Influence of Sodium Glucose Cotransporter 2 Inhibition on Physiological Adaptation to Endurance Exercise Training

J Clin Endocrinol Metab. 2019 Jun 1;104(6):1953-1966. doi: 10.1210/jc.2018-01741.


Context: The combination of two beneficial antidiabetes interventions, regular exercise and pharmaceuticals, is intuitively appealing. However, metformin, the most commonly prescribed diabetes medication, attenuates the favorable physiological adaptations to exercise; in turn, exercise may impede the action of metformin.

Objective: We sought to determine the influence of an alternative diabetes treatment, sodium glucose cotransporter 2 (SGLT2) inhibition, on the response to endurance exercise training.

Design, participants, and intervention: In a randomized, double-blind, repeated measures parallel design, 30 sedentary overweight and obese men and women were assigned to 12 weeks of supervised endurance exercise training, with daily ingestion of either a placebo or SGLT2 inhibitor (dapagliflozin: ≤10 mg/day).

Outcome measurements and results: Endurance exercise training favorably modified body mass, body composition (dual-energy x-ray absorptiometry), peak oxygen uptake (graded exercise with indirect calorimetry), responses to standardized submaximal exercise (indirect calorimetry, heart rate, and blood lactate), and skeletal muscle (vastus lateralis) citrate synthase activity (main effects of exercise training, all P < 0.05); SGLT2 inhibition did not influence any of these physiological adaptations (exercise training × treatment interaction, all P > 0.05). However, after endurance exercise training, fasting blood glucose was greater with SGLT2 inhibition, and increased insulin sensitivity (oral glucose tolerance test/Matsuda index) was abrogated with SGLT2 inhibition (exercise training × treatment interaction, P < 0.01).

Conclusion: The efficacy of combining two beneficial antidiabetes interventions, regular endurance exercise and SGLT2 inhibition, was not supported. SGLT2 inhibition blunted endurance exercise training-induced improvements in insulin sensitivity, independent of effects on aerobic fitness or body composition.

Trial registration: NCT02371187.

Publication types

  • Clinical Trial, Phase II
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Physiological / drug effects*
  • Adolescent
  • Adult
  • Benzhydryl Compounds / adverse effects
  • Blood Glucose / analysis
  • Blood Glucose / drug effects
  • Blood Glucose / physiology
  • Combined Modality Therapy / adverse effects
  • Combined Modality Therapy / methods
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / therapy*
  • Double-Blind Method
  • Endurance Training / methods*
  • Exercise Therapy / methods*
  • Female
  • Glucosides / adverse effects
  • Humans
  • Insulin / blood
  • Insulin / metabolism
  • Insulin Resistance / physiology
  • Male
  • Middle Aged
  • Physical Endurance / drug effects
  • Physical Endurance / physiology
  • Sedentary Behavior
  • Sodium-Glucose Transporter 2 / metabolism
  • Sodium-Glucose Transporter 2 Inhibitors / adverse effects*
  • Treatment Outcome
  • Young Adult


  • Benzhydryl Compounds
  • Blood Glucose
  • Glucosides
  • Insulin
  • SLC5A2 protein, human
  • Sodium-Glucose Transporter 2
  • Sodium-Glucose Transporter 2 Inhibitors
  • dapagliflozin

Associated data