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SGLT2 Inhibition Increases Fasting Glucagon but Does Not Restore the Counterregulatory Hormone Response to Hypoglycemia in Participants with Type 1 Diabetes

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posted on 02.12.2021, 16:16 authored by Schafer C. Boeder, Justin M. Gregory, Erin R. Giovannetti, Jeremy H. Pettus
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 (n = 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.


Research in this publication was supported by a grant from JDRF under award number 2-SRA-2018-606-M-B (awarded to J.H.P), and by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health under award number K23DK123392 (to J.M.G.). J.M.G was supported by a JDRF Career Development Award (5-ECR-2020-950-A-N).