Comparative physicochemical and structural characterisation studies establish high biosimilarity between BGL-ASP and reference insulin aspart.

Biosimilar insulin analogues are increasing market access for diabetic patients globally. Scientific establishment of biosimilarity is cornerstone of this key change in the medical landscape. BGL-ASP is a biosimilar insulin aspart developed by BioGenomics Limited, India. BioGenomics has considered a stepwise approach in generating the totality of evidence required to establish similarity with reference product. Insulin aspart is a recombinant rapid-acting human insulin analogue utilised in the treatment of type-1 and type-2 diabetes mellitus. The single amino acid substitution at position B28 where proline is replaced with aspartic acid results in a decreased propensity to form hexamers, thus increasing the absorption rate on subcutaneous administration compared to native insulin. In order to establish the safety and efficacy of BGL-ASP, the critical quality attributes (CQAs) of BGL-ASP are identified based on the impact created on biological activity, pharmacokinetic/pharmacodynamic (PK/PD), immunogenicity and safety. The CQAs of insulin aspart are related to product structure, purity and functionality and are characterised using a series of state-of-the-art orthogonal analytical tools. The primary protein sequence, the secondary, tertiary and quaternary structure are found to be highly similar for BGL-ASP and reference product. The product related impurities of insulin aspart and the assay content are determined using high performance liquid chromatography (HPLC) based analysis and is similar for BGL-ASP and reference insulin aspart sourced from United States of America (US), Europe Union (EU) and India. The safety, efficacy and immunogenicity of BGL-ASP is also found to be comparable with reference product and is confirmed through the clinical trials conducted as recommended by International Council for Harmonisation of Technical Requirements of Pharmaceuticals for Human Use (ICH) and European Medicines Agency (EMA) guidelines. The data encompassed in this study demonstrates that reference insulin aspart and BGL-ASP are highly similar in terms of structural, physicochemical, and biological properties, thus confirming its safety and efficacy for usage as potential alternative economical medicinal treatment for diabetes mellitus.

Study protocol for a randomised open-label clinical trial examining the safety and efficacy of the Android Artificial Pancreas System (AAPS) with advanced bolus-free features in adults with type 1 diabetes: the 'CLOSE IT' (Closed Loop Open SourcE In Type 1 diabetes) trial.

INTRODUCTION: Multiple automated insulin delivery (AID) systems have become commercially available following randomised controlled trials demonstrating benefits in people with type 1 diabetes (T1D). However, their real-world utility may be undermined by user-associated burdens, including the need to carbohydrate count and deliver manual insulin boluses. There is an important need for a 'fully automated closed loop' (FCL) AID system, without manual mealtime boluses. The (Closed Loop Open SourcE In Type 1 diabetes) trial is a randomised trial comparing an FCL AID system to the same system used as a hybrid closed loop (HCL) in people with T1D, in an outpatient setting over an extended time frame. METHODS AND ANALYSIS: Randomised, open-label, parallel, non-inferiority trial comparing the Android Artificial Pancreas System (AAPS) AID algorithm used as FCL to the same algorithm used as HCL. Seventy-five participants aged 18-70 will be randomised (1:1) to one of two treatment arms for 12 weeks: (a) FCL-participants will be advised not to bolus for meals and (b) HCL-participants will use the AAPS AID algorithm as HCL with announced meals. The primary outcome is the percentage of time in target sensor glucose range (3.9-10.0 mmol/L). Secondary outcomes include other glycaemic metrics, safety, psychosocial factors, platform performance and user dietary factors. Twenty FCL arm participants will participate in a 4-week extension phase comparing glycaemic and dietary outcomes using NovoRapid (insulin aspart) to Fiasp (insulin aspart and niacinamide). ETHICS AND DISSEMINATION: Approvals are by the Alfred Health Ethics Committee (615/22) (Australia) and Health and Disability Ethics Committees (2022 FULL 13832) (New Zealand). Each participant will provide written informed consent. Data protection and confidentiality will be ensured. Study results will be disseminated by publications, conferences and patient advocacy groups. TRIAL REGISTRATION NUMBERS: ACTRN12622001400752 and ACTRN12622001401741.

Pharmacokinetic similarity of switching SAR341402 insulin aspart biosimilar and NovoLog insulin aspart versus continuous use of NovoLog in adults with type 1 diabetes: The GEMELLI X trial.

