Direct effects of glucagon-like Peptide-1 receptor agonists on mitochondrial function in human-derived in vitro models: A systematic review and meta-analysis

Figures

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  Fig. 1. PRISMA flow diagram of the study selection process. Flowchart summarizing the identification, screening, eligibility assessment, and inclusion of studies evaluating the effects of GLP-1 RAs on mitochondrial function in humans. A total of 1547 records were identified through database searches, with 344 duplicates removed prior to screening. Following title/abstract screening and full-text assessment, 17 studies met the inclusion criteria for qualitative synthesis, of which 11 were eligible for quantitative analysis. Reasons for exclusion at the full-text stage included inappropriate study design, outcomes, interventions, or use of non-human models. Detailed search strategy provided in Supplementary Methods. Abbreviations: PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

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  Fig. 2. Forest plots evaluating the effects of GLP-1 receptor agonists on bioenergetic outcomes. (A) Forest plot of standardized mean differences for bioenergetic outcomes, including ATP-linked oxygen consumption, basal respiration, and maximal respiration, comparing GLP-1 receptor agonist treatment with control conditions. (B) Forest plot of standardized mean differences for bioenergetic outcomes restricted to adipose tissue studies. (C) Forest plot of standardized mean differences for adipose tissue bioenergetic outcomes stratified by GLP-1 receptor agonist type and treatment (ST and LT = short and long term treatments). Squares represent individual study effect sizes weighted by study variance, horizontal lines indicate 95% confidence intervals, and diamonds represent pooled random-effects estimates. Corresponding numerical meta-analysis results are shown in Supplementary Table 1–3. Letter suffixes denote distinct effect sizes derived from the same study. Multiple effect sizes were included when studies reported separate mitochondrial outcomes, treatment conditions, agonist doses, or cell models that could be analyzed independently. ST = short-term liraglutide treatment (24 h); LT =…

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  Fig. 3. Forest plots evaluating the effects of GLP-1 receptor agonists on mitochondrial ROS (MitoROS) and mitochondrial membrane potential (MMP) outcomes. (A) Forest plot of standardized mean differences for MitoROS outcomes comparing GLP-1 receptor agonist treatment with control conditions. (B) Forest plot of standardized mean differences for MMP outcomes comparing GLP-1 receptor agonist treatment with control conditions. Red boxes are provided for illustrative purposes to identify effect sizes that are subsequently classified as statistical outliers. Outlier status was determined using a robust fit (Cauchy) diagnostic procedure and not by visual inspection of the forest plots. (C) Forest plot of standardized mean differences for MMP outcomes excluding Liu et al. (2022). (D) Forest plot of standardized mean differences for MMP outcomes stratified by GLP-1 receptor agonist type. Drug labels correspond to the terminology used in the original studies and identify individual study-level effect sizes rather than pooled pharmacological categories. Exenatide represents the synthetic form of exendin-4 and is pharmacologically equivalent. Red boxes are provided for illustrative purposes to…