Lispro Research Articles

Impact of Ultra-Rapid Insulin on Boost and Ease-Off in the Cambridge Hybrid Closed-Loop System for Individuals With Type 1 Diabetes.

The objective was to evaluate the safety and efficacy of ultra-rapid-acting insulin with the Boost and Ease-off features of the Cambridge hybrid closed-loop system. A secondary analysis of Boost and Ease-off from two double-blind, randomized, crossover hybrid closed-loop studies comparing (1) Fiasp to insulin aspart (n = 25), and (2) Lyumjev to insulin lispro (n = 26) was carried out. Mean glucose on initialization of Boost and Ease-off, change in glucose 60 and 120 minutes after initialization, duration and frequency of use, mean glucose, and time in, above, and below target glucose range were calculated for periods of Boost use, Ease-off use, or neither. Participants used Boost for longer with Fiasp than insulin aspart (median [interquartile range, IQR] = 75 [53-125] minutes vs 60 [49-75] minutes; P = .01). Mean glucose on Boost initialization with Fiasp was 238 ± 62 mg/dL compared with 218 ± 45 mg/dL with insulin aspart (P = .08). Fiasp use resulted in a greater glucose reduction 120 minutes after Boost initialization [-59 ± 34 mg/dL vs -43 ± 31 mg/dL; P = .02]. There were no statistically significant differences in sensor glucose endpoints during Boost or Ease-off periods between Fiasp and aspart. There were no statistically significant differences during Boost or Ease-off periods when comparing Lyumjev with insulin lispro. There were no safety issues when using Boost and Ease-off with ultra-rapid insulins. The use of Fiasp and Lyumjev during Boost or Ease-off resulted in comparable safety and efficacy to using insulin aspart and lispro.

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.

6849 Insulin Edema in newly diagnosed T1DM Pediatric Patient

Abstract Disclosure: A. Ansar: None. K. McNerney: None. Background: Insulin edema is a rare complication of insulin therapy, especially in the pediatric populations. The pathogenesis is not fully understood but has been linked to Insulin’s role in renal sodium handling and vascular permeability. It has been seen with the initiation of insulin in newly diagnosed patients or the intensification of insulin therapy in those with poor glycemic control.Clinical Case: A previously healthy 12 year old girl presented to the ED with polyuria, polydipsia and fatigue. She was alert and oriented but had kussmaul breathing. She was tachycardic but all other vitals were appropriate. Lab work up showed that she was in DKA with pH 7.07 and bicarbonate 7 mmol/L. Her corrected sodium and electrolytes were normal. Her HbA1C was elevated at 11.7% (4.0-5.6%). Initial fluid resuscitation was performed with 20 mL/kg NS fluids. She was transferred to our Pediatric ICU and was started on the DKA protocol consisting of intravenous insulin infusion at 0.1 unit/kg per hour and 2-bags of dextrose and non-dextrose containing intravenous fluids. She was given a new diagnosis of Type 1 Diabetes. She was transitioned to subcutaneous insulin 22 hours later with multiple daily injections with insulin lispro and glargine, with total dose of insulin at 0.7 unit/kg per day. She was transferred to the general care floor and received diabetes education while in the hospital. On the fifth day after discharge, patient started complaining of leg tightness, puffiness around her eyes and generalized swelling of both feet. She returned to the ED, where she was found to be hemodynamically stable and normotensive with a blood pressure of 113/54 mmHg. Her weight had increased 8.8 kg from the weight at discharge. Her physical exam was notable facial and bilateral periorbital edema, abdominal distension, and 2+ bilateral non-pitting non-tender edema of both legs extending to her medial malleolus. Neurologic exam was performed which was unremarkable. Work up was performed to rule out other causes of edema, including a complete blood count, electrolytes, kidney and liver function tests, all of which were normal. She received 20 mg of furosemide and was instructed to perform fluid restriction to 1 L/m2/day and sodium restriction to <2 grams per day at home. She followed up in clinic 3 days after her ED visit where her weight had decreased by 4.2 kg and her edema had mostly resolved with only 1+ bilateral non-pitting edema. Her total dose of insulin remained at 0.7 unit/kg per day, with acceptable blood glucose levels at home. Her fluid restriction was discontinued and patient was instructed to follow up as usual, and she had no further edema in follow-up. Conclusion: This was a rare case of a newly diagnosed pediatric patient presenting with Insulin edema, which is essential for clinicians to recognize, so they can identify patients presenting with this uncommon side effect to rule out conditions that may present in a similar manner. Presentation: 6/2/2024

