Search

Aims: To perform an integrated analysis of the safety and efficacy of dasiglucagon, a glucagon analogue available in a ready‐to‐use aqueous formulation, to treat severe hypoglycaemia (SH) in type 1 diabetes (T1D). Materials and Methods: An integrated analysis of dasiglucagon safety was conducted on data from two placebo‐controlled trials (placebo‐controlled pool) and two placebo‐controlled and four non‐placebo‐controlled trials (broad pool) in adults with T1D. An integrated analysis of dasiglucagon efficacy was conducted of pooled data and within demographic subgroups from the two placebo‐controlled and two non‐placebo‐controlled trials in adults with T1D. Results: Dasiglucagon had a similar safety and tolerability profile to that of reconstituted glucagon. In the placebo‐controlled datasets, no serious adverse events (AEs), AEs leading to withdrawal from the trial, or deaths were reported. The most common causally related AEs were nausea (56.5%) and vomiting (24.6%). The broad pool safety analysis showed similar results. Dasiglucagon efficacy in time to plasma glucose recovery from insulin‐induced SH was similar to that of reconstituted glucagon (median 10.0 and 12.0 minutes, respectively) and superior to placebo (median 40.0 minutes; P < 0.0001). The median recovery time was consistent across all placebo‐controlled trial subgroups. Conclusions: Dasiglucagon was well tolerated and effective as a rapid rescue agent for insulin‐induced SH in people with T1D. [ABSTRACT FROM AUTHOR]

Background: Ultra rapid lispro (URLi) is a novel insulin lispro formulation developed to more closely match physiological insulin secretion and improve postprandial glucose control. This study compared the pharmacokinetics, glucodynamics, safety, and tolerability of URLi and Humalog® in patients with type 1 diabetes mellitus (T1DM). Methods: This was a phase I, two-period, randomised, double-blind, crossover glucose clamp study in younger adult (aged 18–45 years; n = 41) and elderly (aged ≥65 years; n = 39) patients with T1DM. At each dosing visit, patients received either URLi or Humalog (15 units subcutaneously) followed by a 10 h automated euglycaemic clamp procedure. Serum insulin lispro and blood glucose were measured. Results: Insulin lispro appeared in serum 6 min faster, and exposure was 7.2-fold greater over the first 15 min postdose with URLi versus Humalog in both age groups. Exposure beyond 3 h postdose was 39–41% lower, and exposure duration was reduced by 72–74 min with URLi versus Humalog in both age groups. Onset of insulin action was 11–12 min faster, and insulin action was 3-fold greater over the first 30 min postdose with URLi versus Humalog in both age groups. Insulin action beyond 4 h postdose was 44–54% lower, and duration of action was reduced by 34–44 min with URLi versus Humalog in both age groups. Overall exposure and total insulin action remained similar for both treatments. URLi and Humalog were well tolerated. Conclusion: In patients with T1DM, URLi showed ultra-rapid pharmacokinetics and glucodynamics, with the differences between URLi and Humalog in elderly patients mirroring those in younger adults. ClinicalTrials.gov identifier: NCT03166124. [ABSTRACT FROM AUTHOR]

Aim: To characterize the pharmacokinetic and pharmacodynamic properties of dasiglucagon, a novel, stable and liquid formulated glucagon analogue, during hypoglycaemic and euglycaemic conditions in adult patients with type 1 diabetes mellitus. Research Design and Methods: In this randomized double‐blind trial, 17 patients received four single subcutaneous doses (0.03, 0.08, 0.2 and 0.6 mg) of dasiglucagon (4 mg/mL formulation) under euglycaemic (plasma glucose [PG] 5.6 mmol/L [100 mg/dL]) or hypoglycaemic (PG 3.1‐3.7 mmol/L [56‐66 mg/dL]) conditions. For comparison, three doses (0.03, 0.08 and 0.2 mg) of a commercial glucagon formulation (Eli Lilly) were investigated at euglycaemia. Results: Dasiglucagon led to a dose‐dependent and rapid increase in PG levels across all doses tested (mean increases 30 minutes post‐dosing of 2.2 to 4.4 mmol/L [39‐80 mg/dL] from euglycaemia and 1.3 to 5.2 mmol/L [24‐94 mg/dL] from hypoglycaemia), which was higher than the rises elicited by similar doses of commercial glucagon (1.7‐3.9 mmol/L [30‐71 mg/dL]). The median time (range) to an increase in PG of >1.1 mmol/L (20 mg/dL) was <20 (18‐19.5) minutes with 0.03 mg dasiglucagon and, with higher doses, the median times ranged from 9 to 15 minutes (commercial glucagon 13‐14 minutes). In hypoglycaemia, 0.03 and 0.08 mg dasiglucagon re‐established normoglycaemia (PG ≥3.9 mmol/L [70 mg/dL]) within median times of 14 and 10 minutes, respectively. Nausea and vomiting occurred more frequently with dasiglucagon than with commercial glucagon at identical doses which might be attributable to dasiglucagon's higher potency. Conclusion: Dasiglucagon rapidly increased PG at doses of 0.03 to 0.6 mg in a dose‐dependent manner and, therefore, is a good candidate for use in dual‐hormone artificial pancreas systems. [ABSTRACT FROM AUTHOR]

