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IntroductionMetformin is the first choice drug in the treatment of type 2 diabetes mellitus but its administration may be linked to gastrointestinal adverse events limiting its use.ObjectivesThe objective of this systematic review and meta-analysis was to assess the risk of gastrointestinal adverse events related to metformin use in patients with type 2 diabetes treated with metformin.MethodsPUB MED/CINAHL/Web of Science/Scopus were searched from database inception until 08.11.2020 for articles in English and randomized controlled trials related to patients with type 2 diabetes treated with metformin were included.ResultsFrom 5315 publications, we identified 199 potentially eligible full-text articles. Finally, 71 randomized controlled trials were included in the meta-analysis. In these studies, metformin use was associated with higher risk of abdominal pain, diarrhea and nausea comparing to control. The risks of abdominal pain and nausea were highest comparing to placebo. Bloating risk was only elevated when metformin treatment was compared to DPP4i.ConclusionsThe risk of gastrointestinal adverse events such as abdominal pain, nausea and diarrhea is higher in type 2 diabetes patients treated with metformin compared to other antidiabetic drugs. There is a higher risk of bloating and diarrhea with metformin immediate-release than with metformin extended release formulation.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021289975, identifier CRD42021289975.