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Aims Materials and Methods Results Conclusions To investigate glycaemic control in Chinese adults with type 2 diabetes (T2D) initiating, or switching to insulin degludec/insulin aspart (IDegAsp), a co‐formulation of basal, and bolus insulin, in a real‐world setting.A 20‐week, prospective, single‐arm, open‐label, non‐interventional study was conducted in Chinese adults with T2D initiating, or switching to IDegAsp after anti‐hyperglycaemic treatment with oral antidiabetic drugs (OADs), other insulins, or glucagon‐like peptide‐1 receptor agonists. The primary endpoint was a change in HbA1c from baseline to end of the study; the secondary endpoints included a change in fasting plasma glucose and Diabetes Treatment Satisfaction Questionnaire (DTSQ) score.Significant reductions were observed in mean HbA1c and fasting plasma glucose, among both the overall population (N = 878; −1.27%‐points [95% CI: −1.36; −1.19]; p < 0.0001, and −1.61 mmol/L [95% CI: −1.81; −1.41]; p < 0.0001, respectively), and in subgroups switching from OADs only, or basal, or premix insulins ± OADs. The mean total DTSQ score increased from 26.4 (baseline) to 31.6 (end‐of‐study). No significant, or unexpected tolerability, or safety issues were observed. Significant reductions were observed in incidence rates of non‐severe (rate ratio 0.37 [95% CI: 0.24; 0.59]; p < 0.0001) and nocturnal non‐severe (rate ratio 0.45 [95% CI: 0.21; 0.94]; p = 0.0326) hypoglycaemic episodes.In a broad, real‐world Chinese population of adults with T2D, initiating or switching to IDegAsp was associated with improved glycaemic control and lower rates of hypoglycaemia. The use of IDegAsp could be an effective treatment option for those with suboptimal glycaemic control or therapeutic inertia. [ABSTRACT FROM AUTHOR]

Aims: The safety and efficacy of insulin analogue insulin aspart (IAsp) have been demonstrated in a randomised clinical trial in pregnant women with Type 1 diabetes (T1D), and IAsp is widely used during pregnancy. The aim of this study was to assess glycaemic control and safety of IAsp versus other bolus insulins in Type 1 diabetic pregnancy in a real‐world setting. Methods: This was a post hoc analysis of a prospective cohort study of 1840 pregnant women with T1D, treated with IAsp (n = 1434) or other bolus insulins (n = 406) in the Diabetes Pregnancy Registry. The primary (composite) outcome was the proportion of pregnancies resulting in major congenital malformations or perinatal or neonatal death. Secondary outcomes included all HbA1c values measured immediately before and during pregnancy and major hypoglycaemia, as well as abortion, pre‐eclampsia, pre‐term delivery, large for gestational age at birth, stillbirth and fetal malformations. Results: There were no significant differences found in any of the pregnancy outcomes between treatment with IAsp and other bolus insulins in either the crude or propensity score‐adjusted analyses. However, maternal HbA1c was lower in the IAsp group at the end of the third trimester (adjusted difference, −0.16% point [95% CI −0.28;−0.05]; −1.8 mmol/mol [95% CI −3.1;−0.6]; p = 0.0046). Conclusions: No significant differences in safety or pregnancy outcomes were demonstrated when comparing treatment with IAsp versus other bolus insulins in women with T1D during pregnancy. The observed improvement in HbA1c with IAsp in late pregnancy should be confirmed in other studies. [ABSTRACT FROM AUTHOR]

Purpose of Review: Postprandial hyperglycemia, or elevated blood glucose after meals, is associated with the development and progression of various diabetes-related complications. Prandial insulins are designed to replicate the natural insulin release after meals and are highly effective in managing post-meal glucose spikes. Currently, different types of prandial insulins are available such as human regular insulin, rapid-acting analogs, ultra-rapid-acting analogs, and inhaled insulins. Knowledge about diverse landscape of prandial insulin will optimize glycemic management. Recent Findings: Human regular insulin, identical to insulin produced by the human pancreas, has a slower onset and extended duration, potentially leading to post-meal hyperglycemia and later hypoglycemia. In contrast, rapid-acting analogs, such as lispro, aspart, and glulisine, are new insulin types with amino acid modifications that enhance their subcutaneous absorption, resulting in a faster onset and shorter action duration. Ultra-rapid analogs, like faster aspart and ultra-rapid lispro, offer even shorter onset of action, providing better meal-time flexibility. The Technosphere insulin offers an inhaled route for prandial insulin delivery. The prandial insulins can be incorporated into basal-bolus, basal plus, or prandial-only regimens or delivered through insulin pumps. Human regular insulin, aspart, lispro, and faster aspart are recommended for management of hyperglycemia during pregnancy. Ongoing research is focused on refining prandial insulin replacement and exploring newer delivery methods. Summary: The article provides a comprehensive overview of various prandial insulin options and their clinical applications in the management of diabetes. [ABSTRACT FROM AUTHOR]

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]

Patients with diabetes mellitus increase significantly every year. The increasing number of people with diabetes mellitus results in increased insulin requirements. There are two types of insulin used for diabetes mellitus treatment: human insulin and insulin analogues. Escherichia coli, Pichia pastoris, Saccharomyces cerevisiae, or Hansenula polymorpaha has been used to produce human insulin and insulin analogues. Pichia pastoris can produce glargine in large quantities, and the insulin protein produced will be secreted outside the cell to facilitate the purification process. The advantage of glargine has a long working time of up to 24 hours. Hence, glargine is more effective because patients with diabetes receive glargine injections only once daily. The research started with cloning the glargine gene, transforming pPICZαA-G plasmid into Pichia pastoris, and testing glargine production. 20 recombinant Pichia pastoris colonies were selected and regenerated. Eight recombinant Pichia pastoris colonies were tested for glargine production, and six colonies were detected producing glargine by electrophoresis SDS-PAGE gel stained with Coomassie blue. This study aims to produce glargine using Pichia pastoris as an expression system capable of producing glargine extracellularly, thus simplifying the purification process. [ABSTRACT FROM AUTHOR]

Introduction: Insulin degludec (degludec), an ultra-long-acting basal insulin analogue, provides equivalent glycemic control to other basal insulin analogues, with lower risk of hypoglycemia and flexible dosing. Chinese TREsiba AudiT (CN-TREAT) investigated outcomes with degludec in people with type 2 diabetes (T2D) in routine clinical practice in China. Methods: This was a retrospective chart review study in adults with T2D initiating or switching to degludec at 50 sites in China between January 2020 and July 2021. The primary endpoint was change in glycated hemoglobin (HbA1c) from baseline to end of study (EOS; week 20). Secondary endpoints included change from baseline to EOS in fasting plasma glucose (FPG), self-measured plasma glucose (SMPG), daily insulin dose, and rate of hypoglycemia. Results: Data from 936 participants were included (499 insulin-naïve; 437 insulin-experienced). Mean (95% confidence interval [CI]) HbA1c change from baseline to EOS was − 1.48%-points (− 1.57; − 1.38; P < 0.0001) overall: − 1.95%-points (− 2.08; − 1.81; P < 0.0001) in insulin-naïve participants and − 0.95%-points (− 1.08; − 0.82; P < 0.0001) in insulin-experienced participants. Mean (95% CI) changes in FPG and SMPG were − 2.27 mmol/L (− 2.69; − 1.85; P < 0.0001) and − 2.89 mmol/L (− 3.52; − 2.25; P < 0.0001), respectively, with similar reductions in insulin-naïve and insulin-experienced subgroups. Rate of hypoglycemia did not change statistically significantly from baseline to EOS overall, or in insulin-experienced participants, except when adjusted for baseline hypoglycemia. Basal insulin dose did not change statistically significantly in insulin-experienced participants. Conclusion: In routine clinical practice in China, initiation or switching to degludec was associated with improvements in glycemic control in people with T2D, with no increased risk of hypoglycemia. Trial Registration: ClinialTrials.gov, NCT04227431. [ABSTRACT FROM AUTHOR]

