Pharmacokinetic and pharmacodynamic bioequivalence of Gan & Lee insulin analogues aspart (rapilin®), lispro (prandilin®) and glargine (basalin®) with EU- und US-sourced reference insulins.

AIM: For the successful approval and clinical prescription of insulin biosimilars, it is essential to show pharmacokinetic (PK) and pharmacodynamic (PD) bioequivalence to the respective reference products sourced from the European Union and the United States. METHODS: Three phase 1, randomized, double-blind, three-period crossover trials compared single doses of the proposed biosimilar insulin analogues aspart (GL-Asp, n = 36), lispro (GL-Lis, n = 38) and glargine (GL-Gla, n = 113), all manufactured by Gan & Lee pharmaceuticals, to the respective EU- and US-reference products in healthy male participants (GL-Asp and GL-Lis) or people with type 1 diabetes (GL-Gla). Study participants received 0.2 U/kg (aspart and lispro) or 0.5 U/kg (glargine) of each treatment under automated euglycaemic clamp conditions. The clamp duration was 12 h (aspart and lispro) or 30 h (glargine). Primary PK endpoints were the total area under the PK curves (AUCins.total ) and maximum insulin concentrations (Cins.max ). Primary PD endpoints were the total area under the glucose infusion rate curve (AUCGIR.total ) and maximum glucose infusion rate (GIRmax ). RESULTS: Bioequivalence to both EU- and US-reference products were shown for all three GL insulins. Least squares mean ratios for the primary PK/PD endpoints were close to 100%, and both 90% and 95% confidence intervals were within 80%-125% in all three studies. There were no noticeable differences in the safety profiles between test and reference insulins, and no serious adverse events were reported for the GL insulins. CONCLUSION: GL-Asp, GL-Lis and GL-Gla are bioequivalent to their EU- and US-reference products.

Bioequivalence of Reference and Biosimilar Preparations of Premixed Biphasic Insulin Aspart: A Comparative Clamp Study.

Biphasic insulin aspart 30 is a premixed formulation containing a soluble fraction of insulin aspart (30%) and a protamine-crystallized fraction (70%) that was developed to combine the rapid-acting and prolonged advantages of commercially available insulins. The aim of this bioequivalence study was to compare the pharmacokinetics (PKs) of GP-bi-asp and Novo-bi-asp, and evaluate the pharmacodynamic (PD) properties as well as the safety of these drugs in the hyperinsulinemic euglycemic clamp (HEC) procedure. This was a phase 1, randomized, double-blind, 2-sequence, 2-period crossover study. Thirty-four male volunteers who met the inclusion criteria underwent the HEC procedure following a single subcutaneous injection of 0.4 IU/kg of either GP-bi-asp or Novo-bi-asp in the abdomen. After the treatment, the subjects' plasma glucose levels were monitored for 24 hours and the glucose infusion rate (GIR) was adjusted to maintain the target blood glucose level. The PD parameters were calculated using GIR values. Insulin aspart concentrations were measured in blood plasma using validated ELISA assays to evaluate the PK parameters of the investigated drugs. The 90% confidence intervals for the geometric mean ratios of PK (Cins and AUCins-T ) parameters of Gp-bi-asp and Novo-bi-asp were close to 100% and within the 80%-125% limits for establishing bioequivalence. The safety profiles of both drugs were also comparable.

Efficacy of switching from basal-bolus insulin therapy to twice-daily insulin degludec/insulin aspart co-formulation plus insulin aspart in patients with poorly controlled type 2 diabetes.

OBJECTIVE: The aim of this study was to evaluate the efficacy of twice-daily (BID) insulin degludec/insulin aspart (IDegAsp) co-formulation + once-daily (OD) bolus insulin aspart (IAsp) injection (IDegAsp BID-Plus) as simplified intensive insulin therapy in patients with poorly controlled type 2 diabetes mellitus (T2DM) with basal-bolus insulin therapy (BBIT). PATIENTS AND METHODS: The retrospective study included 155 patients who switched from BBIT to IDegAsp BID-Plus. After the initiation of the treatment, 73 patients continued regular follow-up and insulin doses, number of injections, hemoglobin A1c (HbA1c) levels, and other parameters were recorded from their files at baseline, 24, and 52 weeks. RESULTS: The mean age of the study population was 54.3±10.2 years, the duration of T2DM was 9.7±5.7 years, fasting plasma glucose (FPG) was 252.7±66.7 mg/dl, and HbA1c levels were 10.5±1.5%. Among the included patients, 15 patients received five injections, 51 patients received four injections, and 7 patients received three injections per day. There was a significant decrease in HbA1c (respectively; 10.46±1.54%, 7.97±1.24%, 7.98±1.23%, baseline and 6th-month p<0.001, baseline and 12th-month p<0.001), FPG (respectively; 251.6±66.5 mg/dl, 136.1±34.7 mg/dl, 125.4±67.0  mg/dl, baseline and 6th-month p<0.001, baseline and 12th-month p<0.001) and daily dose of insulin (respectively; 102.9±29.0 Unit, 73.2±18.2 U,  63.7±20.3 Unit, baseline and 6th-month p<0.001, baseline and 12th-month p<0.001) at the end of week 24 and 52. CONCLUSIONS: Based on real-world data, this study demonstrated that IDegAsp BID-Plus treatment provides rapid and sustainable blood glucose control with lower insulin doses and fewer injections than previous intensive insulin therapy.

