Long-acting Insulin Analogues Research Articles

Sensitive and label-free SPR biosensing platforms for high-throughput screening of plasma membrane receptors interactions with insulin-like targets of hypoglycaemic activity

Progress in medical sciences aims for tailored therapy of civilization diseases like diabetes. Preclinical screening of new medicines superior to insulin should include the verification of their affinity to the membrane receptors naturally stimulated by this hormone: insulin receptor isoforms A and B and insulin-like growth factor receptor. Considering that the affinity constants obtained using different experimental conditions are incomparable, it is essential to develop a robust and reliable method to analyze these interactions. The versatile SPR platform developed in this study enables the evaluation of the bioactivity of hypoglycaemic molecules. Thanks to the comprehensive characterization of miscellaneous aspects of the analytical platform, including the design of the SPR biosensor receptor layer, ensuring interaction specificity, as well as the quality control of the standards used (human insulin, HI; long-acting insulin analog: glargine, Gla), the feasibility of the method of equilibrium and kinetic constants determination for insulin-like targets was confirmed. SPR assays constructed in the direct format using IR-A, IR-B, and IGF1-R receptor proteins show high sensitivities and low detection limits towards insulin and glargine detection in the range of 18.3–53.3 nM with no signs of mass transport limitations. The improved analytical performance and stability of SPR biosensors favor the acquisition of good-quality kinetic data, while preservation of receptors activity after binding to long-chain carboxymethyldextran, combined with spontaneous regeneration, results in stability and long shelf life of the biosensor, which makes it useful for label-free insulin analogs biosensing and thus extensive screening in diabetic drugs discovery.

Single Center Evaluation of Long-Term Results of Glargin U-300 in Insulin Naive Patients In a Real-World Setting

Objective: Insulin therapy stands as one of the most effective and well-established therapeutic options for managing glycemic control in Diabetes Mellitus (DM). Glargine 300 U/mL (Gla-300) represents a new long-acting insulin analog, which has demonstrated a decrease in the risk of hypoglycemia and a reduction in the total number of injections due to prolonged insulin absorption. In this study, we investigated the long-term effects of Gla-300 on Fasting Plasma Glucose (FPG) and HbA1c levels, as well as the incidence of hypoglycemia in insulin-naive patients admitted to the Internal Medicine outpatient clinic, over a period of 0, 3, 6, 12, and 24 months.. Material and Methods: Between January 2018 and June 2022, insulin-naive patients diagnosed with Type 2 Diabetes Mellitus (T2DM) who initiated treatment with Gla-300 and sought care at the Internal Medicine outpatient clinic were subjected to retrospective analysis. Results: The study included 49 insulin-naive patients. A statistically significant decrease was observed in Fasting Plasma Glucose (FPG) (p = 0.03) and HbA1c (p = 0.02) levels during the 24-month follow-up period of Glargine U-300. Additionally, a significant reduction in both FPG (p < 0.01) and HbA1c (p < 0.01) values was achieved at the time of diagnosis and at 3 months. Hypoglycemia was reported in only 1 patient (2%) during our study, indicating a very low hypoglycemia rate. Conclusion: Diabetes mellitus (DM) poses a significant public health challenge, resulting in economic burden and diminished quality of life. Developed to address these challenges, Gla-300 serves as a long-acting basal insulin that effectively reduces the risk of hypoglycemia while offering targeted glycemic control, as evidenced by our study findings. In Turkey, there is a pressing need for multicenter, prospective real-world studies that incorporate parameters such as insulin dosage and weight monitoring.

