Prerequisite for Basal-Bolus: adjusting insulin to foodadjusting insulin to food

„The insulin dose and action profile needs to be balanced against the expected carbohydrate intake“

Quantitation of carbohydrate:

e.g. Grams, Exchanges, Portions/Servings

The Influence of other nutriteints on glycemic control and long-term prognosis

eg fat, fibre, sucrose

The impact and psychological effect of dietary counselling methods

Areas of controversaryAreas of controversary

ISPAD Consensus Guidelines



Grüßer et al., Kirchheim publishing company 2005

Estimation of carbohydrate content: list of Estimation of carbohydrate content: list of servings symbolising 1 cabohydrate unit (KE)servings symbolising 1 cabohydrate unit (KE)



Prandial insulin dose

Insulin per CH U / 10g CH

Morning 1,5 – 2,5(3+)

Lunch 1,0 – 1,5

Dinner 1,5 – 2,0

Bedtime 0,5 –1,0

Small children and during the remission phase regularly need less than 1U per 10g CH

CH = Carbohydrate


Akademisches Lehrkrankenhausexample-plan of a 9year old girl

NightBedtimeEveningLunchMorning

110

70

5

0

0,5

0

110

80

0

0

0,25

0

100

60

0

3

0,75

3 / 1

02your Standard dose

of longacting insulin (U)

46your Standard dose

of shortacting insulin (U)

1,01,5your CH-rule:

for 10g CH you inject (U)

3 / 13 / 1 / 1your standard CH-distribution

remark: bedtime glucose <100 + 5g CH; <80 + 10g CH; <60 + 15g CH

100100your target (mg/dl)

5040your BG-rule:one unit of regular insulin lowers your blood glucose

name: Marlene D., 9 years weight: 30 (kg) physician: Dr.Danne date: 23.7.2006



Number of outpatient visits and average HbA1cNumber of outpatient visits and average HbA1cNumber of outpatient visits and average HbA1cNumber of outpatient visits and average HbA1c

8,2 8,3

7,98,1

7,5

7,97,7 7,7 7,8

8,7

8,3

9 9

6,5

7

7,5

8

8,5

9

9,5

1 2 3 4 5 6 7 8 9 10 11 12 13

Outpatient visits in the year and number of patients

Me

dia

n o

f H

bA

1c

of

the

pa

tien

ts Mean number of visits: 6.0 (1 - 13)

n = 43 30 36 39 33 55 70 58 60 32 7 4 1

Kinderkrankenhaus auf der Bult (n=468)Kinderkrankenhaus auf der Bult (n=468)Kinderkrankenhaus auf der Bult (n=468)Kinderkrankenhaus auf der Bult (n=468)



Children with diabetes need age appropriate education for a good quality of life and a

dedicated team…



Hürter & Travis:Einführungskurs für Kinderund Jugendliche mit Diabetesmellitus, 3. Auflage 1984

Zuppinger et al.: Du und ich sind zuckerkrank, 1980

The past in diabetes education of children



Age appropriate education and care:Age appropriate education and care:Age appropriate education and care:Age appropriate education and care:

adolescentsadolescents

parentsparentsteachersteachers

childrenchildren



„Diabetes Buch für Kinder“, P. Hürter et al., Kirchheim Verlag

Example of structured education for 6 to Example of structured education for 6 to 12year olds: the „Jan-Program“…12year olds: the „Jan-Program“…

Age appropriate

Positive choice of words

Playful exercises

Examples of everyday life



„Diabetes bei Jugendlichen: ein Schulungsprogramm“, K. Lange et al., Kirchheim publishing company

……and the „Adolescent program“ for 12 and aboveand the „Adolescent program“ for 12 and above

More abstract exercises

More theoretical background

More assignment of responsability

Experiment: How does your favorite ice cream affect blood glucose ?



Results of pediatric CSII therapyResults of pediatric CSII therapyIn EuropeIn Europe



Reading out the pump memory: an electronic Reading out the pump memory: an electronic logbook of pump therapylogbook of pump therapy



Indications for CSII in the European Pedpump Survey

• Recurrent Hypoglycemia n=338• Flexibility/Lifestyle n=292• High HbA1c n=265• Dawn Phenomenon n=131• Needlephobia n=54



4

6

8

10

12

14

18

0 5 10 15 20

R = -0.367

16

Average number of daily boluses

Ce

ntr

ally

de

term

ine

d H

bA

1c (

%)

N 1086

Age (years) 11.9 4.2

Diabetes Duration (ys) 5.9 3.6

CSII Duration (ys) 2.0 1.4

Low number of daily boluses is associated with poorer HbA1c

Danne et al, Diabetologia (2008); epub



Demographic data of patients in relation to average daily bolus number.

