Mixed Insulin Research Articles

Novel Autologous Dendritic Cell Therapy AVT001 for Type 1 Diabetes

BackgroundCD8+ T regulatory (Treg) cells that recognize the nonclassical class 1b molecule Qa-1/human leukocyte antigen E (Q/E CD8+ Treg cells) are important in maintaining self-tolerance. We sought to investigate the role that these T cells play in type 1 diabetes (T1D) pathogenesis and whether an intervention targeting this mechanism may delay T1D progression.MethodsWe conducted a phase 1/2, randomized, double-blind, placebo-controlled trial of the autologous dendritic cell therapy AVT001 that included participants at least 16 years of age, within 1 year of T1D diagnosis, and with ex vivo evidence of a defect in Q/E CD8+ Treg function. Patients were randomly assigned in a 2:1 ratio to AVT001 or placebo, which was administered in three monthly intravenous infusions. The primary end point was safety; efficacy end points included changes from baseline in C-peptide area under the curve (AUC) during a 4-hour mixed meal, hemoglobin A1c (HbA1c), and insulin dose.ResultsSixteen patients received AVT001, and nine received placebo. Similar rates and severity of adverse events were observed in both groups. None of the patients in the AVT001 group had serious adverse events through visit day 360. Compared with placebo, treatment with ATV001 was associated with less decline from baseline log-transformed C-peptide AUC (nmol/l), with the treatment effect between AVT001 and placebo at day 150 of 0.09 (95% confidence interval [CI], 0.03 to 0.15) and at day 360 of 0.10 (95% CI, 0.04 to 0.15). No clear differences in change in HbA1c and insulin dose from baseline were observed between groups. Estimated treatment effects of AVT001 versus placebo at day 360 were −0.17% (95% CI, −0.60 to 0.26%) for HbA1c and −0.06 U/kg/day (95% CI, −0.14 to 0.02) for daily insulin dose.ConclusionsIn this phase 1/2 trial, AVT001 did not result in dose-limiting adverse events. Potential signals of efficacy observed here warrant further evaluation in a fully powered trial. (Funded by Avotres Inc. and the Division of Diabetes, Endocrinology, and Metabolic Diseases; ClinicalTrials.gov number, NCT03895996.)

Synergistic quantification of mixed insulin preparations using time domain NMR techniques

Diabetes patients often rely on tailored insulin therapies, necessitating precise blends of various insulin types to achieve optimal pharmacokinetic profiles, including the quantity and action duration of insulin absorption into the bloodstream. This study aimed to develop an accurate quantification method for mixed insulin preparations, consisting of Insulin-NPH and Insulin Regular in ratios varying between 0:100–100:0. Time Domain NMR (TD-NMR) techniques, T2 relaxation times, and T1T2 maps were used to analyze the mixtures. Individually, neither technique provided a reliable determination of insulin ratios. However, the integration of both methods through chemometrics has been proven to be a synergistic approach, yielding a robust quantification technique suitable for quality control in the assessment of mixed insulin drugs. This innovative combined TD-NMR method is non-invasive, cost-effective, and user-friendly, offering at the same time a significant potential for preventing health complications associated with improper insulin dosing. Furthermore, our work elucidates the broader applicability of converging multiple TD-NMR techniques for analyzing intricate mixtures.

Estimated Sustainable Cost-Based Prices for Diabetes Medicines

The burden of diabetes is growing worldwide. The costs associated with diabetes put substantial pressure on patients and health budgets, especially in low- and middle-income countries. The prices of diabetes medicines are a key determinant for access, yet little is known about the association between manufacturing costs and current market prices. To estimate the cost of manufacturing insulins, sodium-glucose cotransporter 2 inhibitors (SGLT2Is), and glucagonlike peptide 1 agonists (GLP1As), derive sustainable cost-based prices (CBPs), and compare these with current market prices. In this economic evaluation, the cost of manufacturing insulins, SGLT2Is, and GLP1As was modeled. Active pharmaceutical ingredient cost per unit (weighted least-squares regression model using data from a commercial database of trade shipments, data from January 1, 2016, to March 31, 2023) was combined with costs of formulation and other operating expenses, plus a profit margin with an allowance for tax, to estimate CBPs. Cost-based prices were compared with current prices in 13 countries, collected in January 2023 from public databases. Countries were selected to provide representation of different income levels and geographic regions based on the availability of public databases. Estimated CBPs; lowest current market prices (2023 US dollars). In this economic evaluation of manufacturing costs, estimated CBPs for treatment with insulin in a reusable pen device could be as low as $96 (human insulin) or $111 (insulin analogues) per year for a basal-bolus regimen, $61 per year using twice-daily injections of mixed human insulin, and $50 (human insulin) or $72 (insulin analogues) per year for a once-daily basal insulin injection (for type 2 diabetes), including the cost of injection devices and needles. Cost-based prices ranged from $1.30 to $3.45 per month for SGLT2Is (except canagliflozin: $25.00-$46.79) and from $0.75 to $72.49 per month for GLP1As. These CBPs were substantially lower than current prices in the 13 countries surveyed. High prices limit access to newer diabetes medicines in many countries. The findings of this study suggest that robust generic and biosimilar competition could reduce prices to more affordable levels and enable expansion of diabetes treatment globally.

