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

KINDERKRANKENHAUS AUF DER BULT für Kinder und Jugendliche

Akademisches Lehrkrankenhaus

Thomas Danne

Kinderkrankenhaus auf der Bult, Hannover, Germany

Diabetes Control: Goals and reality – European perspective



• Targets are important• We don´t need age-dependent or

„individual“ targets• No phases of diabetes have less risk

for late complications• It is feasible to reach target HbA1c <

7.5% for half of the children with diabetes with access to intensive insulin treatment

• Is HbA1c the right target ?

Agenda


Akademisches LehrkrankenhausPlasma blood glucose and A1C goals for type 1 diabetes by age group

Values by age Before meals Bedtime/overnight A1C Rationale

Toddlers and preschoolers (<6 years)

100–180 110–200 <8.5 (but >7.5) High risk and vulnerability to hypoglycemia

School age (6–12 years)

90–180 100–180 <8% Risks of hypoglycemia and relatively low risk of complications prior to puberty

Adolescents and young adults (13–19 years)

90–130 90–150 <7.5%* Risk of hypoglycemia• Developmental and psychological issues

Key concepts in setting glycemic goals:• Goals should be individualized and lower goals may be reasonable based on benefit–risk assessment• Blood glucose goals should be higher than those listed above in children with frequent hypoglycemia or hypoglycemia unawareness• Postprandial blood glucose values should be measured when there is a disparity between preprandial blood glucose values and A1C levels

Silverstein J, Klingensmith G, Copeland K, Plotnick L, Kaufman F, Laffel L, Deeb L, Grey M, Anderson B, Holzmeister LA, Clark N; American Diabetes Association. Care of children and adolescents with type 1 diabetes: a statement of the American Diabetes Association. Diabetes Care. 2005 Jan;28(1):186-212.





SWEDEN: A change in HbA1c reference affects metabolic control:SWEDEN: A change in HbA1c reference affects metabolic control:Targets are important !Targets are important !

222320192017181712171413N =

9.59.5

9.09.0

8.58.5

8.08.0

7.57.5

7.07.0

6.56.5

6.06.0

5.539424439374141393237383627293232 33334036373842404035364135384442 32364033

9090 9191 9292 9393 9494 9595 9696 9797 9898 9999 0000 0101

Mono SMono SHPLCHPLC

DCA 2000DCA 2000DCCT calibrationDCCT calibration

DCA 2000 DCA 2000 Swedish calibrationSwedish calibration

1.4% diff.

1.1% diff.

YearsYears

p=n.sp=0.003p=0.01

HbA1c, %

Hanas R. Psychological impact of changing the scale of reported HbA1c results affects Hanas R. Psychological impact of changing the scale of reported HbA1c results affects metabolic control. Diabetes Care 2002;25:2110-1.metabolic control. Diabetes Care 2002;25:2110-1.

p=n.sp=0.04 p=n.s(significance vs. year

before change)

Data from 49 patients born 1971-1989Data from 49 patients born 1971-1989



• Children’s Hospital, Leicester Royal Infirmary, United Kingdom• Clinique Pédiatrique, Centre Hospitalier de Luxembourg, Luxembourg • Department of Endocrinology & Diabetes, Royal Children's Hospital, Australia • Barn- och ungdomskliniken, Universitetssjukhuset Södra Grev Rosengatan Sweden • IJsselland ziekenhuis, The Netherlands • Endocrinology and Diabetes Research Group, Hospital de Cruces, Spain • Clinica Pediatrica, Ospedale Policlinico, Italy • The Hospital for Sick Children, University of Toronto, Canada • Diabetes-Zentrum, Kinderkrankenhaus auf der Bult, Germany • Hôpital Universitaire des Enfants Reine Fabiola Diabetology Clinic, Belgium • Department of Paediatrics Trinity College, National Childrens Hospital , Ireland • Peijas Hospital, Finland • Children's Hospital of Los Angeles, USA • Pediatric Clinic, Medical Faculty Department of Endocrinology & Genetics, Republic of Macedonia • Paediatric Dept. L, Glostrup University Hospital, Denmark • Dept. of Pediatrics, Haukeland Hospital, Norway • National Center of Childhood Diabetes, Schneider Children's Medical Center of Israel, • Royal Hospital for Sick Children, Glasgow, Scotland • University Childrens Hospital, Zurich , Switzerland • Department of Paediatrics, Nihon University School of Medicine, Tokyo, Japan • Centro di Diabetologia, University of Parma, Italy • Department of Psychology, University of Wollongong, Australia • NovoNordisk, Denmark

Hvidore-Adolescent-Study 2008



Hvidore-Adolescent-Study 2008• 2,269 potential study patients visited outpatient department during

recruitment phase• 2062 (91%) adolescents filled out the questionnaire• 2036 (90%) gave a sample for a central HbA1c determination • age 14.4 ±2.3 years; • 50.6% male; • Diabetes duration 6.1± 3.5 years • mean HbA1c = 8.2% ± 1.4 • significant differences between centers (F = 12.3; p<0.001)• Center average HbA1c ranged between 7.4 to 9.3% • 152 diabetes-professionals answered the tam questionnaire (pediatric

diabetologists (46%) and diabetes nurse educators (32%)• of 21 centres 6 had no dietitian, 11 had no psychosocial team

member, while 3 centers had a psychologist/psychiater and social worker a part of their team.