AIM: To assess whether multiple switches between SAR341402 biosimilar insulin aspart (SAR-Asp) and the insulin aspart reference product (NovoLog; NN-Asp) leads to equivalent pharmacokinetic (PK) exposure compared with continuous use of NN-Asp in adults with type 1 diabetes (T1D). MATERIALS AND METHODS: This multicentre, open-label, phase 3 study randomized (1:1) 210 subjects with T1D treated with once-daily insulin glargine U100 as basal insulin to four 4-week periods of alternating multiple daily injections of SAR-Asp and NN-Asp (NN-Asp for the first 4 weeks, SAR-Asp in the last 4 weeks; switching group) versus 16 weeks of continuous NN-Asp (non-switching group). At week 16, a single dose (0.15 U/kg) of SAR-Asp in the switching group (n = 95) or NN-Asp in the non-switching group (n = 105) was given in the morning before breakfast. Primary PK endpoints were area under the plasma concentration curve (AUC) and maximum plasma concentration (Cmax ) of SAR-Asp versus NN-Asp after the single dose at week 16. RESULTS: The extent of PK exposure was similar between the two treatments (SAR-Asp in the switching group and NN-Asp in the non-switching group) at week 16, with point estimates of treatment ratios close to 1. The 90% confidence intervals for AUC treatment ratios were contained within 0.8-1.25. For Cmax in the primary analysis set, the upper confidence limit was 1.32. This was because of the profiles of three participants with implausible high values. A prespecified sensitivity analysis excluding implausible values showed results contained within 0.8-1.25. CONCLUSIONS: PK exposure of SAR-Asp (switching group) and reference NN-Asp (non-switching group) were similar, supporting interchangeability between these two insulin aspart products.

Associations of bolus insulin injection frequency and smart pen engagement with glycaemic control in people living with type 1 diabetes.

AIM: To evaluate whether both bolus insulin injection frequency and smart pen engagement were associated with changes in glycaemic control, using real-world data from adults with type 1 diabetes (T1D). MATERIALS AND METHODS: Adults using a smart pen (NovoPen 6) to administer bolus insulin (fast-acting insulin aspart or insulin aspart) alongside continuous glucose monitoring were eligible for inclusion. Smart pen engagement was characterized by number of days with pen data uploads over the previous 14 days. Glycaemic control was evaluated by analysing glucose metrics. RESULTS: Overall, data from 1194 individuals were analysed. The number of daily bolus injections was significantly associated with time in range (TIR; 3.9-10.0 mmol/L [70-180 mg/dL]; P < 0.0001). Individuals administering, on average, three daily bolus insulin injections had an estimated 11% chance of achieving >70% TIR. The probability of achieving >70% TIR increased with the mean number of daily bolus injections. However, the percentage of TIR was lower on days when individuals administered higher-than-average numbers of injections. The observed mean number of daily bolus injections administered across the study population was lower than the optimal number required to reach glycaemic targets (4.8 injections vs. 6-8 injections). Smart pen engagement was significantly associated with improved TIR. CONCLUSIONS: Glycaemic control was associated with daily bolus insulin injection frequency and smart pen engagement. A treatment regimen combining an optimal bolus injection strategy, and effective smart pen engagement, may improve glycaemic control among adults with T1D.

Unexpected evolution of a monster case of insulin-induced skin lipohypertrophy.

In this journal, in 2020, we published the case of a 74-year-old female outpatient with type-2 diabetes mellitus who self-injected insulin four times a day according to the basal-bolus regimen, with an high glycemic variability and an high rate of severe hypoglycemic episodes. Three years before, we had found two extraordinarily large skin lipohypertrophies, with large underlying fluid collections with high insulin concentration. A long educational and intensive training completely repaired the skin lesions with the disappearance of the subcutaneous insulin reservoirs. Glycemic variability has been reduced dramatically, severe hypoglycemia has almost completely disappeared and the daily dose of insulin has been reduced by 38%. However, this extraordinary, albeit unexpected, result was achieved in five years.

Faster-acting insulin aspart versus insulin aspart in the treatment of type 1 or type 2 diabetes during pregnancy and post-delivery (CopenFast): an open-label, single-centre, randomised controlled trial.

