Content uploaded by Klemen Dovc
Author content
All content in this area was uploaded by Klemen Dovc on Sep 29, 2020
Content may be subject to copyright.
ORIGINAL ARTICLE
Improved Metabolic Control in Pediatric
Patients with Type 1 Diabetes:
A Nationwide Prospective 12-Year Time Trends Analysis
Klemen Dovc, MD,
1
Sasa Starc Telic, MD,
1
Lara Lusa, PhD,
2
Nina Bratanic, MD,
1
Mojca Zerjav-Tansek, MD,
1
Primoz Kotnik, MD, PhD,
1
Magdalena Avbelj Stefanija, MD, PhD,
1
Tadej Battelino, MD, PhD,
1,3
and Natasa Bratina, MD, PhD
1
Abstract
Background: This study estimated temporal trends of metabolic control over 12 years in a national cohort of childhood-onset
type 1 diabetes.
Subjects and Methods: Data from the prospective childhood-onset diabetes register, which included 886 case subjects from 0
to 17.99 years of age at diagnosis and at least 1 year of follow-up until the age of 22.99 years, were analyzed using
multivariable linear and logistic regression models in the observational period between 2000 and 2011.
Results: Hemoglobin A1c (HbA1c) significantly decreased over 12 years, from 78 mmol/mol (interquartile range [IQR], 68–
88 mmol/mol) (9.26% [IQR, 8.41–10.24%]) in the year 2000 to 61 mmol/mol (IQR, 55–67 mmol/mol) (7.75% [IQR, 7.20–
8.30%]) in the year 2011 (P<0.001). HbA1c was significantly associated with age, treatment modality, and duration of
diabetes (P<0.001), with females having on average 1.02% higher HbA1c (P=0.01; 95% confidence interval [CI] 1.005–1.035).
The overall use of insulin pumps was 74%. The incidence rate of severe acute complications was low: 1.07 per 100 patient-
years for severe diabetic ketoacidosis (95% CI 0.81–1.40) and 1.21 per 100 patient-years for severe (requiring intravenous or
intramuscular therapy) hypoglycemia (95% CI 0.81–1.40).
Conclusions: The metabolic control of the entire nationwide pediatric type 1 diabetes population significantly improved
during the 12-year observational period with a low rate of severe acute complications events. The improvement was asso-
ciated with the treatment modality. Additional efforts and solutions are necessary to further improve metabolic control and
the quality of life of young people with type 1 diabetes.
Introduction
The primary goal in the treatment of type 1 diabetes
(T1D) is to maintain blood glucose levels as close to
normal as possible with the aim of reducing the risk for de-
veloping chronic complications.
1
The strategies for the treat-
ment of infants and young children may differ from those
intended for teenagers or adults, but finally aim at the same
primary goal.
2
Current guidelines for adult
3
and pediatric
2
T1D popula-
tions suggest that the hemoglobin A1c (HbA1c) level should
be below 53 mmol/mol (7%) or 58 mmol/mol (7.5%), re-
spectively. Only a minority of patients can safely achieve
these goals.
4
The increase of severe hypoglycemia (SH) rate,
commonly associated with a reduction in HbA1c,
1
precludes
many patients from reaching the target metabolic control.
Intensified insulin delivery usually consists of either mul-
tiple daily injections (MDI) or continuous subcutaneous in-
sulin infusion (CSII) and is based on self-monitoring of blood
glucose and recently also on real-time continuous glucose
monitoring.
5
CSII is considered as safe and effective as MDI in
all pediatric age groups
6
and is in some
7,8
—but not all
9
—
pediatric T1D population studies associated with better
metabolic control compared with MDI. Its use is steadily in-
creasing.
10,11
Recent data indicate that in many countries
outside the United States only a few pediatric T1D patients are
treated with CSII.
10,12,13
However, treatment modality is not
always associated with an improvement in HbA1c level.
14
The aim of this study was to analyze temporal trends of
metabolic control and possible factors influencing metabolic
control, including treatment modality, in the Slovene pediat-
ric T1D population over the last 12 years.
1
Department of Pediatric Endocrinology, Diabetes and Metabolism, University Medical Center-University Children’s Hospital, Ljubljana,
Slovenia.
2
Institute for Biostatistics and Medical Informatics,
3
Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
DIABETES TECHNOLOGY & THERAPEUTICS
Volume 16, Number 1, 2014
ªMary Ann Liebert, Inc.
DOI: 10.1089/dia.2013.0182
33
Study Design and Methods
Data on the entire pediatric T1D population, which in-
cluded 886 case subjects from 0 to 17.99 years of age at diag-
nosis and at least 1 year of follow-up until the age of 22.99
years, were collected from the prospective Slovene childhood-
onset T1D register.
