Optimizing the Interaction of Exercise Volume and Metformin to Induce a Clinically Significant Reduction in Metabolic Syndrome Severity: A Randomised Trial

Insulin resistance is a central mediating factor of the metabolic syndrome (MetS), with exercise training and metformin proven antidotes to insulin resistance. However, when the two therapies are combined there is conflicting data regarding whether metformin blunts or improves exercise training-induced adaptations. The volume of exercise (duration, intensity, and frequency) on the interaction of exercise training and metformin has yet to be investigated. The aim of this study is therefore to explore the impact of a combination of different exercise volumes and metformin on MetS severity. This is a secondary analysis of data from one of the sites of the ‘Exercise in Prevention of Metabolic Syndrome’ (EX-MET) study. Ninety-nine adults with MetS were randomized into a 16-week exercise program completing either: (i) moderate-intensity continuous training (MICT) at 60–70% of peak heart rate (HRpeak) for 30 min/session ( n = 34, 150 min/week); (ii) high-volume high-intensity interval training (HIIT) consisting of 4 × 4 min bouts at 85–95% HRpeak, interspersed with 3 min of active recovery at 50–70% HRpeak ( n = 34, 38 min/session, 114 min/week); or (iii) low volume HIIT, 1 × 4 min bout of HIIT at 85–95% HRpeak ( n = 31, 17 min/session, 51 min/week). Metformin intake was monitored and recorded throughout the trial. MetS severity was calculated as z-scores derived from MetS risk factors assessed at pre- and post-intervention. Sixty-five participants had complete pre- and post-intervention data for MetS z-score, of which 18 participants (28%) were taking metformin. Over the 16-week intervention, a similar proportion of participants clinically improved MetS severity (Δ ≥ −0.87) with metformin (8/18, 44%) or without metformin (23/47, 49%) ( p = 0.75). While there were no between-group differences ( p = 0.24), in those who did not take metformin low-volume HIIT had more likely responders (10/15, 67%) compared to MICT (6/16, 38%) and high-volume HIIT (7/16, 44%). In those taking metformin, there was a lower proportion of participants who clinically improved MetS severity following high-volume HIIT (1/6, 17%) compared to MICT (2/4, 50%) and low-volume HIIT (5/8, 63%), but with no between-group difference ( p = 0.23). Moreover, in those who performed high-volume HIIT, there was a statistically significantly higher proportion ( p = 0.03) of likely non-responders with improved MetS severity in participants taking metformin (4/6, 67%) compared to those not taking metformin (3/16, 19%). In individuals with MetS, the effect of high volume HIIT on MetS severity may be blunted in those taking metformin. These findings need to be confirmed in a larger study.