Does metformin therapy influence the effects of intensive lifestyle intervention? Exploring the interaction between first line therapies in the Look AHEAD trial

  • Tasuku Terada
    Division of Cardiac Prevention and Rehabilitation, Exercise Physiology and Cardiovascular Health Lab, University of Ottawa Heart Institute, Ottawa, ON K1C 4W7, Canada
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  • Normand G. Boulé
    Corresponding author at: University of Alberta, Faculty of Kinesiology, Sport, and Recreation, and Alberta Diabetes Institute, 1-052 Li Ka Shing Centre for Health Research Innovation, Edmonton, AB T6G 2E1, Canada.
    Faculty of Kinesiology, Sport, and Recreation, and Alberta Diabetes Institute, University of Alberta, 1-052 Li Ka Shing Centre for Health Research Innovation, Edmonton, AB T6G 2E1, Canada
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Published:January 14, 2019DOI:


      • In this subsample of the Look AHEAD trial, 60% of participants were treated with metformin at baseline.
      • Metformin use was associated with small differences in response to intensive lifestyle interventions (ILI).
      • For some outcomes, such as fasting plasma glucose, those treated with metformin had slightly poorer responses to ILI.



      Metformin and lifestyle intervention are frequently prescribed together as first-line treatments for type 2 diabetes. However, little is known about their interplay. We investigated if the effects of a lifestyle intervention on glycemia, body mass and cardiorespiratory fitness (CRF) were influenced by metformin therapy.


      Participants randomized to intensive lifestyle intervention (ILI) or diabetes support and education (DSE) from the Look AHEAD trial were categorized into metformin therapy vs. no metformin. A two-by-two ANCOVA (i.e., metformin therapy vs. no metformin by ILI vs. DSE) was used to examine the changes in glycated hemoglobin A1C, fasting plasma glucose (FPG), body mass, and CRF over the first year post-randomization, with a primary interest in the metformin-by-lifestyle interaction effect.


      Data from 1982 participants were analyzed. There was a significant metformin-by-lifestyle interaction effect on A1C (p = 0.031) and FPG (p = 0.043), resulting from larger reductions associated with metformin therapy compared to no metformin following DSE, but slightly smaller reduction associated with metformin therapy compared to no metformin following ILI. Metformin therapy was associated with smaller weight loss (−4.7 ± 6.2 vs. −5.7 ± 6.3 kg; main effect: p = 0.001) but not with differential CRF changes when compared to no metformin.


      The interaction between metformin therapy and lifestyle intervention on glycemia highlights the complicated nature of combining therapies. While the small influence of background metformin therapy on intensive lifestyle intervention should not discourage the concomitant use of these therapies, our results showed that, for individuals undergoing intensive lifestyle therapy, background metformin therapy conferred little additional benefits.


      CRF (cardiorespiratory fitness), DSE (diabetes support and education), FPG (fasting plasma glucose), ILI (intensive lifestyle intervention), MET (metabolic equivalent)


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