15,16
The observational period was from
January 1, 2000 to December 31, 2011. All outpatient visits and
measurements took place approximately every 3 months at
the University Children’s Hospital Ljubljana, Ljubljana, Slo-
venia. Six full-time endocrinologists and six diabetes educa-
tors (148 patients per full-time equivalent) were working in
the multidisciplinary team together with two psychologists,
one dietitian, and one social worker.
In total, 21 patients who had other forms of diabetes mel-
litus, concomitant Addison’s disease, cancer, or autoimmune
neurological disease or were transferred to a center outside
Slovenia after less than 1 year of follow-up were excluded
from this analysis. Attrition from the register before the age of
18 years was followed.
Data for individual patients were available for at least three
visits annually. The HbA1c level was determined centrally
with the same immunochemical method throughout the ob-
servation period using the DCA 2000 +analyzer (Bayer Di-
agnostics, Tarrytown, NY). The accuracy of the DCA 2000 +
analyzer was verified routinely every 3 months by the hos-
pital laboratory quality-assurance program and annually by
the provider, who issued a certificate. Data on severe acute
complications were collected from medical records. Diabetic
ketoacidosis (DKA) was defined as an event requiring hos-
pitalization and intravenous therapy, and SH was defined as
an event with a loss of consciousness and/or seizures re-
quiring hospitalization and intramuscular and/or intrave-
nous therapy.
17
The study protocol was approved (number
22/12/09) by the Slovene Medical Ethics Committee. Patients
and/or parents gave their informed consent for the anony-
mous use of data.
Statistical methods
Numerical variables were presented as median and inter-
quartile range (IQR) or as mean and SD values. The primary
outcome measure was HbA1c. The secondary outcomes were
body mass index (BMI) SD score (SDS), daily insulin dose
(units/kg), and severe DKA and SH events. Repeated out-
come measurements obtained from the same patient were
averaged over 6-month periods.
Multivariable linear regression models were used to ex-
amine the association between HbA1c and patient charac-
teristics; HbA1c was log
2
-transformed to reduce the
skewness of its distribution. The covariates were gender,
age, year of measurement, treatment modality, BMI SDS,
and duration of diabetes. The association of the same cov-
ariates with the probability of suboptimal (HbA1c >7.5%)
and poor (HbA1c >9%) metabolic control
2
was assessed
using logistic regression models. Model selection was not
performed, and all the covariates were included in the re-
gression models as fixed effects. To avoid the implicit as-
sumption that the effect of the continuous covariates on
outcome was linear (on the log-transformed scale or on the
logit scale), restricted cubic splines
18
were used to flexibly
model the relationship between covariates and outcome (five
knots were used, placed at the 5
th
,25
th
,50
th
,75
th
,and95
th
percentiles). To take into account the multiple measurements
repeated in each patient, the analyses were adjusted for a
subject variable as a random effect. The association of the
covariates with outcomes and the nonlinear relationship
between continuous covariates and outcome were assessed
by likelihood ratio tests. The estimated shape of the rela-
tionship between each continuous covariate and outcome
was represented graphically, using specified values for other
covariates, reported in the figure legends. It is important that
these choices did not influence the estimated shape of the
relationship between the covariates and outcome, but only
the estimated value of the outcome and the size of the con-
fidence intervals. For this reason all the figures were re-
scaled, and the starting point on the y-axes was set to 0.
Therefore, the values on the y-axes can be interpreted as
estimated differences from the starting point.
Results of multiple regression analyses were presented as
multiple adjusted HbA1c mean ratios or odds ratios (OR),
with 95% confidence intervals (CIs).
BMI was transformed into SDS for gender and age ac-
cording to United Kingdom Cole reference tables. For the
regression models, when BMI SDS was missing, we imputed
the average BMI SDS value of the previous and next available
measurement.
Incidence rates of severe DKA and SH were calculated as
events per 100 patient-years, and their 95% CI was based on
the Poisson distribution.
The Pvalues of all statistical tests were two-sided, and 95%
CI were reported. For all analyses differences were considered
significant at values of P£0.05. Statistical analyses were per-
formed using R statistical language.
19
The multiple mixed-
effect regression models were fitted using the nlme and lme4
R package.
19
Results
The median HbA1c decreased from 78 mmol/mol (IQR,
68–88 mmol/mol) to 61 mmol/mol (IQR, 55–67 mmol/mol)
(from 9.26% [IQR, 8.41–10.24%] to 7.75% [IQR, 7.20–8.30%])
(P<0.001, Mann–Whitney test) (Fig. 1). The mean values were
79 mmol/mol (9.42%) (SD, 1.5) and 62 mmol/mol (7.80%)
(SD, 0.96), respectively (P<0.001, two-sample ttest).