Resolution of insulin resistance, lactic acidosis, and decrease in mechanical support requirements in patients post orthotopic heart transplant with the use of long-acting insulin glargine

ObjectiveThis study investigates the efficacy of using a long-acting insulin analog, along with the infusion of regular insulin, in achieving appropriate glycemic control and correcting lactic acidosis in patients post orthotopic heart transplant who demonstrate severe lactic acidosis and insulin resistance.MethodsThis was a retrospective study of two cohorts (IRB FLA 20-003) of patients post orthotopic heart transplant with severe lactic acidosis and insulin resistance who were admitted to a tertiary intensive care unit and treated with (group 1) or without long-acting insulin analog (group 2) within the first 24 h of admission to the intensive care unit. Insulin resistance is defined as the requirement for intravenous regular insulin infusion of more than 20 units/h without the ability to achieve appropriate serum glucose level (120–180 mg /dL). Severe lactic acidosis is defined as arterial lactic acid of more than 10 mmol/L. The following parameters were investigated: time to correct lactic acidosis, duration of postoperative mechanical ventilation, the need for periprocedural mechanical circulatory support, and 28-day mortality.ResultsThe 28-day mortality was zero in both groups. Two patients required periprocedural mechanical support in group one, and ten patients required mechanical support in group two (RR = 0.224, 95%, confidence interval 0.052–0.95, Z = 2.029, p = 0.042). Three patients required tracheostomy in group one, and four patients required tracheostomy in group two (RR 0.84, 95 confidence interval 0.20–3.48, Z = 0.23, P = 0.81). Wilcoxon rank-sum test was used to compare time to correct lactic acidosis, with lactic acid resolution being faster in group one (X¯\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\overline{X}$$\\end{document}1 = 19.7 h, SD ± 12.6 h X¯\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\overline{X}$$\\end{document}2 = 29.3 h, SD ± 19.6 h, Z-value − 2.02, p-value 0.043). The duration of mechanical ventilation was less in group one (X¯\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\overline{X}$$\\end{document}1 = 29 h, SD ± 12.7 h, X¯\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\overline{X}$$\\end{document}2 = 55.1 h, SD ± 44.5 h, Z-value: − 1.92, p-value 0.05).ConclusionAdministration of low-dose long-acting insulin glargine led to the resolution of the lactic acidosis, insulin resistance, and decreased requirements for pressor and inotropic support, which led to decreased need for mechanical circulatory support.

Pharmacokinetics and bioavailability of a new long-acting insulin analog in healthy Chinese volunteers: an open, randomized, single-dose, two-period and two-sequence cross-over study.

Objectives: INS068 is a novel, soluble, and long-acting insulin analog. In this study, we evaluated the pharmacokinetics and relative bioavailability of two formulations of INS068 in healthy Chinese subjects: a reference formulation packaged in vials and administered via syringe (R), and a test formulation packaged and administered via pen injector (T). Methods: A randomized, open-label, two-period, two-sequence crossover study was conducted with 24 healthy Chinese subjects. Subjects were randomized and administered subcutaneously in the abdomen at 0.4 U/kg of test or reference INS068 injection according to an open crossover design. INS068 concentrations in the serum were measured using LC-MS/MS, and the pharmacokinetic parameters of maximum concentration (Cmax) and area under the concentration-time curve (AUC0-t and AUC0-∞) were used to evaluate relative bioavailability. Results: After a single dose at 0.4 U/kg, the median Tmax of INS068 was 12 h for both formulations, and the mean t1/2 for T and R was 13.0 h and 12.6 h, respectively. The geometric means of Cmax and AUC0-∞ were 3.99 nmol/L and 120 h·nmol/L for the T, and 4.05 nmol/L and 117 h·nmol/L for the R, respectively. The geometric mean ratios of Cmax, AUC0-t and AUC0-∞ of T over R were 98.7% (90% CI: 92.7%-105.2%), 102.6% (90% CI: 100.0%-105.3%) and 102.8% (90% CI: 100.1%-105.5%). Conclusion: The overall PK profile of the two formulations of INS068 injection was comparable in healthy subjects, and the pen injector of INS068 had adequate safety and tolerability, supporting it as a new formulation in a phase III study and bridging PK data from early phase clinical trials. Clinical Trial Registration: clinicaltrials.gov, identifier: NCT05336071.

