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Aims: To investigate the pharmacokinetic/pharmacodynamic properties of once‐weekly insulin icodec in individuals with type 1 diabetes (T1D). Materials and Methods: In this randomized, open‐label, two‐period crossover trial, 66 individuals with T1D (age 18–64 years; glycated haemoglobin ≤75 mmol/mol [≤ 9%]) were to receive once‐weekly icodec (8 weeks) and once‐daily insulin glargine U100 (2 weeks) at individualized fixed equimolar total weekly doses established during up to 10 weeks' run‐in with glargine U100 titrated to pre‐breakfast plasma glucose (PG) of 4.4–7.2 mmol/L (80–130 mg/dL). Insulin aspart was used as bolus insulin. Blood sampling for icodec pharmacokinetics was performed from the first icodec dose until 35 days after the last dose. The glucose infusion rate at steady state was assessed in glucose clamps (target 6.7 mmol/L [120 mg/dL]) at 16–52 h and 138–168 h after the last icodec dose and 0–24 h after the last glargine U100 dose. Icodec pharmacodynamics during 1 week were predicted by pharmacokinetic‐pharmacodynamic modelling. Hypoglycaemia was recorded during the treatment periods based on self‐measured PG. Results: Icodec reached pharmacokinetic steady state on average within 2–3 weeks. At steady state, model‐predicted daily proportions of glucose infusion rate during the 1‐week dosing interval were 14.3%, 19.6%, 18.3%, 15.7%, 13.1%, 10.6% and 8.4%, respectively. Rates and duration of Level 2 hypoglycaemic episodes (PG <3.0 mmol/L [54 mg/dL]) were 32.8 versus 23.9 episodes per participant‐year of exposure and 33 ± 25 versus 30 ± 18 min (mean ± SD) for icodec versus glargine U100. Conclusions: The pharmacokinetic/pharmacodynamic properties of icodec suggest its potential to provide basal coverage in a basal‐bolus insulin regimen in people with T1D. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) bioequivalence (BE) of MYL‐1601D biosimilar with originator, NovoLog (Ref‐InsAsp‐US), and NovoRapid (Ref‐InsAsp‐EU). Materials and Methods: This was a double‐blind, randomized, crossover study that enrolled 71 healthy subjects to receive a single subcutaneous dose (0.2 U/kg) of each formulation under automated euglycaemic clamp conditions (ClampArt, level 81 mg/dL, duration 12 hours postdose). Primary PK endpoints were area under the plasma insulin aspart concentration‐time curve from 0 to 12 hours (AUC0‐12h) and maximum plasma insulin aspart concentration (Cmax). Primary PD endpoints were area under the glucose infusion rate (GIR) time curve from 0 to 12 hours (AUCGIR0‐12h) and maximum GIR (GIRmax). Insulin aspart in plasma was quantified using immunoaffinity purification followed by ultraperformance liquid chromatography and tandem mass spectrometric detection. The pairwise comparisons of geometric least square mean (LS‐mean) ratio for a 90% confidence interval (CI) of primary PK, and 90% CIs (MYL‐1601D vs. Ref‐InsAsp‐US) and 95% CIs (MYL‐1601D vs. Ref‐InsAsp‐EU) of primary PD variables, were to be within 80% to 125% to show BE. Results: MYL‐1601D showed PK BE to both Ref‐InsAsp‐US (AUC0‐12h geometric LS‐mean ratio 102.17, 90% CI [100.26; 104.11]; Cmax 106.13 [100.71; 111.85]) and Ref‐InsAsp‐EU (AUC0‐12h 101.84 [100.04; 103.67]; Cmax 105.74 [101.09; 110.60]). Likewise, MYL‐1601D showed PD BE to Ref‐InsAsp‐US (AUCGIR_0‐last 99.93; 90% CI [95.74; 104.30]; GIR_max 100.12 [94.46; 106.12]) and Ref‐InsAsp‐EU (AUCGIR_0‐last 96.42; 95% CI [91.17; 101.98]; GIR_max 95.10 [89.37; 101.19]). All three insulin aspart products were well tolerated. Conclusion: MYL‐1601D showed BE to Ref‐InsAsp‐US and Ref‐InsAsp‐EU with a comparable safety profile. [ABSTRACT FROM AUTHOR]

