SGLT2 Inhibitor Dapagliflozin Increases Skeletal Muscle and Brain Fatty Acid Uptake in People With Type 2 Diabetes - A Randomized, Double-Blind, Placebo-Controlled, Positron Emission Tomography Study

Objective: The aim of this study was to investigate the impact of the sodium-glucose transporter 2 inhibitor dapagliflozin on tissue fatty acid (FA) uptake in skeletal muscle, the brain, small intestine, and subcutaneous and visceral adipose tissue in people with type 2 diabetes by using positron emission tomography (PET). Research Design and Methods: In a 6-week randomized, double-blinded, placebo-controlled trial, 53 patients with type 2 diabetes treated with metformin received either dapagliflozin 10 mg or placebo daily. Tissue FA uptake was quantified at baseline and at end-of-treatment with PET and the long-chain fatty acid analogue radiotracer 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid ([18F]FTHA). Treatment effects were assessed using ANCOVA, and the results are reported as least square means and 95 % CIs for the difference between groups. Results: 38 patients (dapagliflozin N=21, placebo N=17) completed the study. After 6 weeks, skeletal muscle FA uptake was increased by dapagliflozin vs placebo (1.0 [0.07, 2.0] µmol.100 g-1.min-1, P=.032), whereas the uptake was not significantly changed in the small intestine, visceral and subcutaneous adipose tissue. Dapagliflozin treatment significantly increased whole-brain FA uptake (0.10 [0.02, 0.17] µmol.100 g-1.min-1, P=.01), an effect observed in both gray and white matter regions. Conclusions: Six weeks of treatment with dapagliflozin increases skeletal muscle and brain fatty acid uptake, partly driven by a rise in FFA availability. This finding is in accordance with previous indirect measurements showing enhanced fatty acid metabolism in response to SGLT2 inhibition, and extends the notion of a shift towards increased fatty acid utilization to muscle and brain.