Experiences from the Hvidøre Study Group on Childhood

Diabetes.

Henrik B. Mortensen, Department of Henrik B. Mortensen, Department of Paediatrics, Glostrup University Paediatrics, Glostrup University

HospitalHospital

The Hvidøre Study Group on Childhood Diabetes The purpose of the group to improve the The purpose of the group to improve the

management of children and adolescents management of children and adolescents with type 1 diabetes on a worldwide scale by:with type 1 diabetes on a worldwide scale by:

Stimulating research Stimulating research Improve the quality of careImprove the quality of care Disseminate knowledge of childhood Disseminate knowledge of childhood

diabetes diabetes   

The Hvidøre Study Group on Childhood Diabetes The task for the group is to establish a The task for the group is to establish a

research network to carry out multicenter research network to carry out multicenter investigations to share and compare data on investigations to share and compare data on childhood diabetes. childhood diabetes.

The Study Group consist of medical doctors The Study Group consist of medical doctors all specialized in paediatrics from 22 centres all specialized in paediatrics from 22 centres from 18 countries in Europe, North America from 18 countries in Europe, North America and Japanand Japan

Members of the Hvidøre Study Group on Childhood Diabetes

H.B. Mortensen, DenmarkH.B. Mortensen, Denmark S. Greene, U.K. S. Greene, U.K.

H.-J. Aanstoot, Netherlands H.-J. Aanstoot, Netherlands H.M.C.V. Hoey, Ireland H.M.C.V. Hoey, Ireland

J. Aman, Sweden J. Aman, Sweden E.A. Kaprio, Finland E.A. Kaprio, Finland

J.A. Atchison, USA J.A. Atchison, USA M. Kocova, Macedonia M. Kocova, Macedonia

F. Chiarelli, ItalyF. Chiarelli, Italy P. Martul, Spain P. Martul, Spain

D. Daneman, Canada D. Daneman, Canada N. Matsuura, Japan N. Matsuura, Japan

T. Danne, GermanyT. Danne, Germany O. Søvik, Norway O. Søvik, Norway

H. Dorchy, Belgium H. Dorchy, Belgium K.J. Robertson, U.K K.J. Robertson, U.K

B. Dinesen, Denmark B. Dinesen, Denmark E.J. Schoenle, Switzerland E.J. Schoenle, Switzerland

P. Garandeau, FranceP. Garandeau, France P.G.F. Swift, U.K P.G.F. Swift, U.K

R.W. Holl, GermanyR.W. Holl, Germany R.M. Tsou, Portugal R.M. Tsou, Portugal

P. Hougaard, DenmarkP. Hougaard, Denmark M. Vanelli, Italy M. Vanelli, Italy

Publications

Comparison of metabolic control in a cross-sectional study Comparison of metabolic control in a cross-sectional study of 2.873 children and adolescents with IDDM from 18 of 2.873 children and adolescents with IDDM from 18 countries. Diabetes Care 1997;20:714-720.countries. Diabetes Care 1997;20:714-720.

Insulin management and metabolic control of Type 1 Insulin management and metabolic control of Type 1 diabetes in childhood and adolescence in 18 countries. diabetes in childhood and adolescence in 18 countries. Diabetic Medicine 1998; 15:752-759.Diabetic Medicine 1998; 15:752-759.

Persistent center differences over 3 years in glycemic Persistent center differences over 3 years in glycemic control and hypoglycemia in a study of 3,805 children and control and hypoglycemia in a study of 3,805 children and adolescents with type 1 diabetes.adolescents with type 1 diabetes. Accepted for publication: Accepted for publication: Diabetes CareDiabetes Care

Good Metabolic Control is Associated with Better Quality of Good Metabolic Control is Associated with Better Quality of Life in 2,101 Adolescents with Type 1 Diabetes. SubmittedLife in 2,101 Adolescents with Type 1 Diabetes. Submitted

The Hvidøre Study Group on Childhood Diabetes Metabolic control and insulin management in the Metabolic control and insulin management in the

real worldreal world

The relation between HbAThe relation between HbA1c1c and insulin regimens and insulin regimens over a three year periodover a three year period

Metabolic control and quality of lifeMetabolic control and quality of life

Study designMulticenter cross-sectional investigation with 22 Multicenter cross-sectional investigation with 22 participating paediatric departments from 18 countriesparticipating paediatric departments from 18 countriesin Europe, Japan and North America.in Europe, Japan and North America.

The HbAThe HbA1c1c concentration was determined once and concentration was determined once andanalyzed both locally and centrally at The Stenoanalyzed both locally and centrally at The StenoDiabetes Center, Denmark.Diabetes Center, Denmark.

Age, sex, duration of diabetes, height, body weight,Age, sex, duration of diabetes, height, body weight,insulin regimen and number of severe hypoglycaemicinsulin regimen and number of severe hypoglycaemicevents were recorded.events were recorded.

