Insulin Analogues Research Articles

Safety and efficacy of different basal insulin in type 2 diabetes mellitus with chronic kidney disease in Ramadan: prospective observational study

BackgroundDiabetic kidney disease populations are categorized as high risk for fasting in Ramadan due to various potential fasting-related complications. Insulin analogues are recommended to be used in place of human insulin during fasting, as they carry a lower risk of hypoglycaemia and stable glycaemic variability. A paucity of data exits on the safety and efficacy of different basal insulin types during fasting for this population. This study aims to evaluate the safety and efficacy of three basal insulin among patients with Type 2 Diabetes Mellitus and concomitant mild to moderate chronic kidney disease who are keen to fast during Ramadan.Materials and methodsA single-centered, prospective observational study was conducted among 46 patients with type 2 diabetes mellitus and concomitant chronic kidney disease stage 2 and 3 who were on three different types of basal insulin (Glargine U-100, Levemir, and Insulatard), fasted in Ramadan 2022. All variables were listed as median (IQR). Hypoglycaemia events and glycemic variability obtained from Freestyle Libre continuous glucose monitoring were compared between insulin groups. Changes in glycated haemoglobin, fasting plasma glucose, renal profile, body weight, body mass index, and waist circumference pre and post-Ramadan were evaluated. ResultsThe glycaemic variability was found highest in Insulatard with a median (IQR) of 37.2(33)% versus Levemir 34.4(32.4)% versus Glargine U-100 36.8(30.6)%, p = NS. Levemir had reported the lowest median time of below range of 2.5(13)% followed by Glargine 4(25)% and Insulatard 5(8)%; p = NS. The findings of this study indicated that glycated haemoglobin, fasting plasma glucose, renal profile, body weight, body mass index, and waist circumference did not alter statistically between the three groups post-Ramadan. Individually, Insulatard showed a significant reduction in weight and waist circumference (0.9kg, p = 0.026; 0.44 cm, p = 0.008) while Levemir showed a reduction in waist circumference (0.75cm, p = 0.019).ConclusionThis study revealed that Insulatard, Levemir, and Glargine demonstrated similar levels of safety and efficacy among those with diabetic kidney disease who observed fasting during Ramadan.

The status of blood glucose monitoring and its influencing factors in Chinese patients with type 2 diabetes initiating premixed insulin: A prospective real-world study

ObjectiveThis study aimed to assess the current state of self-monitoring of blood glucose (SMBG) in Chinese patients initiating premixed insulin and its influential factors. Research Design and MethodsThis is a single-arm, multi-center, prospective real-world study enrolling a total of 8214 adult patients with type 2 diabetes mellitus (T2DM) newly initiated premixed insulin analogues. Each patient was followed up for 12 weeks, and the data related to SMBG was collected at week 1, week 4, week 8 and week 12, while data related to glycated hemoglobin were collected at week 1 and week 12. The primary outcome was the frequency of SMBG over 12 weeks. ResultsAt week 12, 83.3 % monitored blood glucose at least once, while 20.3 % of participants continued SMBG every week. The average monitoring frequency was 4.78 times/week over the first 4 weeks and 3.33 times/week over 12 weeks. The patients with a higher frequency of SMBG had better control of blood glucose. ConclusionsThis study found that most T2DM patients would take SMBG but the adherence decreased over time. The adherence to SMBG in Chinese T2DM patients was influenced by age, insulin dosage, education level, and diabetes duration. SMBG benefited the improvement of glycemic control.

Hypoglycemia in Pregnant Women with Type 1 Diabetes: Is It Inevitable?

