Background: GLP-1 analogues are a relatively new class of medications that form the cornerstone of diabetes treatment. They possess invaluable glucose-lowering properties without hypoglycemic effects as well as strong cardioprotective effects. The gut microbiome has become the focus of numerous studies, demonstrating its influence not only on the gut but also on the overall well-being of the entire body. However, the effects of GLP-1 analogs on gut microbiota remain uncertain. Scope of review: Our systematic review (based on PRISMA guidelines) aimed to gather knowledge on the effects of GLP-1 analogue medications on the composition, richness, and abundance of gut microbiota in both animal and human models. Conclusions: Thirty-eight studies were included in this systematic review. GLP-1 analogues have demonstrated a notable impact on the composition, richness, and diversity of gut microbiota. We can conclude, following the obtained research results of our study, that liraglutide promotes the growth of beneficial genera relevant for beneficial metabolic functions. Exenatide and exendin-4 administration showed various effects on the microbiome composition in animal and human studies. In animal models, it increased genera associated with improved metabolism; however, in human models, genera linked to better metabolic functions and escalated inflammation increased. Following dulaglutide administration, increases in Bacteroides, Akkermansia, and Ruminococcus, genera connected to an improved metabolic model, were significant. Finally, varied results were obtained after semaglutide treatment, in which A. muciniphila, known for its positive metabolic functions, increased; however, microbial diversity decreased. Semaglutide treatment provided various results indicating many confounding factors in semaglutide’s impact on the gut microbiota. Results varied due to dissimilarities in the studied populations and the duration of the studies. Further research is essential to confirm these findings and to better recognize their implications for the clinical outcomes of patients.

Glucose-dependent insulinotropic polypeptide is one of the principal incretin hormones involved in the regulation of glucose homeostasis, lipid metabolism, and adipocyte function. Increasing evidence indicates that its biological actions differ substantially between adipose tissue depots. The aim of this narrative review with a structured literature search was to summarize current evidence on the role of GIP in visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT), incorporating preclinical, clinical, and genetic data. Animal studies have demonstrated that VAT is characterized by higher expression of the GIP receptor (GIPR) and greater sensitivity to the lipogenic and proinflammatory effects of GIP. Activation of GIPR in VAT promotes lipid accumulation, inflammation, and insulin resistance. Conversely, pharmacological blockade or genetic deletion of GIPR confers protection against diet-induced obesity and leads to improvements in metabolic parameters. In SAT, GIP exerts more heterogeneous and metabolically context-dependent effects that differ according to insulin sensitivity and obesity status. Moreover, under specific conditions, GIP may promote lipolysis in SAT, distinguishing its actions in this depot from those observed in VAT. These observations may help explain the efficacy of dual and triple incretin receptor agonists, including tirzepatide and retatrutide, which produce significant improvements in body weight and metabolic outcomes. Collectively, current evidence supports a depot-specific and context-dependent role of GIP in adipose tissue biology and underscores the therapeutic potential of targeting the GIP/GIPR axis in obesity and metabolic disease.

Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), originally developed for the treatment of type 2 diabetes (T2D), are increasingly used for the management of overweight and obesity in children and adolescents. However, the impact of concomitant lifestyle interventions, which vary in scope, structure, and intensity, remains unclear. Methods: A systematic search of PubMed, Scopus, and ClinicalTrials.gov was conducted from April to December 2025 (last update: 12 December 2025), in accordance with the PRISMA 2020 statement. Randomized and observational studies including patients aged 6–19 years with overweight or obesity, with or without T2D, treated with GLP-1 RAs or dual GIP/GLP-1 agonists, were included. Anthropometric outcomes, metabolic parameters, and the scope and structure of concomitant nutritional and behavioral interventions were assessed. Results: Fifteen studies (12 interventional [RCT/non-RCT] and 3 observational), including 1448 participants, were analyzed: liraglutide (n = 6), exenatide (n = 5), semaglutide (n = 1), dulaglutide (n = 1), tirzepatide (n = 1), and lixisenatide (n = 1). Intervention duration ranged from 6 to 68 weeks. Reported BMI reductions varied across studies and pharmacological agents, with semaglutide trials reporting reductions of up to −16.1%. Lifestyle interventions were heterogeneously reported, ranging from general dietary advice to structured, multidisciplinary programs including nutritional counseling, physical activity, and behavioral or family support. Due to heterogeneity in study design and reporting, the independent contribution of lifestyle interventions could not be determined. Conclusions: Available evidence suggests that GLP-1 RAs may represent an effective therapeutic option for children and adolescents with obesity and metabolic disorders. However, available evidence is largely derived from studies incorporating inconsistently reported lifestyle interventions, limiting the ability to disentangle pharmacological and lifestyle effects. Standardized reporting and studies specifically designed to assess their independent and combined effects are needed. Future research should standardize the reporting of lifestyle protocols (e.g., using TIDieR), incorporate validated measures of eating behavior, food preferences, and dietary intake, and use designs (e.g., factorial or stratified randomization of lifestyle intensity) that allow for the pharmacological and behavioral contributions to be quantified separately. This review highlights a critical and previously underexplored methodological gap regarding the structure and reporting of lifestyle co-interventions in pediatric GLP-1 trials.