Median age of the cohort at diabetes onset was 9.61 years
(IQR, 5.90–13.08) and decreased significantly with time: it was
12.68 years (IQR, 8.91–14.66) in the year 2001 and 7.53 years
(IQR, 4.99–10.83) in the year 2010 (P<0.001) (Fig. 2). Median
follow-up time was 5.00 years (IQR, 2.50–8.00). The numbers
of available 6-month averages of measurements per patient
were 10 for HbA1c (IQR, 6–16), nine for BMI SDS (IQR, 5–14),
and eight for daily insulin dose (IQR, 4–12). Of the total, 4.2%
(n=37) patients were lost to our follow-up.
The median BMI SDS increased from 0.40 (IQR, -0.17 to
0.99) to 0.5 (IQR, -0.15 to 1.18) (P=0.47), whereas daily in-
sulin dose decreased from 0.76 units/kg (IQR, 0.60–0.88) to
0.70 units/kg (IQR, 0.60–0.80) (P<0.001).
All patients were treated with either MDI or CSII, of whom
8.9% (79 patients) were treated exclusively with MDI, in-
cluding 28 patients (4.3% of CSII) who decided not to use CSII
after a short trial. The overall use of CSII was 74%. When
patients were treated with CSII, median time from disease
onset to the start of CSII was 8.81 (IQR, 6.32–10.93) years in
2001 and 0.59 (IQR, 0.14–2.00) years in 2010 (P<0.001).
34 DOVC ET AL.
In the entire group of patients, the incidence rate of severe
acute complications was 1.07 per 100 patient-years for severe
DKA (95% CI 0.81–1.40) and 1.21 per 100 patient-years for SH
(95% CI 0.65–1.21). Forty-four (5.0%) patients had at least one
episode of DKA, and 47 (5.3%) patients had at least one epi-
sode of SH. Data on severe acute complications rate per each
year are presented in Table 1.
Association between HbA1c and patient
characteristics
The (log-transformed) HbA1c level significantly and non-
linearly (P<0.001) decreased in the observational period. The
change between year 2000 and 2011 remained significant,
when the multivariable regression analysis was adjusted for
FIG. 1. Median hemoglobin A1c (HbA1c) (with interquartile range) by year of measurement (year of measurement/median
HbA1c) with total number of patients under observation (N) and continuous subcutaneous insulin infusion (CSII) percentage
by each year from 2000 to 2011.
FIG. 2. Median age (with interquartile range) at diabetes onset (year of measurement/age at diagnosis) with total number
of patients with newly diagnosed type 1 diabetes (N) in each year from 2000 to 2011.
METABOLIC CONTROL IN YOUTH WITH T1D 35
possible differences in patient characteristics (age, gender,
treatment modality, BMI SDS, and duration of diabetes) over
time (Fig. 3A and B and Table 2): on average, the estimated
HbA1c was 1.12 times higher (95% CI 1.11–1.14) in the year
2001 compared with 2011. The probability of suboptimal
(HbA1c >7.5%) and poor (HbA1c >9%) metabolic control
was significantly higher in the year 2001 compared with 2011
(OR =9, 95% CI 6–12; and OR =25, 95% CI 17–33, respectively)
(Table 2 and Fig. 3B). Females had on average 1.02 times
higher values of HbA1c compared with males (P=0.009, 95%
CI 1.00–1.04) and had a higher probability of suboptimal
metabolic control (OR =1.45, 95% CI 1.1–2.0, P=0.02) and a
statistically nonsignificant higher probability of poor meta-
bolic control (OR =1.3, 95% CI 0.9–1.9, P=0.20). Age and
duration of diabetes were significantly and nonlinearly
(P<0.001) associated with log
2
-HbA1c (Table 2). The HbA1c
level initially decreased as age increased. However, the rela-
tionship was inverted during adolescence as larger values of
HbA1c were estimated for older patients. After the end of
adolescence, the HbA1c level decreased with age again. The
HbA1c level increased for patients who had a longer duration
of diabetes until about the sixth year of duration; after that, the
value of HbA1c remained constant. Similar results were ob-
served for suboptimal and poor metabolic control (Table 2).
The association between BMI SDS and HbA1c was small
and not significant (P=0.053) (Table 2), in that patients with
both high and low BMI SDS were more likely to have sub-
optimal or poor metabolic control (Fig. 3C) (P=0.001 and
P=0.039, respectively).