BACKGROUND: Faster-acting insulin aspart (faster aspart) is considered safe for use during pregnancy and breastfeeding but has not been evaluated in this population. We aimed to evaluate the effect of faster aspart versus insulin aspart on fetal growth, in women with type 1 or type 2 diabetes during pregnancy and post-delivery. METHODS: This open-label, single-centre, superiority trial was conducted at Rigshospitalet, Copenhagen, Denmark. Participants aged 18 years or older with type 1 or type 2 diabetes were stratified by diabetes type and insulin treatment modality (multiple daily injections or insulin pump), randomly assigned 1:1 to faster aspart or insulin aspart, from 8 weeks and 0 days (8+0) of gestation to 13+6 weeks of gestation, and followed up until 3 months post-delivery. Primary outcome was infant birthweight SD score. Secondary outcomes included HbA1c as well as maternal and fetal outcomes in all participants during the trial. This trial is registered with ClinicalTrials.gov, NCT03770767. FINDINGS: Between Nov 11, 2019 and May 10, 2022, 109 participants were included in the faster aspart group and 107 in the insulin aspart group. Primary outcome data were available in 203 (94%) of 216 participants, and no participants discontinued treatment during the trial. Mean birthweight SD score was 1·0 (SD 1·4) in the faster aspart group versus 1·2 (1·3) in the insulin aspart group; estimated treatment difference -0·22 [-0·58 to 0·14]; p=0·23. At 33 weeks of gestation, mean HbA1c was 42 mmol/mol (SD 6 mmol/mol; 6·0% [SD 0·9%]) versus 43 mmol/mol (SD 7 mmol/mol; 6·1% [SD 1·2%]); estimated treatment difference -1·01 (-2·86 to 0·83), p=0·28. No additional safety issues were observed with faster aspart compared with insulin aspart. INTERPRETATION: Treatment with faster aspart resulted in similar fetal growth and HbA1c, relative to insulin aspart, in women with type 1 or type 2 diabetes. Faster aspart can be used in women with type 1 or type 2 diabetes during pregnancy and post-delivery with no additional safety issues. FUNDING: Novo Nordisk. TRANSLATION: For the Danish translation of the abstract see Supplementary Materials section.

Effects of dietary intervention combined with insulin aspart on serum nesfatin-1 and CTRP12 levels and pregnancy outcomes in pregnant women with gestational diabetes mellitus.

To analyze the effects of dietary intervention combined with insulin aspart on the serum levels of nesfatin-1, C1q/TNF related protein-12 (CTRP12), and pregnancy outcomes in pregnant women with gestational diabetes mellitus (GDM). In this retrospective cohort study, 513 women with GDM admitted to Tangshan Central Hospital (Tangshan, China) between January 2019 and December 2022 were selected and divided into an observation group (dietary intervention combined with insulin aspart therapy; n = 284) and a control group (insulin aspart therapy, n = 229). The general characteristics, clinical outcomes, serum nesfatin-1 and CTRP12 levels, 2-hour postprandial blood glucose levels, pregnancy outcomes, and perinatal outcomes of the 2 groups were compared. After treatment, the total effective rate in the observation group was significantly higher than that of the control group (97.54% vs 86.03%, respectively; P < .001). Compared with the pretreatment levels, nesfatin-1 and CTRP12 levels were decreased in both groups; nesfatin-1 and CTRP12 levels in the observation group were significantly higher than those in the control group. After treatment, the preprandial and 2-hour postprandial blood glucose levels in the observation group were significantly lower than those in the control group. Compared with the control group, the observation group had significantly fewer cesarean sections, and a significantly lower incidence of postpartum hemorrhage, premature rupture of membranes, and other adverse pregnancy outcomes. After treatment, the risks of preterm birth, macrosomia, fetal distress, neonatal asphyxia, neonatal hypoglycemia, and other adverse perinatal outcomes were significantly lower in the observation group than in the control group. In pregnant women with GDM, dietary intervention combined with insulin aspart can improve clinical outcomes; reduce nesfatin-1, CTRP12, and blood glucose levels; and reduce the incidence of adverse pregnancy outcomes.

Probing the molecular interactions between cholinium-based ionic liquids and insulin aspart: A combined computational and experimental study.