Comparison of Insulin Analogs and Human Insulins: A Narrative Review

Abstract Introduction Since insulin analogs have pharmacological properties that are similar to the normal physiological action of insulin, it has been suggested that they provide better glucose control and less rates of hypoglycemia compared to human insulins. Methods We performed a narrative, nonsystematic review of the literature including clinical trials, systematic reviews, meta-analyses, and professional guidelines related to the comparison of human insulins and insulin analogs in terms of glucose control, safety profile, and cost. Results Long-acting basal insulins result in mild improvement in glucose control and less rates of nocturnal hypoglycemic compared to neutral protamine Hagedorn insulin, mainly among patients with type 1 diabetes. Rapid-acting insulin analogs provide better glucose control and lower rates of hypoglycemia compared to regular insulin among patients with type 1 diabetes, whereas no advantage has been shown for insulin analogs among patients with type 2 diabetes for glucose control or hypoglycemia. Premixed insulin analogs provided no advantage in glucose control and inconsistent benefit in lowering the rates of hypoglycemia compared to human premixed insulins among patients with type 2 diabetes. The cost of insulin analogs is significantly higher than human insulins, and favorable cost-effectiveness has only been demonstrated for rapid-acting insulin analogs in type 1 diabetes. Conclusion Currently available evidence supports the use of rapid-acting insulin analogs and possibly long-acting basal insulin over human insulins for patients with type 1 diabetes. For patients with type 2 diabetes, the use of long-acting insulin analogs may be recommended for selected patients who are at an increased risk of significant hypoglycemia, while no clear benefits of meal insulin analogs over human insulins have been observed.

Current Status of Weekly Insulin Analogs and Their Pharmacokinetic/Pharmacodynamic Evaluation by the Euglycemic Clamp Technique.

Diabetes mellitus represents a significant global health threat characterized by hyperglycemia caused by inadequate insulin secretion and/or insulin resistance. Exogenous insulin supplements had been recognized as a crucial treatment for achieving successful glycemic control in patients with Type 1 and most patients with Type 2 diabetes. Over the past century, substantial progress has been made in the development of novel insulin formulations, including the super-fast-acting and long-acting basal insulin analogs, of which the latter is indispensable for the management of nocturnal fasting and intraprandial blood glucose within the normal physiological range. Recently, combining chemical and genetic engineering with drug optimization have resulted in a formidable evolution in ultra-long-acting weekly insulin. Here, the current state of once-weekly insulin analogs and the euglycemic clamp technique used in the early clinical development to elucidate the pharmacokinetics and pharmacodynamics of this type of novel weekly insulin analogs were systematically overviewed.

1803-PUB: Effectiveness and Safety of the Insulin Degludec U100 vs. Glargine U300 in People with Type 1 diabetes—The IneoxPlus Real-World Study

Objective: The INEOX-Plus study aims to compare the efficacy and safety of Deg-U100 and Gla-U300 in people with T1d incorporated to the Flash Glucose Monitoring (FGM) technology for over 6 months. Materials and Methods: Cross-sectional study in 161 of the 260 T1D participants of the INEOX randomized study (NCT 03328845) who were initially randomized between 2017 and 2019 to receive Gla-U300 or Deg-U100 insulin and incorporated to FGM technology after. Participants were re-evaluated in the INEOX_Plus visit, at an average 2.8 years after the final INEOX visit. Sociodemographic variables, insulin dose, plasma HbA1c and episodes of severe hypoglycemia and ketosis in the previous year were collected together with data on Freestyle libre 2® system downloaded from the last 90 days: sensor use, number of daily scans, GMI, mean glucose, CV, TIR 70-180, TBR 69-54, TBR <54, TAR 181-250, TAR >250 and hypoglycemia events- number/90 days and rate/year-. Results: 90 men (56%) and 71 women (44%), mean age 44±11 years, with diabetes evolution of 23.5±10 years belonging to the INEOX study accepted to participate; 75 subjects (46%) used Gla-U300 and 86 (54%) Deg-U100. A significant reduction in HbA1c was observed between the final INEOX and INEOX-Plus visit (7.65±1.04% vs 7.43±0.84%, p= 0.002) regardless of the type and dose of second-generation long-acting insulin analogue used. There were no episodes of severe hypoglycemia or ketoacidosis reported. We did not find significant differences in insulin doses, HbA1c and FGM metrics except in the Hypoglycemia events incidence rate -213.65 vs 260.05 events/person/year; p=0.001 - for Gla-U300 vs Deg-U100 respectively. Conclusions: For people with T1D in routine clinical follow-up with FGM, Gla-U300 and Deg-U100 insulin have a similar effect on the efficacy and safety variables except for significantly lower incidence rate of yearly hypoglycemia events for Gla-U300 users. Disclosure M.S.Ruiz de adana: None. L.I.Navas vela: None. C.Maldonado-araque: None. G.Olveira: Other Relationship; Abbott Diabetes, Novo Nordisk, Speaker's Bureau; Lilly. G.Rojo martínez: None. M.E.Domínguez-lópez: None. M.Vallejo mora: None. N.Colomo: None. F.Linares: None. V.Morillas: Other Relationship; Boehringer Ingelheim and Eli Lilly Alliance. M.Vallejo herrera: None. S.Alonso gallardo: None. M.Padilla fuentes: None. Funding Instituto de Salud Carlos III (PI 17/00861)

