Dasiglucagon Effects on QTc in Healthy Volunteers: A Randomized, Placebo-Controlled, Dose-Escalation, Double-Blind Study.

Background: Dasiglucagon is a novel glucagon analog that is stable in aqueous formulation and approved for use in severe hypoglycemia. Concentration QTc analyses are critical for assessing risk of drug-induced QTc prolongation and potential for fatal cardiac arrhythmias such as torsades de pointes. Objective: The aim of this study was to determine whether dasiglucagon treatment resulted in any clinically relevant effect on cardiac repolarization in healthy volunteers. Methods: This double-blind, placebo-controlled, dose-escalation Phase I trial was conducted at a single center in Germany between November 2018 and June 2019. Sixty healthy volunteers aged 18 to 45 years were randomized within dose cohorts to receive intravenous dasiglucagon, intravenous placebo, or subcutaneous dasiglucagon. In the intravenous administration cohorts, doses ranged from 0.03 mg to 1.5 mg. The subcutaneous administration cohort received the approved 0.6 mg dose. In the intravenous administration cohorts, serial electrocardiograms were extracted from continuous Holter monitors at prespecified time points beginning the day before dosing and through 24 hours postdose. Heart rate, PR interval, and QRS duration were evaluated. Concentration-QT analyses corrected by Fridericia's formula (QTcF) were performed using both a linear mixed-effects and a maximum estimated effect (Emax) model. Results: At the doses studied, dasiglucagon did not have any clinically relevant effect on heart rate, PR interval, or QRS duration. A minor prolongation of the QTcF interval was observed without any clear dose or concentration dependency. Both the linear and Emax models predicted mean and 90% CIs of placebo-corrected change in QTcF remained below 10 ms (the threshold of regulatory concern), although the linear model did not fit the data well at low dasiglucagon plasma concentrations. In the Emax model, the Emax of dasiglucagon was 3.6 ms (90% CI, 1.23-5.95 ms), and the amount to produce half the effect of Emax) was 426.0 pmol/L (90% CI, -48.8 to 900.71 pmol/L). The treatment effect-specific intercept was -0.44 ms (90% CI, -2.37 to 1.49 ms). The most frequently observed treatment-emergent adverse events reported in the trial were gastrointestinal disorders such as nausea and vomiting. Conclusions: Dasiglucagon does not cause clinically relevant QTc prolongation in concentrations up to ≈30,000 pmol/L, a level 5-fold higher than the highest observed plasma concentrations in clinical trials investigating use of the approved 0.6 mg SC dose. ClinicalTrials.gov Identifier: NCT03735225; EudraCT identifier: 2018-002025-32. (Curr Ther Res Clin Exp. 2022; 83:XXX-XXX).

Defective insulin secretion by chronic glucagon receptor activation in glucose intolerant mice.

Stimulation of insulin secretion by short-term glucagon receptor (GCGR) activation is well characterized; however, the effect of long-term GCGR activation on ß-cell function is not known, but of interest, since hyperglucagonemia occurs early during development of type 2 diabetes. Therefore, we examined whether chronic GCGR activation affects insulin secretion in glucose intolerant mice. To induce chronic GCGR activation, high-fat diet fed mice were continuously (2 weeks) infused with the stable glucagon analog ZP-GA-1 and challenged with oral glucose and intravenous glucose±glucagon-like peptide 1 (GLP1). Islets were isolated to evaluate the insulin secretory response to glucose±GLP1 and their pancreas were collected for immunohistochemical analysis. Two weeks of ZP-GA-1 infusion reduced insulin secretion both after oral and intravenous glucose challenges in vivo and in isolated islets. These inhibitory effects were corrected for by GLP1. Also, we observed increased ß-cell area and islet size. We conclude that induction of chronic ZP-GA-1 levels in glucose intolerant mice markedly reduces insulin secretion, and thus, we suggest that chronic activation of the GCGR may contribute to the failure of ß-cell function during development of type 2 diabetes.

Molecular mechanisms of decreased steroid responsiveness induced by latent adenoviral infection in allergic lung inflammation.

BACKGROUND: We recently reported that allergic lung inflammation in guinea pigs became steroid resistant in the presence of latent adenoviral infection. OBJECTIVE: We sought to investigate the molecular mechanisms that underlie steroid resistance in adenoviral infection. METHODS: Guinea pigs with a latent adenoviral infection were sensitized and challenged with ovalbumin (OVA) and given daily injections of budesonide (20 mg/kg administered intraperitoneally). Sham-infected animals received either saline challenge without budesonide injection or OVA challenge with or without budesonide. The inflammatory response in the lung was measured by means of quantitative histology. Eotaxin, monocyte chemoattractant protein 1 (MCP-1), and RANTES expression in the lung were analyzed by means of Northern blotting, and the binding activity of activator protein 1 (AP-1) and nuclear factor kappaB in nuclear extracts from the lung was analyzed with electrophoretic mobility shift assays. RESULTS: OVA challenge increased eosinophil infiltration and eotaxin and MCP-1 mRNA expression in the lungs, and glucocorticoids reduced these increases in the sham-infected, but not the adenovirus-infected, animals. Changes in binding activity of AP-1, but not nuclear factor kappaB, paralleled changes in eotaxin and MCP-1 mRNA. CONCLUSION: We conclude that latent adenoviral infection inhibits the anti-inflammatory effects of glucocorticoids on allergen-induced eotaxin and MCP-1 expression through AP-1, leading to steroid-resistant allergic lung inflammation.