Real-world study of ethnic differences in glycaemic control and clinical characteristics among insulin-naïve people with type 2 diabetes initiating biphasic insulin aspart 30/70: A retrospective, observational cohort study in England.

AIMS: This study investigated the ethnic differences in glycaemic levels and clinical characteristics among insulin-naïve people with type 2 diabetes (T2D) initiating biphasic insulin aspart 30/70 (BIAsp 30) in primary practice in England. MATERIALS AND METHODS: Retrospective, observational cohort study utilizing data from the Clinical Practice Research Datalink Aurum database, including White, South Asian, Black and Chinese insulin-naïve adults with T2D, initiating BIAsp 30. The index date was that of the first BIAsp 30 prescription. Endpoints included change in glycated haemoglobin (HbA1c) and body mass index (BMI) 6 months post index. RESULTS: In total, 11 186 eligible people were selected (9443 White, 1116 South Asian, 594 Black, 33 Chinese). HbA1c decreased across all subgroups 6 months post index: estimated %-point changes [95% CI of -2.32 (-2.36; -2.28) (White); -1.91 (-2.02; -1.80) (South Asian); -2.55 (-2.69; -2.40) (Black); and -2.64 (-3.24; -2.04) (Chinese)]. The BMI increased modestly 6 months post index in all subgroups [estimated changes (95% CI) kg/m2 : White, 0.92 (0.86; 0.99); South Asian, 0.60 (0.41; 0.78); Black, 1.41 (1.16; 1.65); and Chinese, 0.32 (-0.67; 1.30)]. In the overall population, hypoglycaemic event rates increased from 0.92 events per 100 patient-years before the index to 3.37 events per 100 patient-years post index; event numbers were too low to be analysed by subgroup. CONCLUSIONS: Among insulin-naïve people with T2D initiating BIAsp 30, clinically meaningful HbA1c reductions in all ethnicities were observed. Some ethnic groups had larger reductions than others, but differences were small. In all groups, small BMI increases were seen, with small differences observed between groups. Hypoglycaemia rates were low.

Initiating or Switching to Insulin Degludec/Insulin Aspart in Adults with Type 2 Diabetes in Malaysia: Results from a Prospective, Non-interventional Real-World Study.

Objectives: Insulin degludec (IDeg)/insulin aspart (IAsp; IDegAsp) is a co-formulation of 70% IDeg and 30% IAsp. According to several randomized controlled trials, IDegAsp is effective and safe for patients with type 2 diabetes mellitus (T2DM). A subgroup analysis of the ARISE study was conducted to explore the safety and efficacy of IDegAsp among Malaysian patients with T2DM in real-world settings. Methodology: ARISE, an open-label, multicenter, non-interventional, prospective study was conducted between August 2019 and December 2020. Adult Malaysian patients with T2DM who were enrolled from 14 sites received IDegAsp as per the local label for 26 weeks. The primary endpoint was change in glycated hemoglobin (HbA1c) levels from baseline to end of study (EOS). Results: Of the 182 patients included in the full analysis set, 159 (87.4%) completed the study. From baseline to EOS, HbA1c (estimated difference [ED]: -1.3% [95% CI: -1.61 to -0.90]) and fasting plasma glucose levels (ED: -1.8 mmol/L [95% CI: -2.49 to -1.13]) were significantly reduced (p<0.0001). The patient-reported reduced hypoglycemic episodes (overall and nocturnal) during treatment. Overall, 37 adverse events were observed in 23 (12.6%) patients. Conclusion: Switching or initiating IDegAsp treatment resulted in significant improvements in glycemic control and a reduction in hypoglycemic episodes.

A co-formulation of pramlintide and insulin A21G (ADO09) improves postprandial glucose and short-term control of mean glucose, time in range, and body weight versus insulin aspart in adults with type 1 diabetes.

