Efficacy of Metformin Treatment with Respect to Weight Reduction in Children and Adults with Obesity: A Systematic Review.

BACKGROUND: Obesity and its related complications are increasing health issues. Since generally only minor weight loss is obtained with lifestyle intervention, additional pharmacological therapies such as metformin are often used. OBJECTIVE: We conducted a systematic review to provide an overview of the efficacy of ≥ 6 months of metformin treatment in children and adults with respect to weight, insulin resistance, and progression toward type 2 diabetes mellitus (T2DM). METHODS: In September 2018, we searched PubMed, Embase, and the Cochrane Library for studies published in English using the keywords metformin, obesity/overweight, and weight loss. Prospective studies reporting weight/body mass index (BMI) as a primary or secondary outcome in patients with overweight/obesity with ≥ 6 months' metformin treatment were included. Included subjects were children and adults with overweight/obesity who received ≥ 6 months of metformin and/or lifestyle intervention, and/or placebo and/or lifestyle intervention, and/or standard care. Studies were independently screened by two reviewers. Data were extracted by one and verified by the other reviewer, and both reviewers assessed the risk of bias using the Cochrane risk-of-bias tool. RESULTS: Our review includes 15 pediatric and 14 adult studies. In children, after 6 months, more than half the studies reported a greater reduction in BMI with metformin versus controls. Only six studies had an intervention of > 6 months, and these studies found no further improvement in BMI in the metformin users, though their BMI was lower than that of controls. Three studies showed a significant improvement in insulin sensitivity in the metformin versus the control group. Adults using metformin experienced and maintained small decreases in weight irrespective of duration of intervention. In 11 of 14 studies, a greater reduction in weight/BMI was observed with metformin than with placebo. Progression toward T2DM was significantly reduced in adults using metformin, ranging from 7 to 31%. The safety and tolerability of metformin, withdrawal of participants, and comparison with other drugs were not taken into account. CONCLUSIONS: The effects of metformin on weight/BMI vary, with smaller reductions in children than in adults. This could be because of differences in adherence, daily dosage, and insulin status. Metformin significantly reduced the progression toward T2DM in adults. Therefore, metformin should be considered as a treatment for obesity and its related complications.

Long-term metformin treatment in adolescents with obesity and insulin resistance, results of an open label extension study.

BACKGROUND/OBJECTIVES: Off-label metformin is nowadays frequently used for the treatment of obesity in adolescents. However, studies on long-term metformin treatment in adolescents with obesity are scarce. Therefore, an 18 month open label extension study following an 18 months randomized placebo-controlled trial (RCT) on the efficacy, safety, and tolerability of metformin in adolescents with obesity and insulin resistance was performed. SUBJECTS/METHODS: After completion of the RCT, metformin was offered to all participants with a body mass index standard deviation score (BMI-sds) > 2.3 and Homeostasis Model Assessment for Insulin Resistance (HOMA-IR) ≥ 3.4. Endpoints were change in BMI and HOMA-IR. RESULTS: Overall, 31/42 participants completed the extension study (74% girls, median age 14.8 (11.6 - 17.9), BMI 31.2 (22.3 - 45.1), HOMA-IR 3.4 (0.2 - 8.8)). At start, 22/42 (52.4%) participants were eligible for metformin of which 13 (59.0%) agreed with treatment. In participants who continued metformin, an increase was observed in BMI (+2.2 (+0.2 to +9.0)) and HOMA-IR (+13.7 (+1.6 to +48.3)). In metformin naive participants, BMI stabilized after an initial decrease (+0.5 (-2.1 to +5.1)). For HOMA-IR, a decrease was observed (-1.1 (-4.6 to +1.4)). CONCLUSION: While metformin treatment in metformin naive participants seems to result in an initial decrease in BMI and HOMA-IR, there is no evidence for sustained effect after prolonged use in adolescents. Limited compliance and/or insufficient dose may explain the differences in long-term effects between adolescents and adults.

