KINDERKRANKENHAUS AUF DER BULT
für Kinder und Jugendliche
Akademisches Lehrkrankenhaus
Diabetes Control: Goals and reality –
European perspective
Thomas Danne
Kinderkrankenhaus auf der Bult, Hannover, Germany
KINDERKRANKENHAUS AUF DER BULT
für Kinder und Jugendliche
Akademisches Lehrkrankenhaus
Agenda
• 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 ?
KINDERKRANKENHAUS AUF DER BULT
für Kinder und Jugendliche
Akademisches Lehrkrankenhaus
Plasma 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.
KINDERKRANKENHAUS AUF DER BULT
für Kinder und Jugendliche
Akademisches Lehrkrankenhaus
KINDERKRANKENHAUS AUF DER BULT
für Kinder und Jugendliche
Akademisches Lehrkrankenhaus
SWEDEN: A change in HbA1c reference affects metabolic control:
Targets are important !
Data from 49 patients born 1971-1989
Mono S
HbA1c, % HPLC
DCA 2000
DCCT calibration
DCA 2000
Swedish calibration
9.5
9.0
1.4% diff.
8.5
8.0
7.5
1.1% diff.
7.0
p=n.s p=0.04 p=n.s
(significance vs. year
before change)
6.5
6.0
p=n.s p=0.003 p=0.01
5.5
N = 13 14 17 12 17 18 17 20 19 20 23 22 32 32 29 27 36 38 37 32 39 41 41 37 39 44 42 39 42 44 38 35 41 36 35 40 40 42 38 37 36 40 33 33 33 40 36 32
90
91
92
93
94
95
96
97
98
99
Hanas R. Psychological impact of changing the scale of reported HbA1c results affects
metabolic control. Diabetes Care 2002;25:2110-1.
00
01 Years
KINDERKRANKENHAUS AUF DER BULT
für Kinder und Jugendliche
Akademisches Lehrkrankenhaus
Hvidore-Adolescent-Study 2008
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
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
KINDERKRANKENHAUS AUF DER BULT
für Kinder und Jugendliche
Akademisches Lehrkrankenhaus
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.
adjusted HbA1c (%)
target HbA1c of teammembers
Team-Target and HbA1c
KINDERKRANKENHAUS AUF DER BULT
für Kinder und Jugendliche
Akademisches Lehrkrankenhaus
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
no target
8.0 – 9.0 %
7.5 – 7.9%
7.0 – 7.4%
< 7.0
1
8
10
9
2
3
3
5
4
5
5
6
6
7
7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
22 2 7 6 10 10 5 5 7 7 9 6 9 8 5
mean HbA1c of adolescents in center
(adjusted for age, diabetes duration and gender):
8,8
8,0
8
7
7,7
7,4 7,6
8,0 8,1
8,2 8,2 8,2
8,3
9,1
8,8 8,8
8,4 8,4
2 3
Hvidore Group
(2008) submitted
7,7 7,8 7,9
225 125 90 125 175 175 225 30 125 50 225 225 225 225 70 90 225 175 175 175 125
1
Number of team
members answering
9,0
8,6
8.2 ± 1.4 %
Center number
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18 19 20 21
Number of
adolescents in treated
in center
Center number
KINDERKRANKENHAUS AUF DER BULT
für Kinder und Jugendliche
Akademisches Lehrkrankenhaus
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
20.0
7.58
7.68
7.74
7.80
7.89
8.00
16.7
52.4
33.3
20.0
40.
100.0
83.3
42.9
100.