8145 Type 2 Diabetes In A Patient With IMAGe Syndrome

Abstract Disclosure: N. Mulpuri: None. S. Mirfakhraee: None. J. Abramowitz: None. Background: Individuals with mutations that lead to deficiency of POLE1 (a catalytic subunit of polymerase epsilon) may have clinical features of IMAGe syndrome (intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenital, and genitourinary anomalies) in addition to distinctive facial features and variable immunodeficiency. Of 15 reported cases in the literature, none were previously characterized with type 2 diabetes mellitus (T2DM). Clinical case: This is a 25-year-old woman with a history of IMAGe syndrome (confirmed mutation in the POLE gene). With regards to IMAGe syndrome history, during the prenatal period, she had growth restriction in the third trimester with delivery at 38 weeks. At 4 years-old, she presented with adrenal crisis and was started on glucocorticoid and mineralocorticoid therapy, now taking hydrocortisone 2.5mg three times daily (8.6 mg/m2/day) and fludrocortisone 0.05mg daily. Initial labs in the adult endocrine clinic were notable for serum glucose 339 mg/dL (65-99 mg/dL), undetectable estradiol (< 15 pg/ml) with FSH 6.8 mIU[JA1] /mL and LH 2.0 mIU/mL, TSH 1.25 mIU/L (0.40-4.50 mIU/dL), FT4 0.7 ng/dL (0.8-1.8 ng/dL). The patient denied any history of T2DM. She also denied polyuria, polydipsia, or weight loss. There was no stigmata of peripheral insulin resistance on exam. Subsequent labs included HbA1c 8.9%, fructosamine 417 mcmol/L (200-285 mcmol/L), insulin 18.4 mcIU/mL (2.6-24.9 mcIU/mL), and C-peptide 3.9 ng/dL (1.1-4.4 ng/dL) with serum glucose 164 mg/dL. Islet cell, insulin, and GAD-65 antibodies were undetectable. CT abdomen/pelvis did not show any pancreatic mass or anomalies. Initially, prandial insulin (lispro 3 units prior to each meal) was initiated given post-prandial hyperglycemia noted on continuous glucose monitoring. Low-dose levothyroxine, 25 mcg daily, was initiated given concern for secondary hypothyroidism, with subsequent normalization of serum thyroxine. HbA1c improved to 7.4% six months later. Ultimately, she transitioned to sitagliptin 25 mg daily and her latest HbA1c was 6.2% three years after initial diagnosis of T2DM. Conclusion: Of the 15 cases of IMAGe syndrome with mutations in POLE described in Logan et al, none were noted to have diabetes. The patient described above was diagnosed with new-onset diabetes at age 21, presumably T2DM in the context of undetectable antibodies and high-normal C-peptide. Interestingly, she did not have any typical stigmata of peripheral insulin resistance. Glucocorticoids used for the treatment of adrenal insufficiency in patients with IMAGe syndrome can contribute to development of T2DM. Patients with IMAGe syndrome on chronic glucocorticoids should be monitored for hyperglycemia and diabetes. Additionally, glucocorticoid doses should be optimized to balance mitigating side effects such as hyperglycemia and osteoporosis while preventing adrenal crisis. Presentation: 6/3/2024

12599 Early Remission Of Chromosome 6 Q 24-related Neonatal Diabetes Mellitus

Abstract Disclosure: R. Pratibha: None. K. Dummula: None. Introduction: Chromosome 6q24 imprinting abnormalities represent the predominant cause of transient neonatal diabetes mellitus (TNDM), accounting for over two-thirds of cases with an estimated prevalence of 1 in 400,000. While remission typically manifests by 3 months of age, herein we detail a case of Chromosome 6q24-related TNDM exhibiting remission by 1.5 months of age. We share our clinical experience in managing this case without hypoglycemia and using C-Peptide levels as a monitoring tool to track the resolution. Case: A female infant, born at 36 weeks via elective C-section due to fetal growth restriction and oligohydramnios, was closely monitored in the nursery for potential hypoglycemia. Contrary to the expectation, she displayed escalating hyperglycemia, necessitating insulin infusion within 25 hours of birth. Apgar scores were 7 and 9, and the birth weight was 2095 g (6th percentile). Maternal history included impaired glucose tolerance in a previous pregnancy with borderline glucose tolerance during this gestation. The newborn physical exam was unremarkable except for mild macroglossia. Despite initial blood glucose (BG) of 52 mg/dl, it rose to 257 mg/dL by 16 hours. Insulin drip was started at 24 hours due to BG of 304 mg/dL. The monogenic diabetes panel obtained on day of life (DOL) #2 was negative; no acidosis was observed. The C- Peptide was low at 0.2 ng/ml. Insulin infusion was continued until DOL # 20. A trial of glyburide commenced on DOL #9 while on Insulin drip, yielded minimal response, prompting a transition to short-acting insulin for correction of hyperglycemia (>250 mg/dL). C-peptide level during sulfonylurea (SU) trial remained low (0.5 ng/mL). The infant required 2 to 3 corrections per day with 0.05 units of Lispro Insulin, with the last dose administered at 44 days. She did not receive any long-acting Insulin. As of her last follow-up at the endocrine clinic at 57 days of age, the infant is thriving well and has normal blood glucose levels. The 6q24 Methylation-MLPA study showed duplication of 6q24 on the paternally inherited chromosome 6. Significantly, she never encountered hypoglycemia during her hospital stay. The C-peptide increased to 0.8 ng/ml at DOL#37 and had normalized to 1.3 ng/mL by DOL#57 indicating remission of TNDM. Conclusion: 6q24-related TNDM may often be characterized by features such as small for gestational age (SGA), macroglossia, umbilical hernia, cardiac and renal abnormalities. Early presentation of hyperglycemia with this phenotype must prompt its diagnostic evaluation. Early resolution by 1.5 months as seen in our case is uncommon. Uniquely, we used C-peptide as a tracking tool to guide resolution and manage insulin therapy. Presentation: 6/3/2024