The human body has abundant mechanisms to counteract hypoglycemia and prevent neuroglycopenia primarily involving the secretion of glucagon and adrenalin. Within several years from the onset of diabetes, people with type 1 diabetes lose their ability to mount a counterregulatory response to hypoglycemia and develop hypoglycemia unawareness, thus being at risk for deteriorating to a state of severe hypoglycemia and neuroglycopenia. Pregnant individuals with type 1 diabetes are particularly prone to experience severe hypoglycemia during the first half of pregnancy. This may be not only due to the institution of strict glycemic control and the nausea and vomiting prevalent during the early months of pregnancy, but also because the counterregulatory responses are further diminished during pregnancy. Severe hypoglycemia during early pregnancy does not appear to increase the risks of spontaneous abortion or congenital fetal malformations, but the potential long-term effects on the fetus are unknown. Recent technological advances have contributed to improved glycemic control and time in range as well as decreased risk of hypoglycemia in people with diabetes. These advances include treatment with insulin analogs, use of continuous glucose monitors, and closed-loop systems for administration of insulin. Limited studies have demonstrated that pregnant individuals with type 1 diabetes may also benefit from these modalities. While ongoing research continues to explore the adjustment of closed-loop systems for optimal use during pregnancy, more effort is needed to explore the optimal use of these modalities in pregnancy. KEY POINTS: · People with type 1 diabetes have diminished counterregulatory responses to hypoglycemia and frequently develop hypoglycemia unawareness.. · Pregnant individuals with type 1 diabetes are at increased risk for severe hypoglycemia particularly during the first half of pregnancy.. · Use of insulin analogs and newer technologies for insulin administration may lower the risk of hypoglycemia in pregnant individuals with type 1 diabetes..

Investigation of Severe Hypoglycemia Risk Among Patients with Diabetes Treated with Ultra-Rapid Lispro in Japan.

There is no information on the incidence of severe hypoglycemia in real-world patients with diabetes receiving ultra-rapid lispro (URLi). This post-marketing, observational, safety study assessed the incidence proportion and incidence rate of the first severe hypoglycemia event requiring a hospital visit in URLi-treated patients. It also compared the risk of severe hypoglycemia between patients treated with URLi or other rapid-acting insulin analogs (RAIAs). Claims data were obtained from a nationwide hospital-based administrative database in Japan (Medical Data Vision). Adults with diabetes who initiated URLi or other RAIA on/after June 01, 2020, were followed up through May 31, 2023. Severe hypoglycemia was identified using a validated algorithm. Incidence proportion and incidence rate of the first severe hypoglycemia event requiring a hospital visit was described in URLi-treated patients (descriptive analysis). These outcomes were also compared against propensity score (PS)-matched other RAIA-treated patients (comparator; comparative analysis). Hazard ratio (HR) and 95% confidence interval (CI) was estimated with a Cox proportional hazards model. The descriptive analysis' URLi-treated cohort included 17,838 patients [mean (standard deviation, SD) age 65.9 (15.7) years; 58.3% male]. The majority had type 2 diabetes (75.7%). The incidence proportion of the first severe hypoglycemia event requiring a hospital visit was 0.6% (95% CI 0.5, 0.8) and the incidence rate was 1.7 per 100 person-years (95% CI 0.7, 4.3). The comparative analysis included 10,592 URLi-treated and 52,917 comparator-treated patients. The incidence rate of severe hypoglycemia did not significantly differ between these cohorts (HR 0.8; 95% CI 0.5, 1.1; p=0.132;. This study did not show a statistically significant increase in the incidence and risk of the first severe hypoglycemia event requiring a hospital visit in real-world URLi-treated patients in Japan, compared with a PS-matched cohort of other RAIA-treated patients.

Type 1 Diabetes (T1D) in Children under 5 Years of Age: Multicentric Study of 22 Cases

Introduction: The incidence of T1D is increasing worldwide, particularly in young children under 6 years of age. The objective of this study was to describe the characteristics of type 1 diabetes in children under 5 years of age in our resource-limited country setting. Materials and Methods: This was a retrospective, descriptive study over a period from January 2018 to July 2022 in Dakar. All type 1 diabetic children under 5 years of age were included except those with an unusable file or less than 6 months of follow-up. Results: We collected 22 records of children aged 0 to 5 years, with a prevalence of 7.8% of all children followed in the two centers. The socioeconomic level was considered average for 54% of patients. Ketoacidosis was the main mode of discovery in our patients (86%). The nutritional status was good for 77% of the children followed and 5% were overweight. The average HbA1c was 10.57 ± 0.5%. Analog insulins were the main insulins used by our patients, (64%). The average daily dose of insulin was 1.08 IU /kg. The diet was normal in the majority of patients (90%). No patient had a chronic complication during follow-up. Severe hypoglycemia was noted in 20% of cases. All our patients benefited from daily glycemic monitoring and had a notebook available. The monitoring rate was 3 checks, i.e. one check before each meal. No deaths were reported. Conclusion: Diabetes in children under 5 years of age is not common. The majority of children are on insulin analogues with a glycemic control far from optimal. A prospective study could allow us to better identify the problems in order to provide appropriate solutions.