Aims: To investigate the efficacy and safety of ultra‐rapid lispro (URLi) versus insulin lispro in predominantly Chinese patients with type 1 diabetes (T1D) in a prospective, randomized, double‐blind, treat‐to‐target, phase 3 study. Materials and Methods: Following a lead‐in period, during which insulin glargine U‐100 or insulin degludec U‐100 was optimized, patients were randomly assigned (1:1) to URLi (n = 176) or insulin lispro (n = 178). The primary objective was to test the noninferiority of URLi to insulin lispro in glycaemic control (noninferiority margin = 0.4% for glycated haemoglobin [HbA1c] change from baseline to week 26), with testing for the superiority of URLi to insulin lispro with regard to 1‐ and 2‐hour postprandial glucose (PPG) excursions during a mixed‐meal tolerance test and HbA1c change at week 26 as the multiplicity‐adjusted objectives. Results: From baseline to week 26, HbA1c decreased by 0.21% and 0.28% with URLi and insulin lispro, respectively, with a least squares mean treatment difference of 0.07% (95% confidence interval −0.11 to 0.24; P = 0.467). URLi demonstrated smaller 1‐ and 2‐hour PPG excursions at week 26 with least squares mean treatment differences of −1.0 mmol/L (−17.8 mg/dL) and −1.4 mmol/L (−25.5 mg/dL), respectively (p < 0.005 for both) versus insulin lispro. The safety profiles of URLi and insulin lispro were similar. Conclusions: In this study, URLi administered in a basal‐bolus regimen demonstrated superiority to insulin lispro in controlling PPG excursions, with noninferiority of HbA1c control in predominantly Chinese patients with T1D. [ABSTRACT FROM AUTHOR]

Context. There are evidences that excessive production of reactive oxygen species is one of important abnormalities that contribute to development of chronic diabetic complications. Objective. To test the effect of intensive insulin therapy with analogues through the examining the level of oxidative stress parameters. Subjects and Methods. Comparison of data obtained by prospective analysis in 49 patients with T1DM was used, before and after six months of intensive insulin analog therapy. Results. The values of all three investigated parameters of oxidative stress malondialdehyde (MDA); xanthine oxidase (XO) and nitrates and nitrites (NOx) in our population with T1DM compared to the control (group of 42 voluntary blood donors) are statistically higher. The levels of antioxidant protection parameters compared to the control group also differ; the activities of catalase and glutathione peroxidase (GPx) are statistically higher in our population of T1DM patients compared to the control and superoxide dismutase (SOD) activities are statistically lower. The values of all three examined parameters of oxidative stress decrease after six months of intensive insulin analog therapy and were statistically lower after the therapy: for MDA p<0.001, for XO p<0.01 and for NOx p<0.05. The activities of catalase (p<0.001) and GPx (p<0.01) both decrease with therapy, while the activity of SOD is highest after the sixth month of therapy (p<0.001). Conclusion. In our patients with T1DM compared to the control the level of oxidative stress is significantly higher. Intensive insulin analog therapy with aspart and glargine promotes predominantly the improvement of oxidative stress, and in a less degree antioxidant protection. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the effectiveness and safety profile of switching to insulin glargine 300 U/mL (Gla‐U300) in patients with uncontrolled type 2 diabetes (T2D) on basal insulin in Saudi Arabia. Materials and Methods: We conducted a multicentre retrospective study that retrieved the medical records of adult T2D patients switched to Gla‐U300 because of poor glycaemic control on their basal insulin. Data covering 6 months ± 30 days before and after the switch were retrieved. Results: Data from 718 patients were analysed. The mean HbA1c decreased significantly 6 months after switching to Gla‐U300, with a mean reduction of 0.7% (95% confidence interval [CI] 0.6%‐0.9%; P <.001). The percentage of patients with HbA1c levels of less than 7% increased from 6.4% before switching to 10.3% after switching to Gla‐U300. The percentage of patients achieving the predefined individualized HbA1c goal increased from 8.6% before switching to 17.3% after switching to Gla‐U300. The mean daily insulin dose decreased from a baseline level of 32.2 (± 14.7) to 31.0 (± 15) U (P =.09). About 36.1 of the patients required adjustment to the initial dose. Gla‐300 was well tolerated; 4.5% of the patients experienced overall confirmed or symptomatic hypoglycaemia, compared with 15.3% before switching to Gla‐U300. The incidence of severe hypoglycaemia after switching was 0.6% (n = 4 patients), compared with 1% before switching. Conclusions: Real‐world evidence supports the effectiveness of switching to Gla‐U300 from first‐generation basal insulin in T2D in Saudi Arabia. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract Background Insulin therapy regimens for people with type 1 diabetes (PWT1D) should mimic the physiological insulin secretion that occurs in individuals without diabetes. Intensive insulin therapy, whether by multiple daily injections (MDI) or continuous subcutaneous insulin infusion (CSII), constitutes the fundamental therapy from the initial stages of type 1 diabetes (T1D), at all ages. This review is an authorized literal translation of part of the Brazilian Diabetes Society (SBD) Guidelines 2021–2022. This evidence-based guideline supplies guidance on insulin therapy in T1D. Methods The methods were published elsewhere in earlier SBD guidelines and was approved by the Internal Institutional Steering Committee for publication. Briefly, the Brazilian Diabetes Society indicated fourteen experts to constitute the Central Committee, designed to regulate the method review of the manuscripts, and judge the degrees of recommendations and levels of evidence. SBD Type 1 Diabetes Department drafted the manuscript selecting key clinical questions to do a narrative review using MEDLINE via PubMed, with the best evidence available, including high-quality clinical trials, metanalysis, and large observational studies related to insulin therapy in T1D, by using the Mesh terms [type 1 diabetes] and [insulin]. Results Based on extensive literature review the Central Committee defined ten recommendations. Three levels of evidence were considered: A. Data from more than one randomised clinical trial (RCT) or one metanalysis of RCTs with low heterogeneity (I2

Aim: To determine whether the use of long‐acting insulin analogues is associated with an increased risk of incident diabetic retinopathy (DR) among patients with type 2 diabetes. Methods: Using data from the Clinical Practice Research Datalink Aurum, this retrospective, population‐based cohort study included patients with type 2 diabetes who initiated a long‐acting insulin analogue (glargine, detemir, degludec) or Neutral Protamine Hagedorn (NPH) insulin. The primary outcome was incident DR. We used Cox proportional hazards models with inverse probability of treatment weighting to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for incident DR with insulin analogues versus NPH insulin. Results: There were 66 280 new users of long‐acting insulin analogues and 66 173 new users of NPH insulin. The incidence rate of DR was 101.7 per 1000 person‐years (95% CI, 98.7‐104.8) for insulin analogues and 93.2 (95% CI, 90.0‐96.5) per 1000 person‐years for NPH insulin. Compared with the current use of NPH insulin, insulin analogues were not associated with the risk of incident DR (HR 1.04, 95% CI, 0.99‐1.09). The adjusted HRs were 0.84 (95% CI, 0.66‐1.07) for proliferative DR and 1.02 (95% CI, 0.97‐1.08) for non‐proliferative DR. Conclusions: Compared with NPH insulin, long‐acting insulin analogues were not associated with the risk of incident DR among patients with type 2 diabetes. This finding provides important reassurance regarding the safety of long‐acting insulin analogues with respect to incident DR. [ABSTRACT FROM AUTHOR]

Aim: To determine the kinase activity profiles of human pancreatic beta cells downstream of glucagon‐like peptide‐1 receptor (GLP‐1R) balanced versus biased agonist stimulations. Materials and Methods: This study analysed the kinomic profiles of human EndoC‐βh1 cells following vehicle and GLP‐1R stimulation with the pharmacological agonist exendin‐4, as well as exendin‐4–based biased derivatives exendin‐phe1 and exendin‐asp3 for acute (10‐minute) versus sustained (120‐minute) responses, using PamChip protein tyrosine kinase and serine/threonine kinase assays. The raw data were filtered and normalized using BioNavigator. The kinase analyses were conducted with R, mainly including kinase‐substrate mapping and Kyoto Encyclopedia of Genes and Genomes pathway analysis. Results: The present analysis reveals that kinomic responses are distinct for acute versus sustained GLP‐1R agonist exposure, with individual responses associated with agonists presenting specific bias profiles. According to pathway analysis, several kinases, including JNKs, PKCs, INSR and LKB1, are important GLP‐1R signalling mediators, constituting potential targets for further research on biased GLP‐1R downstream signalling. Conclusion: The results from this study suggest that differentially biased exendin‐phe1 and exendin‐asp3 can modulate distinct kinase interaction networks. Further understanding of these mechanisms will have important implications for the selection of appropriate anti‐type 2 diabetes therapies with optimized downstream kinomic profiles. [ABSTRACT FROM AUTHOR]