7

8

9

10

adju

sted

HbA

1c (

%)

11 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

mean HbA1c of adolescents in centermean HbA1c of adolescents in center(adjusted for age, diabetes duration and gender):(adjusted for age, diabetes duration and gender):

8.2 ± 1.48.2 ± 1.4 %%Hvidore Group (2008) submitted

7,4 7,6 7,7 7,7 7,8 7,98,0 8,0 8,1 8,2 8,2 8,2 8,3

8,4 8,48,6

8,8 8,8 8,89,0

9,1

0%10%20%30%40%50%60%70%80%90%

100%

8 3 5 5 6 7 22 2 7 6 10 10 5 5 7 7 9 6 9 8 5

< 7.0

7.0 – 7.4%

7.5 – 7.9%

8.0 – 9.0 %

no target

225225 125 9090 125 175 175 225 30 125 50 225225 225 225 225225 7070 9090 225225 175 175 175 125

Number of adolescents in treated in center

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Center number

Center number

Number of team members answering

targ

et H

bA1c

of t

eam

mem

bers

Team-Target and HbA1c



Team Member Targets & Glycaemic Control<7.0 7-7.4 7.5-7.9 8-9.0 No specific Target Centre Mean

HbA1c

100.0 7.40

100.0 7.58

20.0 40. 40.0 7.68

100.0 7.74

16.7 83.3 7.80

57.1 42.9 7.89

52.4 42.9 4.8 8.00

100. 8.02

100.0 8.08

60.0 40.0 8.18

40.0 40.0 10.0 10.0 8.23

33.3 44.4 22.2 8.24

20.0 60.0 20.0 8.27

60.0 20.0 20.0 8.36

80.0 20.0 8.45

20.0 20.0 60.0 8.59

33.3 44.4 22.2 8.76

100.0 8.82

75.0 25.0 8.83

60.0 20.0 20.0 8.98

20.0 60.0 20.0 9.05



18

10.62.0

127

9.61.4

466

8.71.1

694

8.01.1

600

7.51.3

Nmean

SD

parents happy

31

8.42.3

18

8.91.3

189

8.91.3

627

8.31.3

1056

7.91.3

Nmean

SD

parents ideal

13

10.52.1

141

9.61.5

473

8.61.2

691

8.11.2

639

7.41.2

Nmeanl

SD

adolescent happy

47

8.11.6

25

8.91.0

205

8.81.3

713

8.41.3

975

7.91.4

Nmeanl

SD

adolescent ideal

Don´t know

8.0 – 9.07.5-7.97.0-7.4<7.0target

Relationship between targets of parents and adolescents and achieved HbA1c



Beta t p

Step 1

Age .069 3.077 .002

Gender -.054 -2.517 .012

Diabetes Dration .123 5.432 .000

Insulin dose (Units/kg) .139 6.414 .000

Insulin Regimen (BD Freemix)

.050 2.247 .025

Center rank .337 15.251 .000

.041 2.025 .043

-.060 -3.136 .002

.066 3.236 .001

.090 4.627 .000

.047 2.362 .018

.164 7.596 .000

Beta t p

Adolescent Target “happy with”

.298 11.910 .000

Parents Target “happy with”

.244 10.339 .000

Adolescent Target “Ideal”

-.060 -2.757 .006

Team Target - coherent -.096 -2.728 .006

Step 2

Multiple Regressionsanalysis proves the role of targets and team interaction for center differences



Hvidore-Group 2008

• A lower target HbA1c and a bigger consistency between team members within a center is associated with a lower average center HbA1c.

• Clear and consistent setting of targets is associated with the Outcome in adolescents with diabetes.

• Differences in treatment targets are an important factor contributing to center differences



Influencing Microangiopathy Through Lowering The HbA1c In Randomised Studies

DCCT

Type of Diabetes 1

Number of patients 1441

Progress. Retinopathy

„1,5“

Kummamoto

110

2

UKPDS

3867

Progress. Nephropathy

Progress. Neuropathy

5(4-7)

4(3-11)

10(6-50)

7(6-11)

5(4-19)

5(4-7)

5(3-16)

Follow-up (years) 6,5 6 10

HbA1c-change 9,1->7,2 9,1->7,0 7,9->7,0

Parameter

NNTDuration of study (95% CI)



Ra

te o

f Ba

ckg

roun

d-R

etin

opa

thy

(per

10

0 p

atie

nt-y

ears

)

< 7 7-8 8-9 9-10 10-11 > 110

2

4

6

8

10

Average HbA1c (%)

Danne et. al, Diab Care 17: 1390-96, 1994

Berlin Retinopathy-Study (1977-94): Berlin Retinopathy-Study (1977-94): Continuous Exponential Relationship between Continuous Exponential Relationship between

retinopathy and long-term-HbA1cretinopathy and long-term-HbA1cVirtually all children with diabetes from West-Berlin

N= 494, 262 boys, 232 girls

Median age at onset: 11 (1 to 17) years

Annual fluoresceine angiograms

Median follow-up: 9 years



Should risk of severe hypoglycemia Should risk of severe hypoglycemia influence the targets in young children ?influence the targets in young children ?