Modern Insulin, Device, and Technology: Tips For Clinicians

Insulin has been a lifesaving treatment for people with diabetes since its discovery in 1921. However, the way insulin is delivered evolved over time. Modern insulin, devices, and technology have transformed the management of diabetes and improved the quality of life for millions of people worldwide.Modern insulins are designed to match the needs of people with diabetes better. Traditional insulins, such as regular and NPH insulin, have a delayed onset and peak, making it difficult to manage blood sugar levels. Newer insulins, such as rapid-acting insulin analogs like aspart, glulisine, and lispro, have a faster onset and shorter duration of action, allowing for greater dosing and timing flexibility. Long-acting insulin analogs, like glargine and detemir, provide more consistent blood sugar control and less hypoglycemia risk.Insulin delivery devices have also advanced significantly. The most common device is the insulin pen, which looks like a large pen and uses disposable insulin cartridges. The pen has replaced traditional syringes and vials for many people with diabetes, offering greater convenience and ease of use. Insulin pumps are also becoming more popular, especially among people with type 1 diabetes. A pump delivers insulin through a catheter inserted under the skin, which can be programmed to provide a continuous infusion of insulin or a bolus dose before meals.Technological advancements have also revolutionized diabetes management. Continuous glucose monitoring (CGM) systems use a small sensor inserted under the skin to measure glucose levels every few minutes, providing real-time data to help people make more informed decisions about insulin dosing and food choices. Some CGM systems also offer alerts for high and low blood sugar levels, making it easier to avoid dangerous fluctuations. Automated insulin delivery systems, also known as closed-loop systems or artificial pancreas systems, use CGM data to automatically adjust insulin delivery, reducing the burden of constant monitoring and decision-making for people with diabetes.In summary, modern insulin, devices, and technology have greatly improved the management of diabetes, allowing for better blood sugar control and a better quality of life for people with diabetes. As technology continues to advance, the future of diabetes management looks promising. Bangladesh J Medicine 2023; Vol. 34, No. 2(1) Supplement: 191

Long-acting insulin analogues and the risk of diabetic retinopathy among patients with type 2 diabetes: A population-based cohort study.

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. 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. 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. 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.