Subcutaneous Insulin Infusion Versus Multiple Administrations of Insulin Analogs: Is Either Method Associated with Better Quality of Life in Pediatric Patients with Type 1 Diabetes Mellitus?

Objectives − Type 1 Diabetes Mellitus (DM1) requires demanding treatment in order to achieve good metabolic control. Our aim was to assess whether either method of insulin administration (multiple daily administrations of insulin analogues (MDIA) or continuous subcutaneous insulin infusion (CSII)) is associated with better health-related quality of life (HRQoL).Methods − We conducted a cross-sectional study. Patients aged 10-18 years with a disease duration of at least six months were included. HRQoL was assessed by having patients and their caregivers complete the DISABKIDS-37 questionnaire.Results − Of the 40 patients included, 22 (55%) had CSII. There were no statistically significant differences between subscale scores and overall HRQoL between patients or between parents of patients with CSII or MDIA. CSII patients and parents scored better on all subscales and on the total scale, although without statistically significant differences. There were no statistically significant differences in the subscale scores and overall HRQoL reported by the patients and their parents, but there was a strong correlation between the children’s and parents’ scores (R=0.770; P<0.01), which was similar in patients with CSII or MDIA (R=0.735 vs R=0.790).Conclusion − Although we did not identify statistically significant differences, there was a trend towards a better HRQoL associated with the use of CSII, both from the perspective of the adolescents and their parents. This could influence therapeutic choice. Consistency between the assessments of adolescents and their carers was observed. The choice between MDIA and CSII should be based on individual preferences in order to optimize the HRQoL of adolescents with DM1.

Basal insulin analogues in type 1 diabetes – Does one size fit all? Lessons from the HypoDeg trial based on single-patient outcomes

AimsIn the HypoDeg trial, a randomised crossover trial in people with type 1 diabetes prone to nocturnal severe hypoglycaemia, treatment with insulin degludec (IDeg) resulted in significantly reduced rates of nocturnal symptomatic hypoglycaemia and all-day severe hypoglycaemia compared to insulin glargine U100 (IGlar). We analysed HypoDeg data at a single-patient level to assess the proportion of participants to whom the overall result applied. MethodsPost hoc analysis using single-patient data (n = 133) on nocturnal symptomatic hypoglycaemia, all-day severe hypoglycaemia and HbA1c. The outcome was classified as superior with IDeg, superior with IGlar, or similar between treatments for the three outcomes. We also assessed a composite endpoint based on these outcomes to evaluate the overall superior treatment for each participant. ResultsA higher percentage (38 %) had IDeg as superior treatment compared to IGlar (15 %) for nocturnal symptomatic hypoglycaemia (p < 0.001). There was no difference between the treatments for all-day severe hypoglycaemia or HbA1c. A higher percentage (44 %) had a composite endpoint favouring IDeg compared to IGlar (16 %) (p < 0.001). ConclusionsThe superiority of IDeg was confirmed in many of the participants. However, a minority had IGlar as superior treatment, underscoring the need for individualised basal insulin therapy in clinical practice.

Analysis of multi-disulfide bridges for insulin aspart by stepwise reduction and differentiated alkylation.

