© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Pediatric Diabetes 2014 doi: 10.1111/pedi.12220 All rights reserved

Pediatric Diabetes

Original Article

Metformin treatment to reduce central adiposity after prenatal growth restraint: a placebo-controlled pilot study in prepubertal children ´ ˜ L. Metformin Díaz M, Bassols J, Lopez-Bermejo A, de Zegher F, Ib´anez treatment to reduce central adiposity after prenatal growth restraint: a placebo-controlled pilot study in prepubertal children. Pediatric Diabetes 2014. Background: Children born small-for-gestational-age (SGA) who experience rapid postnatal catch-up in weight are at risk for central adiposity and hyperinsulinemia. Objectives: To study the effects of prepubertal metformin intervention over 24 months on the body composition and endocrine-metabolic profile of catch-up SGA children. Methods: Double-blind, placebo-controlled, pilot study including 23 post-catch-up non-obese prepubertal SGA children [age, 7.7 yr; body mass index standard deviation score (BMI SDS) >50th and 75th for age]. Patients were randomized to receive either placebo or metformin (425 mg/d) for 24 months. Clinical, biochemical [IGF-I, glucose, insulin, lipids, androgens, sex-hormone-binding globulin (SHBG) and high-molecular-weight (HMW)-adiponectin] and imaging [body composition (absorptiometry and MRI; carotid intima-media thickness (ultrasonography)] variables were assessed at baseline, and at 6, 12, and 24 months. Results: After 24 months, metformin-treated children were leaner, had higher SHBG levels, and less total and abdominal fat than placebo-treated children (all p ≤ 0.05). Longitudinal analyses showed that metformin had a significant effect on anthropometric (weight, BMI, and waist) and biochemical variables [glucose, homeostasis model assessment-insulin resistance (HOMA-IR), and triglycerides] (all p ≤ 0.05); and in total and abdominal fat (p = 0.01 and p = 0.02). Conclusions: Prepubertal intervention with metformin reduces central adiposity and improves insulin sensitivity in non-obese catch-up SGA children.

Marta Díaza,b , Judit Bassolsc , c ´ , Abel Lopez-Bermejo Francis de Zegherd and ˜ a,b Lourdes Iba´ nez a Hospital Sant Joan de Deu, ´ University of Barcelona, Esplugues, 08950, ´ Spain; b Centro de Investigacion ´ Biomedica en Red de Diabetes y ´ Enfermedades Metabolicas Asociadas (CIBERDEM), ISCIII, Madrid, Spain; c Department of Pediatrics, Dr Josep Trueta Hospital, Girona Institute for Biomedical Research, Girona, 17007, Spain; and d Pediatric Endocrinology, University Hospital Gasthuisberg, Leuven, 3000, Belgium

Key words: adipose tissue – body composition – catch-up – IGF-I – insulin – metformin – small-for-gestational-age – visceral fat Corresponding author: Lourdes ˜ Iba´ nez, MD, PhD, ´ Hospital Sant Joan de Deu, University of Barcelona, ´ 2, Passeig de Sant Joan de Deu 08950 Esplugues, Barcelona, Spain. Tel: +34-93-2804000x70205; fax: +34 93 2033949; e-mail: [email protected] Submitted 3 June 2014. Accepted for publication 2 September 2014

Low birth weight followed by early postnatal weight gain has been associated with increased metabolic risk in adulthood, including type 2 diabetes and hypertension (1, 2). Most infants born small-for-gestational-age (SGA) develop spontaneous catch-up growth leading

to a normal height and weight from the age of 2 yr onwards (3, 4). We have previously shown that by age 6 yr, SGA-catch-up children who gain weight fast between birth and age 2 yr become hyperinsulinemic and centrally adipose, display more