Hypoglycemia with insulin in post-transplant diabetes mellitus

IntroductionTo prevent hypoglycemic episodes, the management of insulin therapy against post-transplant diabetes mellitus (PTDM) is important. We compared glargine (long-acting insulin) versus NPH isophane (intermediate-acting insulin) as an armamentarium against PTDM. Indeed, the study evaluated PTDM patients with hypoglycemic episodes treated with isophane or glargine. Material and methodsWe evaluated a total number of 231 living-donor renal transplant recipients with PTDM of age ≥ 18 years admitted to the hospital between January 2017 and September 2021. However, patients taking hypoglycemic agents before transplantation were excluded from this study. Out of 231 patients, 52 (22.15%) suffered from PTDM out of whom 26 were treated with glargine or isophane. ResultsAfter applying exclusion criteria, out of 52 PTDM patients 23 were included in the study: 13 PTDM patients were treated with glargine, whereas 10 PTDM patients with isophane. Our analysis revealed 12 episodes of hypoglycemia in glargine-treated PTDM patients compared to 3 in isophane-treated PTDM patients (p = 0.056). Clinically, 9 out of 15 hypoglycemic episodes were nocturnal (60%). Furthermore, no other risk factors were observed in our study population. Detailed analysis showed that both groups had equivalent doses of immunosuppressants and oral hypoglycemic agents. The odds ratio for hypoglycemia in the group treated with isophane compared to that treated with glargine was 0.224 (95% CI, 0.032–1.559). Glargine users recorded significantly lower blood sugar levels before lunch, dinner and at bedtime with p-values of 0.001, 0.009 and 0.001 respectively. A better hemoglobin A1c (HbA1c) level was seen in the glargine vs. isophane group (6.98 ± 0.52 vs. 7.45 ± 0.49, p-value 0.03). ConclusionThe study shows better blood sugar control with long-acting insulin analog, glargine, than with intermediate-actin analog, isophane. Overall, a higher number of hypoglycemic episodes was nocturnal. Long term safety of long-acting insulin analogs needs to be further studied.

Intentional overdose of glargine insulin: Determination of the parent compound in postmortem blood by LC‐HRMS

Insulin glargine is a long-acting insulin analog that is converted after enzymatic cleavage of the arginine pair of the β-chain into its main metabolite M1 (21A -Gly-insulin), which is responsible for the hypoglycemic activity. In all the overdose cases described in the literature, only M1 concentrations have been reported, whereas insulin glargine was always absent or below the limit of quantitation. In this study, we present a case of suicide of a young nurse by injection of insulin glargine in which the parent molecule was found at a toxic concentration in blood. The determination and the discrimination of insulin glargine from human insulin and other synthetic analogs in the blood specimen were performed by liquid chromatography coupled to high-resolution mass spectrometry (Waters XEVO G2-XS QToF) and extraction after precipitation in the presence of bovine insulin (internal standard), with a mixture of acetonitrile/methanol +1% formic acid followed by purification on solid phase extraction cartridges C18. Glargine insulin tested highly positive in the blood with a concentration of 1.06 mg/L. Due to the difficulty in obtaining a M1 pure standard, the metabolite could not be dosed. This unique presence of the parent molecule, reported for the first time, can be explained by inter-individual variability in the rate of conversion to metabolite. Intravenous injection versus subcutaneous injection can also explain the presence of insulin glargine. Finally, the dose injected may have been so high that saturation of the proteolytic enzymes responsible for conversion to M1 should have occurred.

Basal insulin titration algorithms in patients with type 2 diabetes: the simplest is the best (?)

Basal insulin is the first and main component of insulin therapy in patients with type 2 diabetes mellitus (T2DM). Based on the shortcomings of human NPH insulin and the advantages provided by long-acting basal insulin analogues, they are recommended for priority use in patients with T2DM. The leading factor in the success of insulin therapy is titration of its dose with the achievement of the target range of glycemia. Data from clinical trials and real clinical practice indicate that simpler dose titration algorithms ensure better achievement of glycemic goals with a lower risk of hypoglycemia. In addition, simple dose titration algorithms are better accepted by patients and increase satisfaction with treatment. The leading societies of diabetologists ADA/EASD and AACE/ACE recommend the use of simple dose titration algorithms. Recent clinical trials on the effectiveness of the insulin glargine dose titration based on the INSIGHT algorithm, which, unlike the traditional options for changing the dose 1–2 times a week, involves a daily correction of the insulin glargine dose by 1 Unit, have proven its effectiveness and safety. Most patients prefer this type of insulin dose titration. The same titration algorithm can be used for a fixed combination of glargine with lixisenatide, which was also confirmed by the results of clinical trials. In general, simplified options for correcting the basal insulin dose have demonstrated their effectiveness and allow increasing the percentage of patients who manage to achieve the glycemic goal without increasing the risk of hypoglycemia. When prescribing basal insulin, physician must determine the target range of glycemia, demonstrate the titration algorithm that is acceptable for each insulin and which a patient will use to achieve the glycemic goal.