On average, the patients treated with MDI had 1.02 times
higher HbA1c compared with those treated with CSII
(P<0.001) and a higher probability of suboptimal (OR =1.4,
P<0.001) or poor (OR =1.6, P<0.001) metabolic control. The
difference between the two treatments was more pronounced
when the outcome was suboptimal and poor metabolic con-
trol (Table 2).
Discussion
For more than two decades the entire population of Slovene
children with T1D has been treated centrally at the tertiary
institution with a multidisciplinary team including a pediatric
endocrinologist, certified nurse educators, psychologists, di-
etitians, and a social worker.
20
Support and consultations are
offered via an emergency 24/7 telephone line for patients,
families, caregivers, and primary healthcare pediatricians,
regardless of the treatment modality. The same structured
education and management plan, emphasizing frequent self-
monitoring of blood glucose and continuous glucose moni-
toring when possible and consultation via 24/7 telephone
line, is provided for parents as well as for professional care-
givers taking care of children with T1D in either kindergarten
or school or during sport activities.
21
Psychological support
together with regular dietetic consultations is an important
part of regular follow-up in the whole patient population. A
patients’ organization is providing regular annual educa-
tional meetings, publications, and summer camps with in-
formation available on a Web site (www.sladkorcki.si). CSII
was introduced as a standard treatment modality with public
reimbursement in the year 2000.
The observed decrease in median HbA1c level of
16.4 mmol/mol (1.5%) in our cohort differs from the finding of
Table 1. Severe Acute Complications in Each Observational Year
Year
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011
DKA
N633323761839
Rate
a
2.18
(0.80–4.75)
0.94
(0.19–2.74)
0.82
(0.17–2.41)
0.77
(0.16–2.25)
0.48
(0.06–1.73)
0.69
(0.14–2.03)
1.58
(0.64–3.26)
1.31
(0.48–2.84)
0.20
(0.01–1.14)
1.68
(0.72–3.30)
0.61
(0.12–1.77)
1.90
(0.87–3.60)
SH
N647345446936
Rate
a
2.18
(0.80–4.75)
1.25
(0.34–3.21)
1.92
(0.77–3.96)
0.77
(0.16–2.25)
0.96
(0.26–2.45)
1.16
(0.38–2.70)
0.90
(0.25–2.31)
0.87
(0.24–2.23)
1.22
(0.45–2.67)
1.89
(0.86–3.58)
0.61
(0.12–1.77)
1.27
(0.46–2.76)
Patient-years
at risk
275 319.5 364.5 389 417.5 432.5 443 459.5 490 477 495.5 474
Diabetic ketoacidosis (DKA) was defined as an event requiring hospitalization and intravenous therapy. Severe hypoglycemia (SH) was defined as an event with a loss of consciousness and/or
seizures requiring hospitalization and intramuscular and/or intravenous therapy.
a
Rates are the estimated rate per 100 patient-years (95% confidence interval).
N, total number of events.
36 DOVC ET AL.
FIG. 3. Multiple adjusted estimates of (A) average hemoglobin A1c (HbA1c) by year of measurement and probabilities of
suboptimal metabolic control (HbA1c >7.5%) by (B) year of measurement and (C) body mass index (BMI) SD score (SDS). A–C
were rescaled, setting the starting point on the y-axes to zero; therefore, the values on the y-axes can be interpreted as estimated
differences from the starting point.
