The effects of metformin and exercise training on cardiorespiratory, blood pressure, and metabolic adaptations across the spectrum of glucose dysregulation: a systematic review and meta-analysis

Background: Metformin and structured exercise are routinely co-prescribed across the spectrum of glucose dysregulation, under the assumption of a cardiometabolic potentiating effect. Experimental data, however, suggest that metformin might blunt some exercise-induced adaptations, but this potential interaction has not been systematically quantified. Methods: statistic, while publication bias was estimated based on the visual examination of the funnel plot, Egger's test, and selection models. This systematic review with meta-analysis was registered in PROSPERO (CRD420251167325). Findings: peak, blood pressure, and most anthropometric measures, and low to very low for most glycaemic and lipid markers. Most outcomes showed little heterogeneity, and no evidence of publication bias was observed. Interpretation: Across controlled trials, adding metformin to structured exercise modestly attenuated improvements in cardiorespiratory fitness and blood pressure, while glycaemic and lipid indices were unchanged. These findings suggest that co-prescribing metformin and structured exercise may attenuate exercise-induced adaptations. It may therefore be advisable to consider strategies that prioritise physical exercise and support a more individualised approach to sequencing, dosing, and monitoring when metformin is co-initiated with exercise. Future research should examine the effects of combining metformin and exercise on exercise-induced adaptations, including cardiorespiratory fitness, strength, body composition, cardiovascular parameters, and metabolic biomarkers. Funding: None.