AIM: Pramlintide improves postprandial glucose but requires additional injections. We investigated the pharmacokinetics/pharmacodynamics, efficacy and safety of ADO09, pramlintide/insulin A21G co-formulation, in type 1 diabetes (T1D). MATERIALS AND METHODS: This double-blinded, randomized, two-period cross-over study compared prandial administration of ADO09 or insulin aspart over 24 days in T1D using either ≤40 U bolus insulin per day [low-dose group (LD), n = 28] or 40-75 U [high-dose group (HD), n = 16]. Glycaemic responses through continuous glucose monitoring, and pharmacokinetics/pharmacodynamics profiles following mixed-meal-tolerance tests were evaluated at baseline and at the end of treatment. RESULTS: Glucose increments from 0 to 4 h after mixed-meal-tolerance test (primary endpoint) were 39% (not statistically significantly) lower with ADO09 in the low-dose group and 69% lower in the high-dose group. Mean continuous glucose monitoring glucose during ambulatory treatment was lower with ADO09 than with aspart (LD: -8.2 ± 7.9 mg/dl, p = .0001; HD: -7.0 ± 10 mg/ml, p = .0127), and time-in-range (70-180 mg/dl) improved (LD: +4%, p = .0134; HD: +4%, p = .0432). Body weight declined significantly with ADO09 (LD: -0.8 kg; HD: -1.6 kg). Hypoglycaemic events were slightly more frequent with ADO09 versus aspart (LD: 142 vs. 115; HD: 96 vs. 79). Gastrointestinal events occurred more frequently with ADO09 but were generally transient, and no other safety signals were identified. CONCLUSIONS: In comparison with aspart, ADO09 was well tolerated and effective in T1D across a wide range of dosage, significantly improving the average blood glucose level and body weight during 24 days of ambulatory treatment. Meal test profiles confirmed improvement of glycaemic patterns and other responses with ADO09.

Pharmacokinetics and Pharmacodynamics of a Novel U500 Insulin Aspart Formulation: A Randomized, Double-Blind, Crossover Study in People With Type 1 Diabetes.

OBJECTIVE: To evaluate the pharmacokinetics, pharmacodynamics, and safety of a novel U500 insulin aspart formulation (AT278 U500) compared with insulin aspart (IAsp U100). RESEARCH DESIGN AND METHODS: This single-center, randomized, double-blind study was conducted in 38 men with type 1 diabetes (body weight ≤100 kg and total insulin dose <1.2 units/kg/day). Participants received a single dose of either AT278 U500 or IAsp U100 (0.3 units/kg s.c.) in a crossover design, followed by an 8-h euglycemic clamp in the absence of basal insulin. RESULTS: With AT278 U500, onset of appearance in serum was 6 min earlier (P < 0.0001) and reached 50% of maximum concentration 23 min faster (P < 0.0001). Insulin exposure with AT278 U500 was 4.0-fold higher within the first 30 min (95% CI 3.29, 4.90), 1.5-fold higher within the first 60 min (95% CI 1.35, 1.76), and statistically superior up to 90 min postdose (P < 0.05). With AT278 U500, onset of action was 10 min earlier (P < 0.0001) and reached 50% of maximum glucose infusion rate 20 min faster (P < 0.0001). The glucose-lowering effect with AT278 U500 was 8.9-fold higher within the first 30 min (95% CI 5.96, 17.46), 2.4-fold higher within the first 60 min (95% CI 1.92, 3.22), and statistically superior up to 2 h postdose (P < 0.0001). Overall insulin exposure and glucose-lowering effect were comparable. No significant safety findings were observed. CONCLUSIONS: AT278 U500 offers rapid-acting characteristics in a reduced dose volume, with accelerated absorption and onset of action compared with IAsp U100 in the studied population.

Once-weekly semaglutide versus insulin aspart for the treatment of type 2 diabetes in the UK: A long-term cost-effectiveness analysis based on SUSTAIN 11.

AIM: To evaluate the long-term cost-effectiveness of once-weekly semaglutide 1 mg versus insulin aspart in the UK. MATERIALS AND METHODS: Long-term outcomes were projected over patients' lifetimes using the IQVIA CORE Diabetes Model (vers 9.0). SUSTAIN 11 was used to inform baseline cohort characteristics and treatment effects. Patients were modelled to receive once-weekly semaglutide plus basal insulin for 3 years before intensifying to basal-bolus insulin, compared with basal-bolus insulin for lifetimes in the aspart arm. Costs were accounted from a healthcare payer perspective in the UK, expressed in 2021 pounds sterling (GBP). RESULTS: Once-weekly semaglutide 1 mg was associated with improvements in quality-adjusted life expectancy of 0.18 quality-adjusted life years (QALYs) versus insulin aspart, due to a reduced incidence and delayed time to onset of diabetes-related complications. Direct costs were estimated to be GBP 800 higher with semaglutide, with higher treatment costs partially offset by cost savings from avoidance of diabetes-related complications. Once-weekly semaglutide 1 mg was therefore associated with an incremental cost-effectiveness ratio of GBP 4457 per QALY gained versus insulin aspart. CONCLUSIONS: Based on a willingness-to-pay threshold of GBP 20 000 per QALY gained, once-weekly semaglutide 1 mg was projected to be highly cost-effective versus insulin aspart for the treatment of type 2 diabetes in the UK.