Introduction: Many commercially available glucagon products for treatment of severe hypoglycaemia require cumbersome reconstitution and potentially intimidating injection during an emergency. Nasal glucagon (NG) is a novel drug-device combination product consisting of a single-use dosing device that delivers glucagon dry powder through nasal administration. The present study assessed whether 3 mg NG was non-inferior to 1 mg intramuscular glucagon (IMG) in adults with type 1 diabetes. Methods: This randomised, open-label, two-period, crossover trial was conducted at two clinical sites. Hypoglycaemia (plasma glucose [PG] target of < 3.3 mmol/l (60 mg/dl) was induced by an intravenous insulin infusion. Glucagon preparations were given by study staff. Treatment success was defined as an increase in PG to ≥ 3.9 mmol/l (70 mg/dl) or an increase of ≥ 1.1 mmol/l (20 mg/dl) from the PG nadir within 30 min of receiving glucagon. Results: Of the 66 participants included in the primary efficacy analysis who received both NG and IMG, 100% achieved treatment success, thus demonstrating non-inferiority of NG to IMG. All participants achieved treatment success within 25 min with the mean time to treatment success of 11.4 min (NG) and 9.9 min (IMG). No serious adverse events occurred. Forty-eight treatment-emergent adverse events (TEAEs) occurred after NG and 51 after IMG. Most TEAEs were mild and transient. Conclusion: Nasal glucagon was as efficacious and well tolerated as IMG for the treatment of insulin-induced hypoglycaemia in adults and will be as useful as IMG as a rescue treatment for severe hypoglycaemia. Trial Registration: NCT03339453, ClinicalTrials.gov [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]

Background: Fast-acting insulin aspart (faster aspart) is insulin aspart set in a new formulation with faster initial absorption after subcutaneous administration. This study investigated the pharmacokinetic properties, including the absolute bioavailability, of faster aspart when administered subcutaneously in the abdomen, upper arm or thigh. Methods: In a randomised, open-label, crossover trial, 21 healthy male subjects received a single injection of faster aspart at five dosing visits: 0.2 U/kg subcutaneously in the abdomen, upper arm and thigh, intramuscularly in the thigh and 0.02 U/kg intravenously. Blood sampling for pharmacokinetics was performed pre-dose and frequently thereafter until 12 h post-dose (8 h after intravenous administration). Results: Onset of appearance (~3 min), time to 50% of maximum concentration ( t ; ~20 min) and time to maximum concentration ( t ; ~55 min) were all similar between injection regions. Early exposure within the first 2 h after injection (AUC and AUC) as well as maximum concentration ( C ) were comparable for the abdomen and upper arm, but were ~25% lower for the thigh as seen previously for other mealtime insulin products. Total exposure (AUC) was similar for the abdomen, upper arm and thigh, and absolute bioavailability was ~80% after subcutaneous administration of faster aspart in all three injection regions. Conclusion: The current study supports the ultra-fast pharmacokinetic characteristics of faster aspart across different injection regions, with administration in the abdomen and upper arm resulting in greater early exposure than in the thigh. ClinicalTrials.gov identifier: NCT02089451. [ABSTRACT FROM AUTHOR]

Background: Due to population aging, an increasing number of elderly patients with diabetes use insulin. It is therefore important to investigate the characteristics of new insulins in this population. Faster-acting insulin aspart (faster aspart) is insulin aspart (IAsp) in a new formulation with faster absorption. This study investigated the pharmacological properties of faster aspart in elderly subjects with type 1 diabetes mellitus (T1DM). Methods: In a randomised, double-blind, two-period crossover trial, 30 elderly (≥65 years) and 37 younger adults (18-35 years) with T1DM received single subcutaneous faster aspart or IAsp dosing (0.2 U/kg) and underwent an euglycaemic clamp (target 5.5 mmol/L) for up to 12 h. Results: The pharmacokinetic and pharmacodynamic time profiles were left-shifted for faster aspart versus IAsp. In each age group, onset of appearance occurred approximately twice as fast (~3 min earlier) and early exposure (area under the concentration-time curve [AUC] for serum IAsp from time zero to 30 min [AUC]) was greater (by 86% in elderly and 67% in younger adults) for faster aspart than for IAsp. Likewise, onset of action occurred 10 min faster in the elderly and 9 min faster in younger adults, and early glucose-lowering effect (AUC for the glucose infusion rate [GIR] from time zero to 30 min [AUC]) was greater (by 109%) for faster aspart than for IAsp in both age groups. Total exposure (AUC) and the maximum concentration ( C ) for faster aspart were greater (by 30 and 28%, respectively) in elderly than in younger adults. No age group differences were seen for the total (AUC) or maximum (GIR) glucose-lowering effect. Conclusion: This study demonstrated that the ultra-fast pharmacological properties of faster aspart are similar in elderly subjects and younger adults with T1DM. ClinicalTrials.gov Identifier: NCT02003677. [ABSTRACT FROM AUTHOR]