Higher Order Structure Differences Among Insulin Crystalline Drugs Revealed by 2D heteronuclear NMR.

During therapeutic protein development, two-dimensional (2D) heteronuclear NMR spectra can be a powerful analytical method for measuring protein higher order structure (HOS) in solution since the spectra exhibit much higher resolution than homonuclear 1H spectra. However, 2D NMR capabilities for characterizing protein HOS in crystalline states remain to be assessed, given the low 13C natural abundance and intrinsically broader lines in solid-state NMR (SSNMR). Herein, high-resolution heteronuclear correlation (HETCOR) SSNMR was utilized to directly measure intact crystal drug products of insulin human, insulin analogs of insulin lispro and insulin aspart. The fingerprint regions in 2D 1H-13C HETCOR spectra were identified, which distinguished the insulin crystals in their primary structure, HOS heterogeneity and dynamics, as well as the manufacturing processes. The HOS heterogeneity in insulin analogs is consistent with their therapeutic effect of rapid action; while insulin human crystals showed more structural homogeneity, consistent with their slower pharmacokinetics (PK)peak time than insulin analogs. Therefore, heteronuclear NMR could be broadly applicable to study protein drug dosage forms from liquid to solid, yielding improved molecular level structure data for assessing drug HOS in biosimilar drug development.

Once-weekly insulin efsitora alfa versus once-daily insulin degludec in adults with type 1 diabetes (QWINT-5): a phase 3 randomised non-inferiority trial

Insulin efsitora alfa (efsitora) is a once-weekly basal insulin. This phase 3 study aimed to assess the efficacy and safety of efsitora compared with insulin degludec (degludec) in adults with type 1 diabetes. This randomised, 52-week, parallel-design, open-label, treat-to-target non-inferiority study conducted at 82 global health-care centres, randomly assigned (1:1) adults (ie, those aged ≥18 years) with type 1 diabetes glycated haemoglobin A1c (HbA1c) 7·0-10·0% (53·0-85·8 mmol/mol) to efsitora (n=343) or, degludec (n=349), both in combination with insulin lispro. The primary endpoint was the change in HbA1c from baseline to week-26 (non-inferiority margin=0·4%). The trial was registered at ClinicalTrials.gov (NCT05463744) and is completed. Between Aug 12, 2022, and May 7, 2024, of 893 participants enrolled, 692 (77%) participants were randomly assigned to once-weekly efsitora or once-daily degludec, and 623 (90%) participants completed the study. Mean HbA1c decreased from 7·88% (62·66 mmol/mol) at baseline to 7·41% (57·5 mmol/mol) at week 26 with efsitora and from 7·94% (63·3 mmol/mol) at baseline to 7·36% (56·9 mmol/mol) at week 26 with degludec. Mean HbA1c change from baseline to week 26 was -0·51% with efsitora and -0·56% with degludec (estimated treatment difference 0·052%, 95% CI -0·077 to 0·181; p=0·43), confirming a non-inferiority margin of 0·4% for efsitora compared with degludec. Rates of combined level 2 (<54 mg/dL [3·0 mmol/L]) or level 3 severe hypoglycaemia were higher with efsitora compared with degludec (14·03 vs 11·59 events per patient year of exposure; estimated rate ratio 1·21, 95% CI 1·04 to 1·41; p=0·016) during weeks 0-52, with the highest rates during weeks 0-12. Severe hypoglycaemia incidence was higher with efsitora (35 [10%] of 343) versus degludec (11 [3%] of 349) during weeks 0-52. Overall incidence of treatment-emergent adverse events was similar across treatment groups. One death not related to the study treatment occurred in the degludec group. In adults with type 1 diabetes, once-weekly efsitora showed non-inferior HbA1c reduction compared with daily insulin degludec. Higher rates of combined level 2 or level 3 hypoglycaemia and greater incidence of severe hypoglycaemia in participants treated with efsitora compared with participants treated with degludec might suggest the need for additional evaluation of efsitora dose initiation and optimisation in people with type 1 diabetes. Eli Lilly and Company.

