The interaction between metformin and physical activity on postprandial glucose and glucose kinetics: a randomised, clinical trial

Aims/hypothesis: The aim of this parallel-group, double-blinded (study personnel and participants), randomised clinical trial was to assess the interaction between metformin and exercise training on postprandial glucose in glucose-intolerant individuals. Methods: Glucose-intolerant (2 h OGTT glucose of 7.8–11.0 mmol/l and/or HbA _1c of 39–47 mmol/mol [5.7–6.5%] or glucose-lowering-medication naive type 2 diabetes), overweight/obese (BMI 25–42 kg/m ²) individuals were randomly allocated to a placebo study group (PLA, n = 15) or a metformin study group (MET, n = 14), and underwent 3 experimental days: BASELINE (before randomisation), MEDICATION (after 3 weeks of metformin [2 g/day] or placebo treatment) and TRAINING (after 12 weeks of exercise training in combination with metformin/placebo treatment). Training consisted of supervised bicycle interval sessions with a mean intensity of 64% of Watt _max for 45 min, 4 times/week. The primary outcome was postprandial glucose (mean glucose concentration) during a mixed meal tolerance test (MMTT), which was assessed on each experimental day. For within-group differences, a group × time interaction was assessed using two-way repeated measures ANOVA. Between-group changes of the outcomes at different timepoints were compared using unpaired two-tailed Student’s t tests. Results: Postprandial glucose improved from BASELINE to TRAINING in both the PLA group and the MET group (∆PLA: −0.7 [95% CI −1.4, 0.0] mmol/l, p = 0.05 and ∆MET: −0.7 [−1.5, −0.0] mmol/l, p = 0.03), with no between-group difference (p = 0.92). In PLA, the entire reduction was seen from MEDICATION to TRAINING (−0.8 [−1.3, −0.1] mmol/l, p = 0.01). Conversely, in MET, the entire reduction was observed from BASELINE to MEDICATION (−0.9 [−1.6, −0.2] mmol/l, p = 0.01). The reductions in mean glucose concentration during the MMTT from BASELINE to TRAINING were dependent on differential time effects: in the PLA group, a decrease was observed at timepoint (t) = 120 min (p = 0.009), whereas in the MET group, a reduction occurred at t = 30 min (p < 0.001). V̇O _2peak increased 15% (4.6 [3.3, 5.9] ml kg ⁻¹ min ⁻¹, p < 0.0001) from MEDICATION to TRAINING and body weight decreased (−4.0 [−5.2, −2.7] kg, p < 0.0001) from BASELINE to TRAINING, with no between-group differences (p = 0.7 and p = 0.5, respectively). Conclusions/interpretation: Metformin plus exercise training was not superior to exercise training alone in improving postprandial glucose. The differential time effects during the MMTT suggest an interaction between the two modalities. Funding: The Beckett foundation, A.P Møller Foundation, DDA, the Research Foundation of Rigshospitalet and Trygfonden. Trial registration: ClinicalTrials.gov (NCT03316690). [Figure not available: see fulltext.]