Adults with diabetes

Parents of IDDM children(mean age 8.1 years)

- without severe hypo

- with severe hypo

n=78

n=46

n=31

n=15

1.88 ± 0.6

2.94 ± 0.6

2.84 ± 0.6

3.18 ± 0.6

0.001

0.040

No influence: confidence to detect or treat hypoglycaemia in their children

Average Hypoglycaemia Fear Score

Maternal fear of Hypoglycemia in their Children with Insulin dependent Diabetes mellitus Clarke et al.; JPEM 11 (Suppl.1): 189-194, 1998



Can my child die during a hypoglycaemia ?The „dead in bed syndrome“

Author Study Age Group Total Dead in bed Age period (years) deaths (n) (years)

Tattersall (1991) 1989 - 22 12 - 43

Thodarson (1995) 1981-90 0 - 40 240 16 7 - 35

Sartor (1995) 1977-85 0 - 28 33 9 15 - 23

Sudden death of young people with diabetes without complications found „dead in bed“ out of apparent health the day before. Hypoglycaemia as a possible cause.



Why do children with diabetes die ?

Causes of death in children with insulin dependent diabetes 1990-96 Edge JAet al. Arch Dis Child (1999) 81: 318-23

116 deathsca. 150600Children w. Diabetes(0 to 19 years)

83 deathsrelated to DM

33 deaths notrelated to DM

26 at home (9 „dead in bed“)8 on way to hospital

45 in hospitalduring DKA therapy

4 hypoglycemiapossible

10 DKA

10 DKA likely



Influence of social factors on the mortality of adults Influence of social factors on the mortality of adults with type 1 diabeteswith type 1 diabetes

Robinson N. et. al.: Social Deprivation and Mortality in Adults with Diabetes Mellitus. Diab Med (1998) 15:205-212

Odds Ratio (95% CI)

Low social status 1.34 (0.61-2.96)

Left school before age 16 y 3.98 (1.96-8.06)

social housing 2.57 (1.37-4.91)

unemployed 3.10 (1.67-5.79)

Risk factor

800 Patients with type 1 diabetes (Follow-up 8.4 years)



Same targets for all age paediatric age groups – the Hannover approach

• HbA1c below 7.5%• prevent ketoacidosis• prevent school failure• prevent hypoglycemia



The ISPAD Vote September 28th,2007

Majority for age independent targets

Target HbA1c < 8%:

Target HbA1c < 7.5%:

Target HbA1c < 7.0%:



But is the HbA1c

the

right target ?



The DCCT The DCCT Research Group. Research Group. The relationship of The relationship of glycemic exposure glycemic exposure (HbA1c) to the risk (HbA1c) to the risk of development and of development and progression of progression of retinopathy in the retinopathy in the Diabetes Control Diabetes Control and Complications and Complications Trial.Trial. Diabetes 1995; 44: Diabetes 1995; 44: 968-83968-83



5

10

15

20

25

Tim

e o

f dia

gno

sis

of b

ack

gro

un

d r

etin

opa

thie

(D

Md

ura

tion

(ye

ars

)

<6 6-7 7-8 8-9 9-10 10-11 11-12 12-13 >13- 18.9 20.4 20.9 20.3 19.8 19.0 18.5 17.5

Longterm HbA1c (%)

Median Age (Years)Danne et. al, Diab Care 17: 1390-96, 1994

HbA1c is a bad predictor of retinopathy in indvidual adolescents

– the Berlin Retinopathy-Study



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



Hannover Navigator Study Other Measures of Glycemic Control MaskedUnmasked %

DifferenceP-value

Glucose Mean (mg/dL) Mean 172 164 -4.5% 0.0577S.D. 27 24

N 23 23

Glucose S.D. (mg/dL) Mean 61.8 56.1 -9.1% 0.0037S.D. 11.9 14.2

N 23 23

MAGE nadir to

peak events (mg/dL)

Mean 135.2 125.1 -7.4% 0.0462S.D. 28.9 28.1

N 23 23

MAGE peak

to nadir events (mg/dL)

Mean 140.6 126.8 -9.9% 0.0017S.D. 28.3 29.7

N 23 23



Children with diabetes need insulin, love and care …and clear targets

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