Aim: To determine the potential impact of the cross‐reactivity of insulin glargine U‐100 and its metabolites on insulin sensitivity and β‐cell measures in people with type 2 diabetes. Materials and Methods: Using liquid chromatography–mass spectrometry (LC–MS), we measured concentrations of endogenous insulin, glargine and its two metabolites (M1 and M2) in fasting and oral glucose tolerance test‐stimulated plasma from 19 participants and fasting specimens from another 97 participants 12 months after randomization to receive the insulin glargine. The last dose of glargine was administered before 10:00 PM the night before testing. Insulin was also measured on these specimens using an immunoassay. We used fasting specimens to calculate insulin sensitivity (Homeostatic Model Assessment 2 [HOMA2]‐S%; QUICKI index; PREDIM index) and β‐cell function (HOMA2‐B%). Using specimens following glucose ingestion, we calculated insulin sensitivity (Matsuda ISI[comp] index) and β‐cell response (insulinogenic index [IGI], and total incremental insulin response [iAUC] insulin/glucose). Results: In plasma, glargine was metabolized to form the M1 and M2 metabolites that were quantifiable by LC–MS; however, the analogue and its metabolites cross‐reacted by less than 100% in the insulin immunoassay. This incomplete cross‐reactivity resulted in a systematic bias of fasting‐based measures. By contrast, because M1 and M2 did not change following glucose ingestion, a bias was not observed for IGI and iAUC insulin/glucose. Conclusions: Despite glargine metabolites being detected in the insulin immunoassay, dynamic insulin responses can be used to assess β‐cell responsiveness. However, given the cross‐reactivity of the glargine metabolites in the insulin immunoassay, fasting‐based measures of insulin sensitivity and β‐cell function are biased. [ABSTRACT FROM AUTHOR]

Aim: To compare nocturnal glucose profiles according to hourly plasma glucose measurements during treatment with insulin degludec and insulin glargine U100 in a cohort of people with type 1 diabetes prone to nocturnal severe hypoglycaemia. Materials and methods: The HypoDeg trial is a 2‐year investigator‐initiated, randomized, controlled crossover trial in 149 participants randomized to treatment with insulin degludec and insulin glargine U100 for 12 months each. The 51 participants in this predefined substudy stayed at least one night in hospital during each treatment arm for plasma glucose samples to be taken. Endpoints were glucose profiles, including mean plasma glucose, glycaemic variability and risk of hypoglycaemia. Results: There were no differences between treatments regarding mean plasma glucose. We saw a flatter glucose profile during insulin degludec compared with insulin glargine U100 treatment, which had a nadir at 4:00 AM, with a subsequent rise. During treatment with insulin degludec, the participants had lower glycaemic variability, with an estimated treatment difference of −4.3% (95% confidence interval [CI] −8.1 to −0.5; P < 0.05). Participants treated with insulin degludec were less likely to experience nocturnal hypoglycaemia below 3.0 mmol/L (hazard ratio 0.36 [95% CI 0.17‐0.73; P < 0.05]). Conclusion: Based on nocturnal plasma glucose measurements, treatment with insulin degludec compared with insulin glargine U100 administered in the evening results in lower glycaemic variability and lower risk of nocturnal hypoglycaemia without differences in mean plasma glucose. [ABSTRACT FROM AUTHOR]

Background: Studies show that among the drugs most commonly used in judicial litigation in Brazil, are those used to treat diabetes mellitus, especially insulin analogues. Objective: Evaluate the use of the Unified Health System (SUS) by patients with type 1 diabetes mellitus (T1DM), who receive insulin analogues through judicial action, before and after this process. Method: In a retrospective longitudinal observational study, secondary data was used from these patients in Minas Gerais, Brazil, in 2018. Socio-demographic information was collected and related to the follow-up of these patients in the SUS. The McNemar χ2 test was used to compare the proportions of the variables. Results: Of the 89 patients analyzed, women (53.9%) were predominant. Most patients were aged between 20 and 39 years (52.8%), and more than half, 55.1%, use only a private health system. After the judicial action, there was a significant increase (p <0.05) in the number of patients who had consultations in primary health care (from 19.1% to 30.3%) and emergency medical appointments (from 1.1% to 9.0%). Conclusion: It is observed that the majority of patients with T1DM via judicial action in the SUS are not monitored by this health system through examinations, consultations, and hospitalizations. [ABSTRACT FROM AUTHOR]

Keywords: clinical trial; continuous glucose monitoring; CSII; insulin analogues; insulin pump therapy; insulin therapy EN clinical trial continuous glucose monitoring CSII insulin analogues insulin pump therapy insulin therapy 1121 1124 4 03/08/23 20230401 NES 230401 INTRODUCTION Carbohydrate counting to quantify prandial insulin requirement remains a key aspect of type 1 diabetes self-management.[1] This, however, remains challenging, leading to dysglycaemia and increased burden for many people with type 1 diabetes.[2] Current hybrid closed-loop systems still require manual meal (prandial) bolusing due to the relatively slow action of standard rapid-acting insulin. In conclusion, glucose control using the CamAPS FX closed-loop system under conditions of underestimated and missed meal bolus with faster-acting insulin aspart is comparable with insulin aspart. DISCUSSION Use of faster-acting insulin aspart compared to insulin aspart during closed loop when meal boluses were underestimated and missed led to comparable glycaemic outcomes, with no significant differences in closed-loop algorithm-mediated insulin doses. Comparison of faster-acting aspart with insulin aspart under conditions mimicking underestimation or missed meal boluses in type 1 diabetes using closed-loop insulin delivery. [Extracted from the article]

Abstract Background Studies show that among the drugs most commonly used in judicial litigation in Brazil, are those used to treat diabetes mellitus, especially insulin analogues. Objective Evaluate the use of the Unified Health System (SUS) by patients with type 1 diabetes mellitus (T1DM), who receive insulin analogues through judicial action, before and after this process. Method In a retrospective longitudinal observational study, secondary data was used from these patients in Minas Gerais, Brazil, in 2018. Socio-demographic information was collected and related to the follow-up of these patients in the SUS. The McNemar χ2 test was used to compare the proportions of the variables. Results Of the 89 patients analyzed, women (53.9%) were predominant. Most patients were aged between 20 and 39 years (52.8%), and more than half, 55.1%, use only a private health system. After the judicial action, there was a significant increase (p

Aim: To use continuous glucose monitoring (CGM)‐based time‐in‐range (TIR) as a primary efficacy endpoint to compare the second‐generation basal insulin (BI) analogues insulin glargine 300 U/ml (Gla‐300) and insulin degludec 100 U/ml (IDeg‐100) in adults with type 1 diabetes (T1D). Materials and Methods: InRange was a 12‐week, multicentre, randomized, active‐controlled, parallel‐group, open‐label study comparing glucose TIR and variability between Gla‐300 and IDeg‐100 using blinded 20‐day CGM profiles. The inclusion criteria consisted of adults with T1D treated with multiple daily injections, using BI once daily and rapid‐acting insulin analogues for at least 1 year, with an HbA1c of 7% or higher and of 10% or less at screening. Results: Overall, 343 participants were randomized: 172 received Gla‐300 and 171 IDeg‐100. Non‐inferiority (10% relative margin) of Gla‐300 versus IDeg‐100 was shown for the primary endpoint (percentage TIR ≥ 70 to ≤ 180 mg/dl): least squares (LS) mean (95% confidence interval) 52.74% (51.06%, 54.42%) for Gla‐300 and 55.09% (53.34%, 56.84%) for IDeg‐100; LS mean difference (non‐inferiority): 3.16% (0.88%, 5.44%) (non‐inferiority P =.0067). Non‐inferiority was shown on glucose total coefficient of variation (main secondary endpoint): LS mean 39.91% (39.20%, 40.61%) and 41.22% (40.49%, 41.95%), respectively; LS mean difference (non‐inferiority) −5.44% (−6.50%, −4.38%) (non‐inferiority P <.0001). Superiority of Gla‐300 over IDeg‐100 was not shown on TIR. Occurrences of self‐measured and CGM‐derived hypoglycaemia were comparable between treatment groups. Safety profiles were consistent with known profiles, with no unexpected findings. Conclusions: Using clinically relevant CGM metrics, InRange shows that Gla‐300 is non‐inferior to IDeg‐100 in people with T1D, with comparable hypoglycaemia and safety profiles. [ABSTRACT FROM AUTHOR]

