Gastrointestinal adverse events of metformin treatment in patients with type 2 diabetes mellitus: A systematic review, meta-analysis and meta-regression of randomized controlled trials

Front Endocrinol (Lausanne). 2022 Sep 14:13:975912. doi: 10.3389/fendo.2022.975912. eCollection 2022.


Introduction: Metformin 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.

Objectives: The 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.

Methods: PUB 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.

Results: From 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.

Conclusions: The 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 registration:, identifier CRD42021289975.

Keywords: Adverse events; diarrhea; dose; formulation; gastrointestinal; meta-analysis; metformin.

Publication types

  • Meta-Analysis
  • Systematic Review

MeSH terms

  • Abdominal Pain / chemically induced
  • Abdominal Pain / drug therapy
  • Delayed-Action Preparations
  • Diabetes Mellitus, Type 2* / drug therapy
  • Diarrhea / chemically induced
  • Diarrhea / drug therapy
  • Humans
  • Hypoglycemic Agents / adverse effects
  • Metformin* / adverse effects
  • Nausea / chemically induced
  • Nausea / drug therapy
  • Randomized Controlled Trials as Topic


  • Delayed-Action Preparations
  • Hypoglycemic Agents
  • Metformin