Comparison of the Therapeutic Effects of the Combination of Exercise Training with Either a Sodium‐glucose Cotransporter 2 Inhibitor or Metformin in a Murine Model of Type 2 Diabetes
Authors: Linden Melissa A. , Ross Trenton T. , Hamilton Karyn L. , Miller Benjamin F. , Braun Barry , Esler William P. 
Published: November 2023

Pharmacotherapy and lifestyle modifications, including regular exercise (EX), are recommended for the management of type 2 diabetes mellitus (T2D). However, some studies have reported that the combination of metformin (MET), the first line pharmacotherapy, and EX have non‐additive, if not inhibitory, effects on improving glycemic control. Sodium‐glucose cotransporter 2 inhibitors (SGLT2i) are a new class of T2D medication that lower blood glucose by increasing urinary glucose excretion, but the effects of the combination of SGLT2i and EX on glucose lowering remain unclear. The purpose of this study was to determine whether the combination of the SGLT2i, dapagliflozin (DAPA), and EX produced greater improvements in measures of glycemic control than the combination of MET and EX in a murine model. Nine‐week old BKS.Cg‐Dock7m +/+ Leprdb/J mice were randomized (n=9–13/group) to a drug treatment (vehicle, MET, or DAPA) and lifestyle condition (sedentary or EX) for four weeks. EX consisted of five treadmill running sessions/wk, at 50% of Vmax, on a 10% incline, for 45 min/session. MET (300 mg/kg/d), DAPA (3 mg/kg/d), or vehicle (VEH; 0.5% methylcellulose) were administered once daily by oral gavage. Animals were euthanized 2h following the last dose of medication. Neither drug treatment alone or EX alone altered body weight or adiposity compared VEH‐treated mice. Mice that underwent the combination of SGLT2i+ EX therapies had greater body weight (41 vs. 36.8g; p<0.01) and percent body fat (54% vs 49%; p<0.05) compared to VEH. Neither MET, EX, or the combination had an effect on hemoglobin A1c concentrations (HbA1c). However, both MET and MET+EX lowered fasting plasma glucose ~20–35% vs VEH (p<0.0001) and VEH+EX (p<0.001). Surprisingly, fasting glucose concentrations were significantly higher in MET+EX vs MET alone (582 vs. 485 mg/dl, respectively; p< 0.01). Both SGLT2i and SGLT2i+EX lowered HbA1c (p<0.0001) and fasting glucose (p<0.0001) vs VEH and VEH+EX. In contrast to the negative interplay of MET+EX vs MET on indices of glycemic control, the combination of SGLT2i+EX further improved fasting glucose compared to SGLT2i alone (260 vs. 305 mg/dl, respectively; p<0.05), while differences in HbA1c between SGLT2i vs SGLT2i+ EX approached significance (p=0.083). When taken together, these findings suggest that the combination of SGLT2i and EX may have greater benefits on glycemic control than the combination of MET and EX during short‐term exercise training regimens. However, longer term studies are needed in order to confirm these findings and better understand the mechanisms that may contribute to these observations.Support or Funding InformationPfizer provided funding for this study. Authors M.A.L, T.T.R, and W.P.E. are employees and shareholders of Pfizer. B.B. has consulted for Pfizer, Inc. K.L.H., B.F.M, and B.B. have received research funding from Pfizer, Inc.