Despite extensive studies revealing the potential of cholinium-based ionic liquids (ILs) in protein stabilization, the nature of interaction between ILs' constituents and protein residues is not well understood. In this work, we used a combined computational and experimental approach to investigate the structural stability of a peptide hormone, insulin aspart (IA), in ILs containing a choline cation [Ch]+ and either dihydrogen phosphate ([Dhp]-) or acetate ([Ace]-) as anions. Although IA remained stable in both 1 M [Ch][Dhp] and 1 M [Ch][Ace], [Dhp]- exhibited a much stronger stabilization effect than [Ace]-. Both the hydrophilic ILs intensely hydrated IA and increased the number of water molecules in IA's solvation shell. Undeterred by the increased number of water molecules, the native state of IA's hydrophobic core was maintained in the presence of ILs. Importantly, our results reveal the importance of IL concentration in the medium which was critical to maintain a steady population of ions in the microenvironment of IA and to counteract the denaturing effect of water molecules. Through molecular docking, we confirm that the anions exert the dominant effect on the structure of IA, while [Ch]+ have the secondary influence. The computational results were validated using spectroscopic analyses (ultra-violet, fluorescence, and circular dichroism) along with dynamic light scattering measurements. The extended stability of IA at 30 °C for 28 days in 1 M [Ch][Dhp] and [Ch][Ace] demonstrated in this study reveals the possibility of stabilizing IA using cholinium-based ILs.

Functional insulin aspart/insulin degludec-based microneedles for promoting postprandial glycemic control.

Insulin aspart (IAsp) and insulin degludec (IDeg), as the third generation of insulin, have a faster onset time or a more durable action period, which may simulate the secretion of insulin under physiological conditions. Microneedles (MNs) are transdermal delivery devices that may allow diabetic patients to easily deploy transdermal insulin therapy while considerably reducing injection pain. In this study, we investigated the combination of dissolving MNs with IAsp or IDeg therapy as an alternative to daily multiple insulin injections, aiming to improve glycemic control and patient compliance. Mechanical properties of the MNs, structural stability of insulin encapsulated in the MNs, and transdermal application characteristics were studied to assess the practicality of insulin-loaded MNs for diabetes therapy. In vivo experiments conducted on diabetic rats demonstrated that the IAsp- and IDeg-loaded MNs have comparable blood glucose control abilities to that of subcutaneous injections. In addition, the therapeutic properties of insulin-loaded MNs under diverse dietary conditions and application strategies were further investigated to provide new information to support future clinical trials. Taken together, the proposed MNs have the potential to improve balances between glycemic control, hypoglycemia risk, and convenience, providing patients with simpler regimens. STATEMENT OF SIGNIFICANCE: 1. The fabricated functional insulin-loaded dissolving microneedles closely matched the glucose rise that occurs in response to meals, demonstrating promising alternatives for multiple daily insulin injections. 2. The hypoglycemic properties of insulin microneedles were investigated under diverse dietary conditions and application strategies, yielding new information to support future clinical trials. 3. Molecular dynamics simulations were utilized to study the interactions between the insulin and microneedle matrix materials, providing a strategy for theoretically understanding drug stability as well as the release mechanism of drug-loaded microneedles.

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.

Insulin Tregopil: An Ultra-Fast Oral Recombinant Human Insulin Analog: Preclinical and Clinical Development in Diabetes Mellitus.

Insulin therapy is indispensable for achieving glycemic control in all patients with type 1 diabetes mellitus and many patients with type 2 diabetes mellitus. Insulin injections are associated with negative connotations in patients owing to administration discomfort and adverse effects such as hypoglycemia and weight gain. Insulin administered orally can overcome these limitations by providing a convenient and effective mode of delivery with a potentially lower risk of hypoglycemia. Oral insulin mimics the physiologic process of insulin secretion, absorption into the portal circulation, and subsequent peripheral delivery, unlike the subcutaneous route that results in peripheral hyperinsulinemia. Insulin tregopil (IN-105), a new generation human recombinant insulin, methoxy (polyethylene glycol) hexanoyl human recombinant insulin, is developed by Biocon as an ultra-fast onset short-acting oral insulin analog. This recombinant oral insulin is a single short-chain amphiphilic oligomer modified with the covalent attachment of methoxy-triethylene-glycol-propionyl moiety at Lys-ß29-amino group of the B-chain via an amide linkage. Sodium caprate, an excipient in the insulin tregopil formulation, is a permeation enhancer that increases its absorption through the gastrointestinal tract. Also, meal composition has been shown to non-significantly affect its absorption. Several global randomized, controlled clinical trials have been conducted in type 1 and type 2 diabetes patients towards the clinical development of insulin tregopil. The formulation shows post-prandial glucose control that is more effective than placebo throughout the meal period; however, compared with an active comparator insulin aspart, the post-prandial control is more effective mainly in the early post-meal period. It shows a good safety profile with a lower incidence of clinically significant hypoglycemia. This review covers the overall clinical development of insulin tregopil establishing it as an ultra-fast onset, short-acting oral insulin analog for optimizing post-prandial glucose.

