AimsTo evaluate the long‐term safety and efficacy of a simplified basal–bolus regimen of once‐daily insulin degludec/insulin aspart (IDegAsp) with additional IAsp vs. a standard basal–bolus insulin regimen of insulin detemir (IDet) with IAsp in adults with Type 1 diabetes.MethodsThis was an open‐label trial comprising a 26‐week core phase followed by a 26‐week extension phase. Participants were randomized to IDegAsp once daily at the main meal and IAsp at remaining meals (IDegAsp+IAsp), or IDet (once or twice daily) and IAsp at all meals (IDet+IAsp). Insulins were titrated to target plasma glucose of < 5 mmol/l (< 90 mg/dl) at pre‐breakfast (IDegAsp and IDet) and at pre‐meal (IAsp).ResultsAfter 52 weeks, the overall confirmed hypoglycaemia rate was 31.8 episodes/patient‐years of exposure (PYE) with IDegAsp+Asp and 36.7 episodes/PYE with IDet+IAsp, and the rate of nocturnal confirmed hypoglycaemia was significantly lower with IDegAsp+Asp than with IDet+IAsp (3.1 vs. 5.4 episodes/PYE, respectively; P < 0.05). Adverse event rates were comparable between groups. Mean HbA1c decreased from baseline by 0.7% (IDegAsp+IAsp) and 0.6% (IDet+IAsp), achieving 60 or 61 mmol/mol (7.6% or 7.7%, respectively), at Week 52. The mean total daily insulin dose was lower with IDegAsp+IAsp than with IDet+IAsp (ratio: 0.87; 95% CI 0.79–0.95; P = 0.0026).ConclusionsOnce‐daily treatment with IDegAsp and IAsp as bolus insulin for remaining meals was associated with significantly lower risk of nocturnal confirmed hypoglycaemia, improved glycaemic control and showed non‐inferiority compared with IDet+IAsp, the standard of care in Type 1 diabetes.

Objective: The purpose of this study was to determine if the International Hypoglycemia Study Group (IHSG) Level 2 low glucose definition can identify clinically relevant hypoglycemia in clinical trials and offer value as an endpoint for future trials. Research design and methods: A post hoc analysis of the SWITCH (SWITCH 1: n=501, type 1 diabetes; SWITCH 2: n=721, type 2 diabetes) and DEVOTE (n=7637, type 2 diabetes) trials utilizing the IHSG low glucose definitions. Patients in all trials were randomized to either insulin degludec (degludec) or insulin glargine 100 units/mL (glargine U100). In the main analysis, the following definitions were compared: 1) ADA 2005 (plasma glucose [PG] confirmed ≤3.9 mmol/L with symptoms); 2) IHSG Level 2 (glucose confirmed <3.0 mmol/L). Results: In SWITCH 2, the estimated rate ratios of hypoglycemic events indicated increasing differences between treatments with decreasing PG levels until 3.0 mmol/L, following which no additional treatment differences were observed. In SWITCH 2, the IHSG Level 2 definition produced a rate ratio that was lower than the ADA 2005 definition. Similar results were observed for the SWITCH 1 trial. Conclusions: The IHSG Level 2 definition was validated in a series of clinical trials, demonstrating its ability to discriminate between basal insulins. This definition is therefore recommended to be uniformly adopted by regulatory bodies and used in future clinical trials.

Insulin degludec/insulin aspart (IDegAsp) is a soluble coformulation of long-acting insulin degludec and short-acting insulin aspart. This open-label, Phase 1 study aimed to determine the pharmacodynamic and pharmacokinetic properties of IDegAsp in children (6-11 yr), adolescents (12-17 yr), and adults (18-65 yr) with type 1 diabetes mellitus (T1DM). Thirty-eight subjects received single subcutaneous IDegAsp dosing (0.5 U/kg) immediately before a standardized liquid meal (17.3 g carbohydrates/100 mL; adjusted for body weight) followed by plasma glucose (PG) and pharmacokinetic blood sampling for 36 and 57 h, respectively. There were no apparent differences between age groups in PG lowering effect (AUC ), maximum PG excursion (ΔPG ), or maximum PG concentration (PG ) after the standardized meal. Estimated ratios (ERs) for total exposure (AUC ) and maximum concentration (C ) of IAsp in IDegAsp were children/adults, 1.69 (95% confidence interval, CI: 1.02; 2.80) and 1.66 (95% CI: 1.10; 2.51); adolescents/adults, 1.14 (95% CI: 0.76; 1.69) and 1.16 (95% CI: 0.84; 1.61). ERs for total exposure (AUC ) and maximum concentration (C ) of IDeg in IDegAsp were children/adults, 1.42 (95% CI: 0.94; 2.16) and 1.38 (95% CI: 1.09; 1.76); adolescents/adults, 1.23 (95% CI: 0.96; 1.58) and 1.16 (95% CI: 0.95; 1.42). IDegAsp was well tolerated across age groups. The fast onset of prandial coverage of IAsp in IDegAsp and the ultra-long pharmacokinetic properties of IDeg in IDegAsp were preserved in children and adolescents. Exposure to IAsp and IDeg seemed to be higher in children vs. adults, but no differences were observed in PG lowering effect. IDegAsp could be an alternative treatment option in children and adolescents with T1DM.

