Does Metformin Interfere with Cardiorespiratory and Substrate Oxidation Adaptations to Exercise Training in Metabolic Syndrome Patients? A Randomized Placebo-Controlled Trial

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Metformin and aerobic exercise are routinely co-prescribed in the management of metabolic syndrome, yet evidence regarding their interaction on cardiorespiratory fitness and substrate oxidation adaptations remains inconsistent. This study aimed to investigate the effects of combined metformin and aerobic training on peak oxygen uptake (VO2peak), maximal fat oxidation (MFO), submaximal substrate utilization, and perceived exertion in metformin-naïve adults with metabolic syndrome. In this randomized, placebo-controlled trial, 24 metformin-naïve adults with metabolic syndrome were allocated to receive either metformin (1000 mg/day; MET-EX) or a matched placebo (PLA-EX) combined with supervised aerobic training (5 sessions/week, 60% VO2peak, 500 kcal/session) for five weeks; 22 participants (n = 11 per group) completed the protocol. VO2peak, MFO, fat and carbohydrate oxidation, energy expenditure, and rating of perceived exertion (Borg 6–20) were assessed before and after the intervention. The absolute VO2peak gain was modestly attenuated in MET-EX relative to PLA-EX (group × time interaction p = 0.042; +0.11 vs. +0.26 L·min−1), whereas the interaction for relative VO2peak did not reach significance (p = 0.088). In contrast, MFO increased substantially more in MET-EX than in PLA-EX (+0.13 vs. +0.04 g·min−1; p = 0.001), accompanied by greater fat oxidation, energy expenditure, and perceived exertion during moderate-to-high submaximal exercise intensities. Moreover, VO2peak improvement was negatively correlated with age exclusively in MET-EX (r = −0.87, p < 0.001). These findings suggest that metformin induces a dissociated adaptation profile during aerobic training in metabolic syndrome, characterized by enhanced lipid oxidation alongside attenuated cardiorespiratory adaptations and greater perceived effort, particularly in older individuals.