HbA1c analysisSamples were collected locally using the Biorad- HbASamples were collected locally using the Biorad- HbA1c1c

Sample Preparation Kit and mailed to the centralSample Preparation Kit and mailed to the centralLaboratoryLaboratory

Automatic high pressure liquid chromatographyAutomatic high pressure liquid chromatography(Bio- Rad- Variant(Bio- Rad- VariantTMTM))

Normal range is 4.4 – 6.3 (mean 5.4)%Normal range is 4.4 – 6.3 (mean 5.4)%The interassay SD is 0.15%The interassay SD is 0.15%

HbAHbA1c1c results were found to be 0.3% higher than the results were found to be 0.3% higher than the DCCT level by direct sample exchangeDCCT level by direct sample exchange

2 inj.

11

10

9

8

7

62015

HbA

(%

)1C

1050

1.31.21.11.00.90.80.70.60.50.40.3

201510

Insu

lin d

ose

(U/k

g/24

h)

***

**

50

2524232221201918171615

2015

BM

I (k

g/m

)2 *

**

**

10Age (years)Age (years)

50

3 inj.4+ inj.

Female

50

40

30

20

10

02015

MalesFemales

Percentage of childrenusing any pre-mixed insulin

10Age (years)

50

11

10

9

8

7

62015

Short + intermPremixed

Two injections per day

** *

HbA (percent)1C

10Age (Years)

50

Summary

In 3000 children and adolescents only one third had HbAIn 3000 children and adolescents only one third had HbA1c1c values < 8%values < 8%

HbAHbA1c1c increased during maturation of both genders increased during maturation of both genders irrespective of insulin regimenirrespective of insulin regimen

HbAHbA1c1c differed significantly across 22 centres irrespective of differed significantly across 22 centres irrespective of insulin regimen insulin regimen

Adolescent females on 4 or more insulin injections had Adolescent females on 4 or more insulin injections had significantly higher insulin dose and BMI.significantly higher insulin dose and BMI.

The rate of severe hypoglycaemia was related to younger The rate of severe hypoglycaemia was related to younger

age and lower HbAage and lower HbA1c1c level. level.

The Hvidøre Study Group on Childhood Diabetes Metabolic control and insulin management in Metabolic control and insulin management in

the real worldthe real world

The relation between HbAThe relation between HbA1c1c and insulin and insulin regimens over a three year periodregimens over a three year period

Metabolic control and quality of lifeMetabolic control and quality of life

Objectives

To investigate if blood glucose control changes from 1995 to 1998 in an international cohort of children with type 1 diabetes aged 11-18 years in 1998

To analyse differences in blood glucose control among centres in the 3 year period and relate possible changes to insulin regimen and daily insulin dosage

To assess centre differences in incidence of severe hypoglycaemic events

Flow diagram for patients participating in the international cohort investigation

229 DM duration < 1 year in 1995

55 Transferred to other Paed.Clinic178 Transferred to Adult Clinic223 Other (narrow window)105 Unknown 30 Declined

1,767 patients age 8-15 years in ‘95

This study group consisted of891 patients

55 Insufficient data

1 Dead

HbA1c in 1998 (grand mean): 8.9% (1.6%)

Distribution of HbA1c

% o

f pa

tient

s

30

25

20

15

10

5

0

35

40

< 5 5-6 6-7 7-8 8-9 9-10 10-11 11-12 12-13 > 13

HbA1c (%)

Year 1995 1998

HbA1c in 1995 (grand mean): 8.7% (1.6%)

Injection frequency70

60

50

40

30

20

10

0 1995 1998

Number of injections

2

3+

Year

HbA1c in 1995 (grand mean): 8.7% (1.6%)

HbA1c in 1998 (grand mean): 8.9% (1.6%)

% o

f pati

ents

HbA1c by centre for ‘95 and ‘98

The 1995 baseline level, and the three year change for HbA

1c for the 21 centres.

6

7

8

9

10

11

12

Centers sorted by HbA 1c in 1995

HbA1c

percent

*

*****

Centre changes in HbA1c adjusted for sex, age, duration of type 1 diabetes

Number ofinjections HbA1c %

- o ++ 2 6 3o 0 9 1- 0 0 0

Insulin dose HbA1c %

1 7 11 8 30 0 0

+o-

- o +

+) significant increase, o) no significant change, -) significant decrease

Rate of severe hypoglycaemic events according to the Poisson model

Age (13 yr), duration (5 years)

Inci

denc

e p

er 1

00 p

atie

nts

year

s 20

15

10

5

0 5 6 7 8 9 10 11 12 13 14 15

Individual HbA1c (per cent)

above

HbA1c (grand mean): 8.9% (1.6%)

Centres significantly:

different

below

Centres not significantly:

Summary

No significant change in HbANo significant change in HbA1c 1c for the 3 year for the 3 year period despite the use of three or more daily period despite the use of three or more daily insulin injection increased from 42 to 70%.insulin injection increased from 42 to 70%.

