322-OR: SGLT2 Inhibition Has No Effect on the Counterregulatory Response to Hypoglycemia in Subjects with Type 1 Diabetes (T1D)

Individuals with T1D have an ineffective glucagon response to low glucose levels which predisposes them to episodes of hypoglycemia. SGLT-2 inhibitors (SGLT2i) do not increase and may even reduce hypoglycemia in clinical trials, yet the mechanism is unknown. This trial was conducted to determine if SGLT2i improve the counterregulatory response (CR) to hypoglycemia. Subjects with T1D (n=22) received 4 weeks of SGLT2i (dapagliflozin 5 mg daily) and 4 weeks of placebo in a double-blind, random-order, cross-over study. After each phase, subjects underwent a hypoglycemic clamp. During 40 min of hypoglycemia (mean serum glucose 49 mg/dL) CR hormones were serially measured. There was no difference between treatment phases in glucagon or other CR hormones during hypoglycemia [Figure]. Mean ± SE (paired two-tailed t-test) during hypoglycemia for SGLT2i vs. Placebo were: Glucagon (15.4 ± 1.8 vs. 14.8 ± 2.1 pg/mL; P = 0.77), Epinephrine (216 ± 34 vs. 200 ± 28 pg/mL; P = 0.46), Norepinephrine (402 ± 39 vs. 381 ± 25 pg/mL; P = 0.51), GH (9.1 ± 1.3 vs. 8.4 ± 1.8 ng/mL; P = 0.60), and Cortisol (11.4 ± 1.1 vs. 10.3 ± 0.9 mcg/dL; P = 0.18). SGLT2i treatment has no effect on the CR hormone response to hypoglycemia in T1D. These data suggest that any reduction in hypoglycemia that occurs with these agents may be due to behavioral changes (e.g., lower insulin doses, less frequent bolusing), rather than a physiologic mechanism.