Objective: Lipohypertrophy (LHT) is common in insulin-treated patients but its exact impact on insulin absorption and action is unclear.Research Design and Methods: In this crossover study, 13 patients with type 1 diabetes received subcutaneous abdominal injections of 0.15 units/kg insulin lispro into LHT (confirmed by examination and ultrasound) and normal adipose tissue (NAT). On one day, a euglycemic clamp was performed with two injections each into LHT and NAT, and on another day one injection per region was given before a standardized mixed meal (75 g carbohydrates), all in randomized order.Results: Compared with NAT, LHT reduced insulin absorption (mean area under the insulin concentration curve [AUCINS0-4h] 131 vs. 165 h * mU/L [LHT vs. NAT]; Cmax 61 vs. 79 mU/L, P < 0.02, respectively) and effect (areas under glucose infusion rate [GIR] curves [AUCGIR0-4h 625 vs. 775 mg/kg, P < 0.05]) but increased intrasubject variability ([coefficient of variation] AUCINS0-4h 52 vs. 11%, Cmax 55 vs. 15%, AUCGIR0-4h 57 vs. 23%, all P < 0.01). Postprandial blood glucose (BG) concentrations were ≥26% higher with LHT (AUCBG0-5h 731 vs. 513 mg * h/dL, BGmax 199 vs. 157 mg/dL, 2-h BG 150 vs. 104 mg/dL, 5-h BG 145 vs. 81 mg/dL, all P < 0.05) and maximum concentrations occurred later. Hypoglycemia (BG ≤50 mg/dL) occurred numerically less frequently with LHT injection (two vs. six patients), whereas profound hyperglycemia (BG ≥300 mg/dL) only occurred with LHT injection (two patients). Tmax-INS did not differ between LHT and NAT in either study.Conclusions: Insulin absorption and action are blunted and considerably more variable with LHT injection, leading to profound deterioration in postprandial glucose control. [ABSTRACT FROM AUTHOR]

Pharmacokinetics (PK) and pharmacodynamics (PD) of proposed biosimilar Insulin Aspart (MYL-1601D) vs. NovoLog and NovoRapid were compared in a randomized, double-blind, crossover, clamp study. 71 healthy subjects received a single subcutaneous dose (0.2 U/kg) of each formulation under automated euglycemic clamp conditions (ClampArt®, level 81 mg/dl, duration 12h post-dose). Insulin aspart in plasma was quantified using immunoaffinity purification followed by UPLC and tandem mass spectrometric detection. The primary PK and PD results are provided in Table 1. The secondary PK-endpoints (AUCIns.04h, AUCIns.0-6h and AUCIns.0-∞) and PDendpoints (AUCGIR_04h, AUCGIR_0-6h and AUCGIR_6-last) also met BE criteria. Safety was comparable between all three insulin aspart products. Disclosure: Y. Raiter: Employee; Self; Mylan N. V. G. C. l. : None. U. Hövelmann: None. A. Chullikana: Employee; Self; Biocon. M. Liu: Employee; Self; Mylan N. V. C. M. Donnelly: Employee; Self; Mylan N. V., Viatris Inc. T. Lawrence: Employee; Self; Mylan N. V. N. Sengupta: Employee; Self; Biocon. G. Ranganna: Employee; Self; Mylan N. V., Viatris. A. Barve: Employee; Self; Mylan N. V., Stock/Shareholder; Self; Biocon. [ABSTRACT FROM AUTHOR]