Disulfide bridge, an important post-translation modification in protein, plays a key role in stabilizing three-dimensional structure of proteins, maintaining correct folded conformation, and thus regulating the biological activities. Disulfide bridge assignment is essential to understand the essence of life process and to develop protein pharmaceutical. In this study, a novel method termed as stepwise reduction and differentiated alkylation (SRDA) was developed analyzing disulfide connectivity for proteins. As a demonstration, three disulfide bridges in insulin aspart were successfully characterized using this SRDA method combined with LC-HRMSn. Firstly, tris (2-carboxyethyl) phosphine (TCEP) was used to partially reduce disulfide bridges with N-ethylmaleimide (NEM) used to block the generated free thiol. Then, dithiothreitol (DTT) was used to reduce the rest disulfide bonds with iodoacetamide (IAM) used to block the newly generated free thiol. After that, an LC-HRMSn method was established to assign disulfide connectivity for an insulin aspart study material, based on the different mass shifts arising from differentiated alkylation. Moreover, this approach allows for the quantitative analysis of various disulfide bond pairings, which can be applied to studies on the consistency and stability among different batches of samples. The results show that SRDA is a valuable tool for reliable quality control and quality assessment of disulfide-rich proteins such as insulin analogues.

Insulin Stabilization Designs for Enhanced Therapeutic Efficacy and Accessibility.

ConspectusInsulin has remained indispensable in the treatment of diabetes since it was first discovered in 1921. Unlike small molecular drugs, insulin and other protein drugs are prone to degradation when exposed to elevated temperatures, mechanical agitation during transportation, and prolonged storage periods. Therefore, strict cold-chain management is crucial for the insulin supply, requiring significant resources, which can limit the access to insulin, particularly in low-income areas. Moreover, although insulin formulations have advanced tremendously in the last century, insulin treatment still imposes a challenging regimen and provides suboptimal outcomes for the majority of patients. There is an increasing focus on pursuing improved pharmacology, specifically on safer, more user-friendly insulin therapies that minimize the self-management burden. These challenges underscore the need for developing novel insulin formulations with improved stability that are compatible with advanced insulin therapy.Insulin stabilization can be achieved through either chemical modification of insulin or formulation component design. Inspired by insulin-like peptides from invertebrates, we have developed novel stable insulin analogs based on a fundamental understanding of the insulin receptor engagement for insulin bioactivity. We created a novel four-disulfide insulin analog with high aggregation stability and potency by introducing a fourth disulfide bond between a C-terminal extended insulin A-chain and residues near the C-terminus of the B-chain. In an effort to stabilize insulin in its monomeric state to develop ultrafast-acting insulin with rapid absorption upon injection, we have developed a series of structurally miniaturized yet fully active insulin analogs that do not form dimers due to the lack of the canonical B-chain C-terminal octapeptide. Additionally, our study provided strategies for expanding the scope of cucurbit[7]uril (CB[7])-assisted insulin stabilization by engineering safe and biodegradable CB[7]-zwitterionic polypeptide excipients. We also explored insulin N-terminal substitution methods to achieve pH-dependent insulin stabilization without prolonging the duration of action.This Account describes our exploration of engineering stable insulin analogs and formulation design strategies for stabilizing insulin in aqueous solutions. Beyond conventional stabilization strategies for insulin injections, the unmet challenges and recent innovations in insulin stabilization are discussed, addressing the growing demand for alternative, less invasive routes of insulin administration. Additionally, we aim to provide a thorough overview of insulin stabilization from the perspective of commercially available insulin drugs and common pharmaceutical engineering practices in the industry. We also highlight unresolved insulin stabilization challenges and ongoing research strategies. We anticipate that further emphasis on collective efforts of protein engineering, pharmaceutical formulation design, and drug delivery will inform the development of stable and advanced insulin therapy.

Exploring cutting-edge approaches in diabetes care: from nanotechnology to personalized therapeutics.