Efficacy and Safety of Faster Aspart in Comparison to Insulin Aspart Among Indian Women with Gestational Diabetes.

AIMS: The present study aimed to compare the pregnancy outcomes, efficacy, and safety of faster aspart with insulin aspart among Indian women with gestational diabetes. BACKGROUND: In several countries, fast-acting insulin aspart (faster aspart) has been approved for use in pregnancy. There is a lack of data related to maternal glycemic control and fetal and perinatal outcomes with faster aspart in gestational diabetes among the Indian population. OBJECTIVE: To compare and evaluate the efficacy and safety of faster aspart and insulin aspart in the management of gestational diabetes. METHODS: This retrospective study evaluated the medical records of 60 pregnant women diagnosed with gestational diabetes and managed with faster aspart or insulin aspart at a tertiary care center, between March 2019 and September 2020. Self-monitored blood glucose levels recorded at 4 timepoints (fasting, and 1 hour post breakfast, lunch, and dinner) during 6 consecutive days any time before delivery were analyzed. Pregnancy and neonatal outcomes across both groups were compared. RESULTS: The mean postprandial glucose value following dinner was significantly lesser in the faster aspart group compared to the insulin aspart group (123.61 ± 2.52 mg/dL vs. 125.87 ± 2.98 mg/dL, respectively; p=0.0024). Women in the faster aspart group had significantly lower glycemic variability (fluctuations). Lesser number of hypoglycemic events were noted in the faster aspart group (10 vs. 20; p=0.0595). CONCLUSION: Faster aspart was associated with better glycemic control compared to insulin aspart among women with gestational diabetes. Further large-scale studies are needed to validate the outcomes.

The Experience of our Center in Patients Undergoing Insulin Degludec/ Insulin Aspart Co-formulation Therapy.

AIM: A co-formulation containing insulin degludec and insulin aspart (IDegAsp) is available for the treatment of diabetes in Turkey. We aimed to evaluate the clinical results of switching to IDegAsp treatment for Type 2 diabetes. METHODS: A total of 217 patients with type 2 diabetes treated with IDegAsp and having follow-up data were included. The patients were divided into 3 groups. Group 1 switched from basal insulin to IDegAsp, group 2 switched from twice-daily premixed insulin regimen to IDegAsp, and group 3 switched from intensive and thrice-daily premixed insulin regimen to IDegAsp. Groups were evaluated in terms of changes in insulin dose, the number of injections, and changes in HbA1c. RESULTS: The mean follow-up period was 7.5 ± 4.4 months. The mean age was 62.8 ± 12.9 years. The mean duration of diabetes was 15.3 ± 8 years. There was a significant decrease in HbA1c and glucose (p < 0.0001 and p < 0.0001, respectively). HbA1c was significantly reduced in group 1 (p < 0.0001) while insulin dose and the number of injections increased (p < 0.0001 and p < 0.0001, respectively). HbA1c, insulin dose, and the number of injections in group 2 and group 3 (p = 0.001, p = 0.002, p < 0.0001, respectively, and p < 0.0001, p = 0.043, p < 0.0001, respectively) were significantly reduced. CONCLUSION: This study includes real-life experiences involving a remarkable number of patients in the literature. IDegAsp treatment provided effective blood glucose regulation and caused a significant decrease in the insulin dose and the number of injections, resulting in increased quality of life among those who had to receive twice or more insulin injections.

Efficacy and safety of Tregopil, a novel, ultra-rapid acting oral prandial insulin analog, as part of a basal-bolus regimen in type 2 diabetes: a randomized, active-controlled phase 2/3 study.

BACKGROUND: Efficacy and safety of ultra-rapid acting oral prandial insulin Tregopil was compared with insulin aspart (IAsp) in patients with type 2 diabetes (T2D) on insulin glargine and metformin. RESEARCH DESIGN AND METHODS: In this open-label, active-controlled trial, patients with T2D, HbA1c ≥7%-≤9% and 2-h postprandial glucose (PPG) ≥180 mg/dL were randomized 1:1:1 to Tregopil (30 mg, n = 30; 45 mg, n = 31) and IAsp, n = 30. Primary outcome was change from baseline (CFB) in HbA1c at week 24. Secondary outcomes included PPG excursion (PPGE) and PPG assessed from standardized test meal (STM) and 9-point self-monitored blood glucose. RESULTS: The observed mean HbA1c did not improve at week 24 in Tregopil groups (30 mg [0.15%], 45 mg [0.22%] vs. a reduction in IAsp group [-0.77%]). Combined Tregopil group showed better 1-h PPGE control versus IAsp following STM (CFB, estimated treatment difference, 95% CI, -45.33 mg/dL [-71.91, -18.75], p = 0.001) and 1-h PPG trended toward better control. Tregopil showed lower PPGE at 15 min versus IAsp. Clinically significant hypoglycemia was lower with Tregopil versus. IAsp (rate ratio: 0.69). CONCLUSIONS: Tregopil demonstrated an ultrafast, short-duration prandial profile with good safety. While Tregopil's early postprandial effects were comparable to IAsp, its late postprandial effects were inferior. TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT03430856).