Insulin icodec* is a novel basal insulin analog designed for single once-weekly (OW) subcutaneous injection. This randomized, double–blind, double–dummy trial investigated the pharmacokinetics (PK), pharmacodynamics (PD) and safety of insulin icodec. Fifty individuals with type 2 diabetes (insulin treated±metformin; 43 men; mean±SD age 57±5 years, BMI 30.1±2.7 kg/m2, A1C 7.4±0.6%) received OW insulin icodec (12, 20 or 24 nmol/kg) plus once–daily (OD) placebo (N=13, 13, 12) or OD insulin degludec (0.4 U/kg) plus OW placebo (N=12) for 5 weeks in 3 dose level cohorts. PD properties were investigated at close to steady state in 24-h glucose clamps on days 2 and 7 after the last insulin icodec dose. Median tmax,insulin icodec was 16 h and geometric mean t½,insulin icodec was 196 h with no systematic differences between dose levels. The glucose–lowering effect over a weekly dosing interval was derived from the observed PK/PD data using a PK/PD model and showed close to even distribution over the 7 days across all dose levels (Figure). The adverse event (AE) incidence did not increase with increasing insulin icodec dose (100%, 69%, 75%, respectively). There were no serious or severe AEs, severe hypoglycemic episodes or injection site reactions. In conclusion, insulin icodec was safe and well-tolerated and showed PK/PD properties supporting once-weekly administration at clinically relevant dose levels. * Proposed INN. Disclosure: U. Hövelmann: None. L. Brøndsted: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. N.R. Kristensen: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. R. Ribel-Madsen: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. J. DeVries: Advisory Panel; Self; Novo Nordisk A/S, Zealand Pharma A/S. Consultant; Self; Metronom Health. Employee; Self; Profil Institute for Clinical Research. T. Heise: Advisory Panel; Self; Mylan, Novo Nordisk A/S. Research Support; Self; ADOCIA, Aerami, Becton, Dickinson and Company, Biocon, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Gan & Lee Pharmaceuticals, MedImmune, Merck KGaA, Mylan, Nordic Bioscience, Novo Nordisk A/S, Poxel SA, Sanofi, Xeris Pharmaceuticals, Inc., Zealand Pharma A/S. Speaker's Bureau; Self; Eli Lilly and Company, Novo Nordisk A/S. H. Haahr: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. Funding: Novo Nordisk [ABSTRACT FROM AUTHOR]

Background: Absorption of current rapid-acting insulins is too slow for patients with diabetes mellitus to achieve optimal postprandial glucose control. Faster-acting insulin aspart (faster aspart) is insulin aspart in a new formulation with faster early absorption. We compared the pharmacokinetic/pharmacodynamic properties of faster aspart and insulin aspart across a clinically relevant dose range.Methods: In this randomised, double-blind, crossover trial, 46 subjects with type 1 diabetes mellitus received single subcutaneous doses of faster aspart and insulin aspart at 0.1, 0.2 (repeated three times to estimate within-subject variability) and 0.4 U/kg in a euglycaemic clamp setting (target 5.5 mmol/L).Results: Consistently for the three doses, faster aspart demonstrated faster onset and greater early absorption and glucose-lowering effect versus insulin aspart. Across all three doses, onset of appearance occurred approximately twice as fast (approximately 5 min earlier) and early insulin exposure (AUCIAsp,0-30min) was approximately 1.5- to 2-fold greater for faster aspart versus insulin aspart. Likewise, onset of action occurred approximately 5 min faster and early glucose-lowering effect (AUCGIR,0-30min) was approximately 1.5- to 2-fold larger for faster aspart versus insulin aspart. Relative bioavailability was approximately 100% and total glucose-lowering effect was similar for faster aspart versus insulin aspart. Dose-concentration and dose-response relationships were comparable between faster aspart and insulin aspart. Within-subject variability in glucose-lowering effect was low for faster aspart (coefficient of variation approximately 20%) and not significantly different from insulin aspart.Conclusion: The faster onset and greater early insulin exposure and glucose-lowering effect with faster aspart versus insulin aspart are preserved across a broad range of doses and consistently observed from day to day. CLINICALTRIALS.Gov Identifier: NCT02033239. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the efficacy and safety of dasiglucagon, a ready-to-use, next-generation glucagon analog in aqueous formulation for subcutaneous dosing, for treatment of severe hypoglycemia in adults with type 1 diabetes.Research Design and Methods: This randomized, double-blind trial included 170 adult participants with type 1 diabetes, each randomly assigned to receive a single subcutaneous dose of 0.6 mg dasiglucagon, placebo, or 1 mg reconstituted glucagon (2:1:1 randomization) during controlled insulin-induced hypoglycemia. The primary end point was time to plasma glucose recovery, defined as an increase of ≥20 mg/dL from baseline without rescue intravenous glucose. The primary comparison was dasiglucagon versus placebo; reconstituted lyophilized glucagon was included as reference.Results: Median (95% CI) time to recovery was 10 (10, 10) minutes for dasiglucagon compared with 40 (30, 40) minutes for placebo (P < 0.001); the corresponding result for reconstituted glucagon was 12 (10, 12) minutes. In the dasiglucagon group, plasma glucose recovery was achieved within 15 min in all but one participant (99%), superior to placebo (2%; P < 0.001) and similar to glucagon (95%). Similar outcomes were observed for the other investigated time points at 10, 20, and 30 min after dosing. The most frequent adverse effects were nausea and vomiting, as expected with glucagon treatment.Conclusions: Dasiglucagon provided rapid and effective reversal of hypoglycemia in adults with type 1 diabetes, with safety and tolerability similar to those reported for reconstituted glucagon injection. The ready-to-use, aqueous formulation of dasiglucagon offers the potential to provide rapid and reliable treatment of severe hypoglycemia. [ABSTRACT FROM AUTHOR]