Aim: To examine changes in racial and ethnic disparities in glucose‐lowering drugs (GLD) use and glycated haemoglobin A1c in US adults with diabetes from 2005 to 2018. Methods: We conducted pooled cross‐sectional analysis using data from the 2005‐2018 Medical Expenditure Panel Surveys, and the 2005‐2018 National Health and Nutrition Examination Survey. Individuals ≥18 years with diabetes were included. Racial and ethnic disparities were measured in (a) newer non‐insulin GLD use; (b) insulin analogue use; (c) non‐insulin GLDs adherence; (d) insulin adherence; and (e) glucose management, along with (f) the proportion of the disparities explained by potential contributing factors. Results: From 2005 to 2018, racial and ethnic disparities persisted in newer GLD use, non‐insulin GLDs adherence, insulin analogue use and glucose management. In 2018, compared with non‐Hispanic white adults, non‐Hispanic black, Hispanic and other race/ethnicity groups had lower rates of using newer GLDs (adjusted risk ratio: 0.44, 0.52, 0.64, respectively; p <.05 for all) and insulin analogues (adjusted risk ratio: 0.93, 0.89, 0.95, respectively; p <.05 for all except other groups), lower non‐insulin GLD adherence (proportion of days covered: −4.5%, −5.6%, −4.3%, respectively; p <.05 for all), higher glycated haemoglobin A1c (0.29%, 0.32%, 0.02%, respectively; p <.05 for all except other group), and similar insulin adherences. Socioeconomic and health status were the main contributors to these disparities. Conclusions: Our findings provide evidence of racial and ethnic disparities in newer GLD use and quality of care in glucose management. Our study results can inform decision‐makers of the status of racial and ethnic disparities and identify ways to reduce these disparities. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the real‐world effectiveness and safety of insulin glargine 300 U/ml (Gla‐300) in achieving glycaemic goals in insulin‐naïve people with type 2 diabetes (T2D) in Mexico, Colombia and Peru (Latin America region) in the A Toujeo Observational Study (ATOS). Materials and Methods: ATOS was a multicentre, prospective, 12‐month observational study, which included 4422 insulin‐naïve adults (age ≥ 18 years) with T2D uncontrolled (HbA1c > 7% and ≤11%) on at least one oral antidiabetic drug (OAD) who initiated Gla‐300 treatment as per routine practice. The primary endpoint was the percentage of participants achieving their predefined individualized HbA1c goal at month 6. Key secondary endpoints included change from baseline in HbA1c, fasting plasma glucose (FPG), fasting self‐monitored blood glucose (SMBG), body weight and incidence of hypoglycaemia. Results: In this subgroup analysis, a total of 314 participants with T2D received Gla‐300. At baseline, mean ± SD age was 56.0 ± 11.6 years, duration of diabetes was 9.7 ± 6.6 years and 65.9% of participants were on at least two OADs. The individualized HbA1c target was achieved by 25.8% of participants (95% confidence interval [CI]: 20.3‐31.9) at month 6 and by 35.3% (95% CI: 28.5‐42.5) at month 12. Gla‐300 treatment improved glycaemic control with meaningful reductions in mean HbA1c, FPG and fasting SMBG. The incidence of hypoglycaemia reported was low and body weight remained stable. Conclusions: In a real‐world setting in the Latin America region, the initiation of Gla‐300 in people with T2D uncontrolled on OADs resulted in improved glycaemic control with a low incidence of hypoglycaemia and no change in body weight. [ABSTRACT FROM AUTHOR]

Background: Insulin therapy regimens for people with type 1 diabetes (PWT1D) should mimic the physiological insulin secretion that occurs in individuals without diabetes. Intensive insulin therapy, whether by multiple daily injections (MDI) or continuous subcutaneous insulin infusion (CSII), constitutes the fundamental therapy from the initial stages of type 1 diabetes (T1D), at all ages. This review is an authorized literal translation of part of the Brazilian Diabetes Society (SBD) Guidelines 2021–2022. This evidence-based guideline supplies guidance on insulin therapy in T1D. Methods: The methods were published elsewhere in earlier SBD guidelines and was approved by the Internal Institutional Steering Committee for publication. Briefly, the Brazilian Diabetes Society indicated fourteen experts to constitute the Central Committee, designed to regulate the method review of the manuscripts, and judge the degrees of recommendations and levels of evidence. SBD Type 1 Diabetes Department drafted the manuscript selecting key clinical questions to do a narrative review using MEDLINE via PubMed, with the best evidence available, including high-quality clinical trials, metanalysis, and large observational studies related to insulin therapy in T1D, by using the Mesh terms [type 1 diabetes] and [insulin]. Results: Based on extensive literature review the Central Committee defined ten recommendations. Three levels of evidence were considered: A. Data from more than one randomised clinical trial (RCT) or one metanalysis of RCTs with low heterogeneity (I2 < 40%). B. Data from metanalysis, including large observational studies, a single RCT, or a pre-specified subgroup analysis. C: Data from small or non-randomised studies, exploratory analysis, or consensus of expert opinion. The degree of recommendation was obtained based on a poll sent to the panellists, using the following criteria: Grade I: when more than 90% of agreement; Grade IIa if 75–89% of agreement; IIb if 50–74% of agreement, and III, when most of the panellist recommends against a defined treatment. Conclusions: In PWT1D, it is recommended to start insulin treatment immediately after clinical diagnosis, to prevent metabolic decompensation and diabetic ketoacidosis. Insulin therapy regimens should mimic insulin secretion with the aim to achieve glycemic control goals established for the age group. Intensive treatment with basal-bolus insulin therapy through MDI or CSII is recommended, and insulin analogues offers some advantages in PWT1D, when compared to human insulin. Periodic reassessment of insulin doses should be performed to avoid clinical inertia in treatment. [ABSTRACT FROM AUTHOR]

Aims: To compare the risk of cardiovascular outcomes associated with long‐acting insulin analogues versus neutral protamine Hagedorn (NPH) insulin among patients with type 2 diabetes. Materials and Methods: We conducted a population‐based retrospective cohort study using the UK Clinical Practice Research Datalink Aurum, linked with hospitalization and vital statistics data. Patients with type 2 diabetes who initiated basal insulin treatment between 2002 and 2018 were included in the study. Exposure was defined as current use of long‐acting insulin analogues or NPH insulin, defined using a time‐varying approach. The primary outcome was major adverse cardiovascular events (MACE; a composite endpoint of myocardial infarction, ischaemic stroke and cardiovascular death). We used a marginal structural Cox proportional hazards model to estimate the hazard ratio (HR) and 95% confidence interval (CI) for MACE with current use of long‐acting insulin analogues versus NPH insulin, and in secondary analyses, by long‐acting insulin molecule. Results: Our cohort included 57 334 patients. A total of 3494 MACE occurred over a mean follow‐up of 1.6 years (incidence rate 37.4, 95% CI 36.2 to 38.7 per 1000 person‐years). Long‐acting insulin analogues were associated with a decreased risk of MACE compared to NPH insulin (HR 0.89, 95% CI 0.83 to 0.96). Conclusions: Current use of long‐acting insulin analogues is associated with a modestly reduced risk of MACE compared to current use of NPH insulin among patients with type 2 diabetes. This study could have important implications for drug plan managers and guideline‐writing committees for recommendations of insulin treatment for type 2 diabetes. [ABSTRACT FROM AUTHOR]