Table 2. Predictors of Metabolic Control, Using Multiple Adjusted Estimated Median
Hemoglobin A1c (HbA1c), Ratio of Log-HbA1c, and Proportion of Patients with HbA1c>7.5%or >9%
by Patient Characteristics and Aspects of Diabetes Management
Variable
Median HbA1c
(IQR)
HbA1c
mean ratio
a
P
HbA1c
>7.5%
Odds ratio
HbA1c >7.5% (CI)
a
P
HbA1c
>9%
Odds ratio
HbA1c >9% (CI)
a
P
Gender
Male 7.80 (7.20–8.60) 1.00 (0.01 62.47 1.00 (0.019 16.84 1.00 (0.204
Female 7.96 (7.30–8.80) 1.02 (1.00–1.04) 67.12 1.45 (1.06–1.98) 20.13 1.28 (0.87–1.90)
Age at measurement (years)
b
1 7.60 (6.90–8.30) 1.00 (<0.001 52.94 1.00 (<0.001 5.88 1.00 (<0.001
5 7.70 (7.20–8.20) 0.97 (0.95–0.98) 62.13 0.72 (0.53–0.96) 4.14 0.86 (0.52–1.42)
10 7.70 (7.10–8.30) 0.94 (0.91–0.97) 57.11 0.51 (0.27–0.94) 10.02 0.84 (0.29–2.39)
15 8.10 (7.40–9.00) 0.96 (0.93–1.00) 71.20 0.64 (0.32–1.25) 24.63 2.72 (0.91–8.08)
20 7.90 (7.20–8.85) 0.95 (0.91–0.99) 66.30 0.35 (0.16–0.77) 21.68 2.76 (0.83–9.20)
Duration of diabetes (years)
b
1 7.40 (6.80–8.14) 1.00 (<0.001 47.75 1.00 (<0.001 8.92 1.00 (<0.001
5 8.00 (7.30–8.80 1.11 (1.10–1.13) 68.26 7.89 (5.87–10.60) 21.80 6.27 (4.09–9.59)
10 8.05 (7.50–8.90) 1.15 (1.12–1.18) 73.60 15.07 (9.31–24.38) 21.25 9.49 (4.99–18.05)
15 8.05 (7.40–8.90 1.17 (1.13–1.21) 71.14 22.63 (11.09–46.18) 22.82 9.77 (3.75–25.46)
Year of measurement
b
2001 9.10 (8.20–10.15) 1.00 (<0.001 89.05 1.00 (<0.001 52.06 1.00 (<0.001
2006 7.65 (7.10–8.20) 0.89 (0.88–0.90) 54.70 0.11 (0.08–0.14) 10.57 0.06 (0.04–0.08)
2011 7.80 (7.20–8.32) 0.89 (0.87–0.90) 62.78 0.11 (0.08–0.16) 9.36 0.04 (0.03–0.06)
BMI SDS
b
0 7.75 (7.10–8.56) 1.00 (0.053 58.92 1.00 (0.001 15.50 1.00 (0.039
-3 8.18 (8.06–8.46) 1.03 (1.00–1.07) 53.45 3.22 (1.39–7.49) 3.45 4.89 (1.49–16.04)
-1 7.70 (7.10–8.55) 1.01 (1.00–1.02) 57.45 1.26 (1.02–1.56) 17.60 1.35 (1.01–1.82)
1 7.95 (7.32–8.80) 1.00 (0.99–1.01) 67.39 1.35 (1.10–1.65) 20.52 1.29 (0.99–1.67)
3 7.75 (7.10–8.20) 0.99 (0.96–1.01) 63.04 1.97 (1.13–3.43) 13.04 1.45 (0.72–2.93)
Treatment modality
MDI 8.40 (7.50–9.50) 1.00 (<0.001 74.58 1.00 (0.004 33.43 1.00 (<0.001
CSII 7.80 (7.20–8.40) 0.98 (0.97–0.99) 61.25 0.72 (0.57–0.91) 13.19 0.61 (0.46–0.80)
Estimates are derived from multiple linear and logistic mixed models including gender, age at measurement, year of measurement,
diabetes duration, body mass index (BMI) SD score (SDS), and treatment modality (multiple daily injections [MDI] or continuous
subcutaneous insulin infusion [CSII]) as fixed effects. Values for age, duration of diabetes, and year of measurement, which were flexibly
modeled using restricted cubic splines, present estimated associations between the variables and the outcomes.
a
Each estimate is adjusted for all the other variables in the table; a value of 1.00 indicates the reference values.
b
Restricted cubic splines were used to flexibly model the relationship between the covariate and the outcome. The variables were not
categorized, and the values of the covariates do not represent categories. The descriptive statistics are based on the subset of patients with the
chosen value of the covariate ( –0.5 for BMI SDS).
CI, confidence interval; IQR, interquartile range.
METABOLIC CONTROL IN YOUTH WITH T1D 37
the Hvidoere study group, which reported stable center dif-
ferences in metabolic control with only two out of 21 pediatric
centers from 19 countries having a decrease in HbA1c level
significantly of roughly 6.6 mmol/mol (0.6%) from 1998 until
2005.
13
However, another study reported a pronounced de-
crease of HbA1c over a period of several years.
14
It is inter-
esting that the small but significant difference in the decrease
of HbA1c level between genders is also reported by some
11,14
studies but not others.
13
The present study demonstrated a clear shift to younger
age at onset of T1D with a median decrease from 12.68 to 7.53
years. A similar decrease was previously shown in other
studies,
22
also including our region.
15,16
The BMI SDS of the entire group increased nonsignificantly
in the first 5 years of diabetes and stabilized thereafter. In-
tensive treatment is associated with an increase in weight in
several studies,
1,13
but the increase in BMI SDS in the present
study was comparable to the secular increase of BMI SDS
during the same period in the general population.
23
BMI SDS
was found to be significantly associated with suboptimal
metabolic control (HbA1c >7.5%), suggesting that patients
with higher or lower BMI SDS are prone to poorer metabolic
control. Because of the observational design the present study
could not investigate the causality of this association.