A Randomized Crossover Trial of Mixed Meal Tolerance Test Response in People with Type1 Diabetes on Insulin Pump Therapy and YG1699 or Dapagliflozin.

YG1699 is a novel inhibitor of sodium-glucose cotransporter 1 (SGLT1) and SGLT2. This double-blind, 3-way crossover trial compared YG1699 to dapagliflozin as an adjunct to insulin in people with type 1 diabetes (T1D) on insulin pump therapy. Treatment periods included four mixed meal tolerance tests (MMTTs) and insulin withdrawal tests per person. Nineteen adults with T1D were randomized to YG1699 10 mg, YG1699 25 mg, and dapagliflozin 10 mg once daily for 1 week in different orders. The primary end point was the difference in area under the curve (AUC) in plasma glucose (AUC0-120min) after an MMTT between treatment groups. Mean change in plasma glucose after an MMTT (AUC0-120min) was lower for YG1699 10 mg vs. dapagliflozin (89.51% of baseline vs. 102.13%, 90% confidence interval (CI) vs. dapagliflozin, -6% to -16%, P = 0.0003) and for YG1699 25 mg (84.83% vs. 102.13%, 90% CI vs. dapagliflozin -13% to -22%, P < 0.0001). At 120 minutes, mean glucose values on no treatment, dapagliflozin, YG1699 10 mg, and YG1699 25 mg were 149 (SE 7.6), 141 (SE 6.1), 128 (SE 6.9), and 115 (SE 7.8) mg/dL, respectively. Insulin dose requirements were lower for YG1699 10 mg and 25 mg vs. dapagliflozin for bolus insulin, and for YG1699 10 mg vs. dapagliflozin for total daily insulin. Safety profiles were similar between treatment groups. YG1699 reduced post-prandial glucose more than dapagliflozin in people with T1D on insulin pump therapy. The results were consistent with dual SGLT1/SGLT2 inhibition by YG1699.

Improved perception of IGLARLIXI therapy compared to mixed insulin when transferred from basal insulin: outcomes reported by patients in the SoliMix study

Since type 2 diabetes mellitus (DM2) is characterized by a progressive loss of pancreatic beta cell function, there is a need to add insulin to current therapy in order to compensate for the disease and prevent the development of complications. The clinical recommendations suggest various options for the intensification of DM2 therapy: both monopreparations of insulin and its combination with aGPP-1. The latter have demonstrated clinical efficacy in achieving glycemic control and a favorable safety profile in clinical trials. Another important issue is the perception of treatment by the patient himself, since for many people, changing therapy or changing the “format” itself (prescribing injections) can be accompanied by additional stress.The purpose of this study was to study the efficacy and safety, as well as the perception of patients with treatment of DM2 when using a fixed combination of insulin glargine/lixisenatide (Iglarlixi) compared with mixed insulin – biphasic aspartame 30.

Early time-restricted carbohydrate consumption vs conventional dieting in type 2 diabetes: a randomised controlled trial

