341-P: Effect of Pitolisant on Glucagon in Human Islets and People with Type 1 Diabetes

In 3D human islet microtissues from nondiabetic donors, pitolisant, a histamine 3 receptor antagonist, increased glucagon secretion >3-fold compared to vehicle control. However, the effect of pitolisant on glucagon was diminished in islets treated with cytokines, insulin, and low glucose to mimic T1D hypoglycemia. The purpose of this study was to determine if pitolisant can restore impaired glucagon secretion response to hypoglycemia in people with T1D. The study was a double-blind randomized placebo-controlled study of five adults (3 on pitolisant and 2 on placebo), 4 men, with long-duration T1D. Patients were domiciled overnight, at baseline and after 7 days of once daily oral pitolisant (36 mg) or matching placebo. Blood glucose levels were kept at 100-120 mg/dL overnight with regular insulin infusion and an insulin tolerance test (ITT) was conducted the following morning. Glucagon was measured by the Mercodia ELISA and glucose by a YSI Glucose Analyzer. Glucose was also assessed using a blinded Dexcom G6 CGM during the trial. Safety tolerability was assessed by standard methods. Mean change (95% CI) from baseline in peak glucagon (pg/ml) was 7.5 (-2.07-17.02) for the pitolisant group and 13.1 (2.08-24.09) for the placebo group. One patient on pitolisant and no patients on placebo returned to blood glucose >/=70 mg/dL during the 180-minute ITT. The pitolisant group required significantly less rescue D50 on-drug vs. at baseline (5 vs. 19 grams, p=0.05), while there was no difference in the placebo group (36 vs. 25 grams). In general, patients on pitolisant had numerically higher mean glucose on CGM during the on-drug period. There were no severe hypoglycemic events and no deaths. Pitolisant was well tolerated. We conclude that pitolisant does not increase glucagon secretion during hypoglycemia in people with T1D but may mitigate hypoglycemia by a glucagon-independent mechanism. The T1D islet microtissue model better predicts the clinical effects of pitolisant on glucagon secretion compared to healthy islets.