The Non-Human Primate in Safety Assessment of a Bifunctional Long-Acting Insulin Analogue.

Species selection plays a pivotal part during non-clinical safety assessment in drug development. If possible, use of non-human primates (NHPs) should be avoided due to ethical considerations. However, limiting factors as lack of pharmacologic activity in other species could necessitate use of NHPs. LAI-PCSK9i is a bi-functional molecule combining a long-acting insulin analogue with a PCSK9 inhibitor peptide aiming to provide glycaemic control and to reduce plasma LDL concentrations. The NHP was chosen for the safety assessment of LAI-PCSK9i being the most relevant species with basal levels and plasma lipid composition closest to humans, while the dog and initially also the minipig were deemed irrelevant due to lack of pharmacologic activity on LDL-lowering and biological differences in lipid profiles. An in vivo tolerability and toxicokinetic study of LAI-PCSK9i in NHPs showed recurrent and severe hypoglycaemia at very low doses. Therefore, the minipig was re-evaluated and a follow-up study thoroughly assessing blood glucose and cholesterol levels and clinical signs illustrated that minipigs dosed with LAI-PCSK9i, tolerated the compound and LAI-PCSK9i decreased glucose and LDL over time. This work underlines that careful consideration is required when selecting species during safety assessment in drug development. The tolerability issue in NHPs led to the subsequent selection of the minipig for safety evaluation of LAI-PCSK9i although as a suboptimal alternative, which unexpectedly had a measurable pharmacologic response on LDL lowering. In conclusion, the NHPs may be unsuitable as test species for safety assessment of long-acting insulin analogues due to high sensitivity to recurring hypoglycaemic episodes.

Metabolic Impact of Frailty Changes Diabetes Trajectory

Diabetes mellitus prevalence increases with increasing age. In older people with diabetes, frailty is a newly emerging and significant complication. Frailty induces body composition changes that influence the metabolic state and affect diabetes trajectory. Frailty appears to have a wide metabolic spectrum, which can present with an anorexic malnourished phenotype and a sarcopenic obese phenotype. The sarcopenic obese phenotype individuals have significant loss of muscle mass and increased visceral fat. This phenotype is characterised by increased insulin resistance and a synergistic increase in the cardiovascular risk more than that induced by obesity or sarcopenia alone. Therefore, in this phenotype, the trajectory of diabetes is accelerated, which needs further intensification of hypoglycaemic therapy and a focus on cardiovascular risk reduction. Anorexic malnourished individuals have significant weight loss and reduced insulin resistance. In this phenotype, the trajectory of diabetes is decelerated, which needs deintensification of hypoglycaemic therapy and a focus on symptom control and quality of life. In the sarcopenic obese phenotype, the early use of sodium-glucose transporter-2 inhibitors and glucagon-like peptide-1 receptor agonists is reasonable due to their weight loss and cardio-renal protection properties. In the malnourished anorexic phenotype, the early use of long-acting insulin analogues is reasonable due to their weight gain and anabolic properties, regimen simplicity and the convenience of once-daily administration.

Predictors of success and failure in achieving glycemic control targets in patients with type 2 diabetes on basal insulin: review of the real-world evidence studies