Aims/hypothesisEarly time-restricted carbohydrate consumption (eTRC) is a novel dietary strategy that involves restricting carbohydrate-rich food intake to the morning and early afternoon to align with circadian variations in glucose tolerance. We examined the efficacy, feasibility and safety of eTRC in individuals with type 2 diabetes under free-living conditions.MethodsIn this randomised, parallel-arm, open label, controlled trial, participants with type 2 diabetes and overweight/obesity (age 67.2±7.9 years, 47.8% women, BMI 29.4±3.7 kg/m2, HbA1c 49±5 mmol/mol [6.6±0.5%]) were randomised, using computer-generated random numbers, to a 12 week eTRC diet or a Mediterranean-style control diet with matched energy restriction and macronutrient distribution (50% carbohydrate, 30% fat and 20% protein). The primary outcome was the between-group difference in HbA1c at 12 weeks. Body composition, 14 day flash glucose monitoring and food diary analysis were performed every 4 weeks. Mixed meal tolerance tests with mathematical beta cell function modelling were performed at baseline and after 12 weeks.ResultsTwelve (85.7%) participants in the eTRC arm and 11 (84.6%) participants in the control arm completed the study, achieving similar reductions in body weight and fat mass. The two groups experienced comparable improvements in HbA1c (−3 [−6, −0.3] mmol/mol vs −4 [−6, −2] mmol/mol, corresponding to −0.2 [−0.5, 0]% and −0.3 [−0.5, −0.1]%, respectively, p=0.386), fasting plasma glucose, flash glucose monitoring-derived glucose variability and mixed meal tolerance test-derived glucose tolerance, insulin resistance, insulin clearance and plasma glucagon levels, without changes in model-derived beta cell function parameters, glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide and non-esterified fatty acid levels. The two diets similarly reduced liver function markers and triglyceride levels, being neutral on other cardiometabolic and safety variables. In exploratory analyses, diet-induced changes in body weight and glucometabolic variables were not related to the timing of carbohydrate intake.Conclusions/interpretationThe proposed eTRC diet provides a feasible and effective alternative option for glucose and body weight management in individuals with type 2 diabetes, with no additional metabolic benefits compared with conventional dieting.Trial registrationClinicalTrials.gov NCT05713058FundingThis study was supported by the European Society for Clinical Nutrition and Metabolism (ESPEN) and the Italian Society of Diabetology (SID).Graphical

A first-in-human, open-label Phase 1b and a randomised, double-blind Phase 2a clinical trial in recent-onset type 1 diabetes with AG019 as monotherapy and in combination with teplizumab

Aims/hypothesisWe hypothesised that islet beta cell antigen presentation in the gut along with a tolerising cytokine would lead to antigen-specific tolerance in type 1 diabetes. We evaluated this in a parallel open-label Phase 1b study using oral AG019, food-grade Lactococcus lactis bacteria genetically modified to express human proinsulin and human IL-10, as a monotherapy and in a parallel, randomised, double-blind Phase 2a study using AG019 in combination with teplizumab.MethodsAdults (18–42 years) and adolescents (12–17 years) with type 1 diabetes diagnosed within 150 days were enrolled, with documented evidence of at least one autoantibody and a stimulated peak C-peptide level >0.2 nmol/l. Participants were allocated to interventions using interactive response technology. We treated 42 people aged 12–42 years with recent-onset type 1 diabetes, 24 with Phase 1b monotherapy (open-label) and 18 with Phase 2a combination therapy. In the Phase 2a study, after treatment of the first two open-label participants, all people involved were blinded to group assignment, except for the Data Safety Monitoring Board members and the unblinded statistician. The primary endpoint was safety and tolerability based on the incidence of treatment-emergent adverse events, collected up to 6 months post treatment initiation. The secondary endpoints were pharmacokinetics, based on AG019 detection in blood and faeces, and pharmacodynamic activity. Metabolic and immune endpoints included stimulated C-peptide levels during a mixed meal tolerance test, HbA1c levels, insulin use, and antigen-specific CD4+ and CD8+ T cell responses using an activation-induced marker assay and pooled tetramers, respectively.ResultsData from 24 Phase 1b participants and 18 Phase 2a participants were analysed. No serious adverse events were reported and none of the participants discontinued AG019 due to treatment-emergent adverse events. No systemic exposure to AG019 bacteria, proinsulin or human IL-10 was demonstrated. In AG019 monotherapy-treated adults, metabolic variables were stabilised up to 6 months (C-peptide, insulin use) or 12 months (HbA1c) post treatment initiation. In participants treated with AG019/teplizumab combination therapy, all measured metabolic variables stabilised or improved up to 12 months and CD8+ T cells with a partially exhausted phenotype were significantly increased at 6 months. Circulating preproinsulin-specific CD4+ and CD8+ T cells were detected before and after treatment, with a reduction in the frequency of preproinsulin-specific CD8+ T cells after treatment with monotherapy or combination therapy.Conclusions/interpretationOral delivery of AG019 was well tolerated and safe as monotherapy and in combination with teplizumab. AG019 was not shown to interfere with the safety profile of teplizumab and may have additional biological effects, including changes in preproinsulin-specific T cells. These preliminary data support continuing studies with this agent alone and in combination with teplizumab or other systemic immunotherapies in type 1 diabetes.Trial registrationClinicalTrials.gov NCT03751007, EudraCT 2017-002871-24FundingThis study was funded by Precigen ActoBioGraphical