100.0
60.0
40.0
44.4
60.0
60.0
80.0
20.0
33.3
20.0
40.0
57.1
4.8
42.9
20.0
20.0
8.02
8.08
8.18
8.23
8.24
8.27
8.36
60.0
8.45
8.59
75.0
60.0
22.2
100.0
25.0
20.0
8.76
8.82
8.83
8.98
60.0
20.0
40.0
40.0
22.2
20.0
20.0
20.0
44.4
10.0
10.0
20.0
9.05
KINDERKRANKENHAUS AUF DER BULT
für Kinder und Jugendliche
Akademisches Lehrkrankenhaus
Relationship between targets of parents and
adolescents and achieved HbA1c
<7.0
7.0-7.4
7.5-7.9
8.0 – 9.0
Don´t
know
N
meanl
SD
975
713
205
25
47
7.9
8.4
8.8
8.9
8.1
1.4
1.3
1.3
1.0
1.6
N
meanl
SD
639
691
473
141
13
7.4
8.1
8.6
9.6
10.5
1.2
1.2
1.2
1.5
2.1
N
mean
SD
1056
627
189
18
31
7.9
8.3
8.9
8.9
8.4
1.3
1.3
1.3
1.3
2.3
N
mean
SD
600
694
466
127
18
7.5
8.0
8.7
9.6
10.6
1.3
1.1
1.1
1.4
2.0
target
adolescent
ideal
adolescent
happy
parents
ideal
parents
happy
KINDERKRANKENHAUS AUF DER BULT
für Kinder und Jugendliche
Akademisches Lehrkrankenhaus
Multiple Regressionsanalysis proves the role of targets
and team interaction for center differences
Beta
t
p
Beta
t
p
Age
.069
3.077
.002
.041
2.025
.043
Gender
-.054
-2.517
.012
-.060
-3.136
.002
Diabetes Dration
.123
5.432
.000
.066
3.236
.001
Insulin dose (Units/kg)
.139
6.414
.000
.090
4.627
.000
Insulin Regimen (BD
Freemix)
.050
2.247
.025
.047
2.362
.018
Center rank
.337
15.251
.000
.164
7.596
.000
Step 1
Step 2
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
KINDERKRANKENHAUS AUF DER BULT
für Kinder und Jugendliche
Akademisches Lehrkrankenhaus
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
KINDERKRANKENHAUS AUF DER BULT
für Kinder und Jugendliche
Akademisches Lehrkrankenhaus
Influencing Microangiopathy Through Lowering The
HbA1c In Randomised Studies
Parameter
DCCT
Kummamoto
UKPDS
Type of Diabetes
Number of patients
1
1441
„1,5“
110
2
3867
Follow-up (years)
6,5
6
10
HbA1c-change
9,1->7,2
9,1->7,0
7,9->7,0
4
(3-11)
5
(4-19)
10
(6-50)
NNTDuration of study (95% CI)
Progress. Retinopathy
Progress. Nephropathy
Progress. Neuropathy
5
(4-7)
7
(6-11)
5
(4-7)
5
(3-16)
KINDERKRANKENHAUS AUF DER BULT
für Kinder und Jugendliche
Akademisches Lehrkrankenhaus
Rate of Background-Retinopathy
(per 100 patient-years)
Berlin Retinopathy-Study (1977-94):
Continuous Exponential Relationship between
retinopathy and long-term-HbA1c
Virtually all children
with diabetes from
West-Berlin
10
8
6
N= 494,
262 boys, 232 girls
4
Median age at onset:
11 (1 to 17) years
2
Annual fluoresceine
angiograms
0
<7
7-8
Danne et. al, Diab Care 17: 1390-96, 1994
8-9 9-10 10-11 > 11
Average HbA1c (%)
Median follow-up:
9 years
KINDERKRANKENHAUS AUF DER BULT
für Kinder und Jugendliche
Akademisches Lehrkrankenhaus
Should risk of severe hypoglycemia
influence the targets in young children ?
KINDERKRANKENHAUS AUF DER BULT
für Kinder und Jugendliche
Akademisches Lehrkrankenhaus
Maternal fear of Hypoglycemia in their Children with
Insulin dependent Diabetes mellitus
Clarke et al.; JPEM 11 (Suppl.1): 189-194, 1998
Average Hypoglycaemia Fear Score
Adults with diabetes
n=78
1.88 ± 0.6
0.001
Parents of IDDM children
n=46
2.94 ± 0.6
n=31
2.84 ± 0.6
(mean age 8.1 years)
- without severe hypo
0.040
- with severe hypo
n=15
3.18 ± 0.6
No influence:
confidence to detect or treat hypoglycaemia in their children
KINDERKRANKENHAUS AUF DER BULT
für Kinder und Jugendliche
Akademisches Lehrkrankenhaus
Can my child die during a hypoglycaemia ?
The „dead in bed syndrome“
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.