Diabetes mellitus (DM) is a persistent condition characterized by high levels of glucose in the blood due to irregularities in the secretion of insulin, its action, or both. The disease was believed to be incurable until insulin was extracted, refined, and produced for sale. In DM, insulin delivery devices and insulin analogs have improved glycemic management even further. Sulfonylureas, biguanides, alpha-glucosidase inhibitors, and thiazolidinediones are examples of newer-generation medications having high efficacy in decreasing hyperglycemia as a result of scientific and technological advancements. Incretin mimetics, dual glucose-dependent insulinotropic polypeptide, GLP-1 agonists, PPARs, dipeptidyl peptidase-4 inhibitors, anti-CD3 mAbs, glucokinase activators, and glimins as targets have all performed well in recent clinical studies. Considerable focus was placed on free FA receptor 1 agonist, protein tyrosine phosphatase-1B inhibitors, and Sparc-related modular calcium-binding protein 1 which are still being studied. Theranostics, stem cell therapy, gene therapy, siRNA, and nanotechnology are some of the new therapeutic techniques. Traditional Chinese medicinal plants will also be discussed. This study seeks to present a comprehensive analysis of the latest research advancements, the emerging trends in medication therapy, and the utilization of delivery systems in treating DM. The objective is to provide valuable insights into the application of different pharmaceuticals in the field of diabetes mellitus treatment. Also, the therapeutic approach for diabetic patients infected with COVID-19 will be highlighted. Recent clinical and experimental studies evidence the Egyptian experience. Finally, as per the knowledge of the state of the art, our conclusion and future perspective will be declared.

Research Progress on Peptide Drugs for Type 2 Diabetes and the Possibility of Oral Administration.

Diabetes is a global disease that can lead to a range of complications. Currently, the treatment of type 2 diabetes focuses on oral hypoglycemic drugs and insulin analogues. Studies have shown that drugs such as oral metformin are useful in the treatment of diabetes but can limit the liver's ability to release sugar. The development of glucose-lowering peptides has provided new options for the treatment of type 2 diabetes. Peptide drugs have low oral utilization due to their easy degradation, short half-life, and difficulty passing through the intestinal mucosa. Therefore, improving the oral utilization of peptide drugs remains an urgent problem. This paper reviews the research progress of peptide drugs in the treatment of diabetes mellitus and proposes that different types of nano-formulation carriers, such as liposomes, self-emulsifying drug delivery systems, and polymer particles, should be combined with peptide drugs for oral administration to improve their absorption in the gastrointestinal tract.

Subcutaneous fast-acting insulin analogues ± long-acting insulin vs IV insulin infusion in DKA: updated meta-analysis of randomised trials.

Diabetic ketoacidosis (DKA) is often treated with intravenous regular insulin infusion (IVRII). Subcutaneous fast-acting insulin analogues (FAIAs); either alone or combined with subcutaneous long-acting insulin (LAI); might be useful to treat DKA. Our meta-analysis updated on their benefits and safety in DKA. We searched major electronic databases for randomised trials on subcutaneous FAIAs ± subcutaneous LAI vs IVRII in DKA. Primary outcomes were all-cause in-hospital mortality, time to resolution of DKA and hyperglycemia, in-hospital DKA recurrence and hospital readmission for DKA post-discharge. Secondary outcomes included resource utilisation and patient satisfaction. Safety outcomes were adverse events. Reviewers assessed risk of bias and quality of evidence using GRADE. We performed a priori subgroup and trial sequential analyses on primary outcomes. Seven trials enrolled 351 mainly adult patients (255/351) with mild to moderate DKA. No trials studied subcutaneous FAIA and subcutaneous LAI. Their risk of bias was high or unclear in several domains. No all-cause in-hospital mortality and DKA recurrence were reported. No trial investigated hospital readmission for DKA post-discharge. There was no difference in mean time to resolution of DKA (mean difference = -0.70, 95% CI -2.18 to 0.79 h, p = 0.36) or hyperglycemia [blood glucose < 250 mg/dL (13.9 mmol/L)] (mean difference = -0.17, 95% CI -1.10 to 0.76 h, p = 0.72) between subcutaneous FAIA and IVRII groups. There were largely no subgroup effects. Both groups had similar secondary outcomes. Hypoglycemia was the most common adverse event. Quality of evidence was low to very-low for all outcomes. The only possible trial sequential analysis for time to resolution of DKA was inconclusive. There was low- to very-low quality evidence that subcutaneous FAIA did not affect patient-centered outcomes in mainly adult patients with mild to moderate DKA compared to IVRII.

Icodec ONWARDS: A review of the first once-weekly diabetes treatment for nurse practitioners and physician assistants.

