Individuals with type 1 diabetes
have an impaired glucagon counterregulatory response to hypoglycemia. Sodium-glucose
cotransporter (SGLT) inhibitors increase glucagon concentrations. We evaluated
whether SGLT inhibition restores the glucagon counterregulatory hormone
response to hypoglycemia. Adults
with type
1 diabetes (<i>n</i> = 22) were
treated with the SGLT2 inhibitor dapagliflozin (5 mg daily) or placebo for 4
weeks in a randomized, double-blind, crossover study. After each treatment phase,
participants underwent a hyperinsulinemic hypoglycemic clamp. Basal glucagon concentrations
were 32% higher following dapagliflozin versus placebo, with a median
within-participant difference of 2.75 pg/mL (95% CI 1.38-12.6). However, increased basal glucagon levels did
not correlate with decreased rates of hypoglycemia, and thus do not appear to
be protective in avoiding hypoglycemia. During hypoglycemic clamp, SGLT2
inhibition did not change counterregulatory hormone concentrations, time to
recovery from hypoglycemia, hypoglycemia symptoms, or cognitive function. Thus,
despite raising basal glucagon concentrations, SGLT inhibitor treatment did not
restore the impaired glucagon response to hypoglycemia. We propose that
clinical reduction in hypoglycemia associated with these agents is a result of
changes in diabetes care (e.g., lower insulin doses or improved glycemic
variability) as opposed to a direct, physiologic effect of these medications on
alpha cell function.
SGLT2 Inhibition Increases Fasting Glucagon but Does Not Restore the Counterregulatory Hormone Response to Hypoglycemia in Participants with Type 1 Diabetes