Basal insulin (BI) is the main therapeutic option for patients with type 2 diabetes (T2D) who have not reached glycemic targets on oral antidiabetic drugs and/or glucagon-like peptide-1 receptor agonists. The results of epidemiological studies indicate that the majority of patients with T2D do not achieve the targeted parameters of glycemic control on BI in the real-world settings. In this review the results of real-world evidence studies assessing predictors of success or failure of BI therapy in patients with T2D are we summarized. A number of studies have demonstrated that delayed initiation of insulin therapy with a high level of glycated hemoglobin A1c (HbA1c) at the start of the treatment reduces achieving glycemic control targets on BI. Hypoglycemia in the first weeks or months of BI treatment may reduce the adherence and persistence to treatment and likelihood of achieving treatment targets. In real-world evidence studies, glargine 300 U/mL and degludec, the long-acting second-generation insulin analogues, have shown greater potential in reduction of HbA1c levels with a lower risk of hypoglycaemia compared to other BIs. In the DUNE, ATOS, and some others studies, a lack of insulin dose titration in newly initiated BI users and those who needed treatment intensification was demonstrated. Poor treatment adherence and persistence (missed injections, incorrect dose selection, and temporary or permanent discontinuation of insulin therapy), deviations in insulin injection technique, and formation of lipohypertrophy at the injection sites are also common problems that prevent good glycemic control in these patients. Therefore, patient education with a focus on injection technique, dose titration and prevention of hypoglycemia, as well as the use of the second-generation BI analogs, increases the chances for achieving glycemic control targets in patients with T2D who initiate or need to intensify BI therapy.

Current Insights on the Use of Insulin and the Potential Use of Insulin Mimetics in Targeting Insulin Signalling in Alzheimer’s Disease

Alzheimer's disease (AD) and type 2 diabetes (T2D) are chronic diseases that share several pathological mechanisms, including insulin resistance and impaired insulin signalling. Their shared features have prompted the evaluation of the drugs used to manage diabetes for the treatment of AD. Insulin delivery itself has been utilized, with promising effects, in improving cognition and reducing AD related neuropathology. The most recent clinical trial involving intranasal insulin reported no slowing of cognitive decline; however, several factors may have impacted the trial outcomes. Long-acting and rapid-acting insulin analogues have also been evaluated within the context of AD with a lack of consistent outcomes. This narrative review provided insight into how targeting insulin signalling in the brain has potential as a therapeutic target for AD and provided a detailed update on the efficacy of insulin, its analogues and the outcomes of human clinical trials. We also discussed the current evidence that warrants the further investigation of the use of the mimetics of insulin for AD. These small molecules may provide a modifiable alternative to insulin, aiding in developing drugs that selectively target insulin signalling in the brain with the aim to attenuate cognitive dysfunction and AD pathologies.

Management of Individuals With Diabetes at High Risk for Hypoglycemia: An Endocrine Society Clinical Practice Guideline.

Hypoglycemia in people with diabetes is common, especially in those taking medications such as insulin and sulfonylureas (SU) that place them at higher risk. Hypoglycemia is associated with distress in those with diabetes and their families, medication nonadherence, and disruption of life and work, and it leads to costly emergency department visits and hospitalizations, morbidity, and mortality. To review and update the diabetes-specific parts of the 2009 Evaluation and Management of Adult Hypoglycemic Disorders: Endocrine Society Clinical Practice Guideline and to address developing issues surrounding hypoglycemia in both adults and children living with diabetes. The overriding objectives are to reduce and prevent hypoglycemia. A multidisciplinary panel of clinician experts, together with a patient representative, and methodologists with expertise in evidence synthesis and guideline development, identified and prioritized 10 clinical questions related to hypoglycemia in people living with diabetes. Systematic reviews were conducted to address all the questions. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess the certainty of evidence and make recommendations. The panel agreed on 10 questions specific to hypoglycemia risk and prevention in people with diabetes for which 10 recommendations were made. The guideline includes conditional recommendations for use of real-time continuous glucose monitoring (CGM) and algorithm-driven insulin pumps in people with type 1 diabetes (T1D), use of CGM for outpatients with type 2 diabetes at high risk for hypoglycemia, use of long-acting and rapid-acting insulin analogs, and initiation of and continuation of CGM for select inpatient populations at high risk for hypoglycemia. Strong recommendations were made for structured diabetes education programs for those at high risk for hypoglycemia, use of glucagon preparations that do not require reconstitution vs those that do for managing severe outpatient hypoglycemia for adults and children, use of real-time CGM for individuals with T1D receiving multiple daily injections, and the use of inpatient glycemic management programs leveraging electronic health record data to reduce the risk of hypoglycemia. The recommendations are based on the consideration of critical outcomes as well as implementation factors such as feasibility and values and preferences of people with diabetes. These recommendations can be used to inform clinical practice and health care system improvement for this important complication for people living with diabetes.

