Scientists reviewed studies to see how diabetes medicines, including tirzepatide, change tiny gene‑regulating molecules called miRNAs. They found that these drugs do alter miRNA levels, and some changes might hint at how well a person will respond, but the data are still limited and not reliable enough for everyday use.

<b>Background/Objectives</b>: Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder characterized by insulin resistance, impaired insulin secretion, and chronic hyperglycemia. Recent studies have identified microRNAs (miRNAs), a class of small non-coding RNAs that regulate gene expression at the post-transcriptional level, as modulators of pathways involved in T2DM pathophysiology. Dysregulated miRNA expression has been detected in various samples collected from patients with T2DM, implicating these molecules in disease onset and progression. <b>Methods</b>: We systematically searched PubMed, Scopus, and Web of Science for studies published from the earliest available records to 18 August 2025 using the following Boolean search terms: "miRNA AND gliclazide", "miRNA AND glibenclamide", "miRNA AND gliquidone", "miRNA AND glimepiride", "mirRNA AND metformin", "miRNA AND pioglitazone", "miRNA AND rosiglitazone", "miRNA AND sitagliptin", "miRNA AND vildagliptin", "miRNA AND alogliptin", "miRNA and saxagliptin", "miRNA AND linagliptin", "miRNA AND liraglutide", "miRNA and dulaglutide", "miRNA AND semaglutide", "miRNA AND tirzepatide", "miRNA AND lixisenatide", "miRNA AND empagliflozin", "miRNA AND dapagliflozin", miRNA AND insulin glargine", "miRNA AND insulin detemir", "miRNA AND insulin degludec", "miRNA AND insulin aspart", "miRNA AND insulin glulisine", and "miRNA AND insulin lispro". Additionally, gray literature was searched in ClinicalTrials.gov, the EU Clinical Trials Register (EudraCT), and the ISRCTN Registry to identify unpublished studies. Studies were eligible for inclusion if they were clinical interventional studies assessing the impact of currently available antidiabetic treatments on miRNA expression. Only articles published in English were considered. The risk of bias was evaluated using the RoB2 (Risk of Bias 2) and ROBINS-I (Risk Of Bias In Non-randomized Studies-of Interventions) tools. Study characteristics and major findings were tabulated. <b>Results</b>: A total of 1263 manuscripts was identified initially. After removing duplicates, 726 articles remained for further screening. Ultimately, 17 manuscripts reporting interventional clinical trials on the effects of antidiabetic treatment on miRNA were included, encompassing a total of 1093 patients. Key findings included treatment-associated changes in miRNA expression and their potential utility for the prediction of clinical outcomes. <b>Conclusions</b>: Current evidence supports the hypothesis that antidiabetic treatments modulate miRNA expression, with some findings showing predictive value for metabolic outcomes. However, the available data remain limited and of low grade of certainty, and further large-scale clinical studies are needed to provide deeper insights into these associations.