Diabetes management is challenged by the complexity of treatment regimens and the need for frequent injections, affecting patient adherence and quality of life. Insulin icodec, a once-weekly basal insulin analog, represents a significant innovation, potentially simplifying diabetes care and improving outcomes. This review aims to evaluate the safety, efficacy, and clinical implications of insulin icodec for individuals with type 1 and type 2 diabetes, highlighting its potential to affect current treatment paradigms. A review was conducted comparing once-weekly insulin icodec with daily basal insulin analogs using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to ensure transparent reporting of systematic reviews. A search was performed in the following databases: PubMed, Google Scholar, Embase, and ClinicalTrials.gov, focusing on efficacy and safety outcomes. Insulin icodec has demonstrated effective glycemic management and a safety profile comparable to daily basal insulins. Its extended half-life and steady-state glucose-lowering effect have the potential to reduce the burden of daily injections and improve patient adherence. The introduction of once-weekly insulin icodec represents an advancement in diabetes care. For front-line clinicians, this innovation aligns with the need for more straightforward medication regimens. Coupled with continuous glucose monitoring systems, it enables a more personalized and efficient approach to diabetes management, with the potential to improve patient satisfaction and clinical outcomes. This underscores the impact of integrating such advancements into practice, highlighting the role of nurse practitioners and physician assistants in adopting these innovations to optimize patient care.

Analysis of the dynamics of a complex, multipathway reaction: Insulin dimer dissociation.

The protein hormone insulin forms a homodimer that must dissociate to bind to its receptor. Understanding the kinetics and mechanism of dissociation is essential for rational design of therapeutic analogs. In addition to its physiological importance, this dissociation process serves as a paradigm for coupled (un)folding and (un)binding. Based on previous free energy simulations, insulin dissociation is thought to involve multiple pathways with comparable free energy barriers. Here, we analyze the mechanism of insulin dimer dissociation using a recently developed computational framework for estimating kinetic statistics from short-trajectory data. These statistics indicate that the likelihood of dissociation (the committor) closely tracks the decrease in the number of (native and nonnative) intermonomer contacts and the increase in the number of water contacts at the dimer interface; the transition state with equal likelihood of association and dissociation corresponds to an encounter complex with relatively few native contacts and many nonnative contacts. We identify four pathways out of the dimer state and quantify their contributions to the rate, as well as their exchange, by computing reactive fluxes. We show that both the pathways and their extents of exchange can be understood in terms of rotations around three axes of the dimer structure. Our results provide insights into the kinetics of insulin analogues and, more generally, how to characterize complex, multipathway processes.

Safety Profiles Related to Dosing Errors of Rapid-Acting Insulin Analogs: A Comparative Analysis Using the EudraVigilance Database.

Diabetes is a widespread condition that can lead to multiple and severe complications. Rapid-acting insulin analogs (RAIAs) and long-acting insulin analogs are prescribed for the effective management of diabetes. RAIAs are expected to be associated with a higher number of dosing errors because of their rapid onset, short duration of action, and the need for frequent dosing, compared to other insulin analogs. There are three approved RAIAs on the market: insulin lispro (LIS), insulin aspart (ASP), and insulin glulisine (GLU). The aim of this study is to evaluate the real-world evidence on dosing errors reported for RAIAs in EudraVigilance (EV), an established pharmacovigilance database, in comparison to other insulin analogs and human insulins. A descriptive analysis and a disproportionality analysis were conducted. ASP and LIS were associated with high percentages of adverse drug reactions (ADRs) (22% and 17%, respectively), with over 70% of the reports involving serious ADRs. A higher frequency of cardiac and eye disorder ADRs was observed for LIS compared with ASP and GLU. GLU showed a higher frequency of ADRs in the skin and subcutaneous tissue disorders category. LIS dosing errors accounted for 5% of the total number of cases, while dosing errors for ASP and GLU were less than 3%. The most frequently reported dosing errors involved improper dosing (49%). Although there were fewer dosing errors of RAIAs in comparison to other insulins, the severity of the potential outcome highlights the importance of precise dosing and timing. Improved the monitoring and reporting of these dosing errors could enhance diabetes patient care. Additionally, smart medical devices could improve therapeutic outcomes.