HbAHbA1c1c varied significantly among centres. varied significantly among centres.

Only 2 centres improved their metabolic control Only 2 centres improved their metabolic control significantly in the 3 year period.significantly in the 3 year period.

Fewer severe hypoglycaemic events in Fewer severe hypoglycaemic events in centres with a HbA centres with a HbA1c1c significantly below significantly below the grand mean. the grand mean.

Metabolic Control and Quality of Life

The DCCT study and the recent ISPAD guidelines recommend a treatment target for HbA1c of 7.5% in children and adolescents.

Will strict metabolic control influence the quality of life in adolescents with diabetes?

COMPARISON WITH OTHER QOL STUDIES

AuthorAuthor n n age (yrs) Correlation with QOL age (yrs) Correlation with QOL

Fonagy P,Fonagy P,

Arch Dis Child, 1987Arch Dis Child, 1987 Poor control = better QOL Poor control = better QOL

Ingersoll and Marrero, Ingersoll and Marrero,

Diabetes Educ, 1991Diabetes Educ, 1991 74 74 10.8-20.8 None except health perception 10.8-20.8 None except health perception

Guttman-Bauman,Guttman-Bauman,

Diabetes Care, 1998Diabetes Care, 1998 69 69 10-20 10-20 Good control=better QOL Good control=better QOL

Grey, Grey,

Diabetes Care, 1998Diabetes Care, 1998 52 52 12-20 12-20 None None

Metabolic Control and Quality of Life

The study involved 20 centres in 17 countries in The study involved 20 centres in 17 countries in Europe, Japan and North America.Europe, Japan and North America.

Adolescents aged 10-18 yrs at each study centre Adolescents aged 10-18 yrs at each study centre were invited to participate.were invited to participate.

2,101 adolescents were enrolled.2,101 adolescents were enrolled. Samples and information from 79% of all patients Samples and information from 79% of all patients

registered at the centres were obtained.registered at the centres were obtained.

Demographic data and metabolic control on 2,101 adolescents with type 1 diabetes

Age (yr)

Diabetes duration (yr)

BMI (kg/m2)

HbA1C (%)

Incidence of severe hypoglycemia (events per 100 patient-years)

Boys(n=1085)

13.8 ± 2.1

5.1 ± 3.8

20.8 ± 3.2

8.6 ± 1.6

15.5

Girls(n=1016)

13.8 ± 2.1

5.4 ± 3.8

21.8 ± 3.6

8.9 ± 1.7

15.7

Results as means ± SD Results as means ± SD *Adjusted for Center, + Adjusted for center and age, *Adjusted for Center, + Adjusted for center and age, # Adjusted for center, age and duration of diabetes.# Adjusted for center, age and duration of diabetes.

P-value

0.86*

0.06+

<0.0001#

<0.01#

0.90#

Daily insulin regimen

1 injection

2 injections

3 injections

4 or more injections

Premixed insulin, n (%)

Insulin dose (U/kg/day)

Boys(n=1085)

8

472

295

307

445 (41)

0.94 ± 0.32

Girls(n=1016)

10

380

287

339

407 (40)

1.01 ± 0.32

Results as means ± SD# Adjusted for center, age and duration of diabetes.

P-value

<0.05

0.66

<0.0001#

Patient characteristics on insulin management.

Quality of Life Questionnaires

AdolescentAdolescent - DQOL questionnaire- DQOL questionnaire

- (Ingersoll and Marrero, 1991)- (Ingersoll and Marrero, 1991)

ParentParent - Family Burden questionnaire - Family Burden questionnaire constructedconstructed

Health - Health - - Family Burden questionnaire - Family Burden questionnaire

ProfessionalProfessional

constructedconstructed

Questionnaire for Adolescent DQOL

23 questions on impact of diabetes23 questions on impact of diabetes

11 questions on worries11 questions on worries

17 questions on satisfaction17 questions on satisfaction

1 question on health perception1 question on health perception

Questionnaire for Parents and for Health Professionals

Burden relating to diabetesBurden relating to diabetes a) Medical treatment/nursing tasksa) Medical treatment/nursing tasks

b) Disruption in family routinesb) Disruption in family routinesc) Physical or psychological problems in the childc) Physical or psychological problems in the childd) Restriction in child's social and school activitiesd) Restriction in child's social and school activitiese) Long term health concerns.e) Long term health concerns.

We assessed family burden as one aspect of QOLWe assessed family burden as one aspect of QOL in the family setting, which is of particular in the family setting, which is of particular concern to health professionals. concern to health professionals.