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]

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]

Background and Objective: Individuals with diabetes mellitus may prefer different body regions for subcutaneous insulin administration. This trial investigated whether choice of injection region affects exposure and glucose-lowering effect of once-weekly basal insulin icodec. Methods: In a randomised, open-label, crossover trial, 25 individuals with type 2 diabetes received single subcutaneous icodec injections (5.6 U/kg) in the thigh, abdomen or upper arm (9–13 weeks' washout). Pharmacokinetic blood sampling occurred frequently until 35 days post-dose. Partial glucose-lowering effect was assessed 36–60 h post-dose in a glucose clamp (target 7.5 mmol/L). Steady-state pharmacokinetics following multiple once-weekly dosing were simulated using a two-compartment pharmacokinetic model. Results: Total icodec exposure (area under the curve from zero to infinity after single dose; AUC0–∞,SD) was similar between injection in the thigh, abdomen and upper arm (estimated AUC0–∞,SD ratios [95% confidence interval]: abdomen/thigh 1.02 [0.96–1.09], p = 0.473; upper arm/thigh 1.04 [0.98–1.10], p = 0.162; abdomen/upper arm 0.98 [0.93–1.05], p = 0.610). Maximum icodec concentration (Cmax) after single dose was higher for abdomen (by 17%, p = 0.002) and upper arm (by 24%, p < 0.001) versus thigh. When simulated to steady state, smaller differences in Cmax were seen for abdomen (by 11%, p = 0.004) and upper arm (by 16%, p < 0.001) versus thigh. Geometric mean [coefficient of variation] glucose-lowering effect 36–60 h post-dose was comparable between the thigh (1961 mg/kg [51%]), abdomen (2130 mg/kg [52%]) and upper arm (2391 mg/kg [40%]). Conclusion: Icodec can be administered subcutaneously in the thigh, abdomen or upper arm with no clinically relevant difference in exposure and with a similar glucose-lowering effect. ClinicalTrials.gov Identifier: NCT04582448. [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]

OBJECTIVE-- Pharmacological profiles of biphasic insulin aspart 30/70 (BIAsp 30) once daily (OD), twice daily (b.i.d.), and three times daily (t.i.d.) were compared with other insulin regimens in two crossover glucose clamp studies of insulin-treated type 2 diabetic patients. RESEARCH DESIGNS AND METHODS-- Study 1 consisted of BIAsp 30 OD, b.i.d., and t.i.d. versus biphasic human insulin 30/70 (BHI 30), OD (n = 24). Study 2 examined BIAsp 30 t.i.d. versus basal-bolus therapy (insulin glargine OD plus insulin glulisine t.i.d.) (n = 24). Pharmacokinetics/pharmacodynamics (PK/PD) were investigated over 24 h. RESULTS -- Study 1: PK and PD were markedly different between BIAsp 30 OD and BHI 30 OD: the maximum insulin concentration and glucose infusion rate (GIR) were higher for BIAsp 30; time to maximum metabolism was 1.7 h sooner for BIAsp 30. Study 2: both regimens showed three distinct prandial-related GIR peaks. GIR 24-h area under the curve for BIAsp t.i.d. was higher than for basal-bolus therapy: 2,585.2 vs. 2,289.2 mg/kg. CONCLUSIONS-- BIAsp had pharmacological advantages over BHI. BIAsp t.i.d, had a similar PD profile to basal-bolus therapy. [ABSTRACT FROM AUTHOR]