7636 Once-weekly Insulin Icodec versus Once-daily Long-acting Insulins for Type 2 Diabetes Mellitus: Systematic Review and Meta-analysis

Abstract Disclosure: S.G. Ribeiro: None. M.P. Chavez: None. L.C. Hespanhol: None. A.B. Neto: None. M.D. Gauza: None. E. Paqualotto: None. C.A. Balieiro: None. C.C. Padovese: None. J.R. Sa: None. Background: Insulin icodec is a novel, long-acting, once-weekly basal insulin analog. Its comparative efficacy and safety with basal once-daily insulins in type 2 diabetes mellittus is uncertain. Objective: Evaluate potential efficacy, benefits and risks associated with icodec compared to once-daily basal insulin analogs (degludec or glargine). Methods: We systematically searched PubMed, Cochrane, and Embase for randomized controlled trials (RCTs) published until June 2023 comparing icodec versus long-acting insulin analogs (degludec and glargine) in type 2 diabetes mellitus (T2DM) with at least 12 weeks of follow-up. Binary endpoints were assessed with risk ratios (RRs) and continuous endpoints were compared using weighted mean differences (WMDs), with 95% confidence intervals (CIs). The protocol was registered in PROSPERO (CRD42023452468). Results: A total of seven RCTs and 3,286 patients with T2DM were included, of whom 1,509 (60.6%) received icodec treatment. The follow-up period ranged from 16 to 78 weeks. Compared with once-daily basal insulin analogs, icodec led to a greater improvement in HbA1c (WMD -0.15%; 95% CI -0.21, -0.10; p&amp;lt;0.0001; I²=0%) and time in range (TIR) (WMD 2.83%; 95%CI 0.94; 4.71; p=0.003; I2=22%). Body weight was increased with icodec treatment (WMD 0.78 Kg; 95%CI 0.42, 1.15; p&amp;lt;0.01; I2=86%). There was also a higher rate of injection site reactions (RR 1.89; 95%CI 1.12, 3.18; p=0.016; I²=0%) and nasopharyngitis (RR 1.94; 95%CI 1.11, 3.38; p=0.020; I²=0%) in the icodec group, compared with once-daily regimens. There was no significant difference between groups in fasting plasma glucose. Conclusions: In this meta-analysis of RCTs, insulin icodec led to better control of HbA1c and TIR as compared with once-daily insulin regimens, albeit with increased weight gain and a higher rate of injection site reaction in the Icodec group. Presentation: 6/3/2024

B-150 Chromatographic Separation and Quantitation of Human Insulin and Lispro Analog in Serum Using Liquid Chromatography High-Resolution Mass Spectrometry

Abstract Background Factitious hypoglycemia, a deliberate attempt to induce low blood glucose levels occurring secondary to the surreptitious administration of exogenous insulin, can be difficult to diagnose due to a variety of factors including the increased use of synthetic insulin analogs in clinical practice. Traditional insulin immunoassays demonstrate variable cross-reactivity with commonly prescribed insulin analogues and their metabolites, making it difficult to measure specific analogs. The development of liquid chromatography high resolution accurate mass (LC-HRAM)-mass spectrometry (MS) assays has largely circumvented the limitations of traditional immunoassays for detection and quantitation of insulin analogs. Analytical challenges remain, however, specifically in differentiating lispro, an isomeric human insulin analog formed by the transposition of proline and lysine near the C-terminal end of the B chain, from human insulin in patient samples due to the equivalent mass-to-charge ratios of their precursor ions. Methods Immunoaffinity purification of insulin from calibrators and quality control material prepared by spiking insulin-depleted serum with pharmaceutical insulin preparations, as well as patient samples, was performed using tips coupled with anti-insulin monoclonal antibody. An automated liquid handler was programmed to perform aspiration and dispense cycles. Eluate from the purification protocol was submitted for analysis using a TLX-2 multiplex LC system paired with a Thermo Scientific Q Exactive Plus mass spectrometer. Various HPLC column chemistries were evaluated, a column passivation procedure was established, and column heater temperature was optimized to identify a combination of parameters yielding the best chromatographic separation of human insulin and lispro. Additionally, parallel reaction monitoring (PRM) targeted tandem mass spectrometry (MS/MS) analysis was utilized in combination with the full scan data to increase specificity through the monitoring of fragment ions produced from human insulin and each insulin analog. Results We found that a 1000 Å Diphenyl, 2.7 µm, 2.1 x 100 mm analytical column in a column heater maintained at a temperature of 80°C allowed for human insulin and lispro to be differentiated as two chromatographically separated extracted ion chromatographic peaks (XICs) and quantified down to 2.5 mcIU/mL with near-baseline separation. Before use, the column required passivation with a high protein buffer (0.05% bovine serum albumin in 20% acetonitrile [ACN] + 0.2% acetic acid) followed by increasingly organic buffers (20% ACN + 0.2% acetic acid and 50% ACN + 0.2% acetic acid). MS/MS was used to confirm the presence of analogs detected. Conclusions The LC-HRAM-MS method described here, coupled with optimized column chemistry, column passivation, and proper column temperature control allows for chromatographic separation of human insulin and lispro. Incorporating a PRM scan into the mass spectrometry full scan method provides confirmation of the insulin detected in the XICs. The results obtained from preliminary studies suggest this method is appropriate for use to facilitate the clinical investigation of suspected factitious hypoglycemia with the ability to differentiate isomeric compounds, such as human insulin and lispro.

