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: We conducted a systematic review and meta-analysis of controlled trials in adults with conditions across the spectrum of glucose dysregulation, comparing exercise plus metformin with the same exercise programme plus placebo or no metformin, including studies published between 1 January 2000 and 12 December 2025. Randomised and non-randomised controlled trials were eligible. Outcomes included peak oxygen uptake (VO Findings: Nine studies (n = 827; 14 publications) met the inclusion criteria; all contributed to the meta-analyses. Compared with exercise alone, metformin was associated with smaller improvements in VO 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.