Immunogenicity, Efficacy, and Safety of Biosimilar Insulin Aspart (MYL-1601D) Compared with Originator Insulin Aspart (Novolog®) in Patients with Type 1 Diabetes After 24 Weeks: A Randomized Open-Label Study.

BACKGROUND: MYL-1601D is a proposed biosimilar of originator insulin aspart, Novolog®/NovoRapid® (Ref-InsAsp-US/Ref-InsAsp-EU). OBJECTIVE: This study assessed the immunogenicity, efficacy, and safety of MYL-1601D with Ref-InsAsp-US in patients with type 1 diabetes mellitus (T1D). METHODS: This was a 24-week, open-label, randomized, phase III study. Patients were randomized 1:1 to mealtime MYL-1601D or Ref-InsAsp-US in combination with insulin glargine (Lantus SoloSTAR®) once daily. The treatment-emergent antibody response (TEAR) rate (defined as patients who were anti-insulin antibody [AIA] negative at baseline and became positive at any timepoint post-baseline or patients who were AIA positive at baseline and demonstrated a 4-fold increase in titer values at any timepoint post-baseline) was the primary endpoint. The study also compared the change from baseline in glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), prandial, basal, and total daily insulin, 7-point self-monitored blood glucose (SMBG) profiles, immunogenicity, and adverse events (AEs) including hypoglycemia. RESULTS: In total, 478 patients were included in the intent-to-treat analysis (MYL-1601D: 238; Ref-InsAsp-US: 240) set. The 90% confidence interval (CI) for the primary endpoint was within the pre-defined equivalence margin of ±11.7% and the treatment differences (SE) in TEAR responders between the treatment groups was - 2.86 (4.16) with 90% CI - 9.71 to 3.99. The mean (SD) changes from baseline for HbA1c, FPG, and insulin dosages were similar in both groups at week 24. The safety profiles including hypoglycemia, immune-related events, AEs, and other reported variables were similar between the treatment groups at week 24. CONCLUSIONS: MYL-1601D demonstrated similar immunogenicity, efficacy, and safety profiles to Ref-InsAsp-US in patients with T1D over 24 weeks. CLINICAL TRIAL REGISTRATION CLINICALTRIALS.GOV: NCT03760068.

Hypoglycaemia events with iGlarLixi versus premix biphasic insulin aspart 30 (BIAsp 30) in people with type 2 diabetes advancing from basal insulin: An analysis of the SoliMix trial.

AIMS: To explore details of the incidence and rates of daytime and nocturnal hypoglycaemia, levels of hypoglycaemia, and relationship to glycated haemoglobin (HbA1c), when comparing iGlarLixi versus premixed biphasic insulin aspart 30 (BIAsp 30) in the SoliMix randomized controlled trial. MATERIALS AND METHODS: This exploratory analysis of SoliMix used logistic regression and negative binomial regression analyses to assess between-treatment differences in the incidence and rates of hypoglycaemia by time of day. A negative binomial model was used to derive estimated annualized hypoglycaemia rates as a function of HbA1c. RESULTS: iGlarLixi was associated with lower incidence and rates of American Diabetes Association Level 2 (<54 mg/dL [<3.0 mmol/L]) hypoglycaemia during both night and day versus BIAsp 30. Incidence and rates of Level 1 (<70 to ≥54 mg/dL [<3.9 to ≥3.0 mmol/L]) hypoglycaemia were also mostly shown to be reduced with iGlarLixi versus BIAsp 30. Severe (Level 3) events were too few for analysis (n = 3). iGlarLixi was associated with lower modelled event rates of Level 2 and Level 1 hypoglycaemia over a wide range of HbA1c levels versus BIAsp 30. CONCLUSIONS: These results show that the lower HbA1c levels and weight benefit seen with iGlarLixi versus premixed BIAsp 30 in people with type 2 diabetes advancing their basal insulin therapy in the SoliMix trial are also accompanied by a lower risk of hypoglycaemia at any time of day and across a broad range of HbA1c levels.

Multicenter, Randomized Trial of a Bionic Pancreas in Type 1 Diabetes.