The concomitant small but significant decrease in the daily
insulin dose may be related to the frequent use of CSII,
commonly associated with a lower daily insulin dose.
6,7,13,24
The use of CSII increased in the investigated cohort to an
overall level of use in 74% of patients. This proportion of
pediatric patients using CSII is comparable to some academic
institutions in the United States and Israel and was higher
than in some European countries.
9,13
The CSII discontinuation
rate of 4.3% is comparable with other pediatric reports
25
and
typically lower compared with the adult CSII population.
26
Recent studies show that CSII as an initial treatment at T1D
diagnosis is safe and effective even in the youngest chil-
dren
25,27
with
25
or without
28
better long-term metabolic con-
trol and/or lower risk of SH. The time of CSII initiation after
T1D onset in our study decreased significantly from 8.81 to
0.59 years. Long-term studies are needed to evaluate the
benefit of early initialization of CSII therapy in the pediatric
population.
28
In the current study the insulin delivery regimen was
slightly but significantly associated with HbA1c, favoring
CSII, with stronger association in patients with poor meta-
bolic control. This differs from a recently published study,
14
where only the treatment modality from the last year of ob-
servation was analyzed. Greater impact of CSII on patients
with poorer metabolic control was reported previously.
11
The
percentage of patients treated with CSII increased steadily
during the study, with the CSII initiation time significantly
closer to the disease onset, which likely contributed to the
continuous improvement in HbA1c. However, uniform dia-
betes education with the emphasis on regular self-monitoring
of blood glucose and continuous glucose monitoring, when
possible, carbohydrate counting, telephone communication
for dose adjustments, and problem solving with psychologi-
cal support remained paramount.
The rate of severe acute complications requiring medical
intervention was comparable to those in some other re-
ports.
14,29
Unfortunately, the national register did not include
data on less SH.
The present study has several limitations. Because of the
observational design, the study could not control for several
factors influencing metabolic control and acute complications.
Therefore, observed associations could be biased or may re-
flect only random effects. However, the attrition from the
register was 4.2% as 37 patients were lost to follow-up before
the age of 18 years. The treatment modality selection was
performed according to the International Society for Pediatric
and Adolescent Diabetes guidelines,
2
introducing a selection
bias especially in the first half of our observational period
when CSII use was less frequent. The rate of severe acute
complications events must be interpreted along with their
definition including only cases where the intramuscular or/
and intravenous therapy was administered by healthcare
professionals. The national register does not include data on
less SH or DKA because significant important numbers of
these less severe acute complications routinely resolved
without medical intervention.
In conclusion, the analysis of 886 pediatric patients from a
national childhood-onset diabetes register demonstrated a
significant and clinically meaningful decrease of HbA1c level
over a 12-year observation period. This improvement was
associated with treatment modality. Additional efforts and
solutions are necessary to further improve metabolic control
and the quality of life of young people with T1D.
Acknowledgments
The work was supported in part by the Slovenian National
Research Agency grants J3–4116 and P3–0343. We thank
the certified diabetes educators Ivica Zupancic, RNS, Tadeja
Logar Dolinsˇek, RNS, Ana Gianini, RNS, and Barbara Murn-
Berkopec, RNS, the dietician Andreja Sirca Campa, and the
psychologists Simona Klemencic and Miha Rutar for their
devoted patient care.
Author Disclosure Statement
No competing financial interests exist.
K.D. and S.S.T. collected data, participated in data analysis
and interpretation, and drafted and reviewed the manuscript.
Na.B. contributed to the study concept and design, supervised
the study, participated in data analysis and interpretation, and
reviewed/edited the manuscript. L.L. contributed to the study
concept and design, performed the statistical analysis, and re-
viewed/edited the manuscript. Ni.B., M.Z.-T., P.K., and M.A.S.
participated in data analysis and interpretation and reviewed/
edited the manuscript. T.B. drafted the study concept and de-
sign, supervised the study, participated in data analysis and
interpretation, and reviewed/edited the manuscript.
References
1. Effect of intensive diabetes treatment on the development
and progression of long-term complications in adolescents
with insulin-dependent diabetes mellitus: Diabetes Control
and Complications Trial. The Diabetes Control and Com-
plications Trial Research Group. J Pediatr 1994;125:177–188.
2. Rewers M, Pihoker C, Donaghue K, Hanas R, Swift P, Klin-
gensmith GJ: Assessment of glycemic control and adolescents
with diabetes. Pediatr Diabetes 2009;10(Suppl 12):71–81.