Background: This study assessed pharmacokinetics (PK) and pharmacodynamic postprandial glycemia (PPG) in patients with type 1 diabetes mellitus (T1DM) after a standardized liquid meal following insulin lispro (IL) or regular human insulin (RHI) given by microneedle-based intradermal (ID) versus subcutaneous (SC) delivery. Research Design and Methods: In this randomized, open-label, five-way crossover study, 29 T1DM patients received IL and RHI (0.125 U/kg) at 2 min and 17 min premeal, respectively, by both the SC and ID routes and also received RHI by the ID route at 2 min premeal. Blood glucose was stabilized at 120 mg/dL prior to a standardized 82-g carbohydrate liquid meal. ID delivery used a 34-gauge 1.5-mm steel microneedle, and SC delivery used a 31-gauge 8-mm syringe needle. Results: The 90-min PPG (blood glucose area under the curve for 0-1.5 h) for ID RHI was 14% lower than SC RHI at −17 min ( P < 0.0001) and 11% lower than ID RHI at −2 min ( P = 0.0006). PPG did not differ between ID RHI and SC IL, both at −2 min ( P = 0.8345). ID IL PPG was lower than SC, both at −2 min, but not significantly ( P = 0.10). Both ID IL and ID RHI PK data showed significantly faster uptake and time to maximum concentration, higher maximum concentration, and shorter systemic circulating duration versus SC dosing. ID IL and RHI delivery was generally well tolerated. Conclusions: PPG with RHI administered ID via microneedle was improved versus SC delivery when dosed 17 min premeal. ID RHI provided similar control of PPG as SC IL immediately premeal. Further studies of ID insulin delivery via steel microneedles are warranted. [ABSTRACT FROM AUTHOR]

The efficacy of dasiglucagon 0.6 mg has been investigated in multiple trials in individuals with T1DM. The primary endpoint was time to plasma glucose (PG) recovery from insulin-induced hypoglycemia, defined as first PG increase ≥20 mg/dL after treatment initiation without the need for IV glucose. Different PG sampling schemes were used in phase 2 (5-min intervals) versus phase 3 trials (more frequent sampling). Estimating the true but unmeasured time to recovery for each individual enables for a better comparison between trials when compared to use of observed time only. The true time was calculated using linear interpolation between the 2 time points before and after recovery occurred, assuming a linear PG increase in this limited time interval. The difference between the observed and the estimated true recovery for an individual is illustrated in the figure. The PG sample taken at 10 min is the first sample showing an increase of at least 20 mg/dL from the predose level, leading to an observed time to recovery of 10 min. Linear interpolation estimates the increase of 20 mg/dL to occur at 9 min for this individual. Using interpolated PG values, the median estimated true time to recovery for dasiglucagon was 8.7 min in the phase 2 trial and 9.0 to 9.3 min in phase 3 trials. These data provide further insight into the probable "true time to recovery" and confirm the consistent efficacy of dasiglucagon in the treatment of hypoglycemia. Disclosure: T. Battelino: Advisory Panel; Self; Eli Lilly and Company, Medtronic, Sanofi, Research Support; Self; European Union, National Institute of Diabetes and Digestive and Kidney Diseases, Novartis Pharmaceuticals Corporation, Novo Nordisk, Sanofi, Slovenian Research Agency, Zealand Pharma A/S, Speaker's Bureau; Self; Abbott Diabetes, AstraZeneca, Dexcom, Inc., Eli Lilly and Company, Medtronic, Novo Nordisk, Pfizer Inc., Roche Diabetes Care, Sanofi, Stock/Shareholder; Self; DreaMed Diabetes, Ltd. L. Dimeglio: Advisory Panel; Self; MannKind Corporation. T. Danne: Research Support; Self; Abbott Diabetes, Dexcom, Inc., Eli Lilly and Company, Medtronic, Novo Nordisk, Sanofi, Tandem Diabetes Care, Zealand Pharma A/S, Stock/Shareholder; Self; DreaMed Diabetes, Ltd. A. L. Peters: Advisory Panel; Self; Abbott Diabetes, Eli Lilly and Company, MannKind Corporation, Medscape, Merck & Co., Inc., Novo Nordisk Inc., Zealand Pharma A/S, Other Relationship; Self; Livongo, Research Support; Self; Abbott Diabetes, Dexcom, Inc. T. S. Bailey: Consultant; Self; Abbott Diabetes, LifeScan, Novo Nordisk, Sanofi, Research Support; Self; Abbott, Abbott Diabetes, Biolinq, Capillary Biomedical, Inc., Dexcom, Inc., Eli Lilly and Company, Kowa Research Institute, Inc., Lexicon Pharmaceuticals, Inc., Livongo, Medtronic, Medtrum Technologies, Novo Nordisk, REMD Biotherapeutics, Sanofi, Sanvita, Viacyte, Inc., vTv Therapeutics, Zealand Pharma A/S, Speaker's Bureau; Self; BD, Medtronic, Sanofi. R. Tehranchi: Employee; Self; Zealand Pharma A/S. L. J. Klaff: Research Support; Self; Abbott Diabetes, Dong-A ST Co. Ltd., Gan & Lee Pharmaceuticals, Lexicon Pharmaceuticals, Inc., Lilly Diabetes, Medtronic, Novo Nordisk, Oramed Pharmaceuticals, Inc., Pfizer Inc., REMD Biotherapeutics. T. Pieber: Advisory Panel; Self; ADOCIA, Arecor, AstraZeneca, Eli Lilly and Company, Novo Nordisk A/S, Sanofi, Research Support; Self; AstraZeneca, Novo Nordisk A/S. U. Hövelmann: None. L. Plum-moerschel: None. A. E. Melgaard: Employee; Self; Zealand Pharma A/S. R. Aronson: None. [ABSTRACT FROM AUTHOR]