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Díaz et al. visceral fat even if not overweight, and have low concentrations of high-molecular-weight (HMW) adiponectin and increased levels of circulating insulinlike growth factor-I (IGF-I), as compared to ageand body mass index (BMI)-matched children born appropriate-for-gestational-age (AGA) (5–7). At age 6–8 yr, SGA-catch-up children aggravate their HMW hypoadiponectinemia and visceral adiposity and develop low sex-hormone-binding globulin (SHBG) concentrations and an exaggerated adrenarche with increased dehydroepiandrosterone-sulfate (DHEAS) levels (8, 9). In girls, this sequence may manifest clinically as precocious pubarche (pubic hair 25th centile by age 2 yr (14)]; (iv) BMI standard deviation score (SDS) >50th and 75th centile for age-matched AGA children (greater than 19.0 cm2 in boys and greater than 25.0 cm2 in girls) (6, 7); and (vi) IGF-I concentrations >75th centile for age-matched AGA children (higher than 110 ng/mL in boys and 159 ng/mL in girls) (6, 7). The exclusion criteria were: evidence for a syndromatic, chromosomal, or infectious etiology of SGA, gestation complicated by preeclampsia or gestational diabetes, hypothyroidism, systemic disease or acute illness, concomitant or previous treatments with medications known to affect gonadal function or carbohydrate metabolism, precocious pubarche and pubertal status (11, 16, 17). The children were randomly assigned (1:1) to ® receive metformin (425 mg, Metformina Sandoz , Madrid, Spain) or placebo (manufactured by ACY Fabrik, Madrid, Spain) once daily, at dinner time for 24 months. The randomization was performed at Hospital Sant Joan de D´eu by an independent investigator and was web-based (www.SealedEnvelope.com), with random permuted blocks and strata for age, gender, and BMI. Metformin and placebo were dispensed by the Pharmacy Department at Hospital Sant Joan de D´eu; participants were given a coded vial of pills containing metformin or placebo. This concealled allocation process ensured that all participants and all investigators performing the clinical visits and the assessments were unaware of the allocated treatment. The primary outcomes were insulin resistance (IR), as assessed by the homeostasis model assessment [HOMA (18)], IGF-I, and visceral fat. A positive response was considered when HOMA-IR decreased by 30%, and circulating IGF-I and visceral fat, decreased, respectively, by 15% and by 10% within 24 months. The study was registered as ISRCTN58810841, and was conducted in the two participating centers, without support from pharmaceutical industry, and after approval by the Institutional Review Board of both Hospital Sant Joan de D´eu and Hospital Dr Josep Trueta. The study was initially designed to include 46 patients (23 in each arm), based on the calculated statistical power to detect significant changes in the primary outcomes. At the end of the first year of inclusion it became clear that only a small number of patients fulfilled the stringent inclusion and exclusion criteria, allowing to enroll within the allocated period of time a total of 23 children who were randomized following the initial study design, and thus yielding an unbalanced number of subjects per group. As a Pediatric Diabetes 2014

Early metformin intervention in SGA children SGA Infants born at Hospital Sant Joan de Déu & Dr. Josep Trueta (Jan 2001 – Dec 2006) n=940

Unavailable n=334

Accept participation n=126

Decline participation n=480

Assessed for eligibility (clinical criteria) n=126

Not meeting clinical criteria n=67

Meeting clinical criteria n=59

Meeting MRI & IGF-I criteria n=23

Not meeting MRI & IGF-I criteria n=36

Randomized Placebo n=17

Metformin n=6

Placebo n=14

Metformin n=6

Completed 24 mo SGA: small-for-gestational-age MRI: magnetic resonance imaging IGF-I: insulin-like growth factor I See text for inclusion & exclusion criteria

Fig. 1. Recruitment of the study population.

consequence, the study was reconsidered to become a preliminary, pilot study. The recruitment procedure and matching flow is shown in detail in Fig. 1.

Auxology and assays Weight was measured to the nearest 0.5 kg with an electronic scale and height to the nearest 0.5 cm with a Harpenden stadiometer; SDS for both parameters were derived (14). BMI was calculated as the ratio of weight (in kilograms) to height squared (in meters) and SDS were derived (14). Waist circumference was measured in the supine position at the umbilical level. Blood sampling for endocrine-metabolic indices was performed in the morning and in the fasting state. In the two participating hospitals, glucose was measured by the glucose oxidase method, and serum lipids were measured using automated tests, as described (19); insulin, IGF-I, DHEAS, androstenedione, and SHBG were assessed by immunochemiluminiscence (IMMULITE 2000; Diagnostic Products Corp., Los Angeles, CA, USA), as described (6, 7, 9). All methods had intraand interassay coefficients of variation (CVs) between 4 and 8% within the relevant concentration ranges. The detection limits for insulin, IGF-I, androstenedione, DHEAS, and SHBG were, respectively, 3.6 pmol/L; 25 ng/mL; 0.7 nmol/L; 0.4 μmol/L; and 6 nmol/L; these Pediatric Diabetes 2014

values were assigned to samples with a concentration below these limits. HOMA-IR was estimated from fasting insulin and glucose levels (18). HMW adiponectin was assessed with a sandwich enzyme-linked immunosorbent assay (ELISA) kit (Linco Research, St. Charles, MO, USA), at Hospital Sant Joan de D´eu, as described (11). Samples were kept frozen at −80◦ C until assay and were assayed concomitantly.