Bolus per day <2 2-4 4-7 7-12 >12

n 6 102 429 424 87

Age (years) a 17 (5) 16 (16) 13 (18) 12 (19) 11 (17)

Number of severe hypoglycaemic episodes

0 2 9 5 1

Number of DKA episodes

1 2 7 6 0

Diabetes duration(years)

11.2 (10.8) 6.3 (18.8) 5.7 (17.1) 4.9 (15.4) 3.6 ( 17.5)

CSII duration (years)

4.1 (3.0) 2.2 (14.2) 1.6 (9.4) 1.7 (7.4) 1.5 (4.9)

Insulin dose (U/kg/day)

0.75 ± 0.14 0.74 ± 0.22 0.81 ± 0.56 0.77 ± 0.38 0.80± 0.64

Average number of daily boluses

1.8 ± 0.2 3.3 ± 0.5 5.5 ± 0.8 8.9 ± 1.3 14.6 ± 1.9

HbA1c (%) 10.4 ± 1.8 9.3 ± 1.9 8.2 ± 1.2 7.7 ± 1.0 7.3 ± 0.9



R = -0.3127

4

6

8

10

12

14

16

18

0 20 40 60 80 100% Bolus of total daily dose

cen

tra

l Hb

A1

cHiger Percentage of Bolus vs. Basal is associated

with better HbA1c




Percent of Basal Insulin of total dose in CSII (%)

Agegroup N Mean

(%)

Standard

Deviation

Total 1041 43.57 13.58

Preschool 139 34.09 15.93

Prepubertal 314 42.03 12.44

Adolescent 588 46.43 13.58

Significant differences between groups p<0.001




Changes in Insulin Therapy 1986 - 2007Kinderkrankenhaus auf der Bult

n = 339 n = 425 n = 521 n = 458 n = 471 n = 510 n = 530 n = 545

91

60

32

1810

5,9 3,9 1,19

40

68

82

7065

5753

20

29,6

39,443,5

0

20

40

60

80

100

1986 1990 1994 1999 2003 2004 2005 2006

Pro

po

rtio

n o

f p

ati

ents

in %

Conventional two injection therapyIntensived Insulin Therapy (MDI)

53

43,5

2007n = 589

1,1

CSII



Insulin Therapy in Different Age Groups

Kinderkrankenhaus auf der Bult, Hannover, Germany (n=545)

27,6

51,456,7 60,0

69

45,239,8

33,3

0

20

40

60

80

100

0 – 6ys.(n=58)

6 – 12ys.(n=146)

12 – 18ys.(n=266)

18ys. and above(n=75)

Per

cent

age

of p

atie

nts

%

0 / 1 Inj. 2 Inj. 3 Inj. 4 Inj. CSII



Improvement of glycemic control: Levels of HbA1c 1994 - 2007

0

5

10

15

20

25

30

35

40

45

50

55

60

< 7,5 % 7.5 - 9.0 % > 9.0 %

1994 n = 5181995 n = 5271996 n = 5121997 n = 4731998 n = 4541999 n = 4582000 n = 4682001 n = 4532002 n = 4692003 n = 4712004 n = 5102005 n = 5302006 n = 5452007 n = 560

Proportion of patients (%)

Individual yearly median of HbA1c (norm 5.0 + 0.8 %)



Insulin Therapy MDI vs. CSII

HbA1c by frequencies HbA1c by age MDICSII

13,7±4.1 5,3±4.1 7,6±1.28

12,1±4.9 5,6±3.9 7,5±0,99

287

237

MDI

CSII

Age D-DurationSevreHypo´s

HbA1C

Kinderkrankenhaus auf der Bult 2006 (n=545)

MDICSII



The Future part 1: Glucose Sensors in Outpatient Management

Backside of arm

Abdomen



Expectations and Caveats

Quotes from Navigator patients ….

• „Why do my sensor values not match my blood glucose values ?“

• „Great then I will never have to do a blood glucose again!“

•„This gives me a completely new perspective on when I eat and how I choose my food.“



The new information with CGM: Glycemic variabilityComparison blinded FreeStyle Navigator vs. HbA1c

Glucose Mean vs. HbA1c Glucose S.D. vs. HbA1c

r=0.801p<0.0001

r=0.675p=0.0004

German Diabetes Association 2008



The new information with CGM: HypoglycemiaComparison blinded FreeStyle Navigator vs. HbA1c

Proportion of time hyperglycemic vs. HbA1c

r=0.772p=0.0140

r=-0.258p=0.2353

Proportion of time hypoglycemic vs. HbA1c

German Diabetes Association 2008



France04

ONSET

Hannover

Vienna

LeipzigAngers

Warsaw

The Pediatric ONSET – Study prospective, multicenter, randomised

• 160 Patients • 5 European pediatric centers• 2007 bis 2009• study period 1 year from T1D

onset

Parameter: HbA1c, C-Peptide,

Glucose-Profiles,

Safety, Quality of Life



Learning to live with diabetes with

„biofeedback“ on your glucose values



Tobias, 3 years, T1D since 6 months, HbA1c 6.0%

ONSET



The Future Part II

Networking in Pediatric Outpatient Care



• EU funding of the Public Health Agency (PHEA) regarding: Health information (HI 2007)

• 1.7 Supporting the exchange of information and experience on good practice

• Kick-Off April 2008

• Duration 36 Months • SWEET’s main objective is to improve secondary

prevention, diagnosis and control of Type 1 and 2 diabetes in children and adolescents by supporting the development of Centres of Reference (CORs) for paediatric and adolescent diabetes services across the EU.

Better control in Paediatric and adolescent diabetes: working of create Centres of Reference



• Czech Republic• France• Germany• Greece• Luxembourg• Netherlands• Poland• Romania•Sweden• U.K.

Darker colour higher icidence of type 1 diabetes



SCIENCE

EDUCATION ADVOCACY

All types of

diabetes inchildren and adolescents

714 members90 countries

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K INDER K RANKENHAUS AUF DER B ULT für Kinder und Jugendliche Akademisches Lehrkrankenhaus...

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