Long-term treatment with metformin in obese, insulin-resistant adolescents: results of a randomized double-blinded placebo-controlled trial.

BACKGROUND: As adolescents with obesity and insulin resistance may be refractory to lifestyle intervention therapy alone, additional off-label metformin therapy is often used. In this study, the long-term efficacy and safety of metformin versus placebo in adolescents with obesity and insulin resistance is studied. METHODS: In a randomized placebo-controlled double-blinded trial, 62 adolescents with obesity aged 10-16 years old with insulin resistance received 2000 mg of metformin or placebo daily and physical training twice weekly over 18 months. Primary end points were change in body mass index (BMI) and insulin resistance measured by the Homeostasis Model Assessment for Insulin Resistance (HOMA-IR). Secondary end points were safety and tolerability of metformin. Other end points were body fat percentage and HbA1c. RESULTS: Forty-two participants completed the 18-month study (66% girls, median age 13 (12-15) years, BMI 30.0 (28.3 to 35.0) kg m(-2) and HOMA-IR 4.08 (2.40 to 5.88)). Median ΔBMI was +0.2 (-2.9 to 1.3) kg m(-2) (metformin) versus +1.2 (-0.3 to 2.4) kg m(-2) (placebo) (P=0.015). No significant difference was observed for HOMA-IR. No serious adverse events were reported. Median change in fat percentage was -3.1 (-4.8 to 0.3) versus -0.8 (-3.2 to 1.6)% (P=0.150), in fat mass -0.2 (-5.2 to 2.1) versus +2.0 (1.2-6.4) kg (P=0.007), in fat-free mass +2.0 (-0.1 to 4.0) versus +4.5 (1.3 to 11.6) kg (P=0.047) and in ΔHbA1c +1.0 (-1.0 to 2.3) versus +3.0 (0.0 to 5.0) mmol mol(-1) (P=0.020) (metformin versus placebo). CONCLUSIONS: Long-term treatment with metformin in adolescents with obesity and insulin resistance results in stabilization of BMI and improved body composition compared with placebo. Therefore, metformin may be useful as an additional therapy in combination with lifestyle intervention in adolescents with obesity and insulin resistance.

Population-Based Studies on the Epidemiology of Insulin Resistance in Children.

BACKGROUND: In view of the alarming incidence of obesity in children, insight into the epidemiology of the prediabetic state insulin resistance (IR) seems important. Therefore, the aim of this systematic review was to give an overview of all population-based studies reporting on the prevalence and incidence rates of IR in childhood. METHODS: PubMed, Embase, and Cochrane library were searched in order to find all available population-based studies describing the epidemiology of IR in pediatric populations. Prevalence rates together with methods and cut-off values used to determine IR were extracted and summarized with weight and sex specific prevalence rates of IR if available. RESULTS: Eighteen population-based studies were identified, describing prevalence rates varying between 3.1 and 44%, partly explained by different definitions for IR. Overweight and obese children had higher prevalence rates than normal weight children. In seven out of thirteen studies reporting sex specific results, girls seemed to be more affected than boys. CONCLUSION: Prevalence rates of IR reported in children vary widely which is partly due to the variety of definitions used. Overweight and obese children had higher prevalence and girls were more insulin resistant than boys. Consensus on the definition for IR in children is needed to allow for comparisons between different studies.

Long term trends in oral antidiabetic drug use among children and adolescents in the Netherlands.