3. American Diabetes Association: Standards of medical care in
diabetes—2013. Diabetes Care 2013;36(Suppl 1):S11–S66.
38 DOVC ET AL.
4. Eeg-Olofsson K, Cederholm J, Nilsson PM, Gudbjo
¨rnsdo
´ttir
S, Eliasson B; Steering Committee of the Swedish National
Diabetes Register: Glycemic and risk factor control in type 1
diabetes: results from 13,612 patients in a national diabetes
register. Diabetes Care 2007;30:496–502.
5. Phillip M, Danne T, Shalitin S, Buckingham B, Laffel L,
Tamborlane W, Battelino T; Consensus Forum Participants:
Use of continuous glucose monitoring in children and ado-
lescents. Pediatr Diabetes 2012;13:215–228.
6. Phillip M, Battelino T, Rodriguez H, Danne T, Kaufman F;
European Society for Paediatric Endocrinology; the Lawson
Wilkins Pediatric Endocrine Society; International Society
for Pediatric and Adolescent Diabetes; American Diabetes
Association; European Association for the Study of Diabetes:
Use of insulin pump therapy in the pediatric age-group:
Consensus statement from European Society for Paediatric
Endocrinology, the Lawson Wilkins Pediatric Endocrine
Society, and the International Society for Pediatric and
Adolescent Diabetes, endorsed by American Diabetes As-
sociation and the European Association for the Study of
diabetes. Diabetes Care 2007;30:1653–1662.
7. Pan
´kowska E, B1azik M, Dziechciarz P, Szypowska A, Sza-
jewska H: Continuous subcutaneous insulin infusion vs.
multiple daily injections in children with type 1 diabetes: a
systematic review and meta-analysis of randomized control
trials. Pediatr Diabetes 2009;10:52–58.
8. Misso ML, Egberts KJ, Page M, O’Connor D, Shaw J: Con-
tinuous subcutaneous insulin infusion (CSII) versus multiple
insulin injections for type 1 diabetes mellitus. Cochrane
Database Syst Rev 2010;(1):CD005103.
9. Pickup JC, Sutton AJ: Severe hypoglycaemia and glycaemic
control in Type 1 diabetes: meta-analysis of multiple daily
insulin injections compared with continuous subcutaneous
insulin infusion. Diabet Med 2008;25:765–774.
10. Renard E: Insulin pump use in Europe. Diabetes Technol
Ther 2010;12(Suppl 1):S-29–S-32.
11. Nimri R, Weintrob N, Benzaquen H, Ofan R, Fayman G,
Phillip M: Insulin pump therapy in youth with type 1 dia-
betes: a retrospective paired study. Pediatrics 2006;117:
2126–2131.
12. Danne T, Battelino T, Jarosz-Chobot P, Kordonouri O, Pa
´n-
kowska E, Ludvigsson J, Schober E, Kaprio E, Saukkonen T,
Nicolino M, Tubiana-Rufi N, Klinkert C, Haberland H, Va-
zeou A, Madacsy L, Zangen D, Cherubini V, Rabbone I, Toni
S, de Beaufort C, Bakker-van Waarde W, van den Berg N,
Volkov I, Barrio R, Hanas R, Zumsteg U, Kuhlmann B, Aebi
C, Schumacher U, Gschwend S, Hindmarsh P, Torres M,
Shehadeh N, Phillip M; PedPump Study Group: Establishing
glycaemic control with continuous subcutaneous insulin
infusion in children and adolescents with type 1 diabetes:
experience of the PedPump Study in 17 countries. Diabeto-
logia 2008;51:1594–1601.
13. de Beaufort CE, Swift PG, Skinner CT, Aanstoot HJ, Aman J,
Cameron F, Martul P, Chiarelli F, Daneman D, Danne T,
Dorchy H, Hoey H, Kaprio EA, Kaufman F, Kocova M,
Mortensen HB, Njølstad PR, Phillip M, Robertson KJ,
Schoenle EJ, Urakami T, Vanelli M; Hvidoere Study Group
on Childhood Diabetes 2005: Continuing stability of center
differences in pediatric diabetes care: do advances in dia-
betes treatment improve outcome? The Hvidøre Study
Group on Childhood Diabetes. Diabetes Care 2007;30:2245–
2250.
14. Rosenbauer J, Dost A, Karges B, Hungele A, Stahl A, Ba
¨chle
C, Gerstl EM, Kastendieck C, Hofer SE, Holl RW; DPV In-
itiative and the German BMBF Competence Network Dia-
betes Mellitus: Improved metabolic control in children and
adolescents with type 1 diabetes: a trend analysis using
prospective multicenter data from Germany and Austria.
Diabetes Care 2012;35:80–86.