BACKGROUND: Currently available semiautomated insulin-delivery systems require individualized insulin regimens for the initialization of therapy and meal doses based on carbohydrate counting for routine operation. In contrast, the bionic pancreas is initialized only on the basis of body weight, makes all dose decisions and delivers insulin autonomously, and uses meal announcements without carbohydrate counting. METHODS: In this 13-week, multicenter, randomized trial, we randomly assigned in a 2:1 ratio persons at least 6 years of age with type 1 diabetes either to receive bionic pancreas treatment with insulin aspart or insulin lispro or to receive standard care (defined as any insulin-delivery method with unblinded, real-time continuous glucose monitoring). The primary outcome was the glycated hemoglobin level at 13 weeks. The key secondary outcome was the percentage of time that the glucose level as assessed by continuous glucose monitoring was below 54 mg per deciliter; the prespecified noninferiority limit for this outcome was 1 percentage point. Safety was also assessed. RESULTS: A total of 219 participants 6 to 79 years of age were assigned to the bionic-pancreas group, and 107 to the standard-care group. The glycated hemoglobin level decreased from 7.9% to 7.3% in the bionic-pancreas group and did not change (was at 7.7% at both time points) in the standard-care group (mean adjusted difference at 13 weeks, -0.5 percentage points; 95% confidence interval [CI], -0.6 to -0.3; P<0.001). The percentage of time that the glucose level as assessed by continuous glucose monitoring was below 54 mg per deciliter did not differ significantly between the two groups (13-week adjusted difference, 0.0 percentage points; 95% CI, -0.1 to 0.04; P<0.001 for noninferiority). The rate of severe hypoglycemia was 17.7 events per 100 participant-years in the bionic-pancreas group and 10.8 events per 100 participant-years in the standard-care group (P = 0.39). No episodes of diabetic ketoacidosis occurred in either group. CONCLUSIONS: In this 13-week, randomized trial involving adults and children with type 1 diabetes, use of a bionic pancreas was associated with a greater reduction than standard care in the glycated hemoglobin level. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; ClinicalTrials.gov number, NCT04200313.).

A comparison of the rapid-acting insulin analogue glulisine with lispro and aspart for the pump treatment of patients with type 1 diabetes.

AIMS: (1) To describe the population of patients with type 1 diabetes (T1DM) using the rapid-acting insulin analogue glulisine versus lispro and aspart during continuous subcutaneous insulin infusion (CSII); (2) to describe insulin relative effectiveness based on hemoglobin A1c (HbA1c), fasting blood glucose (FBG) and dose; (3) to determine rates of hyperglycemia, hypoglycemia, and diabetic ketoacidosis (DKA). METHODS: The analysis used March 2021 data from the Diabetes-Patienten-Verlaufsdokumentation registry, which contains data of 618,903 patients with diabetes. Patients were propensity-matched by age, sex, and diabetes duration. RESULTS: Overall, 42,736 patients of any age were eligible for analysis based on insulin pump usage with either glulisine (N = 707) or lispro/aspart (N = 42,029) between 2004 and 2020. Patients receiving glulisine were older (median 20.0 vs. 16.2 years), equally often male (47.2% vs. 47.8%) and had a longer diabetes duration (median 9.4 vs. 7.4 years). After propensity score matching, 707 pairs remained (total N = 1414). Patient characteristics between groups were similar. Achieved HbA1c values were also comparable: 8.04%, 64 mmol/mol versus 7.96%, 63 mmol/mol for glulisine and lispro/aspart [LS mean difference 0.08 (95%CI - 0.08, 0.25)]. FBG was 9.37 mmol/L (168.9 mg/dL) and 9.58 mmol/L (172.6 mg/dL) in the glulisine and lispro/aspart groups [LS mean diff. - 0.21; (95%CI - 1.13, 0.72)]. Total daily insulin doses and prandial to total insulin ratios were also similar. Glulisine group patients had higher rates of lipodystrophy (0.85% vs. 0.71%) (LS mean diff. 0.18 [95% CI - 1.01, 1.38]) and non-severe DKA (3.11% vs. 0.57%; p = 0.002). Fewer patients in the glulisine group had severe hypoglycemic events (7.66 vs. 9.09; p = 0.333) and severe ketoacidosis events (0.57% vs. 1.56%; p = 0.082) but more had hypoglycemic coma events (p = 0.773), although the differences were not statistically significant. CONCLUSIONS: Insulin glulisine had comparable glucose control to lispro/aspart. The use of glulisine was less frequent in the present analysis compared to the previous trials.

Comparative efficacy and safety of two insulin aspart formulations (Rapilin and NovoRapid) when combined with metformin, for patients with diabetes mellitus: a multicenter, randomized, open-label, controlled clinical trial.