The first preparation of insulin extracted from a pancreas and made suitable for use in humans after purification was achieved 100 years ago in Toronto, an epoch-making achievement, which has ultimately provided a life-giving treatment for millions of people worldwide. The earliest animal-derived formulations were short-acting and contained many impurities that caused adverse reactions, thereby limiting their therapeutic potential. However, since then, insulin production and purification improved with enhanced technologies, along with a full understanding of the insulin molecule structure. The availability of radio-immunoassays contributed to the unravelling of the physiology of glucose homeostasis, ultimately leading to the adoption of rational models of insulin replacement. The introduction of recombinant DNA technologies has since resulted in the era of both rapid- and long-acting human insulin analogues administered via the subcutaneous route which better mimic the physiology of insulin secretion, leading to the modern basal-bolus regimen. These advances, in combination with improved education and technologies for glucose monitoring, enable people with diabetes to better meet individual glycaemic goals with a lower risk of hypoglycaemia. While the prevalence of diabetes continues to rise globally, it is important to recognise the scientific endeavour that has led to insulin remaining the cornerstone of diabetes management, on the centenary of its first successful use in humans. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

In time, prescription of insulin therapy (IT) becomes inevitable for many patients with type 2 diabetes mellitus (DM) to achieve and maintain the target hypoglycemic range.According to the current guidelines, the addition of basal insulin to glucose-lowering therapy in patients with insufficient control of type 2 diabetes, gradual titration of its dose in accordance with a fasting blood glucose level is an effective and safe method for initiating IT. The properties of modern long-acting insulin analogues are considered. Glargine 300 U/ml is a modern analogue of long-acting insulin that is intended to be used once a day. The glargine molecule forms the basis of the drug. Increasing the concentration of glargine per volume unit and formation of a smaller subcutaneous depot led to a change in the pharmacokinetic properties of the drug. Glargine 300 IU/ml provides a more stable, long-term, predictable action with low glycemic variability as compared with glargine 100 IU/ml, which reduces the risk of hypoglycemia. The sugar-reducing efficacy and safety of insulin glargine 300 U/ml as evidenced by the findings of the international clinical phase III EDITION studies are discussed. Insulin glargine 300 U/ml showed a similar decrease in HbA1c levels compared to insulin glargine 100 U/ml with an improved safety profile (lower risk of developing episodes of confirmed or severe hypoglycemia at all times of the day, including the nighttime) and a less pronounced effect on the body weight of patients with type 2 diabetes. The efficacy and safety of the use of glargine 300 U/ml has been confirmed in type 2 diabetes patients with chronic kidney disease and the elderly. In the BRIGHT study, glargine 300 U/ml showed comparable glycemic control when it is being compared.

Introduction: Poor drug compliance affects clinical outcome and increases healthcare costs in various disease setting. Several type II diabetes mellitus patients, not controlled on oral hypoglycaemics eventually require insulin therapy. Antidiabetic treatment is to be taken lifelong and in such a setting insulin price variation imposes a huge economic burden on poor diabetic patients. Moderating drug cost is associated with improved adherence to the medication regimen. Aim: To study the variation in cost amongst various brands of insulin analogues. Materials and Methods: This was an observational, cross-sectional study. Data regarding the 116 formulations and cost of 18 types of insulin preparations was collected from sources like Current Index of Medical Specialties (CIMS), National Pharmaceutical Pricing Authority (NPPA), Government of India official website (https://nppaimis.nic.in/nppaprice/pharmasahidaamweb.aspx) and compared with its lowest counterpart. The cost ratio and percentage cost variation was analysed and expressed as percentages. Results: This study showed a noticeable variation in the prices of insulin analogues. The highest percentage of cost variation was found for Insulin (Highly Purified) Zinc-40 IU (135.17%), followed by Insulin (Analogue) Glargine-100 IU (109.31%). The lowest percentage were for: Insulin (Human-Isophane Recombinant)-40 IU (1.40%), and Insulin (Analogue) Aspart- 100 IU (6.26%). Conclusion: A noticeable variation in cost prices was observed especially in commonly used intermediate acting insulin that help basal glycaemic control. Similarly, the lowest variation was observed with recombinant counterparts as an effect of pre-existing high prices of each. Need for vital medication like insulin at affordable costs has incited national and global efforts to make it cheaper and accessible to maximum beneficiaries.

Abstract The Global Diabetes Compact was launched by the World Health Organization in April 2021 with one of its important goals to increase the accessibility and affordability of life-saving medicine—insulin. The rising prevalence of diabetes worldwide is bound to escalate the demand for recombinant insulin therapeutics, and currently, the majority of recombinant insulin therapeutics are produced from E. coli inclusion bodies. Here, a comprehensive review of downstream processing of recombinant human insulin/analogue production from E. coli inclusion bodies is presented. All the critical aspects of downstream processing, starting from proinsulin recovery from inclusion bodies, inclusion body washing, inclusion body solubilization and oxidative sulfitolysis, cyanogen bromide cleavage, buffer exchange, purification by chromatography, pH precipitation and zinc crystallization methods, proinsulin refolding, enzymatic cleavage, and formulation, are explained in this review. Pertinent examples are summarized and the practical aspects of integrating every procedure into a multimodal purification scheme are critically discussed. In the face of increasing global demand for insulin product, there is a pressing need to develop a more efficient and economical production process. The information presented would be insightful to all the manufacturers and stakeholders for the production of human insulins, insulin analogues or biosimilars, as they strive to make further progresses in therapeutic recombinant insulin development and production.

Aims: To provide real‐world data on the addition of basal insulin (BI) in people with type 2 diabetes mellitus (PWD2) suboptimally controlled with glucagon‐like peptide‐1 receptor agonist (GLP‐1RA) therapy. However, real‐world data on the addition of BI to GLP‐1RA therapy are limited. Materials and Methods: We used a US electronic medical record data source (IBM® Explorys®) that includes approximately 4 million PWD2 to assess the real‐world impact of adding the second‐generation BI analogue insulin glargine 300 U/mL (Gla‐300) to GLP‐1RA therapy. Insulin‐naïve PWD2 receiving GLP‐1RAs who also received Gla‐300 between March 1, 2015 and September 30, 2019 were identified; participants were required to have data for ≥12 months before, and ≥6 months after, addition of Gla‐300. Results: The mean (standard deviation [SD]) age of participants (N = 271) was 57.9 (10.8) years. Baseline glycated haemoglobin (HbA1c) was 9.16% and was significantly reduced (−0.97 [SD 1.60]%; P < 0.0001) after addition of Gla‐300; a significant increase in the proportion of PWD2 achieving HbA1c control was observed after addition of Gla‐300 (HbA1c <7.0%: 4.80% vs. 22.14%, P < 0.0001; HbA1c <8.0%: 19.56% vs. 51.29%, P < 0.0001). The incidence of overall (8.49% vs. 9.59%; P = 0.513) and inpatient/emergency department (ED)‐associated hypoglycaemia (0.37% vs. 0.74%; P = 1.000), as well as overall (0.33 vs. 0.46 per person per year [PPPY]; P = 0.170) and inpatient/ED‐associated hypoglycaemia events (0.01 vs. 0.04 PPPY; P = 0.466) were similar before and after addition of Gla‐300. Conclusions: In US real‐world clinical practice, adding Gla‐300 to GLP‐1RA significantly improved glycaemic control without significantly increasing hypoglycaemia in PWD2. Further research into the effect of adding Gla‐300 to GLP‐1RA therapy is warranted. [ABSTRACT FROM AUTHOR]

Insulin analogues and large bioactive peptides may be used by athletes to enhance performance and are banned by the World Anti‐Doping Agency (WADA). In addition to insulin analogues, the large peptides include a structurally diverse set of peptides including analogues of growth hormone releasing hormone (GHRH), insulin‐like growth factor‐1 (IGF‐1), and mechano‐growth factor (MGF). Detection of this class of peptides is difficult due to their absorptive losses and presence at very low concentrations in urine. In this report, a high throughput method is described that allows sensitive detection of four classes of large peptides in one assay. Sample extraction is performed by ultrafiltration to concentrate the urine followed by solid phase extraction in a 96‐well micro‐elution plate. Peptides in the urine samples are detected on a triple quadrupole mass spectrometer coupled to standard flow liquid chromatography. The method was validated and evaluated for limit of detection, limit of identification, specificity, precision, carryover, recovery, matrix interference, and post‐extraction stability. The limit of detection for insulin analogues is between 5 and 25 pg/ml and between 5 and 50 pg/ml for the other peptide classes. Specificity was good with no detection of interfering peaks in blank urine samples. Carryover from a high concentration sample was not observed and the post‐extraction stability was between 77% and 107%. The method was able to detect insulin analogues in three diabetic urine samples. Increased screening for this class of peptides will improve detection and deterrence. [ABSTRACT FROM AUTHOR]

