Sex differences in the risk of metformin-associated gastrointestinal adverse events: A systematic review and meta-analysis.

Evidence regarding sex-related differences in metformin-associated gastrointestinal adverse events (GIAEs) remains limited. This systematic review and meta-analysis aimed to determine whether sex influences the risk of metformin-associated GIAEs. We included observational studies (5 cohorts and 1 case-control) and a randomized controlled trial identified through searches of Ovid MEDLINE, Ovid EMBASE, and CENTRAL from inception to June 2026. Eligible studies reported metformin-associated GIAEs separately in females and males, while studies in which GIAEs could not be attributed to metformin were excluded. Risk of bias was assessed using the Newcastle-Ottawa Scale for observational studies and the Cochrane Risk of Bias tool for randomized trials. Odds ratios (ORs) with 95% confidence intervals (CIs) were pooled using a random-effects meta-analysis. Seven studies (five cohort studies, one case-control study, and one randomized controlled trial) involving 7,968 participants (3,106 females and 4,862 males) were included. Females had significantly higher odds of metformin-associated GIAEs than males (OR 1.85, 95% CI 1.58-2.17), with consistent findings in sensitivity analyses. Females may have a higher risk of metformin-associated GIAEs than males, highlighting the importance of considering sex differences when prescribing metformin and monitoring gastrointestinal intolerance.