Efficacy and Tolerability of Insulin Degludec Versus Other Long-acting Basal Insulin Analogues in the Treatment of Type 1 and Type 2 Diabetes Mellitus: A Systematic Review and Meta-analysis

PurposeThe goal of this study was to compare the efficacy and tolerability of insulin degludec with those of other long-acting insulin analogues (insulin glargine and insulin detemir) in patients with type 1 or 2 diabetes mellitus (T1D or T2D). MethodsThose randomized controlled trials comparing insulin degludec with other long-acting insulin analogues in the treatment of patients with T1D or T2D published on or before August 21, 2022, were retrieved from PubMed, Web of Science, the Cochrane Library, and EMBASE. The efficacy end points were the changes from baseline in hemoglobin A1c and fasting plasma glucose (FPG). The tolerability end point was the prevalence of hypoglycemia confirmed throughout the treatment period. FindingsData from a total of 20 trials (19,048 patients) were included. The differences in the reductions in glycosylated hemoglobin between insulin degludec and other long-acting basal insulin analogues (insulin glargine and insulin detemir) used for the treatment of patients with T1D or T2D were not significant. However, the reduction in FPG was greater with insulin degludec (–0.370 mmol/L; 95% CI, –0.473 to –0.267 mmol/L; P ≤ 0.001). Throughout the treatment periods of all of the available trials, the estimated rate ratios of overall and nocturnal hypoglycemia were significantly decreased with insulin degludec compared with insulin glargine or insulin detemir in patients with T1D or T2D; the differences in the risks for severe hypoglycemia were not significant. ImplicationsCompared with other long-acting insulin analogues (insulin glargine and insulin detemir), insulin degludec was associated with a significantly decreased FPG, with lower prevalences of overall and nocturnal hypoglycemia.

Evaluation of the effectiveness of long-acting insulin analogs in patients with type 2 diabetes mellitus

Evaluation of the effectiveness of long-acting insulin analogs in patients with type 2 diabetes mellitus

ATOS study: effectiveness and safety of insulin glargine 300 U/mL in the real world clinical practice in insulin-naïve type 2 diabetic patients in the Russian Federation

Rationale: Basal insulin glargine 300 U/mL (Gla-300) is a second-generation basal insulin analogue that has comparable efficacy and lower variability compared to the first generation long-acting insulin analogue glargine 100 U/mL.
 Aim: To assess the effectiveness and safety of Gla-300 in insulin-nave type 2 diabetic patients in the real world practice in Russia.
 Materials and methods: ATOS (NCT03703869) was a 12-month, prospective observational international multicenter study. The study included 4422 adults ( 18 years) with uncontrolled type 2 diabetes (HbA1c 7 and 11%) with 1 oral anti-hyperglycemic drug and for whom the treating physician had decided to add Gla-300. We performed a post-hoc sub-analysis of the study participants recruited in Russia.
 Results: The Russian study group included 1493 patients receiving Gla-300. At 6 months, 25.9% of the patients achieved their predefined individualized HbA1c target and 53.3% achieved their HbA1c target at month 12. Their mean ( SD) HbA1c level decreased from 9.3 0.9% at baseline to 7.6 0.7% and 7.2 0.7 at months 6 and 12. The incidence of hypoglycemia was generally low; overall, severe hypoglycemia was reported only in 0.07% and 0.13% of the patients at 6 and 12 months. The baseline average daily dose of Gla-300 was 13.2 4.9 Units; it to 23.6 9.1 and 26.0 9.8 Units at months 6 and 12.
 Conclusion: In the real world setting, initiation of insulin Gla-300 in type 2 diabetic patients who had been out of their target glucose range with oral hypoglycemic agents is associated with improved glycemic control and low risk of hypoglycemia.