Aim: To evaluate 26 weeks of liraglutide treatment in type 1 diabetes (T1D) by subgroups in the ADJUNCT ONE and ADJUNCT TWO trials.Materials and Methods: ADJUNCT ONE and ADJUNCT TWO were randomized controlled phase 3 trials in 1398 and 835 participants with T1D treated with liraglutide (1.8, 1.2, or 0.6 mg) or placebo (adjuncts to insulin). This post hoc analysis evaluated treatment effects by subgroups: HbA1c (< or ≥8.5%), body mass index (BMI; < or ≥27 kg/m 2 ), and insulin regimen (basal bolus or continuous subcutaneous insulin infusion). Results:In both trials at week 26, reductions in HbA1c, body weight, and daily insulin dose did not differ significantly (P > .05) by baseline HbA1c or BMI. Risk of clinically significant hypoglycaemia or hyperglycaemia with ketosis did not differ significantly (P > .05) by baseline HbA1c, BMI, or insulin regimen. At week 26 in ADJUNCT ONE, these risks did not differ (P > .05) between treatment groups. Placebo-adjusted reductions in HbA1c, body weight, and insulin dose (À0.30%-points, À5.0 kg, and À12%, respectively, with liraglutide 1.8 mg), were significant (P < .05), greater than at week 52, and similar to those in ADJUNCT TWO (À0.35%, À4.8 kg, and À10%, respectively, with liraglutide 1.8 mg). Conclusions:In ADJUNCT ONE and ADJUNCT TWO, the efficacy and glycaemic safety of liraglutide did not depend on subgroups, leaving residual beta-cell function as the only identified variable impacting the effect of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in T1D. These findings support a role for GLP-1 RAs as adjuncts to insulin in T1D, warranting further study.

Introduction: DUAL II Japan (NCT02911948) was a 26-week, phase 3a randomized, treat-totarget trial which compared the efficacy and safety of IDegLira with degludec in 210 Japanese patients with type 2 diabetes (T2D) uncontrolled on premixed or basal insulin therapy. The DUAL II Japan trial presented the opportunity for a post hoc analysis to examine the safety and efficacy of switching patients from a premixed regimen (containing both basal and bolus insulin components) to IDegLira. Methods: Patients from DUAL II Japan were stratified according to prior insulin regimen (premixed or basal insulin). The following endpoints were assessed in this post hoc analysis by pre-trial insulin regimen: change in HbA 1c , body weight, daily total insulin dose, nine-point self-measured blood glucose, and severe or blood glucose-confirmed hypoglycemia (defined as severe or plasma glucose less than 56 mg/dL). Results: This post hoc analysis included 39 patients who switched from premixed insulin to IDegLira. The treatment effect in this population was independent of insulin type at baseline (premixed or basal; interaction test, P = 0.2535). In patients switching from premixed insulin to IDegLira, mean [standard deviation (SD)] HbA 1c was 8.26% (0.73) at baseline and 6.68% (0.93) at week 26. Mean (SD) body weight was reduced by 1.5 (2.9) kg. At week 26, daily insulin dose was 34.2 dose steps. After 26 weeks, the mean prandial increment was smaller at all meals with IDegLira irrespective of pre-trial insulin regimen. Rate of hypoglycemic events was 2.59 events/patient-year of exposure over the 26 weeks. Conclusion: This post hoc study is the first to evaluate the switch from premixed insulin to IDegLira in patients with uncontrolled T2D. IDegLira initiation resulted in improved HbA 1c Enhanced Digital Features To view enhanced digital features for this article go to https://doi.org/10.6084/ m9.figshare.10260689.