Impact of monotherapy and combination therapy with glucagon-like peptide-1 receptor agonists on exosomal and non-exosomal MicroRNA signatures in type 2 diabetes mellitus: a systematic review

BACKGROUND: Glucagon-like peptide-1 receptor agonist (GLP-1RAs) is a potent therapy for type 2 diabetes mellitus (T2DM) and obesity, especially in patients who are resistant to long-term insulin therapy. Although microRNAs have been linked to GLP-1 signaling, their role in GLP-1RA monotherapy and combination therapy remains unclear. This review synthesizes current evidence of GLP-1RA-induced exosomal and non-exosomal miRNA changes in human and animal models of T2DM. METHODS: Scopus, PubMed/Medline, Web of Science, and Google Scholar searches returned 83 studies, of which 11 met the study eligibility criteria (PROSPERO No: CRD42024586000). RESULTS: Human studies showed GLP-1RA combined with metformin modulated non-exosomal miR-27b, miR-130a, and miR-210a, which were linked to cardiovascular health. In T2DM patients on metformin, higher baseline miR-378-3p or miR-126-3p correlated with greater HbA1c improvement after one year of GLP-1RA therapy. Notably, > 5% weight loss correlated with higher baseline levels of miR-15a-5p. Preclinical findings suggested GLP-1RA monotherapy increased cardiovascular action via non-exosomal miR-29b-3p, miR-34a-5p, miR-26a-5p, miR-181a-5p, and miR-93-5p. Silencing non-exosomal miR-204, miR-375, or miR-139-5p augmented exendin-4/liraglutide monotherapy-induced glucose-stimulated insulin secretion. Interestingly, GLP-1RA monotherapy reduced hepatic lipid accumulation in T2DM models with comorbid NAFLD via ABHD6 mRNA modulation by non-exosomal miR-5120. No clinical studies reported exosomal miRNAs, but a preclinical study linked GLP-1RA-induced exosomal let-7c-2-3p/miR-322-3p to bone protection in estrogen-deficient T2DM models. CONCLUSION: GLP-1RAs, both as first-line and second-line therapies, are beneficial for T2DM complicated by obesity, NAFLD, cardio-metabolic disease, and postmenopausal osteoporosis. Longitudinal trials that incorporate innovative multi-omics approaches are essential for distinguishing their miRNA expression pattern from other anti-diabetics.