AIM: The aim of the study was to document long term trends in oral antidiabetic drug (OAD) use among children and adolescents in the Netherlands. METHODS: A population-based cohort study was conducted using the Dutch PHARMO Database Network. All patients younger than 20 years old with at least one OAD dispensing were identified. Age-adjusted and age-specific incidence (1999-2011) and prevalence (1998-2011) rates of OAD use were calculated. Trends over time were assessed using joinpoint regression software. A subset of PHARMO Database Network (including community pharmacy dispensing records linked to general practitioner data (OPD-GP database)) was used to assess indications for OADs. RESULTS: In 2011, the overall age-adjusted incidence and prevalence rates of OAD use were 20.7/100 000 (95% CI 19.2, 22.1) person-years (PY) and 53.8/100 000 (95% CI 51.5, 56.1) persons, respectively. The average annual percentage change (AAPC) in the overall age-adjusted incidence rates from 1999 to 2011 was 18.9% (95% CI 4.5, 35.2). The incidence and prevalence rates of OAD use were higher among females and older age categories. The increases in rates of OAD use were mainly driven by metformin. For only 50% of the 98 patients in the OPD-GP database, indications for OAD prescriptions were reported with type 1 diabetes (n = 20), type 2 diabetes (n = 16), and overweight/obesity (n = 10). CONCLUSIONS: Incidence and prevalence rates of OAD use in children and adolescents substantially increased in the Netherlands, especially among older age categories (10-14 and 15-19 years) and females. The main indications for use of OADs were type 1 and 2 diabetes and overweight/obesity.

Global trends in the incidence and prevalence of type 2 diabetes in children and adolescents: a systematic review and evaluation of methodological approaches.

AIMS/HYPOTHESIS: This study aimed to systematically review what has been reported on the incidence and prevalence of type 2 diabetes in children and adolescents, to scrutinise the methodological issues observed in the included studies and to prepare recommendations for future research and surveillances. METHODS: PubMed, the Cochrane Database of Systematic Reviews, Scopus, EMBASE and Web of Science were searched from inception to February 2013. Population-based studies on incidence and prevalence of type 2 diabetes in children and adolescents were summarised and methodologically evaluated. Owing to substantial methodological heterogeneity and considerable differences in study populations a quantitative meta-analysis was not performed. RESULTS: Among 145 potentially relevant studies, 37 population-based studies met the inclusion criteria. Variations in the incidence and prevalence rates of type 2 diabetes in children and adolescents were mainly related to age of the study population, calendar time, geographical regions and ethnicity, resulting in a range of 0-330 per 100,000 person-years for incidence rates, and 0-5,300 per 100,000 population for prevalence rates. Furthermore, a substantial variation in the methodological characteristics was observed for response rates (60-96%), ascertainment rates (53-99%), diagnostic tests and criteria used to diagnose type 2 diabetes. CONCLUSIONS/INTERPRETATION: Worldwide incidence and prevalence of type 2 diabetes in children and adolescents vary substantially among countries, age categories and ethnic groups and this can be explained by variations in population characteristics and methodological dissimilarities between studies.

High mortality rate after extubation failure after pediatric cardiac surgery.

The objective of this study was to evaluate the different causes of extubation failure and the consequent mortality rates in a pediatric population after cardiac surgery. We studied 184 consecutive patients with a median age of 9 months (range, 0-165). In 158 patients, extubation was successful (group A). Nine patients were reintubated for upper airway obstruction and finally extubated successfully (group B). Seventeen patients were reintubated for cardiorespiratory failure, finally leading to death in 11 of 17 patients (65%) (group C). Group B patients were younger and had a longer intubation period compared to group A patients. Group C patients had more reoperations (30% vs 4% in group A patients, p < 0.001), a lower PaO2 on admission at the intensive care unit as well as just prior to extubation, a lower base deficit before extubation, and needed more inotropic support during their stay in the intensive care unit. We conclude that extubation failure after pediatric cardiac surgery due to cardiorespiratory failure is a bad prognostic sign. Patients with high inotropic support and a low PaO2 prior to extubation are especially at risk and probably need careful evaluation before final extubation.

Acute renal insufficiency and renal replacement therapy after pediatric cardiopulmonary bypass surgery.