Author
Study
period
Tattersall (1991)
1989
Thodarson (1995)
1981-90
Sartor (1995)
1977-85
Age Group Total
(years)
deaths
0 - 40
0 - 28
Dead in bed
(n)
Age
(years)
-
22
12 - 43
240
16
7 - 35
33
9
15 - 23
KINDERKRANKENHAUS AUF DER BULT
für Kinder und Jugendliche
Akademisches Lehrkrankenhaus
Why do children with diabetes die ?
ca. 150600
Children w. Diabetes
(0 to 19 years)
116 deaths
33 deaths not
related to DM
83 deaths
related to DM
45 in hospital
during DKA therapy
26 at home (9 „dead in bed“)
8 on way to hospital
4 hypoglycemia 10 DKA
possible
Causes of death in children with insulin dependent
diabetes 1990-96
10 DKA likely
KINDERKRANKENHAUS AUF DER BULT
für Kinder und Jugendliche
Akademisches Lehrkrankenhaus
Influence of social factors on the mortality of adults
with type 1 diabetes
800 Patients with type 1 diabetes (Follow-up 8.4 years)
Risk factor
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)
Robinson N. et. al.: Social Deprivation and Mortality in Adults with
Diabetes Mellitus. Diab Med (1998) 15:205-212
KINDERKRANKENHAUS AUF DER BULT
für Kinder und Jugendliche
Akademisches Lehrkrankenhaus
Same targets for all age paediatric age
groups – the Hannover approach
• HbA1c below 7.5%
• prevent ketoacidosis
• prevent school failure
• prevent hypoglycemia
KINDERKRANKENHAUS AUF DER BULT
für Kinder und Jugendliche
Akademisches Lehrkrankenhaus
The ISPAD Vote
September 28th,2007
Majority for age
independent targets
Target HbA1c < 8%:              
Target HbA1c < 7.5%:         
                           
Target HbA1c < 7.0%:         
KINDERKRANKENHAUS AUF DER BULT
für Kinder und Jugendliche
Akademisches Lehrkrankenhaus
But is the HbA1c
the
right target ?
KINDERKRANKENHAUS AUF DER BULT
für Kinder und Jugendliche
Akademisches Lehrkrankenhaus
The DCCT
Research Group.
The relationship of
glycemic exposure
(HbA1c) to the risk
of development and
progression of
retinopathy in the
Diabetes Control
and Complications
Trial. Diabetes 1995; 44:
968-83
KINDERKRANKENHAUS AUF DER BULT
Time of diagnosis of background
retinopathie (DMduration (years)
für Kinder und Jugendliche
Akademisches Lehrkrankenhaus
25
HbA1c is a bad predictor of
retinopathy in indvidual adolescents
– the Berlin Retinopathy-Study
20
15
10
5
Longterm HbA1c (%)<6
Median Age (Years) -
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
Danne et. al, Diab Care 17: 1390-96, 1994
KINDERKRANKENHAUS AUF DER BULT
für Kinder und Jugendliche
Akademisches Lehrkrankenhaus
The new information with CGM: Glycemic variability
Comparison blinded FreeStyle Navigator vs. HbA1c
Glucose Mean vs. HbA1c
r=0.801
p<0.0001
Glucose S.D. vs. HbA1c
r=0.675
p=0.0004
German Diabetes Association 2008
KINDERKRANKENHAUS AUF DER BULT
für Kinder und Jugendliche
Akademisches Lehrkrankenhaus
Hannover Navigator Study
Other Measures of Glycemic Control
Masked Unmasked
%
Difference
P-value
Glucose Mean (mg/dL)
Mean
S.D.
N
172
27
23
164
24
23
-4.5%
0.0577
Glucose S.D. (mg/dL)
Mean
S.D.
N
61.8
11.9
23
56.1
14.2
23
-9.1%
0.0037
MAGE nadir to
peak events (mg/dL)
Mean
S.D.
N
135.2
28.9
23
125.1
28.1
23
-7.4%
0.0462
MAGE peak
to nadir events (mg/dL)
Mean
S.D.
N
140.6
28.3
23
126.8
29.7
23
-9.9%
0.0017
KINDERKRANKENHAUS AUF DER BULT
für Kinder und Jugendliche
Akademisches Lehrkrankenhaus
Children with diabetes need insulin,
love and care …and clear targets