Evaluation of serum lipid in diabetic patients on differenttypes of treatment

Diabetes mellitus is chronic metabolic disorder which causes many complications. These are subdivided into microvascular complication affecting retina, kidney and peripheral nerves and macrovascular complications (atherosclerosis) affecting the major arterial systems including coronary arteries. Abnormal lipid metabolism is common in DM and it play an important role in the macrovascular complications. In this case control study 150 diabetic patients on different regimens of treatment were investigated for hyperlipidemia and compared to each other and to 50 apparently healthy control. Comparison of each group of diabetic patients with the control group was as follow; regarding total cholesterol there was no significant difference, higlyceride was significantly higher in group 2 (mixed insulin and oral hypoglycemic therapy), and group 3 (oral hypoglycemic drugs therapy) (P&lt;0.001) in comparison with control group, while in group I (only insulin therapy) it was lower than the control group, but the difference was siatistically not significant, HDL was significantly lower in all groups in comparison with control group and the least value of HDL was found in group 3 (P&lt;0.001). Regarding LDL there was no significant difference in comparison with the control group, while VLDL was higher in group 2 and 3 than the control group and the difference was significant (P&lt;0.001). Comparison of the measured parameters among three groups of diabetic patients was as follow; regarding total cholesterol and LDL there was no significant difference among these three groups. Triglycerides and VLDL were significantly lower in group 1 (P&lt;0.001), while HDL was significantly lower in group 3 (P&lt; 0.001). Cholesterol, triglycerides and VLDL were significantly higher in females in group 2 (P&lt;0.05). Regarding HDL and LDL no significant difference was found between males and females. In group I triglyceride was higher in those with 5 - l0 years treatment, while in group 2 &amp; 3 there was no significant difference in measured parameters regarding the duration of treatment

Mixed insulin can improve control of prednisolone-induced hyperglycaemia.

Hyperglycaemia is a common side effect of prednisolone, although there are no widely accepted guidelines for the management of glucocorticoid-induced hyperglycaemia (GIH). Our institution uses mixed insulin in a pre-breakfast or pre-breakfast and pre-lunch regimen, with the rationale that this profile of insulin action matches the physiological effect of prednisolone on blood glucose levels (BGLs). Evaluate the use of the mixed insulin (NovoMix30) in a pre-breakfast or pre-breakfast and pre-lunch regimen as management for GIH in a tertiary hospital setting. We retrospectively evaluated all inpatients coprescribed prednisolone ≥7.5 mg and NovoMix30 for at least 48 hoursover a 19-month period. BGLs were evaluated with repeated-measures analysis within four time periods across the day, beginning from the day prior to NovoMix30 administration. A total of 53 patients were identified. NovoMix30 significantly reduced BGLs in the morning (mean 12.7 ± 4.5 vs. 9.2 ± 3.9 mmol/L, P < 0.001), afternoon (mean 13.6 ± 3.8 vs. 11.9 ± 3.8 mmol/L, P = 0.001) and evening (12.1 ± 3.8 vs. 10.8 ± 3.8 mmol/L, P = 0.01). With uptitration of insulin over 3 days, 43% of all BGLs were within the target range, compared with 23% on day 0 (P < 0.001). The final median dose of NovoMix30 was 0.15 (0.10-0.22) units/kg bodyweight, or 0.40 (0.23-0.69) units/mg of prednisolone, which is lower than our hospital guideline recommends. One overnight hypoglycaemic event was observed. Mixed insulin as a pre-breakfast or pre-breakfast and pre-lunch regimen can target the hyperglycaemic pattern induced by prednisolone and minimise overnight hypoglycaemia. However, higher doses of insulin than those used in our study are likely required for optimal BGL control.

Follow-up of Patients After Total Pancreatectomy and Islet Cell Autotransplantation at Off-Site Islet Isolation Facility.

Total pancreatectomy with islet autotransplantation (TPIAT) is a definitive management for intractable pain in patients with chronic pancreatitis. Islet autotransplantation (IAT) allows for the preservation of beta-cells to prevent complications of long-term diabetes. Our study follows TPIAT recipients for up to 12 years to determine the procedure's efficacy completed with an off-site islet isolation facility. Patient demographics, mixed meal tolerance test measures, glycosylated hemoglobin, insulin requirements, and homeostatic model assessment for insulin resistance values were collected prior to surgery and at the most recent follow-up. Forty-four patients (median age, 46.0 years; range, 20-78 years) underwent TPIAT for CP. At an overall median follow-up time of 845.5 days (range, 195-4470 days) 8 patients were insulin independent and 36 patients were insulin dependent. At the most recent follow-up, islet yield per kilogram was the strongest indicator of insulin independence. Homeostatic model assessment for insulin resistance values were comparable between insulin independent and dependent cohorts. Our long-term follow-up data suggest that IAT can effectively reduce insulin requirements and improve post-operative glycemic control.

