The LIFE-MET trial: effect of insulin sensitization on pubertal progression following lifestyle intervention and/or treatment with metformin in girls with early puberty and overweight: study protocol for a randomized, placebo-controlled trial

BACKGROUND: Puberty in girls is occurring earlier worldwide with a declining trend over the recent decades, resulting in increased attention on the accompanying risks of psychosocial challenges and adverse health outcomes for the affected girls. Diverse mechanisms have been proposed as mediators of the tendency for earlier pubertal maturation, including a shift toward a more sedentary lifestyle and changes in dietary habits leading to childhood obesity. Several studies have demonstrated a potential association between the rise in childhood obesity prevalence and the decline in the age at which puberty begins. Increased insulin resistance is thought to play a role in this connection, and previous studies indicated that improved insulin sensitivity following either treatment with metformin or weight loss could delay pubertal progression in girls with overweight.

METHODS: LIFE-MET is a randomized, placebo-controlled, four-arm, multicenter trial of girls (n = 80) with overweight and early puberty. Allocation to metformin or placebo will be double-blinded. Eligible girls will be randomly assigned to one of the four study arms: Metformin + lifestyle intervention (N = 20), Metformin alone (N = 20), Placebo + lifestyle intervention (N = 20), Placebo alone (N = 20). The intervention period is 6 months with a follow-up after an additional 6 months. The primary outcome is the change in bone age from baseline to 12 months, as a marker of pubertal progression. Secondary outcomes include changes in body composition, Tanner stage, fitness level, sex hormones, insulin resistance, and age at menarche.

DISCUSSION: New strategies not only for the treatment but also for the prevention of both overweight and early puberty are needed. The LIFE-MET trial is a randomized controlled trial with a combination of lifestyle intervention including online, virtual reality training and a pharmacological intervention consisting of metformin and/or placebo, to our knowledge the first of its kind. We expect that this intervention will have a beneficial effect on both pubertal progression, daily physical activity level, and body composition. Additionally, a healthier body composition may have beneficial effects on long-term co-morbidities related to early puberty.

TRIAL REGISTRATION: Clinical Trial Information System (CTIS): 2024-511009-50-00. Approved 04/30/2024. https://euclinicaltrials.eu/search-for-clinical-trials/?lang=en&EUCT=2024-511009-50-00 .