15. Radosevic B, Bukara-Radujkovic G, Miljkovic V, Pejicic S,
Bratina N, Battelino T: The incidenceoftype1diabetesin
Republic of Srpska (Bosnia and Herzegovina) and Slove-
nia in the period 1998–2010. Pediatr Diabetes 2012;14:
273–279.
16. Patterson CC, Dahlquist GG, Gyu
¨ru
¨s E, Green A, Solte
´sz G;
EURODIAB Study Group: Incidence trends for childhood
type 1 diabetes in Europe during 1989–2003 and predicted
new cases 2005–20: a multicentre prospective registration
study. Lancet 2009;373:2027–2033.
17. Clarke W, Jones T, Rewers A, Dunger D, Klingensmith GJ:
Assessment and management of hypoglycemia in children
and adolescents with diabetes. Pediatr Diabetes 2009;
10(Suppl 12):134–145.
18. Harrell FE Jr, Lee KL, Pollock BG: Regression models in
clinical studies: determining relationships between predic-
tors and response. J Natl Cancer Inst 1988;80:1199–1202.
19. R Development Core Team: R: A Language and Environ-
ment for Statistical Computing. R Foundation for Statistical
Computing. 2009. www.R-project.org (accessed May 27,
2013).
20. Cinek O, Sumnı
´k Z, de Beaufort C, Rurik I, Vazeou A,
Mada
´csy L, Papo NL, Danne T; SWEET Group: Hetero-
geneity in the systems of pediatric diabetes care across the
European Union. Pediatr Diabetes 2012;13(Suppl 16):5–14.
21. Bratina N, Battelino T: Insulin pumps and continuous glu-
cose monitoring (CGM) in preschool and school-age chil-
dren: how schools can integrate technology. Pediatr
Endocrinol Rev 2010;7(Suppl 3):417–421.
22. Dahlquist GG, Nystro
¨m L, Patterson CC; Swedish Child-
hood Diabetes Study Group; Diabetes Incidence in Sweden
Study Group: Incidence of type 1 diabetes in Sweden among
individuals aged 0–34 years, 1983–2007: an analysis of time
trends. Diabetes Care 2011;34:1754–1759.
23. Blu
¨her S, Meigen C, Gausche R, Keller E, Pfa
¨ffle R, Sabin M,
Werther G, Odeh R, Kiess W: Age-specific stabilization in
obesity prevalence in German children: a cross-sectional
study from 1999 to 2008. Int J Pediatr Obes 2011;6:199–206.
24. Sulli N, Shashaj B: Long term benefits of continuous sub-
cutaneous insulin infusion in children with type 1 diabetes: a
4-year follow-up. Diabet Med 2006;23:900–906.
25. Sulmont V, Souchon PF, Gouillard-Darnaud C, Fartura A,
Salmon-Musial AS, Lambrecht E, Mauran P, Abely M: Me-
tabolic control in children with diabetes mellitus who are
younger than 6 years at diagnosis: continuous subcutaneous
insulin infusion as a first line treatment? J Pediatr 2010;
157:103–107.
26. Ronsin O, Jannot-Lamotte MF, Vague P, Lassman-Vague V:
Factors related to CSII compliance. Diabetes Metab 2005;
31:90–95.
27. Berghaeuser MA, Kapellen T, Heidtmann B, Haberland H,
Klinkert C, Holl RW; German Working Group for Insulin
Pump Treatment in Paediatric Patients: Continuous subcu-
taneous insulin infusion in toddlers starting at diagnosis of
type 1 diabetes mellitus. A multicenter analysis of 104 pa-
tients from 63 centres in Germany and Austria. Pediatr
Diabetes 2008;9:590–595.
28. Shalitin S, Lahav-Ritte T, Lebenthal Y, Devries L, Phillip M:
Does the timing of insulin pump therapy initiation after type
METABOLIC CONTROL IN YOUTH WITH T1D 39
1 diabetes onset have an impact on glycemic control? Dia-
betes Technol Ther 2012;14:389–397.
29. Svensson J, Johannesen J, Mortensen HB, Nordly S; Danish
Childhood Diabetes Registry: Improved metabolic outcome
in a Danish diabetic paediatric population aged 0–18 yr: re-
sults from a nationwide continuous registration. Pediatr
Diabetes 2009;10:461–467.
Address correspondence to:
Tadej Battelino, MD, PhD
Department of Pediatric Endocrinology, Diabetes and Metabolism
UMC-University Children’s Hospital
Bohoriceva 20
SI-1525 Ljubljana, Slovenia
E-mail: tadej.battelino@mf.uni-lj.si
40 DOVC ET AL.