ABSTRACT Objective: The aim of this study was to evaluate the frequency of hypoglycemia and the treatment satisfaction in patients with type 1 diabetes (T1D) using insulin analogues. Subjects and methods: This observational retrospective study included 516 adult patients with T1D from 38 cities in Southern Brazil. Demographics and clinical data were collected using a self-report questionnaire. Hypoglycemia was defined as an event based on either symptoms or self-monitored blood glucose < 70 mg/dL. Treatment satisfaction was evaluated using the Diabetes Treatment Satisfaction Questionnaire status version (DTSQs) and with a specific question with scores ranging from 0–10. Common mental disorders were assessed using the General Health Questionnaire (GHQ-12). Results: Overall, the mean age was 38 ± 14 years and 52% of the participants were women. The median diabetes duration was 18 years. The scores for insulin analogue treatment satisfaction were higher than those for previous treatments. DTSQ scores had a median value of 32 (interquartile range 29–35) and remained unchanged over time. The percentage of patients with hypoglycemia (including severe and nocturnal) was comparable across groups divided according to duration of use of insulin analogues. Most patients (n=395, 77%) screened positive for common mental disorders. Conclusions: Patient satisfaction with insulin analogue treatment was high and remained unchanged with time. Episodes of hypoglycemia also remained unchanged over time among patients using insulin analogues.

Objective To investigate the effects of subcutaneous injection of quick acting insulin analogues on blood glucose level and MCP-1 in patients with hyperglycemic crisis. Methods A total of 89 patients with hyperglycemia crisis in our hospital from March 2017 to November 2018 were randomly divided into observation group (n = 45, subcutaneous injection of insulin analogue after insulin injection with micropump stopped) and control group (n = 44, insulin analogues were administered subcutaneously 1 hour before the insulin micropump was discontinued). The mean blood glucose values and blood glucose fluctuation amplitude of patients in the two groups were measured at 0.5 and 1 h before pump withdrawal and 0.5, 1 and 2 h after pump withdrawal. White blood cell index (WBC), urine ketone body, monocyte chemochemic protein-1 (MCP-1), insulin resistance index (HOMAIR), osmotic pressure and anionic gap were detected in 2 groups > 24 h, and the changes of patients status were analyzed. Results There was no significant difference in blood glucose fluctuation between 2 groups at 0.5 h before pump stop, 0.5, 1 and 2 h after pump stop (P > 0.05). There were no differences in homA-IR, WBC, MCP-1, urine ketone body, osmotic pressure and anionic gap between 2 groups before and after insulin analogue injection at different time points for 24 h (P > 0.05). Conclusion For patients with hyperglycemic crisis, the conversion of subcutaneous insulin injection can be carried out simultaneously when the intravenous pump injection of insulin is stopped, and there is no effect on the blood glucose fluctuation, HOMA-IR, MCP-1, urinary ketone body, WBC, osmotic pressure and anion gap indexes 24 hours before and after injection. [ABSTRACT FROM AUTHOR]

Aim: To determine the effect of insulin on the resistance of subcutaneous tissue to the flow of infusion fluids. Materials and methods: Thirty subjects with type 1 diabetes wore two Accu‐Chek Spirit Combo insulin pumps with Accu‐Chek FlexLink infusion sets (Roche Diabetes Care, Mannheim, Germany) for 7 days. One pump was filled with insulin aspart (Novo Nordisk, Bagsvaerd, Denmark) and used for continuous subcutaneous insulin infusion (CSII). The other pump was filled with insulin diluting medium (IDM; Novo Nordisk) and used to deliver IDM subcutaneously at rates identical to those employed for CSII. Both infusion sites were assessed daily by measuring the pressure required to infuse various bolus amounts of IDM. Results: On day 1, maximum pressure (Pmax) and tissue flow resistance (TFR; calculated from measured pressure profiles) were similar for both infusion sites (P > 0.20). During the subsequent study days, the Pmax and TFR values observed at the IDM infusion site remained at levels comparable to those seen on day 1 (P > 0.13). However, at the site of CSII, Pmax and TFR progressively increased with CSII duration. By the end of day 7, Pmax and TFR reached 25.8 */2.11 kPa (geometric mean */geometric standard deviation) and 8.64 */3.48 kPa*s/μL, respectively, representing a remarkable 3.5‐ and 20.6‐fold increase relative to the respective Pmax and TFR values observed on day 1 (P < 0.001). Conclusion: Our results suggest that insulin induces a progressive increase in the resistance of subcutaneous tissue to the introduction of fluid; this has important implications for the future design of insulin pumps and infusion sets. [ABSTRACT FROM AUTHOR]

Insulin-induced lipoatrophy is a rare skin complication in patients with diabetes mellitus. It is characterized primarily by localized subcutaneous atrophy of the fatty tissue at the site of frequent insulin injection. We report a clinical case of a 38-year-old woman with lipoatrophy, developed during treatment with insulin analogues. Lipoatrophic zone formation began 3 months after the treatment was initiated. A lipoatrophic defect developed on the thighs and the upper outer arms, resulting from repeated insulin injections at the same site. Regarding lipoatrophic areas, treatment with topical administration of corticosteroids was attempted but without a significant clinical effect. The best prevention from lipoatrophy development is education of patients regarding rotation of insulin injection sites and more frequent needle change.

Indeed, Roche immunoassay is known to specifically detect endogenous insulin and to have a negligible cross-reactivity with recombinant insulin analogues [[1]], whereas Siemens method recognizes both endogenous insulin and the analogues [[2]]. Keywords: Hypoglycemia; Insulinemia; Insulin analogues; Immunoassays cross-reactivity EN Hypoglycemia Insulinemia Insulin analogues Immunoassays cross-reactivity 315 317 3 01/23/23 20230201 NES 230201 Automated immunoassays allow for measuring insulin in the context of hypoglycemia. When hidden insulin injections are suspected, we suggest to consider, early in the diagnosis process, two insulin quantification methods bearing different cross-reactivity for insulin analogues. [Extracted from the article]

Background: Diabetic kidney disease is the leading cause of chronic kidney disease (CKD) and end‐stage kidney disease (ESKD) worldwide. ESKD has a high prevalence in patients with diabetes mellitus (DM). CKD increases the chances of hypoglycaemia by different mechanisms, causes insulin resistance and a decrease in insulin metabolism. Both the "Kidney Disease: Improving Global Outcomes" (KDIGO) and "American Diabetes Association" (ADA) guidelines recommend the use of insulin as part of treatment, but the type of basal insulin is not specified. Methods: We reviewed the literature to determine whether first‐ and second‐generation basal insulins are effective and safe in CKD patients. We reviewed specific pivotal studies conducted by pharmaceutical laboratories, as well as independent studies. Conclusions: Basal insulins are safe and effective in patients with CKD and diabetes mellitus but we do not have specific studies. Given that CKD is one of the main complications of type 2 DM, and insulin specific treatment in the final stages, the absence of studies is striking. Real‐life data are also important since trials such as pivotal studies do not fully represent actual patients. Treatment should be individualized until we have specific trials in this type of population. [ABSTRACT FROM AUTHOR]