OBJECTIVE: This phase 3 confirmatory diabetes mellitus treatment study compared the safety and efficacy of Rapilin and NovoRapid insulin asparts in combination with metformin. METHODS: This 24-week, open-label, randomized, active-controlled, noninferiority phase 3 confirmatory study conducted across centers in China aimed to enroll patients with type 2 diabetes mellitus and blood sugar glucose inadequately controlled by oral antidiabetic drugs. Randomized patients received subcutaneous mealtime Rapilin or NovoRapid (3:1) injections, with metformin. The primary objectives were to demonstrate noninferiority (margin of 0.4%) in HbA1c change from baseline and compare safety profiles of Rapilin versus NovoRapid after 24 weeks. Secondary outcomes included 2-h postprandial plasma glucose (PPG), fasting plasma glucose (FPG), and patients achieving HbA1c <7.0% and ≤6.5%. RESULTS: 590 patients with type 2 diabetes mellitus were randomized to Rapilin (n = 441) and NovoRapid (n = 149) groups. After 24 weeks, the mean HbA1c change from baseline was -2.20% (Rapilin) and -2.32% (NovoRapid); the estimated treatment difference based on least-square means was 0.04% (95% CI: -0.17, 0.26), meeting the noninferiority criteria for Rapilin versus NovoRapid. Comparable improvements were reported for mean 2-hour PPG (6.14 and 6.29 mmol/L), FPG (2.02 and 1.70 mmol/L), and patients with HbA1c <7.0% (52.6% and 51.0%) and ≤6.5% (34.2% and 30.9%), in the Rapilin and NovoRapid groups, respectively, with no significant safety or immunogenicity outcome differences. CONCLUSIONS: Rapilin demonstrated non-inferior glycemic control, and matching safety and immunogenicity to NovoRapid in patients with type 2 diabetes mellitus also receiving metformin over 24 weeks. TRIAL REGISTRATION: ChiCTR20003129041.

What is the value of faster acting prandial insulin? Focus on ultra rapid lispro.

Rapid-acting insulins (RAIs) have been instrumental in the management of diabetes because of their improved postprandial glucose (PPG) control compared with regular human insulin. However, their absorption rate and time action following subcutaneous administration still falls short of the normal physiological response to meal consumption, increasing the risk of early postmeal hyperglycaemia and late postmeal hypoglycaemia. Increased demand for faster acting insulins, which can quickly control PPG excursions without increasing the risk of late hypoglycaemia, led to the development of ultra-rapid-acting insulins, including ultra-rapid lispro (URLi). URLi is a novel formulation of insulin lispro with accelerated absorption driven by two excipients: treprostinil, which increases local vasodilation, and citrate, which increases local vascular permeability. Clinical pharmacology studies consistently showed an earlier onset and shorter duration of action with URLi compared with Lispro. In a head-to-head study with Faster aspart, Aspart and Lispro, URLi was absorbed faster, provided earlier insulin action, and more closely matched physiological glucose response than the other insulins tested. URLi's unique pharmacokinetic properties increase its potential for improved PPG control beyond that achieved with RAIs. Indeed, in pivotal phase 3 trials, URLi was superior to Lispro for PPG control both at 1 and 2 hours after a meal in type 1 and type 2 diabetes with multiple daily injections, and in type 1 diabetes with continuous subcutaneous insulin infusion. This was achieved without increasing the risk of hypoglycaemia. In this review, we focus on the clinical and pharmacological evidence for URLi in the treatment of diabetes and discuss the potential benefits and considerations with URLi compared with RAIs.

Long-Term Safety and Clinical Outcomes with Insulin Degludec/Insulin Aspart Treatment in Japanese Patients with Diabetes: A Real-World, Prospective, Observational Study.

INTRODUCTION: Insulin degludec/insulin aspart (IDegAsp) provides effective glycaemic control with an acceptable safety profile in Japanese patients with diabetes in randomised clinical trials. This post-marketing surveillance study assessed long-term safety and clinical outcomes with IDegAsp in a Japanese real-world setting. METHODS: Multicentre, prospective, observational, open-label, single-arm study of Japanese patients with diabetes requiring insulin therapy, who had switched to IDegAsp at their treating physician's discretion in clinical practice. One year after initiating IDegAsp, incidence of adverse events (AEs [primary endpoint]), serious AEs, adverse drug reactions (ADRs), and severe hypoglycaemia (secondary safety endpoints) were assessed in the safety analysis set (SAS). Secondary effectiveness endpoints were change from baseline in glycated haemoglobin (HbA1c) and fasting plasma glucose (FPG) in the effectiveness analysis set (EAS). RESULTS: Overall, 1321 patients were included (SAS, n = 1321; EAS, n = 1285); 4.2% with type 1 diabetes, 95.2% with type 2 diabetes, 0.7% with other/unknown diabetes type. In total, 204 AEs were reported in 132 patients (10.0% of the SAS), at a rate [95% confidence interval (CI)] of 16.2 events/100 patient-years of exposure (PYE) [14.0; 18.4]. By preferred term, 'hypoglycaemia' was the most frequent AE (45 events in 31 patients [2.3%]; rate [95% CI] 3.6 events/100 PYE [2.5; 4.6]). Serious AEs occurred in 4.2% of patients (rate [95% CI] 5.7 events/100 PYE [4.4; 7.0]), and ADRs in 3.1% (rate [95% CI] 4.6 reactions/100 PYE [3.4; 5.8]). Six events of severe hypoglycaemia were reported in five patients (0.4%; rate [95% CI] 0.5 events/100 PYE [0.1; 0.9]). Change from baseline to 1 year was - 0.51% and - 32.1 mg/dL for HbA1c and FPG, respectively (P < 0.0001 for both). CONCLUSION: In Japanese patients with diabetes, initiation of IDegAsp in real-world clinical practice was well tolerated, with no new safety signals, and associated with improved glycaemic control after 1 year. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02821052.