Dasiglucagon was developed to provide a fast and effective treatment for severe hypoglycemia (SH) in people with diabetes. An integrated cross-program analysis was performed to assess the safety of dasiglucagon in a representative population of T1DM. Three randomized, placebo-controlled phase 3 trials (2 in adults and 1 in pediatric subjects) were included in the analysis (212 adults and 41 children/adolescents with T1DM). No severe or adverse events (AEs) leading to withdrawal were reported. Most AEs were mild or moderate in severity. Nausea and vomiting were the most-frequent AEs reported with active treatment both in adults and children. No differences in the frequency of nausea and vomiting were observed between adults receiving dasiglucagon versus glucagon. A higher percentage of adolescents experienced these events with dasiglucagon than with glucagon, while no treatment-related imbalance was observed in the 6- to 11-year-old age group. In the pediatric trial, no relationship between exposure (AUC0-5 hr or Cmax) to dasiglucagon, and nausea and vomiting was found. The majority of nausea and vomiting occurred within 1-3 hr and 2-3 hr of dosing, respectively. In conclusion, dasiglucagon 0.6 mg for treatment of SH was found to be generally safe, and the safety profile of dasiglucagon was consistent with that observed across the class of glucagon products. Disclosure: S. R. Heller: Advisory Panel; Self; Eli Lilly and Company, Novo Nordisk, Zealand Pharma A/S, Consultant; Self; Zealand Pharma A/S, Other Relationship; Self; Dexcom, Inc., Eli Lilly and Company, MannKind Corporation, Novo Nordisk, Speaker's Bureau; Self; AstraZeneca, Novo Nordisk. R. Aronson: None. L. Dimeglio: Advisory Panel; Self; MannKind Corporation. T. Danne: Research Support; Self; Abbott Diabetes, Dexcom, Inc., Eli Lilly and Company, Medtronic, Novo Nordisk, Sanofi, Tandem Diabetes Care, Zealand Pharma A/S, Stock/Shareholder; Self; DreaMed Diabetes, Ltd. T. Battelino: Advisory Panel; Self; Eli Lilly and Company, Medtronic, Sanofi, Research Support; Self; European Union, National Institute of Diabetes and Digestive and Kidney Diseases, Novartis Pharmaceuticals Corporation, Novo Nordisk, Sanofi, Slovenian Research Agency, Zealand Pharma A/S, Speaker's Bureau; Self; Abbott Diabetes, AstraZeneca, Dexcom, Inc., Eli Lilly and Company, Medtronic, Novo Nordisk, Pfizer Inc., Roche Diabetes Care, Sanofi, Stock/Shareholder; Self; DreaMed Diabetes, Ltd. T. S. Bailey: Consultant; Self; Abbott Diabetes, LifeScan, Novo Nordisk, Sanofi, Research Support; Self; Abbott, Abbott Diabetes, Biolinq, Capillary Biomedical, Inc., Dexcom, Inc., Eli Lilly and Company, Kowa Research Institute, Inc., Lexicon Pharmaceuticals, Inc., Livongo, Medtronic, Medtrum Technologies, Novo Nordisk, REMD Biotherapeutics, Sanofi, Sanvita, Viacyte, Inc., vTv Therapeutics, Zealand Pharma A/S, Speaker's Bureau; Self; BD, Medtronic, Sanofi. R. Tehranchi: Employee; Self; Zealand Pharma A/S. L. J. Klaff: Research Support; Self; Abbott Diabetes, Dong-A ST Co. Ltd., Gan & Lee Pharmaceuticals, Lexicon Pharmaceuticals, Inc., Lilly Diabetes, Medtronic, Novo Nordisk, Oramed Pharmaceuticals, Inc., Pfizer Inc., REMD Biotherapeutics. T. Pieber: Advisory Panel; Self; ADOCIA, Arecor, AstraZeneca, Eli Lilly and Company, Novo Nordisk A/S, Sanofi, Research Support; Self; AstraZeneca, Novo Nordisk A/S. U. Hövelmann: None. L. Plum-moerschel: None. A. E. Melgaard: Employee; Self; Zealand Pharma A/S. [ABSTRACT FROM AUTHOR]