Carotid intima-media thickness Carotid intima-media thickness (cIMT) was measured by high-resolution ultrasonography (MyLab™ 25, Esaote, Firenze, Italy) using a linear 12-MHz transducer. Diastolic images were obtained on the right side at the level of the distal common carotid artery, 1 cm away from its bifurcation (19). Averages of five cIMT measurements on the far wall of the artery were used. All cIMT measurements were taken on a separate visit and were performed in each participating hospital by the same observer who was blinded to the allocated treatment; all images were analyzed by the same investigator, also blinded to treatment allocation. Intrasubject CVs for cIMT measurements were less that 6%.

Body composition and abdominal fat partitioning Body composition was assessed by dual-energy X-ray absorptiometry (DXA) with a Lunar Prodigy and

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4 7.8 ± 0.4 38.7 ± 0.3 −2.3 ± 0.3 66 100 1.0 ± 0.6 0.5 ± 0.1 19.0 ± 1 1.1 ± 0.8 65.5 ± 3 204 ± 27 4.8 ± 0.2 1.8 ± 0.9 1.3 ± 0.1 2.1 ± 0.3 0.7 ± 0.1 6.1 ± 1.8 66 ± 18 1.7 ± 0.3 1.8 ± 0.2 9.3 ± 1.2 0.7 ± 0.1 20.1 ± 0.6 70.4 ± 16.5 28.3 ± 2.4 13.8 ± 2.8 0.36 ± 0.01

7.7 ± 0.3 37.8 ± 0.5 −2.5 ± 0.1 54 100 1.6 ± 0.4 0.3 ± 0.3 20.2 ± 0.5 1.7 ± 0.3 68.8 ± 2 199 ± 14 4.7 ± 0.1 1.5 ± 0.3 1.4 ± 0.1 2.5 ± 0.1 0.7 ± 0.1 5.8 ± 0.5 48 ± 4 1.8 ± 0.3 1.4 ± 0.2 11.2 ± 1.1 0.9 ± 0.1 19.7 ± 0.9 89.7 ± 10.7 32.9 ± 3.5 13.6 ± 1.3 0.36 ± 0.01 NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS

p 8.2 ± 0.3 – – 50 100 1.7 ± 0.4 0.3 ± 0.3 21.2 ± 0.6 1.8 ± 0.3 67.5 ± 1 216 ± 17 4.9 ± 0.1 1.1 ± 0.2 1.4 ± 0.1 2.5 ± 0.2 0.9 ± 0.1 7.2 ± 1.1 55 ± 7 2.1 ± 0.3 1.7 ± 0.2 12.3 ± 1.2 1.1 ± 0.1 21.4 ± 1.0 98.5 ± 10.3 34.5 ± 2.5 14.2 ± 1.0 0.33 ± 0.01

Placebo (n = 16) 8.5 ± 0.5 – – 66 100 0.9 ± 0.6 0.3 ± 0.2 19.0 ± 1 0.9 ± 0.7 66.0 ± 4 208 ± 28 4.8 ± 0.2 1.9 ± 0.9 1.5 ± 0.2 2.1 ± 0.2 0.6 ± 0.1 6.3 ± 1.1 80 ± 20 1.8 ± 0.3 1.6 ± 0.2 9.0 ± 1.4 0.6 ± 0.2 21.7 ± 0.8 68.7 ± 15.0 26.5 ± 5.6 16.1 ± 4.2 0.33 ± 0.01

Metformin (n = 6)

6 months

NS – – NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS 0.05 0.02 NS NS NS NS NS

P 8.7 ± 0.3 – – 47 52.9 1.5 ± 0.4 0.3 ± 0.4 21.5 ± 0.6 1.6 ± 0.2 70.1 ± 2 280 ± 27 5.0 ± 0.1 1.4 ± 0.2 1.3 ± 0.1 2.6 ± .02 0.9 ± 0.1 6.7 ± 0.7 54 ± 7 3.6 ± 1.0 2.5 ± 0.4 13.8 ± 1.2 1.1 ± 0.1 23.2 ± 1.0 116.0 ± 13.7 41.9 ± 3.5 14.9 ± 1.3 0.34 ± 0.01