Aim: To investigate whether the long‐acting insulin analogue insulin degludec compared with insulin glargine U100 reduces the risk of nocturnal symptomatic hypoglycaemia in patients with type 1 diabetes (T1D). Methods: Adults with T1D and at least one episode of nocturnal severe hypoglycaemia during the last 2 years were included in a 2‐year prospective, randomized, open, multicentre, crossover trial. A total of 149 patients were randomized 1:1 to basal‐bolus therapy with insulin degludec and insulin aspart or insulin glargine U100 and insulin aspart. Each treatment period lasted 1 year and consisted of 3 months of run‐in or crossover followed by 9 months of maintenance. The primary endpoint was the number of blindly adjudicated nocturnal symptomatic hypoglycaemic episodes. Secondary endpoints included the occurrence of severe hypoglycaemia. We analysed all endpoints by intention‐to‐treat. Results: Treatment with insulin degludec resulted in a 28% (95% CI: 9%‐43%; P =.02) relative rate reduction (RRR) of nocturnal symptomatic hypoglycaemia at level 1 (≤3.9 mmol/L), a 37% (95% CI: 16%‐53%; P =.002) RRR at level 2 (≤3.0 mmol/L), and a 35% (95% CI: 1%‐58%; P =.04) RRR in all‐day severe hypoglycaemia compared with insulin glargine U100. Conclusions: Patients with T1D prone to nocturnal severe hypoglycaemia have lower rates of nocturnal symptomatic hypoglycaemia and all‐day severe hypoglycaemia with insulin degludec compared with insulin glargine U100. [ABSTRACT FROM AUTHOR]

Keywords: insulin analogues; insulin therapy; type 2 diabetes EN insulin analogues insulin therapy type 2 diabetes 332 336 5 01/11/22 20220201 NES 220201 PEER REVIEW The peer review history for this article is available at https://publons.com/publon/10.1111/dom.14564. Risk of hypoglycaemia with insulin degludec versus insulin glargine U300 in insulin-treated patients with type 2 diabetes: the randomised, head-to-head CONCLUDE trial. HbA1c levels and rates of hypoglycemia with insulin degludec U200 and insulin glargine U300 stratified by estimated renal function in people with type 2 diabetes: a post hoc analysis from the CONCLUDE trial. [Extracted from the article]

During 1921 to 1922, a team effort by Banting, Macleod, Collip and Best isolated and purified insulin and demonstrated its life‐giving properties, giving rise to the birth of insulin therapy. In the early years (1922‐1950), priorities revolved around the manufacture of insulin to meet demand, improving purity to avoid allergic reactions, establishing insulin standards and increasing its duration of action to avoid multiple daily injections. Shortly after the emergence of insulin, Joslin and Allen advocated the need to achieve and maintain good glycaemic control to realize its full potential. Although this view was opposed by some during a dark period in the history of insulin, it was subsequently endorsed some 60 years later endorsed by the Diabetes Control and Complications Trial and United Kingdom Prospective Diabetes Study. Major scientific advances by the Nobel Laureates Sanger, Hodgkin, Yalow and Gilbert and also by Steiner have revolutionized the understanding of diabetes and facilitated major advances in insulin therapy. The more recent advent of recombinant technology over the last 40 years has provided the potential for unlimited source of insulin, and the ability to generate various insulin 'analogues', in an attempt to better replicate normal insulin secretory patterns. The emerging biosimilars now provide the opportunity to improve availability at a lower cost. [ABSTRACT FROM AUTHOR]

Aims: This study evaluated the effectiveness and safety of switching the basal insulin (BI) in a BI‐supported oral therapy (BOT) to insulin glargine 300 U/ml (Gla‐300) in adults with inadequately controlled type 2 diabetes (T2D). Materials and methods: This was a non‐interventional, multicentre, prospective 12‐month study, conducted in Germany, Austria and Switzerland. The study documented people with T2D with glycated haemoglobin (HbA1c) between 7.5% and 10.0%, currently treated by a non‐Gla‐300 BOT regimen, after the physician had decided to switch the BI to Gla‐300. Primary endpoint was the proportion of patients achieving the fasting plasma glucose (FPG; ≤110 mg/dl) target. Results: In total, 1194 participants comprised the full analysis set, of which 793 completed documentation of 12 months Gla‐300 treatment (FAS‐M12). The main previous BI was insulin glargine 100 U/ml (Gla‐100; 47.2%). Twelve months after switching to Gla‐300, 27.0% of FAS‐M12 participants achieved the FPG target and 44.8% their individualized HbA1c target. The greatest FPG target achievements were seen in previous Gla‐100 (29.3%), and greatest HbA1c target achievements in previous insulin detemir users (57.7%). The mean FPG decreased by −36.3 ± 51.2 mg/dl to 135.5 ± 36.9 mg/dl and mean HbA1c by −0.79 ± 1.01% to 7.45 ± 0.94%. Symptomatic and nocturnal hypoglycaemia incidence significantly decreased over 12 months of Gla‐300 treatment. Body weight remained unchanged. Conclusions: Switching the BI to Gla‐300 in a BOT regimen improved metabolic control and treatment satisfaction in a substantial proportion of patients with T2D and inadequate target achievement within 12 months in clinical practice with a decreased risk of symptomatic and nocturnal hypoglycaemia and without weight gain. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the efficacy and safety of switching from traditional mealtime insulins to fast‐acting insulin aspart (Fiasp) in a "real‐world" clinical practice setting in adult people with type 1 diabetes (PWD1) who were using intermittently scanned or real‐time continuous glucose monitoring (isCGM or rtCGM, respectively). Materials and Methods: Data from 438 adult PWD1 (60% men, age 44.6 ± 16.2 years, diabetes duration 21.5 ± 14.0 years, isCGM/rtCGM: 391/47, multiple daily injections/continuous subcutaneous insulin infusion: 409/29), who initiated Fiasp from January 2018 to May 2020, were analysed. The primary objective was the evolution of time in range (TIR; 70‐180 mg/dL) at 6 and 12 months. Secondary objectives included change in HbA1c, body mass index (BMI), insulin doses, time below range (<70 and <54 mg/dL), and time above range (>180 and >250 mg/dL). Results: TIR improved from 50.3% ± 15.6% to 54.3% ± 15.1% at 6 months (n = 425) and to 55.5% ± 15.2% at 12 months (n = 385) (P <.001), corresponding to 57 min/d at 6 months and 75 min/d at 12 months. Time spent below 54 mg/dL evolved from 3.1% ± 3.3% to 3.1% ± 3.7% and 2.5% ± 3.0% at 6 and 12 months, respectively (P =.011). Also, time spent above 180 mg/dL decreased from 42.3% ± 16.7% at start by 4.2% at 6 months and by 4.6% at 12 months (P <.001). The proportion of people reaching TIR more than 70% increased from 11.0% to 14.8% (P =.002), and those spending less than 4% at time less than 70 mg/dL increased from 36.1% to 42.1% (P =.002). After 12 months, HbA1c, insulin doses, and BMI did not change significantly. Conclusions: In a Belgian real‐world setting of adult PWD1, switching to Fiasp was associated with a 5% increased TIR after 12 months, corresponding to 75 min/d, in combination with less time spent below and above range. [ABSTRACT FROM AUTHOR]

Diabetes, referred to as the first non-infectious epidemic, covers a heterogenous group of metabolic diseases marked by hyperglycemia resulting from a defect of insulin secretion and/or insulin resistance. Highly endocrine active adipocytes, particularly those located in white adipose tissue, constitute a source of cytokines, growth factors and complement component as well as adipocytokines including chemerin and progranulin could be the key molecules in the pathomechanism of hypertension, dyslipidemia, metabolic disorders or diabetes type 2. In this study, it was decided to verify the existence of possible relationships between the plasma concentration of progranulin and chemerin and the values of intermediate indices of insulin sensitivity and insulin resistance in patients, both before and after the 6-month insulin therapy by long-acting insulin analogue and premixed insulin analogue. The level of laboratory parameters in blood plasma collected from the control group and from obese individuals with type 2 diabetes mellitus was estimated with the test kits using enzyme-linked immunosorbent assay (ELISA): the test of Mediagnost E103 GmbH GmbH, Reutlingen, Germany for progranulin; the test of BioVendor R&D, Brno, Czech Republic for chemerin. The aim of this study was to assess the progranulin and chemerin plasma level in obese individuals with type 2 diabetes, before and after 6 months of pharmacological treatment with a long-acting analogue human insulin or premixed insulin. In the blood plasma of untreated diabetics - in contrary to progranulin plasma concentration in diabetic patients after management implementation - progranulin was found to occur in a significantly higher concentration in relation to the level of this protein in the blood plasma of control group individuals. Despite the fact that 6-month therapy, both with the insulin mixture and with the long-acting analogue in people with diabetes, does not significantly affect the plasma chemerin concentration, the high, negative correlation between the progranulin and chemerin levels in the blood of individuals of the control group, and a positive one between the levels of progranulin and chemerin in people with diabetes before and after treatment was found. The conducted studies indicated the modified, in the course of diabetes type 2, mutual quantitative relations between progranulin and chemerin - the biological mediators of systemic metabolism, reflecting their active participation in the pathogenetic changes underlying type 2 diabetes. The obtained study results indicate a modification of mutual relationships of the adipocytokines assessed in the paper - progranulin and chemerin, associated with the development of the systemic inflammatory response occurring in the course of obesity which, by inducing insulin resistance, may consequently lead to type 2 diabetes. Taking into consideration the fact that the plasma progranulin and chemerin concentrations in obese patients with type 2 diabetes subjected to pharmacotherapy have not been assessed so far, it is possible that the obtained study results may cast light on the potential influence of the applied treatment on the systemic changes of the both adipocytokines involved in the pathomechanism of the mentioned disorder and thus create the possibility of implementing new therapeutic strategies in the management of patients with diabetes, which is an increasingly common, fast-spreading metabolic disease considered as a non-infectious epidemic of the 21st century. [ABSTRACT FROM AUTHOR]