PSUN227 A retrospective comparison of Basal Bolus using Glargine U-300 and Glulisine with Premix Insulin

Abstract Objectives The objective of this retrospective analysis was to compare the occurrence of Level 1 hypoglycaemia, Level 2 hypoglycaemia, nocturnal hypoglycaemia and mean HBA1C reduction in patients treated with premixed insulin 30/70 (Insulin Isophane/NPH 70% + Human Insulin/Soluble Insulin 30%) and after initiating a basal bolus regime using Glargine U-300 and Glulisine. Level 1 hypoglycaemia is blood glucose less than 70 mg/dL but above 54 mg/dL. Level 2 hypoglycaemia is blood glucose less than 54 mg/dL. Methodology and Data Analysis Data was collected retrospectively over 6 months on adult outpatients who were on pre mix insulin 30/70 for at least 2 years and who frequently experienced hypoglycaemic episodes and after transitioning these patients to a basal bolus regime Glargine U-300 and Glulisine. Those were having an underlying etiology which would predispose them to hypoglycaemia were excluded. The exclusion criteria included malignancy, drug induced causes except premix insulin, Chronic Kidney disease stage 4 or 5 and acute or chronic hepatic failure. Blood glucose monitoring was done by a 7 point Self Monitoring of Blood Glucose. A total of 30 cases were randomly chosen and data were sought from patients’ home glucose logs, case notes and Electronic health care records. Data were analysed by Microsoft Excel and was compared with paired-T test. Results The average number of Level 1 hypoglycaemic episodes per week on premix insulin dropped from 6.517 to 0.9655 (t = -10.807456, p&amp;lt;0.00001) after initiating the basal bolus regime. The average number of level 2 hypoglycaemic episodes per week dropped from 2.034 to 0.379 (t = -8.733497, p&amp;lt;0.00001) after changing to basal bolus regime. There was also a reduction in the occurrence of average nocturnal hypoglycaemic episodes from 2.655 on pre mix insulin to 0.2068 on the basal bolus regimen (t = -8.635475, p&amp;lt;0.00001).The mean HbA1C reduction was 3.16% in three months after commencing the basal bolus regime (t = -27.554737, p&amp;lt;0.00001). Conclusions Outpatient treatment with the basal bolus regime consisting of Glargine U -300 and Glulisine as compared to the premix insulin use showed a marked reduction in Level 1 and Level 2 hypoglycaemic episodes and nocturnal hypoglycaemic episodes per week. The decreased hypoglycaemic event rates in hypoglycaemia resulted in better compliance and adherence which was reflected as a significant reduction in HbA1C. In the future more retrospective and prospective studies will be helpful with Glargine U-300 and Glulisine. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Insulin antibody as a biomarker to monitor the development of type 2 diabetes in county hospitals in China

BackgroundThe significance of insulin antibody (IA) detection in type 2 diabetes mellitus (T2DM) has received scant attention from county hospitals in China. We aimed to introduce exogenous IA positive rate and its relative factors in T2DM treated with insulin in Xiangshan County of Ningbo City, analyzing the immunogenicity of different kinds of insulin.MethodsPatients who were residents from the Danxi community and six towns (Dongchen, Xizhou, Maoyang, Sizhoutou, Juexi, and Qiangtou) in Xiangshan County and diagnosed with T2DM and treated with insulins at Xiangshan Hospital of TCM Medical and Health Group between August 2019 and June 2020 were identified. Those who met the eligibility criteria were included and assigned to the IA-positive or IA-negative group. The immunogenicity of different insulins was compared between the two groups.ResultsAmong 992 patients, 781 were eligible for IA detection, and 40.2% of them were IA positive. Blood IA was closely associated with fasting and 2-h glucose, insulin, and C peptide levels and higher insulin dosage. Patients receiving basal insulin treatment showed significantly lower blood IA than those treated with mixed human insulin, premixed human insulins, rapid-acting analogs, or a combination of basal and rapid-acting analogs.

No effects of the COVID-19 pandemic on the prescription of insulin in Germany

AimsThe aim of the study was to investigate the change of insulin doses in Germany between 2017 and 2021. MethodsThis retrospective study used data from the longitudinal prescription LRx database (IQVIA) and included all patients with at least two insulin prescriptions per year in 2017–2021. Calculated daily dose (CDD) was assessed in 2017, 2018, 2019, 2020, and 2021, separately. ResultsThe number of patients was comprised between 1,079,894 in 2021 and 1,132,839 in 2018. Median (interquartile range) CDD of basal insulin was relatively stable across the years and ranged between 27.9 (18.5–38.8) in 2021 and 28.3 (18.7–39.5) in 2020. In terms of short-acting insulin, median (interquartile range) CDD slightly decreased from 40.1 (28.2–54.3) in 2017 to 38.1 (27.2–52.2) in 2021. A slight decrease was also observed for mix insulin, from 39.4 (27.5–55.3) in 2017 to 37.9 (26.5–54.2) in 2021. These results were corroborated in most age and sex subgroups. ConclusionsCOVID-19 had no substantial effects on insulin doses in Germany. Further data are warranted to corroborate or refute these findings in other settings and countries.