From Glucose to Neuroprotection: Exploring Antidiabetic Medications as a Novel Approach to Alzheimer's Disease Treatment.

Alzheimer's disease (AD) is a major neurological disorder and a leading cause of dementia, which is characterized by progressive cognitive decline. Emerging research highlights the link between AD and type 2 diabetes mellitus (T2DM), suggesting that shared pathophysiological mechanisms, such as insulin resistance, inflammation, and oxidative stress, contribute to both conditions. This connection has led to the concept of type 3 diabetes.Given these overlaps, antidiabetic drugs are being explored for repurposing as potential AD treatments. Intranasal insulin, metformin, thiazolidinediones, and GLP-1 analogs like liraglutide have shown promise in reducing amyloid-beta levels and inflammation, and improving cognitive functions. Despite encouraging preclinical and early clinical results, challenges remain in translating these findings into safe and effective treatments. Continued research could lead to innovative therapies that address both AD and T2DM, offering improved patient outcomes.

A Unique Government–NGO–Industry Partnership Care Model to Reduce Morbidity and Mortality Among Underprivileged Children With Type 1 Diabetes Mellitus in LMIC: A Pilot Study From Tamil Nadu, India

Abstract Aim: To pilot a 1-year comprehensive type 1 diabetes mellitus program, assessing outcomes on glycemic control and diabetic ketoacidosis (DKA) admissions pre- and post-intervention in underprivileged children with type 1 diabetes mellitus from three selected Government Medical College Hospitals across Tamil Nadu state, through a Government–nongovernmental organization (NGO)–Industry partnership. Materials and Methods: A total of 214 children were identified through the hospital database. Highly focused diabetes mellitus and insulin education along with analog insulins in penfill cartridges in the basal-bolus regime, high quality 800 memory glucometers with 100 glucose strips per month, ultrafine needles, 24/7 telephone support, and monthly review were supported to all the children. Data on baseline characteristics, pre- and post-intervention glycosylated hemoglobin A1c (HbA1c), and DKA admissions were tabulated on Microsoft Excel, and the results were analyzed. Results: A 2.4% reduction in HbA1c and more than 90% reductions in DKA admissions were seen post-intervention compared with baseline. This can potentially translate to huge reductions in mortality and cost savings for all stakeholders. Conclusions: A combined Government–NGO–Industry partnership is the need of the hour to reduce morbidity and mortality associated with type 1 diabetes mellitus among underprivileged children in India. Our model has the potential to serve as a blueprint for type 1 diabetes mellitus care in low- and middle-income countries.

A comparison of the safety and effectiveness of insulin aspart with other bolus insulins in women with pre-existing Type 1 diabetes during pregnancy: A post hoc analysis of a prospective cohort study.

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. 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. 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). 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.