Scripties UMCG - Rijksuniversiteit Groningen
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A retrospective evaluation of 1-year Fitcool poli and long term treatment with off-label metformin in children and adolescents with obesity and insulin resistance

(2018) Wit, M. de (Margreet)

Abstract - part one - Fitcool analysis
Introduction: Obesity is a worldwide increasing health problem. In the past it was considered as
a health problem especially among adults, but it is nowadays an increasing health issue among
children and adolescents as well. Obesity is associated with the development of
metabolic complications such as Diabetes Mellitus type 2 (T2DM) and cardiovascular diseases
(CVD). Therefore early identification and treatment of childhood obesity is warranted to
prevent these complications. The aim of the current study is to give an overview of patients (3-
18 years) visiting the pediatric obesity clinic of the St. Antonius Hospital in 2016, with respect
to complications and treatment effects.
Materials and Methods: In this retrospective study, patients (2-18 years) who had their first
visit at the pediatric obesity outpatient clinic of the St. Antonius Hospital in 2016 were
included. Patients were excluded if they were diagnosed with T2DM. Endpoints were ΔBMI,
ΔBMI-sds and ΔHOMA-IR (Homeostasis Model Assessment for Insulin Resistance) after 6
and 12 months of follow-up. Other points of interest were obesity related (metabolic)
complications such as insulin resistance (IR) and/or glucose intolerance, metabolic syndrome
(MetS) and NAFLD (non-alcoholic fatty liver disease) at time of intake. IR was defined as
HOMA-IR ≥3.4. MetS was diagnosed if at least 3 of the following criteria were present:
obesity (BMI-SDS > 2.3), systolic blood pressure and/or diastolic blood pressure ≥95th
percentile for age, triglycerides ≥1.7mmol/l, HDL <1.03 mmol/l, and FPG ≥5.6mmol/l. An
elevated ALAT, defined as ALAT ≥40 U/L, was an indication for an ultrasonography of the
liver to assess the presence of steatosis hepatis.
Results: 104 patients were included, with a mean age of 10.97 (± 3.38) years. Mean BMI and
BMI-SDS were 28.88 kg/m (± 0.70) and 3.53 (± 0.70), respectively. The population consisted
out of 61.5% boys and 38.5% girls. No significant increase or decrease in ΔBMI, ΔBMI-sds
and ΔHOMA-IR were observed after 6 and 12 months of follow-up. At start, 65.4 % of the
children and adolescents were IR and 17.5% met the criteria MetS. Five (5%) patients were
diagnosed with steatosis hepatis.
Conclusion: A stabilization of weight was observed during follow up. A substantial part of the
children and adolescents visiting the pediatric (obesity) outpatient clinic already have metabolic
alterations such as IR and MetS. These results underline the importance of early detection and
adequate therapy in this population. Because of the limited duration of follow of one year, it is
recommended to re-evaluate these children and adolescents in a year again.
Abstract – part two - effect of metformin treatment
Introduction: Cornerstone of the treatment of obesity is lifestyle therapy, however due to
limited effect on weight on the long term, additional therapies such as metformin are nowadays
frequently studied. Beneficial effects of metformin on the short term are shown, but long-term
results are scarce. The aim of the current study is to evaluate the long-term (>18 months)
treatment effect of (off-label) metformin on BMI, BMI-sds and HOMA-IR in adolescents (≥ 10
years) with obesity (BMI-sds > 2.3) and IR (HOMA-IR ≥ 3.4)
Materials and Methods: In this retrospective study adolescents, aged between 10 and 18 years,
were included if they received metformin treatment for at least 18 months. Criteria to start with
metformin were obesity (defined as BMI-sds > 2.3) and insulin resistance (defined as HOMAIR
≥ 3.4). Patients diagnosed with T2DM were excluded. The primary outcomes were ΔBMI,
ΔBMI-sds and ΔHOMA-IR after 18, 24, 30 and 36 months with off-label metformin treatment.
The secondary outcomes were safety and tolerability of off-label metformin treatment after 18,
24, 30 and 36 months of therapy.
Results: The study population consisted out of 33 patients. Five/33 had reached a follow-up
period of 36 months, 15/33 a period of 30 months, and 25/33 a period of 24 months. A
significance decrease in BMI-sds was seen after 18 months (-0.53; p<0.01). BMI and HOMAIR
showed a decline of -0.53 kg/m (p=0.60) and -0.72 (p=0.15), respectively. After 18 months
of treatment BMI increased and peaked significant at 30 months (+2.95 kg/m ). No significance
differences were observed for ΔBMI, ΔBMI-sds and ΔHOMA-IR at other time points. Gastrointestinal
complaints (nausea, diarrhea, or both) were reported in 14 (42%) patients. Regarding
tolerability, no significant decrease or increase was observed for vitamin B12 and ALAT levels
during follow up.
Conclusion: Metformin is associated with a small, but clinically significant reduction in BMIsds
up to 18 months of therapy. After eighteen months metformin therapy does not result in a
stabilization or decrease in BMI, BMI-sds or HOMA-IR. A possible explanation could be an
insufficient dosage and/or lack of compliance.
General Conclusion: A substantial part of the patients visiting the pediatric (obesity) outpatient
clinic already had metabolic alterations such as IR and MetS. Since these children are at high
risk to develop T2DM and cardiovascular diseases it is crucial to trace those children. When
evaluating metformin, as additional therapy to lifestyle intervention, results up to 18 months are
promising. However, long term treatment (> 18 months) is not resulting in a stabilization or
decrease in BMI, BMI-sds and HOMA-IR. Since compliance and dosage could be important
factors in accomplishing weight loss, this must be taken into account in further research.

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