A 5 Years Audit Report on Diabetic Ketoacidosis Patients from a Tertiary Care Hospital in Saudi Arabia

Objective: To evaluate the causes of high admission rate of diabetic ketoacidosis (DKA) in adults with diabetes mellitus presenting to a tertiary care hospital in Saudi Arabia with specific emphasis on the clinical and biochemical phenotype and identify components of intervention and improve clinical outcomes in these patients. Study Design: Observational study. Place and Duration of the Study: Department of Diabetes &amp; Endocrinology, Armed Forces Hospital Al-Hada, Taif, Kingdom of Saudi Arabia from 1st August 2015 to 31st January 2020. Methodology: One hundred and fifteen patients with diabetes mellitus presenting with diabetic ketoacidosis during the last 5 years were enrolled. Approximately 50 different variables pertaining to the patients at the time of presentation were thoroughly scrutinized. Results: There were 31 (28%) males and 81 (72 %) were females with type 1 DM 92%, type 2 DM 7% and 1% unclassified DM with a mean age of 20.90±7.4 years. 18% were diagnosed to have DM for the first time and others had a mean duration of DM of 8.0±3.6 years with an average daily insulin requirement being 64.0±20.2 units. Moreover 84% of patients were on basal bolus regimen and only 5% were on mixed insulin. 73% of the DKA episodes occurred in 15-25 years of age group. The commonest precipitating factors were non-compliance with insulin (44%) and respiratory tract infections (17%). Most common presenting symptoms were vomiting and abdominal pain present in 81% and 53% of patients. The mean blood sugar on presentation was 463±157.3 mg/dl whereas the mean HbA1c was 14±2.9. The mean pH and bicarbonate levels on presentation were 7.16±0.128 and 7±4.83 meq/L respectively. 80% of the patients were admitted to the general wards however 19% required ICU care. 69% of patients had a history of readmission with DKA and 29% were transferred from another periphery hospital. The mean duration of stay in the hospital was 2±3.8 days and the mortality was 0.9%. Conclusion: A very low mortality rate is witness to excellent acute management of these very sick patients. However a very high non-compliance rate of 44%, combined with a readmission rate of 69% and a mean HbA1c of 14% are very alarming as far as long term prognosis is concerned. Keywords: Diabetes mellitus, Ketoacidosis, Characteristics, DKA, Tertiary level care

A phase 1b open-label dose-finding study of ustekinumab in young adults with type 1 diabetes.

SummaryObjectivesWe assessed the safety of ustekinumab (a monoclonal antibody used in psoriasis to target the IL-12 and IL-23 pathways) in a small cohort of recent-onset (<100 days of diagnosis) adults with type 1 diabetes (T1D) by conducting a pilot open-label dose-finding and mechanistic study (NCT02117765) at the University of British Columbia.MethodsWe sequentially enrolled 20 participants into four subcutaneous dosing cohorts: (i) 45 mg loading weeks 0/4/16, (ii) 45 mg maintenance weeks 0/4/16/28/40, (iii) 90 mg loading weeks 0/4/16, and (iv) 90 mg maintenance weeks 0/4/16/28/40. The primary endpoint was safety as assessed by an independent data and safety monitoring board (DSMB) but we also measured mixed meal tolerance test C-peptide, insulin use/kg, and HbA1c. Immunophenotyping was performed to assess immune cell subsets and islet antigen-specific T cell responses.ResultsAlthough several adverse events were reported, only two (bacterial vaginosis and hallucinations) were thought to be possibly related to drug administration by the study investigators. At 1 year, the 90 mg maintenance dosing cohort had the smallest mean decline in C-peptide area under the curve (AUC) (0.1 pmol/ml). Immunophenotyping showed that ustekinumab reduced the percentage of circulating Th17, Th1, and Th17.1 cells and proinsulin-specific T cells that secreted IFN-γ and IL-17A.ConclusionUstekinumab was deemed safe to progress to efficacy studies by the DSMB at doses used to treat psoriasis in adults with T1D. A 90 mg maintenance dosing schedule reduced proinsulin-specific IFN-γ and IL-17A-producing T cells. Further studies are warranted to determine if ustekinumab can prevent C-peptide AUC decline and induce a clinical response.

100 years of insulin-enormous gratitude for my extra 65 years!

My name is Peter Davies, and with this year being the one hundredth anniversary of insulin, it is a tremendous honour to be invited to write this account of my life with Diabetes.