Evaluation of blood glucose changes with regular versus rapid-acting insulin for hyperglycaemia management in the emergency department.

OBJECTIVES: As emergency department (ED) visits secondary to hyperglycaemia increase, goals should focus on optimising treatment to minimise the length of stay (LOS). Both regular and rapid-acting insulins can effectively treat hyperglycaemia, but have different pharmacokinetic profiles. The purpose of this study is to compare blood glucose (BG) reduction over time in patients receiving subcutaneous regular versus rapid-acting insulin in the ED. METHODS: This retrospective chart review from 1 January 2018 to 31 December 2020 included adult ED patients with a BG ≥200 mg/dl who received subcutaneous regular insulin or insulin aspart. The primary endpoint was a change in BG immediately before and ≥30 min after insulin administration over time. RESULTS: There were 279 patients included in the study (108 regular insulin and 171 insulin aspart). Change in BG over time was 41.5 mg/dl/h in the regular insulin group and 47 mg/dl/h in the insulin aspart group (P = 0.36). There was no difference in hypoglycaemic events, ED LOS, time from insulin administration to discharge and total change in BG during ED stay. Patients who received regular insulin required less additional insulin doses (8.3% vs. 18.1%, P = 0.02), received a greater volume of intravenous fluids (1629 ml vs. 1280 ml, P = 0.02) and higher weight-based dose for the first insulin dose (0.11 units/kg vs. 0.10 units/kg, P = 0.02). CONCLUSION: There was no significant difference in BG reduction between insulin types for hyperglycaemic patients treated in the ED. This suggests that regular insulin and rapid-acting insulin have similar efficacy in the treatment of hyperglycaemia in the ED.

Optimizing The Daily Units Of Insulin; Insulin Degludec Aspart Versus Premixed Insulin Aspart In The Standard Of Care Regimen For Type 2 Diabetics.

BACKGROUND: This study aimed to evaluate the impact of Insulin Degludec Aspart on daily insulin dose in comparison with premixed insulin aspart. METHODS: It was a Quasi-Experimental study conducted in the Department of Pharmacology, Army Medical College, National University of Medical Sciences, Rawalpindi and the Department of Medicine, Pak Emirates Military Hospital, Rawalpindi. One hundred and twenty participants with documented type 2 diabetes, taking premixed insulin aspart therapy were enrolled in the study. Sixty participants were substituted with insulin degludec aspart from premixed insulin aspart. Daily units of insulin were recorded for 12 weeks and compared for both groups. SPSS version 26 was used for analysing the study results. RESULTS: Participants of the insulin degludec aspart group showed a significant reduction in the daily insulin dose compared to the premixed insulin aspart group. Fifty-two units per day were administered in the participants of the premixed insulin aspart patients while insulin degludec aspart participants received 40 units of median daily insulin dose (p-value<0.001). CONCLUSIONS: Insulin degludec aspart proved superior to premixed insulin aspart in a reduction in the daily dose of insulin with insulin degludec aspart.

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.

A Comparison of Faster Insulin Aspart with Standard Insulin Aspart Using Hybrid Automated Insulin Delivery System in Active Children and Adolescents with Type 1 Diabetes: A Randomized Double-Blind Crossover Trial.

Objective: To evaluate the use of faster acting (FIA) and standard insulin aspart (SIA) with hybrid automated insulin delivery (AID) in active youth with type 1 diabetes. Research Design and Methods: In this double-blind multinational randomized crossover trial, 30 children and adolescents with type 1 diabetes (16 females; aged 15.0 ± 1.7 years; baseline HbA1c 7.5% ± 0.9% [58 ± 9.8 mmol/mol]) underwent two unrestricted 4-week periods using hybrid AID with either FIA or SIA in random order. During both interventions, participants were using the hybrid AID (investigational version of MiniMed™ 780G; Medtronic). Participants were encouraged to exercise as frequently as possible, capturing physical activity with an activity monitor. The primary outcome was the percentage of sensor glucose time above range (180 mg/dL [10.0 mmol/L]) measured by continuous glucose monitoring. Results: In an intention-to-treat analysis, mean time above range was 31% ± 15% at baseline, 19% ± 6% during FIA use, and 20% ± 6% during SIA use with no difference between treatments: mean difference = -0.9%; 95% CI: -2.4% to 0.6%; P = 0.23. Similarly, there was no difference in mean time in range (TIR) (78% and 77%) or median time below range (2.5% and 2.8%). Glycemic outcomes during exercise or postprandial periods were comparable for the two treatment arms. No severe hypoglycemia or diabetic ketoacidosis events occurred. Conclusions: FIA was not superior to SIA with hybrid AID system use in physically active children and adolescents with type 1 diabetes. Nonetheless, both insulin formulations enabled high overall TIR and low time above and below ranges, even during and after documented exercise. Trial Registration Clinicaltrials.gov: NCT04853030.