Objective: Treatment of severe hypoglycemia outside of the hospital setting is limited to glucagon formulations requiring reconstitution before use, which may lead to erroneous or delayed glucagon administration. We compared the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics and safety and tolerability of different doses of dasiglucagon, a novel soluble glucagon analog, with approved pediatric and full doses of GlucaGen in insulin-induced hypoglycemia in patients with type 1 diabetes.Research Design and Methods: In this single-center, randomized, double-blind trial, 58 patients with type 1 diabetes received single subcutaneous injections of 0.1, 0.3, 0.6, or 1.0 mg dasiglucagon or 0.5 or 1.0 mg GlucaGen in a state of hypoglycemia (blood glucose target 55 mg/dL) induced by an intravenous insulin infusion.Results: Dasiglucagon demonstrated a dose-dependent and rapid increase in plasma concentrations, reaching a maximum at ∼35 min with a half-life of ∼0.5 h. Dasiglucagon rapidly increased plasma glucose (PG) by ≥20 mg/dL (9-14 min) to PG ≥70 mg/dL (within 6-10 min), similar to GlucaGen, but with a longer-lasting and greater effect on PG. All patients on both treatments reached these end points within 30 min (predefined success criteria). Both treatments were well tolerated. Nausea was the most frequent adverse event, occurring at a similar rate (44-56%).Conclusions: Dasiglucagon was well tolerated and showed an early PD response similar to that of GlucaGen at corresponding doses, suggesting comparable clinical effects of the two glucagon formulations. Dasiglucagon has the potential to become an effective and reliable rescue treatment for severe hypoglycemia in a ready-to-use pen. [ABSTRACT FROM AUTHOR]

Exercise is associated with an increased risk of hypo- or hyperglycemic events and it is difficult to find the optimal balance between carbohydrate uptake, insulin dose, and level and duration of exercise to avoid acute blood glucose deteriorations. The aim of this study was to monitor the impact of exercise on the glucose profile in the 21 hours thereafter in patients with type 1 diabetes managed by CSII before and after a 14 day moderate or intense training program. The 16 male patients (HbA1c 7.3±0.8% (mean±SD); age 39±11 years; BMI 26.0±2.7 kg/m[sup 2]) enrolled into this single center, randomized, open-label study underwent exercise challenges before and after a 14 day moderate (Group A; n=8) or intense (Group B) training program. During the two in-house periods each patient participated in, glucose profiles were registered on the first day (Day 0) with standardized meals. On the second day (Day 1) patients performed 45 min of exercise on a treadmill. Changes in glucose levels were monitored continuously during the following 21 hours after exercise until the morning of Day 2 by means of a microdialysis glucose monitoring system (SCGM 1). The areas under the glucose profiles (calibrated to blood glucose) during the 21 hours after start of the exercise challenge were similar between group A and B, as well as pre- and posttraining (Group A: 2716±270 vs. 2726±211 mg/dL*h and Group B: 2729±368 vs. 2846±456 mg/dL*h). Continuous monitoring revealed numerous hypoglycemic events resulting in a trend towards lower prandial insulin doses. There were no between-group differences in terms of the overall number of hypoglycemic events and the events occurred constantly over time without any specific allocation to single patients. Continuous glucose monitoring provides an insight into what remains otherwise undetected and should therefore help to improve the risk of hypo- and hyperglycemic excursions. [ABSTRACT FROM AUTHOR]

Aim: Exercise is associated with an increased risk of hypoglycemic or hyperglycemic events. The aim of this study was to assess glucose changes during and after physical exercise in patients with type 1 diabetes managed by continuous subcutaneous insulin infusion before and after a 14-day moderate or intense exercise program., Methods: Sixteen male patients [hemoglobin A1c 7.3 +/- 0.8% (mean +/- standard deviation), age 39 +/- 11 years, body mass index 26.0 +/- 2.7 kg/m(2)] were enrolled in this single-center, randomized, open-label study. They underwent exercise challenges before and after a 14-day moderate (group A, n = 8) and intense (group B) exercise program. Changes in glucose levels were monitored continuously by means of a microdialysis technique., Results: Patients in group A trained less intensively than the patients in group B. The treadmill exercise led to a comparable level of challenge in both patient groups. Neither heart rate nor energy consumption differed within the groups or between the groups. Patients in both groups had a comparable basal insulin infusion rate. Prandial insulin doses were higher pretraining than posttraining in both groups. Identical amounts of additional carbohydrates were consumed by the patients in both groups during the 21 h after the exercise challenge. Glucose profiles recorded showed a wide variability. No differences in the glucose profiles with respect to the training intensity could be observed within and between the groups. Patients in group A tended to spend a shorter period of time in hypoglycemia after the exercise challenge posttraining compared to pretraining, but not the patients in group B. The number of hypoglycemic episodes was not different between the groups., Conclusions: The patients with type 1 diabetes exhibit the expected wide variability in glucose profiles before, during, and after physical exercise. Use of continuous glucose monitoring allows handling of this situation without running into the risk of acute metabolic deteriorations., (2010 Diabetes Technology Society.)