Evaluation the effects of insulin on oxidant/antioxidant status in type 1 diabetic patients

Earlier works have revealed increased generation of reactive oxygen species (ROS) and decreased antioxidant levels in type 1 diabetes mellitus (T1DM). The current study aimed to investigate the effect of mixed insulin therapy on oxidative stress and antioxidant status in patients with T1DM. This study involved 75 participants who were divided into three groups: 20 healthy subjects as a control, 25 newly diagnosed patients with T1DM (without treatment) and 30 patients with T1DM treated with insulin (regular and Human Neutral Protamine Hagedorn (NPH)) twice daily. Fasting serum glucose (FSG), serum concentrations of insulin, malondialdehyde (MDA), catalase (CAT), reduced glutathione (GSH), and vitamins (C and E) were measured in all participants. Compared with the healthy control, serum glucose and MDA concentrations were observed to be significantly higher, while significantly lower concentrations of CAT, GSH, and vitamins (C and E) were found in both the treated and untreated diabetic groups. Although insulin therapy caused a significant decrease in blood sugar with a marked elevation in the levels of insulin, CAT, GSH and vitamin E compared to the untreated patients, the changes in the levels of MDA and vitamin C between diabetic groups were not significant. Moreover, the level of insulin resistance was significantly increased in insulin-treated patients as compared to the control and untreated diabetic groups. In conclusion, twice daily treatment with regular and NPH insulin can ameliorate hyperglycemia and improve antioxidant levels in patients with T1DM. However, the insulin regimen used in this study did not reveal a beneficial effect on oxidative stress and insulin resistance. Hence, exogenous antioxidants (vitamins C and E) can be used in combination with insulin to control these parameters.

WILLINGNESS-TO-PAY FOR INSULIN IN DIABETES TREATMENT: A SYSTEMATIC REVIEW AND META-ANALYSIS

Background: Insulin treatment is necessary for all patients with type 1 diabetes and a subset of patients with type 2 diabetes. However, lifetime insulin treatment is relatively costly that has put a heavy financial burden on insulin-dependent diabetics. Several studies thus have been conducted widely to estimate diabetes patients' willingness to pay (WTP) for insulin therapies worldwide. This study aimed to derive the diabetes patients' WTP for insulin therapy from the results of previous research studies. Methods: A systematic review and meta-analysis of diabetes patients’ WTP for insulin was conducted. All studies were searched and derived from PubMed combined with MeSH, Cochrane library combined with MeSH, ScienceDirect, and Springer Nature. The WTP values were estimated for three different types of insulin, including short-acting, rapid-acting insulin; long-acting, slow-acting insulin, and mixed insulin. Review Manager 5.1.4 software was used to conduct the meta-analysis. Results: Twelve studies were identified by the systematic review, in which eight studies were eligible for a meta-analysis. Most studies were conducted in high-income countries (83.3%), mainly in America (41.7%) and Europe (33.3%). The insulin formulation with the highest mean WTP value was Humalog Mix25 insulin, which was recorded at 410.42 USD per month in the UK and more than 120 USD per month in France, Italy, Spain, and Germany; while most of the other insulin formulations had mean WTP values less than 120 USD per month. Compared to diabetes patients, general populations were willing to pay less for insulin, which was observed in the case of Humalog Mix25 insulin (mean 95.77 USD per month vs 205.89 USD per month) and inhaled insulin (mean 50.43 USD per month compared to more than 120 USD per month). The meta-analysis showed the WTP value for insulin was 74.15 USD per month (95% CI; 55.82 - 92.48). Conclusion: This study showed a comparison of WTP values for different insulin formulations worldwide. The mean WTP value for insulin derived from all previous research may provide an initial understanding of the individuals' preference and WTP. This information could contribute to the effort of managing diabetes and reducing the financial burden of this chronic disease.

Discontinuation of diabetes medication in the 10 years before death in Denmark: a register-based study