In Vitro Biological Characterization of Recombinant Insulin Aspart from Biogenomics and Originator Insulin Aspart.

BACKGROUND: Bioassays are used to identify the pharmacological activity of new or chemically unknown compounds, as well as their undesirable effect, including toxicity. Biological assays are also required to ensure the quality, safety, and efficacy of recombinant biologics to confirm its biosimilarity to its originator. In the present study, analytical similarity between the biosimilar and its innovator is established by in vitro bioassays. OBJECTIVE: The objective of this study was to show the comparative in vitro characterization of the recombinant insulin aspart from BioGenomics with its originator insulin aspart, using relevant biological assays. METHODS: In vitro assays such as receptor binding, receptor autophosphorylation, glucose uptake, and mitogenic potential were analyzed for biological characterization of BioGenomics recombinant insulin aspart (BGL-ASP) manufactured by BioGenomics Limited and NovoRapid® as the reference medicinal product (RMP) manufactured by Novo Nordisk. Insulin receptor binding was studied by a state-of-the-art method, surface plasmon resonance (SPR) for biomolecular interactions. The receptor autophosphorylation assay measures the phosphorylated insulin receptor in cell lysates. The glucose uptake assay measures the uptake of glucose by 3T3-L1 cells in the presence of insulin. Lipogenesis was studied in treated 3T3-L1 cells by detecting the accumulation of lipid droplets in the cells. Mitogenic effect was studied by cell proliferation assay using MCF-7 cells. A rabbit bioidentity test was performed by measuring the sudden decrease in blood glucose in the presence of insulin. RESULTS: The binding studies showed that the affinity of BGL-ASP was highly comparable to NovoRapid®. Insulin receptor autophosphorylation, glucose uptake, and lipogenesis demonstrated high similarity to the RMP. The mitogenic assay for BGL-ASP did not show any proliferative effect and was comparable to the RMP. The in vivo bioidentity test showed that the BGL-ASP is highly similar to the innovator, NovoRapid®. CONCLUSION: The biological characterization studies of BGL-ASP demonstrated high binding and functional similarity to NovoRapid®.

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.

Comparative efficacy and safety of Gla-300 versus IDegAsp in insulin-naïve people with type 2 diabetes mellitus uncontrolled on oral anti-diabetics.

AIM: To compare the efficacy and safety of insulin glargine-300 once daily (Gla-300) with insulin degludec/aspart (IDegAsp) once daily in patients with type 2 diabetes (T2D) inadequately controlled on oral anti-diabetic drugs (OADs). MATERIALS AND METHODS: A systematic literature review of randomized controlled trials was followed by an indirect treatment comparison of studies involving insulin naïve adults, inadequately controlled [glycated haemoglobin (HbA1c) ≥7.0%] on OADs, who received Gla-300 or IDegAsp once daily. Outcomes of interest were change in HbA1c, blood glucose, weight and insulin dose, as well as incidence and event rate of hypoglycaemia and other adverse events. RESULTS: Four trials with broadly similar baseline patient characteristics were included in the meta-analyses and indirect treatment comparison. At 24-28 weeks, the indirect comparison of Gla-300 to IDegAsp once daily estimated no statistically significant difference for change in HbA1c (%) from baseline [mean difference of 0.10% (95% CI: -0.20, 0.39; p = .52)]; a statistically significant mean difference of -1.31 kg (95% CI: -1.97, -0.65; p < .05) for change in body weight from baseline; statistically significant odds ratios of 0.62 (95% CI: 0.41, 0.93; p < .05) for incidence of any hypoglycaemia; and 0.47 (95% CI: 0.25, 0.87; p < .05) for incidence of anytime confirmed hypoglycaemia (plasma glucose <3.0-3.1 mmol/L). No significant differences were observed for insulin dose and adverse events. CONCLUSION: In insulin-naïve patients with T2D inadequately controlled on OADs, commencing Gla-300 shows a comparable HbA1c reduction, but with significantly less weight gain and a lower incidence of any and confirmed hypoglycaemia compared with commencing IDegAsp.