[Comparison of efficacy and safety of insulin aspart injection Rishulin and NovoRapid for treatment of diabetes: a multicenter, randomized, open-labeled, controlled trial].

Objective: To compare the efficacy and safety of Tonghua Dongbao's insulin aspart injection (Rishulin) and NovoRapid (Novo Nordisk) in the treatment of diabetes. Methods: A 26-week, randomized, open-label, parallel-group, positive control drug and non-inferiority trial was conducted in 23 centers in China. A total of 563 diabetes with poor blood glucose control treated with insulin for at least 3 months before were included. The subjects were randomized(stratified block random method) into those receiving Rishulin or NovoRapid at a ratio of 3∶1. Both groups were combined with basal insulin (Lantus). The primary endpoint was the change in glycosylated hemoglobin (HbA1c) from baseline to the end of 24 weeks of treatment. Results: For full analysis set, after 24 weeks of treatment, HbA1c level of Ruishulin group decreased from (8.66±1.28)% to (7.77±1.09)% (P<0.001), and that of NovoRapid group decreased from (8.47±1.28) % to (7.65±0.97) % (P<0.001). Treatment difference in HbA1c (NovoRapid group-Ruishulin group) was -0.061% (95%CI -0.320-0.199). HbA1c<7.0% target reacing rates were 24.26% and 21.21% (P=0.456), and HbA1c<6.5% target reacing rates were 9.65% and 6.82% (P=0.310) in Ruishulin group and NovoRapid group, repectively. The standard 2 hours postprandial blood glucose (2hPG) in Ruishulin group decreased from (16.23±5.22) mmol/L to (12.65±4.57) mmol/L (P<0.001), and 2hPG in NovoRapid group decreased from (16.13±5.37) mmol/L to (11.91)±4.21) mmol/L (P<0.001). The fingertips blood glucose at 7-point of both groups exhibited varying degrees of reduction compared with those at baseline, repectively. Positive ratios of specific antibodies were 31.68% in Ruishulin group and 36.36% in NovoRapid group (P=0.320). Ratios of negative to positive were 7.43% and 10.61% (P=0.360), and ratios of positive to negative were 10.40% and 7.58% (P=0.360) in Ruishulin group and NovoRapid group, respectively. The incidence of hypoglycemia was 60.05% and 55.40% (P=0.371), and the incidence of adverse events was 76.60% and 77.70% (P=0.818) in Ruishulin group and NovoRapid group, respectively. Conclusions: Rishulin is not inferior to NovoRapid, and has shown good efficacy and safety. It can be an ideal choice for clinicians in patients with poor blood glucose control with insulin.

Pharmacokinetic and pharmacodynamic similarity between SAR341402 insulin aspart and Japan-approved NovoRapid in healthy Japanese subjects.

This study compared the pharmacokinetic and glucodynamic profiles of biosimilar SAR341402 insulin aspart to Japan-approved insulin aspart (NovoRapid) in healthy Japanese males. In this single-center, randomized, double-blind, single-dose, two-period, crossover study, subjects received 0.3 U/kg of SAR341402 or NovoRapid before undergoing a 10 h euglycemic clamp procedure. Plasma insulin aspart concentrations and blood glucose levels were measured, and glucose infusion rates (GIRs) were assessed. Primary endpoints were maximum plasma insulin aspart concentration (INS-Cmax), area under the plasma insulin concentration-time curve to the last quantifiable concentration (INS-AUClast), area under the GIR-time curve during the clamp (GIR-AUC0-10 h), and maximum GIR (GIRmax). Forty subjects were randomized with 39 completing both treatment periods. Pharmacokinetic exposure showed a mean ratio between products of 1.00 (90% confidence interval [CI] 0.94-1.05) for INS-Cmax and 1.02 (90% CI 1.00-1.04) for INS-AUClast. Glucodynamic activity showed a mean ratio between products of 1.00 (95% CI 0.93-1.06) for GIR-AUC0-10 h and 1.01 (95% CI 0.95-1.08) for GIRmax. The 90% CIs for pairwise treatment ratios were within the predefined equivalence range of 0.80-1.25. Both treatments were well tolerated. We concluded that similar pharmacokinetic exposure and glucodynamic potency were shown for SAR341402 and NovoRapid in healthy Japanese males.