Discontinuation of diabetes medication in the last years of life has been suggested to improve quality of life while deemed safe to implement. However, the extent, patterns, and secular changes in discontinuation of glucose-lowering medication in older people with type 2 diabetes have been scarcely described. We therefore aimed to describe the trends in the use of glucose-lowering medication during the last 10 years of life of older people and explore how key clinical and socioeconomic covariates are associated with these patterns. In this register-based cohort study, all individuals with type 2 diabetes who died aged 80 years or older between Jan 1, 2006, and Dec 31, 2018, were identified through the Danish Diabetes Register and linked to the Danish National Prescription Registry. We followed the population backwards in time from death to date of last medication intake. To estimate the cumulative proportion of people on glucose-lowering medication, a Poisson regression model for the rate of medication as a function of time before death (0 to 10 years before death) and calendar year of death (2006-18) was fitted. Both single-substance and combination glucose-lowering medications were included and categorised as insulins, sulfonylureas, metformin, DPP-4 inhibitors, GLP-1 analogues, SGLT2 inhibitors, acarbose, and thiazolidinediones. Insulin was further subdivided into four groups: fast-acting, intermediate-acting, long-acting, and mixed insulin. To identify which covariates were associated with discontinuation, estimates were adjusted for sex, age at death, diabetes duration at time of death, the total number of diabetes complications at time of death (from no complications to four or more), level of education, immigrant status, and income quartile. 52 523 individuals (28 746 [54·7%] females and 23 777 [45·3%] males) were identified, with a mean age at type 2 diabetes diagnosis of 77 years (SD 8), median age at death of 86 years (IQR 83-90), and median diabetes duration at death of 9 years (IQR 5-14). We found a considerable discontinuation of glucose-lowering medication during the last 10 years of life, with the proportion of people on glucose-lowering medication starting at between 89% (95% CI 87-91) in 2006 and 87% (86-88) in 2018 at 10 years before death and decreasing to between 52% (50-54) in 2006 and 38% (37-39) in 2018 at the time of death. Specifically, we found that the proportion of people on sulfonylureas, at any time before death, decreased substantially from 2006 to 2018, whereas the proportion on metformin and DPP-4 inhibitors increased with calendar year of death. Changes were less pronounced for the remaining medications. The overall discontinuation patterns changed with increasing calendar year of death, such that discontinuation rates increased and occurred earlier (further away from time of death) with increasing calendar year. Discontinuations were generally more pronounced during the last year of life. Proportions of people on medication and patterns of discontinuation, as well as the association with covariates, varied with medication class. Covariates most frequently associated with changes in discontinuation rates were sex, age at death, type 2 diabetes duration at death, and number of complications. For example, females were less likely to receive metformin than males at all years before death (rate ratio 0·91 (95% CI 0·89-0·94, p<0·0001), and there was a negative association between the proportion of individuals on metformin and increasing age at death (rate ratio per year increase 0·96 [0·96-0·96], p<0·0001) and type 2 diabetes duration (0·95 per year increase [0·94-0·95], p<0·0001). Our results suggest that increased focus on and implementation of discontinuation of glucose-lowering medication in recent years might have had an effect on discontinuation patterns, particularly during the last year of life. None.

The first and only combination of basal and prandial insulin analogs degludec and aspart: the position of Russian endocrinologists

Insulin therapy for diabetes mellitus is the most effective way to control glycemia with the progression of the disease and the ineffectiveness of other sugar-lowering drugs. At the same time, the existing limitations of traditional insulin preparations, along with increasing attention to the individualized treatment of this disease, are pushing developers to create drugs that most closely reproduce the effect of natural human insulin. In this regard, the appearance of a combination of insulin analogs, the action profile of which practically imitates insulin secretion by a healthy pancreas, presents new possibilities in the treatment of diabetes mellitus. Insulin degludec / insulin aspart (IDegAsp, Ryzodeg®, Novo Nordisk, Denmark) is the first and only soluble combination preparation containing 70% of the ultra-long-acting insulin analogue degludec and 30% of the ultra-short-acting insulin analogue aspart in one injection, which meets the need for both basal and prandial insulin. The combined drug has nothing in common with traditional mixed insulin preparations (both human and analog) and provides doctors and patients with significant advantages over the latter. The article presents the position of Russian experts-diabetologists with extensive experience in the use of IDegAsp regarding the role and place of the drug in real clinical practice. Data from real clinical practice confirm that IDegAsp is a reasonable choice for starting and intensifying insulin therapy for type 2 diabetes mellitus when basal and prandial glycemic control is required. The use of the drug is most appropriate in patients who are on basal, biphasic, basal-plus/basal-bolus regimens and who do not achieve the goals of glycemic control during prior therapy. One of the leading reasons for choosing IDegAsp may also be a lower risk of developing hypoglycemia compared to insulin analogues of previous generations — biphasic insulin aspart and basal insulin glargine 100 U/ml. In addition, IDegAsp is a simple, flexible and safe insulin therapy for patients on premix therapy and basal-plus/basis-bolus regimens who require basal and prandial glycemic control. IDegAsp is a simple, flexible and safe insulin therapy. The greatest benefit of this drug use can be obtained by patients for whom adherence to a complex therapy regimen is difficult (the elderly, with cognitive impairment, after a stroke, with dementia), as well as patients who have an active lifestyle, accompanied by irregular food intake. It is important to note that since January 1, 2021, there is no need for a decision by a special medical commission to prescribe (IDegAsp) Ryzodeg®. This fact, as well as a significant price reduction at the end of 2020, opens up broader prospects for using the drug in the routine practice of a Russian endocrinologist.