The aim of the study was to investigate renal function and renal replacement therapy after cardiopulmonary bypass surgery in children. Patient characteristics (sex, age, diagnosis), operation type, and death were listed. The study was performed retrospectively using serum creatinine level before, and peak values after, cardiopulmonary bypass surgery for assessment of renal function. Of the children on renal replacement therapy, indication, efficacy, and complications were recorded. In a 5-year period, 1075 children had cardiopulmonary bypass surgery at the Department of Cardiothoracic Surgery at Leiden University Medical Center and Academic Medical Center of Amsterdam. One-hundred eighty (17%) patients developed acute renal insufficiency. Twenty-five (2.3%) patients required renal replacement therapy. Peritoneal dialysis is a safe and effective treatment for children after cardiopulmonary bypass surgery. However, 15 (60%) of 25 children on renal replacement therapy died of nonrenal causes. In 9 out of 10 surviving children, renal function was normal at time of discharge from hospital. Acute renal insufficiency is a frequent complication after open-heart surgery, although renal replacement therapy was infrequently necessary. Peritoneal dialysis is a safe and effective therapeutic measure for children after cardiac bypass surgery.

Continuous intravenous furosemide in haemodynamically unstable children after cardiac surgery.

OBJECTIVE: The commonly used continuous intravenous (i.v.) furosemide dosing schedule after cardiac surgery in children is largely empirical and may not be optimal. This may even be more marked in children after cardiac surgery who are haemodynamically unstable, and in whom transient renal insufficiency may occur. A study was performed to obtain an impression regarding which clinically applicable measures may be used to design a rational scheme for continuous i.v. furosemide therapy in children after cardiac surgery. SUBJECTS AND METHODS: Twelve paediatric patients (5F/7 M, age 0-33 weeks) post-cardiac surgery, who were to receive 3 days of continuous i.v. furosemide treatment, were included in an open study. Blood and urine samples were taken for furosemide, creatinine, and electrolyte levels, and fractionated urinary output was measured. Furosemide in blood and urine was measured using high performance liquid chromatography (HPLC). RESULTS: The mean starting dose of continuous i.v. furosemide was 0.093 (+/- 0.016) mg/kg per hour. The mean dose was increased to 0.175 (+/- 0.045) mg/kg per hour per hour on day 2, and changed to 0.150 (+/- 0.052) mg/kg per hour on day 3. Infusion rates were increased from day 1 to day 2 in ten cases, and decreased from day 2 to day 3 in three cases. Serum furosemide levels never exceeded ototoxic levels. The urinary furosemide excretion rate was inversely related to serum creatinine levels. CONCLUSIONS: This study extends the observation of the beneficial effects of continuous i.v. furosemide also to those children who are haemodynamically unstable after cardiac surgery. However, as the effects of furosemide are dependent on renal function, it can be hypothesised that the dosing schedule may be optimised. Contrary to the currently used dosage schedule in which the dose of furosemide is gradually increased over time, it may be more rational to start with a higher dose and adapt this dose (downward) guided by the observed effect (urine output). Because the infusion rate was increased to 0.2 mg/kg per hour in nine out of 12 patients on day 2 and was never increased further, this suggests that a starting rate of 0.2 mg/kg per hour may be optimal.

[Erroneously prepared oral rehydration solution life-threatening]. / Foutief bereide orale-rehydratievloeistof levensbedreigend.

Two male infants, 6 and 2 months old, children of immigrant parents, were hospitalised because of somnolence and diarrhoea. Both had severe hypernatraemia. The first died during venous cannulation, the second had convulsions with multiple cerebral haemorrhages and severe neurologic damage. Both had received oral rehydration fluid, prescribed by their general practitioner and prepared by their parents. These had dissolved the contents of the package in far too little water, which resulted in solutions that were seven times and twice, respectively, as strong as they should have been. Careful instruction regarding the use and preparation of oral rehydration fluid is of utmost importance, notably with patients with a different cultural or language background.