Translation and cross-cultural adaptation of the questionnaire to each of the 14

languages:

Forward translation from English to the Forward translation from English to the national language of the countrynational language of the country

Backward translation from the national Backward translation from the national language to English language to English

Local lay panel testing Local lay panel testing The consultant and the Originator discussed The consultant and the Originator discussed

the report and prepared the final validationthe report and prepared the final validation

Completion of the questionnaires

Patients and parents completed questionnaires Patients and parents completed questionnaires confidentiallyconfidentially

Staff completed questionnaires independently. Staff completed questionnaires independently. All forms were forwarded to the coordinating center. All forms were forwarded to the coordinating center. All questionnaires were received within 2-3 weeks of All questionnaires were received within 2-3 weeks of

blood collection for glycated haemoglobin. blood collection for glycated haemoglobin. A middle score of 3 was used for missing questions A middle score of 3 was used for missing questions

when at least 70% questions on the relevant when at least 70% questions on the relevant subscale was answered.If <70% answered forms subscale was answered.If <70% answered forms discarded.discarded.

Internal validity and consistency of the multiple item instrument Questionnaire completion rates for adolescents, Questionnaire completion rates for adolescents,

parents and health professionals (93 percent, 89 parents and health professionals (93 percent, 89 percent and 94 percent, respectively)percent and 94 percent, respectively)

Item completion rates for all three groups (98.6–Item completion rates for all three groups (98.6–99.8 percent). 99.8 percent).

Cronbach’s a coefficient values for the Cronbach’s a coefficient values for the questionnaires were: questionnaires were:

Adolescent DQOL- impact 0.79, worries 0.84, Adolescent DQOL- impact 0.79, worries 0.84, satisfaction 0.92;satisfaction 0.92;

Parents 0.80 and health professionals 0.86, Parents 0.80 and health professionals 0.86,

Quality of life scores with age perceived by adolescents, parent and health

professionals

Age, gender, high and low HbAAge, gender, high and low HbA1c 1c selected as selected as 10th (6.8%) and 90th percentiles (10.8%) 10th (6.8%) and 90th percentiles (10.8%)

Illustrate the variation in QOL score due to Illustrate the variation in QOL score due to metabolic control.metabolic control.

All QOL scores were linearly transformed: All QOL scores were linearly transformed:

Best possible score 0Best possible score 0

Worst possible score 100Worst possible score 100

Impact of diabetes in adolescents by age, gender and HbA1C

Years

Age

Imp

act

of

dia

be

tes

1211

22

24

26

28

30

1413 1615 18

F 10.9%

HbA1 C

F 6.8%

M 10.9%

M 6.8%

17

Score

Worries about diabetes in adolescents by age, gender and HbA1C

Score

Wo

rrie

s a

bo

ut

dia

be

tes

1211

15

20

25

30

1413 1615 18

F 10.9%

F 6.8%

M 10.9%

M 6.8%

17

HbA1 C

Years

Age

Satisfaction with life in adolescents by age, gender and HbA1C

Score

Sa

tisf

act

ion

wit

h li

fe

1211

20

25

30

35

1413 1615 18

F 10.9%

F 6.8%

M 10.9%

M 6.8%

17

HbA1 C

Years

Age

Health perception in adolescents by age, gender and HbA1C

Hea

lth

pe

rce

pti

on

1211

15

20

25

30

35

40

1413 1615 18

F 10.9%

F 6.8%

M 10.9%

M 6.8%

17

HbA1 C

Score

Years

Age

Metabolic Control and Quality of Life Key messagesKey messages

First large international multi-language study First large international multi-language study evaluating the relationship between metabolic control and evaluating the relationship between metabolic control and

QOL in 2,101 adolescents with diabetes. QOL in 2,101 adolescents with diabetes.

Lower HbALower HbA1c1c is associated with better QOL of is associated with better QOL of adolescents and lesser perceived family burden by adolescents and lesser perceived family burden by

parents and health professionals.parents and health professionals.

No relation between QOL and the actual insulinNo relation between QOL and the actual insulin

regimenregimen..

Speculation Speculation

Young people with excellent QOL: Young people with excellent QOL:

Good physical and psychological balanceGood physical and psychological balance

Facilitate better metabolic control through Facilitate better metabolic control through

improved self-careimproved self-care

Bad metabolic control = poor QOLBad metabolic control = poor QOL

Conclusion

Our studies showed Our studies showed

No relationship between blood glucose control, No relationship between blood glucose control, insulin dose and number of dailly injections insulin dose and number of dailly injections

Good metabolic control Good metabolic control cancan be achieved without be achieved without increasing the risk of severe hypoglycaemic events increasing the risk of severe hypoglycaemic events

A clear relationship between metabolic control and A clear relationship between metabolic control and quality of lifequality of life