The efficacy of dasiglucagon 0.6 mg, a glucagon analog stable in aqueous formulation, has been established versus placebo in previously reported trials in adults with type 1 diabetes mellitus. An integrated analysis was conducted to investigate efficacy in demographic and other subgroups. To allow as many individuals as possible in the evaluation, the analysis comprised data from 4 trials in adults, including 2 pivotal trials, an additional phase 3 trial, and a phase 2 trial. The trials were conducted under similar conditions with respect to design characteristics, such as target population, background therapy and treatment duration. All trials included efficacy assessments following insulin-induced hypoglycemia and showed consistent efficacy results across trials. The primary endpoint was time to plasma glucose (PG) recovery, defined as first PG increase ≥ 20 mg/dL after treatment initiation without need for rescue intravenous glucose. A total of 220 participants were exposed to dasiglucagon 0.6 mg across trials. Results of the integrated analysis are shown as a Forest plot of median time to PG recovery for dasiglucagon, including 95% confidence intervals by subgroup. In conclusion, the results showed that the efficacy of dasiglucagon was highly consistent across subgroups, with a median time to recovery from insulin-induced hypoglycemia of 10 minutes in most groups. Disclosure: T. Battelino: Advisory Panel; Self; Eli Lilly and Company, Medtronic, Sanofi, Research Support; Self; European Union, National Institute of Diabetes and Digestive and Kidney Diseases, Novartis Pharmaceuticals Corporation, Novo Nordisk, Sanofi, Slovenian Research Agency, Zealand Pharma A/S, Speaker's Bureau; Self; Abbott Diabetes, AstraZeneca, Dexcom, Inc., Eli Lilly and Company, Medtronic, Novo Nordisk, Pfizer Inc., Roche Diabetes Care, Sanofi, Stock/Shareholder; Self; DreaMed Diabetes, Ltd. L. Dimeglio: Advisory Panel; Self; MannKind Corporation. T. Danne: Research Support; Self; Abbott Diabetes, Dexcom, Inc., Eli Lilly and Company, Medtronic, Novo Nordisk, Sanofi, Tandem Diabetes Care, Zealand Pharma A/S, Stock/Shareholder; Self; DreaMed Diabetes, Ltd. T. S. Bailey: Consultant; Self; Abbott Diabetes, LifeScan, Novo Nordisk, Sanofi, Research Support; Self; Abbott, Abbott Diabetes, Biolinq, Capillary Biomedical, Inc., Dexcom, Inc., Eli Lilly and Company, Kowa Research Institute, Inc., Lexicon Pharmaceuticals, Inc., Livongo, Medtronic, Medtrum Technologies, Novo Nordisk, REMD Biotherapeutics, Sanofi, Sanvita, Viacyte, Inc., vTv Therapeutics, Zealand Pharma A/S, Speaker's Bureau; Self; BD, Medtronic, Sanofi. R. Tehranchi: Employee; Self; Zealand Pharma A/S. L. J. Klaff: Research Support; Self; Abbott Diabetes, Dong-A ST Co. Ltd., Gan & Lee Pharmaceuticals, Lexicon Pharmaceuticals, Inc., Lilly Diabetes, Medtronic, Novo Nordisk, Oramed Pharmaceuticals, Inc., Pfizer Inc., REMD Biotherapeutics. T. Pieber: Advisory Panel; Self; ADOCIA, Arecor, AstraZeneca, Eli Lilly and Company, Novo Nordisk A/S, Sanofi, Research Support; Self; AstraZeneca, Novo Nordisk A/S. U. Hövelmann: None. L. Plum-moerschel: None. A. E. Melgaard: Employee; Self; Zealand Pharma A/S. R. Aronson: None. [ABSTRACT FROM AUTHOR]