Placebo (n = 15) 8.9 ± 0.5 – – 66 83.3 0.5 ± 0.3 0.3 ± 0.2 19.1 ± 1 0.8 ± 0.6 64.0 ± 3 260 ± 31 4.8 ± 0.1 0.9 ± 0.3 1.4 ± 0.1 2.2 ± 0.2 0.7 ± 0.1 8.3 ± 1.9 89 ± 20 2.9 ± 0.8 2.5 ± 0.5 10.1 ± 1.6 0.7 ± 0.2 22.5 ± 0.9 90.9 ± 27.2 33.6 ± 7.1 11.4 ± 1.3 0.34 ± 0.01

Metformin (n = 6)

12 months

NS – – NS NS NS NS 0.05 NS NS NS NS NS NS NS NS NS 0.02 NS NS 0.05 0.02 NS NS NS NS NS

P 9.8 ± 0.3 – – 43 47.1 1.5 ± 0.4 0.3 ± 0.4 22.5 ± 0.8 1.6 ± 0.3 73.6 ± 2 352 ± 36 5.2 ± 0.1 2.1 ± 0.3 1.4 ± 0.1 2.5 ± 0.2 0.9 ± 0.1 6.1 ± 0.7 48 ± 6 3.1 ± 0.5 2.8 ± 0.4 16.4 ± 1.6 1.3 ± 0.1 25.7 ± 1.1 136.6 ± 16.7 45.2 ± 3.6 16.2 ± 1.5 0.35 ± 0.01

Placebo (n = 14)

10.0 ± 0.5 – – 66 33.3 0.4 ± 0.3 0.1 ± 0.1 19.5 ± 1 0.5 ± 0.4 66.4 ± 3 267 ± 37 4.8 ± 0.1 1.0 ± 0.5 1.3 ± 0.1 2.1 ± 0.2 0.7 ± 0.1 6.3 ± 1.7 76 ± 22 2.7 ± 0.4 2.5 ± 0.3 11.7 ± 1.6 0.9 ± 0.2 24.6 ± 1.0 94.1 ± 23.1 36.3 ± 6.5 13.4 ± 3.8 0.36 ± 0.01

Metformin (n = 6)

24 months

NS – – NS NS NS NS 0.02 0.02 0.05 NS NS NS NS NS NS NS 0.05 NS NS 0.05 0.05 NS NS NS NS NS

P

BMI, body mass index; cIMT, carotid intima-media thickness; DHEAS, dehydroepiandrosterone sulfate; HOMA-IR, homeostasis model assessment insulin resistance; HMW, high molecular weight; IGF-I, insulin-like growth factor-I; IHLC, intra-hepatic lipid content; NS, not significant; SDS, standard deviation score; SHBG, sex hormone binding globulin. Values are mean ± SEM. General linear models for repeated measures were used to study differences among subgroups at each time point. Bold numbers indicate statistically significant differences

Age (yr) GA (w) BW SDS Sex (% female) Tanner (% tanner 1) Weight SDS Height SDS BMI (kg/cm2 ) BMI SDS Waist (cm) IGF-I (μg/L) Glucose (mmol/L) HOMA-IR HDL-cholesterol (mmol/L) LDL-cholesterol (mmol/L) Triglycerides (mmol/L) HMW-adiponectin (mg/L) SHBG (nmol/L) DHEAS (μmol/L) Androstenedione (nmol/L) Fat mass (kg) Abdominal fat (kg) Lean mass (kg) Subcutaneous fat (cm2 ) Visceral fat (cm2 ) IHLC cIMT (mm)

Metformin (n = 6)

Placebo (n = 17)

Baseline

Table 1. Clinical, biochemical, and imaging variables in the two randomized subgroups (placebo and metformin) at baseline and after 6, 12, and 24 months

Díaz et al.

Pediatric Diabetes 2014

Early metformin intervention in SGA children lunar software (version 3.4/3.5, Lunar Corp, WI, USA) adapted for assessment of children, delivering an irradiation dose of 0.1 mSv per assessment and having scanning precision CVs

Metformin treatment to reduce central adiposity after prenatal growth restraint: a placebo-controlled pilot study in prepubertal children.

Children born small-for-gestational-age (SGA) who experience rapid postnatal catch-up in weight are at risk for central adiposity and hyperinsulinemia...
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