Aim: The aim of the present network meta-analysis is to assess the efficacy and safety across different long and short-acting analogs for the treatment of type 2 diabetes. Methods: A PubMed, EMBASE, and Cochrane Central Register of Controlled Trials databases search (20th May, 2020) for all trials with a duration ≥24 weeks comparing an analogue with another or human insulin was performed. Indirect comparisons were performed by NMA choosing glargine U100 and human regular insulin, as the reference for long- and short-acting analogues, respectively. Primary endpoints were HbA1c at 24, 52, and 104 weeks. The weighted difference in means (WDM) and Mantel-Haenzel Odds Ratio [MH-OR] with 95% Confidence Intervals (CI) were calculated for categorical and continuous variables, respectively. Results: Fifty trials (n = 43) and 7 for basal and prandial analogues, respectively, enrolling 25,554 and 3184 patients with type 2 and 1 diabetes, respectively, were included. At NMA, detemir was less effective than glargine U-100 at 52 weeks. A significant reduction of 24-week HbA1c (WMD [IC]: −0.10 [−0.17, −0.03]%); and risk of total (MH-OR [IC]: 0.80 [0.70, 0.91]), and nocturnal hypoglycemia (MH-OR [IC]: 0.57 [0.45, 0.73]) was observed for basal analogues versus NPH insulin. At NMA, glargine U300 and degludec were associated with a significant reduction in the risk of nocturnal hypoglycemia. No significant differences across different short-acting insulin were observed. Conclusions: This paper supports the use of long-acting analogues, rather than NPH insulin, as basal insulin for the treatment of type 2 diabetes, without any preferences for any individual long-acting analogue over the others. The evidence on short acting analogues is limited. [ABSTRACT FROM AUTHOR]

Aims: To compare time in range (TIR) with use of insulin degludec U100 (degludec) versus insulin glargine U100 (glargine U100) in people with type 2 diabetes. Materials and Methods: We conducted a randomized, crossover, multicentre trial comparing degludec and glargine U100 in basal insulin‐treated adults with type 2 diabetes and ≥1 hypoglycaemia risk factor. There were two treatment periods, each with 16‐week titration and 2‐week maintenance phases (with evaluation of glucose using blinded professional continuous glucose monitoring). The once‐weekly titration (target: 3.9–5.0 mmol/L) was based on pre‐breakfast self‐measured blood glucose. The primary endpoint was percentage of TIR (3.9─10.0 mmol/L). Secondary endpoints included overall and nocturnal percentage of time in tight glycaemic range (3.9–7.8 mmol/L), and mean glycated haemoglobin (HbA1c) and glucose levels. Results: At baseline, participants (n = 498) had a mean (SD) age of 62.8 (9.8) years, a diabetes duration of 15.1 (7.7) years and an HbA1c level of 59.6 (11.0) mmol/mol (7.6 [1.0]%). Noninferiority and superiority were confirmed for degludec versus glargine U100 for the primary endpoint, with a mean TIR of 72.1% for degludec versus 70.7% for glargine U100 (estimated treatment difference [ETD] 1.43% [95% confidence interval (CI): 0.12, 2.74; P = 0.03] or 20.6 min/d). Overall time in tight glycaemic range favoured degludec versus glargine U100 (ETD 1.5% [95% CI: 0.15, 2.89] or 21.9 min/d). Degludec also reduced nocturnal time below range (TBR; <3.9 mmol/L) compared with glargine U100 (ETD −0.88% [95% CI: −1.34, −0.42] or 12.7 min/night; post hoc) and significantly fewer nocturnal hypoglycaemic episodes of <3.0 mmol/L were observed. Conclusions: Degludec, compared with glargine U100, provided more TIR and time in tight glycaemic range, and reduced nocturnal TBR in insulin‐treated people with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Currently, a large amount of data has been accumulated to compare recombinant human insulin with insulin analogues, including meta-analyzes of comparative efficacy and safety, as well as cost-effectiveness data and data on the possible carcinogenicity of new products. Insulin treatment is a necessity for some people with diabetes mellitus (DM) due to the need to maintain optimal blood glucose levels. The authors emphasize the need to keep in mind that new insulin drugs are much more expensive, which may limit their use. Factors such as the effectiveness of treatment, its safety, and patient satisfaction should be taken into account when deciding on the choice of therapy, but the cost of treatment cannot be ignored, given that it is usually reimbursable from the budget. In this regard, insulin therapy should be individually selected taking into account the needs of patients, treatment goals, safety, and cost. The authors propose an analysis of these data on the feasibility of using insulin analogues in comparison with recombinant human insulin for patients with type 1 diabetes and patients with type 2 diabetes and their effectiveness in both types of diabetes. A reasonable policy for the use of insulin therapy should be developed based on available clinical data based on comparative studies in different groups of diabetics and comprehensive analysis of economic data. The feasibility of a new drug should be evaluated and regularly reviewed in light of the practical results of its use in clinical practice. It is also necessary to regularly conduct a retrospective economic analysis to assess the pharmacoeconomic benefits. All of these steps should assist decision-makers and regulators in implementing effective national programs to develop new effective insulin procurement systems. [ABSTRACT FROM AUTHOR]

Basal insulin therapy in combination with oral hypoglycemic drugs has a special effect on fasting blood glucose. It is a simple way of introducing insulin therapy in patients with type 2 diabetes mellitus subjected to further prandial insulin therapy. Treatment with insulin mixtures reduces both fasting blood glucose and postprandial blood sugar, which has a negative effect on the development of vascular complications. With this simple therapy, there are limitations in everyday life and an adverse effect on the dynamics of body weight. Basal-bolus therapy focuses on pathophysiological changes, and with professional training and high-quality self-control provides good results with sufficient flexibility in everyday life. All insulin analogues have advantages over human insulins in terms of treatment outcomes, safety and patient compliance. All types of insulin therapy in clinical practice can be carried out by simple schemes

The paper considers insulin’s specific action on the patient’s body, types of insulin preparations and insulin analogues which are used for the treatment of diabetes, as well as applicable requirements for these products. It was demonstrated that determination of biological activity is one of the key quality parameters of this type of medicines. The paper summarises the methods used for evaluation of insulin and its analogues, which are based both on the hormone’s general action on the body (in vivo: double crossing, euglycemic clamp, etc.), and on certain aspects of the hormone’s interaction with the body systems (in vitro: receptor-binding assay, phosphorylation, metabolic methods). Due to the appearance of insulin biosimilars on the pharmaceutical market, the article raises the issue that the «Biological potency» parameter tested in animals should be kept as part of the product specification. The analysis of the in vivo and in vitro methods of biological activity determination convincingly demonstrates that animal models can not be replaced with the modern analytical methods based on cell cultures. Consequently, animal models are still necessary, as they allow for an adequate assessment of the quality of insulins in terms of «Biological potency». Taking into account the global trend towards reduction of animal testing, the authors point out the need to develop modern methods, the results of which will be comparable to the results of in vivo determination of the biological activity.