ADO09, a co-formulation of pramlintide and insulin A21G, lowers body weight versus insulin lispro in type 1 diabetes.

To study safety, efficacy and weight loss with ADO09, a co-formulation of insulin A21G and pramlintide, in type 1 diabetes. A randomized, two-arm ambulatory 16-week study compared ADO09 with insulin lispro in 80 participants with type 1 diabetes. We compared changes of weight, glycated haemoglobin, glycaemic patterns during continuous glucose monitoring, and insulin doses at baseline and at the end of treatment. A significant and continuing weight loss, the primary endpoint, was observed with ADO09 compared with lispro as prandial insulin. In the whole group, the weight loss with ADO09 relative to lispro was 2.1 kg. Glycaemic control was relatively good (7.7% mean glycated haemoglobin) in both groups and did not change during treatment. Prandial insulin doses were reduced by 21% in the ADO09 group, whereas basal insulin dosage was not modified. Gastrointestinal symptoms were more frequent with ADO09, but no clear difference in hypoglycaemia was observed. These results extend previous observations on the efficacy and safety of this insulin/pramlintide co-formulation. They show a beneficial effect on weight, using less mealtime insulin and without increased hypoglycaemia.

Optimization of a mass spectrometric analytical method for the quality assessment of insulin and its analogs.

The principal aim of this study was to optimize analytical methodology based on mass spectrometry for the evaluation of the quality of recombinant human insulin and its analogs. In this study ESI-MS was used to assess the quality of human insulin, short acting insulin analogs, insulin lispro, insulin aspart and insulin glulisine and long acting analogs including insulin glargine, insulin degludec, and insulin detemir, in respective pharmaceutical formulations. In this study, with the aimed to optimize analytical conditions, different factors influencing the analytical performance such as pH, ionic strength, sample dilution, organic solvent addition were addressed. The study results demonstrated that MS is a suitable technique for the analysis of biotechnological compounds like insulin and its analogs. Although the obtained results provide an important information regarding this methodology, further studies are needed to validate this analytical approach and check for its suitability to be used in the regulatory environment.

Tirzepatide Improved Health-Related Quality of Life Compared with Insulin Lispro in Basal Insulin-Treated Adults with Type 2 Diabetes and Inadequate Glycaemic Control: A Randomised Controlled Phase 3b Trial (SURPASS-6).

Patients with type 2 diabetes (T2D) who require intensification of basal insulin therapy need treatment options that can improve their health-related quality of life (HRQoL) and translate into better outcomes. These analyses compared patient-reported outcomes (PROs) in patients with T2D receiving tirzepatide or insulin lispro. The randomised, open-label, multinational, phase 3b SURPASS-6 trial (NCT04537923) was conducted at 135 medical research centres and hospitals in 15 countries and compared two recommended treatment intensification strategies in people with T2D and inadequate glycaemic control on basal insulin: addition of once-weekly tirzepatide versus addition of prandial insulin lispro. Randomisation was stratified by country, baseline glycated haemoglobin level and metformin use. PROs were measured using the Short Form-36 Health Survey version 2 (SF-36v2) acute form (secondary outcome), EQ-5D-5L, Ability to Perform Physical Activities of Daily Living (APPADL) questionnaire and Impact of Weight on Self-Perceptions (IW-SP) questionnaire (tertiary/exploratory outcomes). PROs were compared for the tirzepatide-pooled dose group (5, 10 and 15 mg) and each tirzepatide dose group versus insulin lispro at 52 weeks using the modified intention-to-treat efficacy analysis set. Between 19 October 2020 and 01 November 2022, 2267 people were assessed and 1428 participants with T2D were randomised. At 52weeks, participants in the tirzepatide-pooled group had statistically significant improved scores across all SF-36v2 domains and both component summary scores compared with insulin lispro-treated participants (p < 0.05), with the largest differences observed in the general health, vitality and mental health domains. Statistically significant improved APPADL and IW-SP total scores, as well as EQ visual analogue scale and EQ-5D-5L index scores (after adjustment for baseline scores), were observed in tirzepatide-pooled participants compared with insulin lispro-treated participants. In adult patients with T2D and inadequate glycaemic control with basal insulin, tirzepatide treatment was associated with greater improvements in HRQoL than prandial insulin therapy in addition to clinically significant improvements in glycaemic and body weight-related parameters.

Multicenter Evaluation of Ultra-Rapid Lispro Insulin with Control-IQ Technology in Adults, Adolescents, and Children with Type 1 Diabetes.

Objective: To evaluate the safety and explore the efficacy of use of ultra-rapid lispro (URLi, Lyumjev) insulin in the Tandem t:slim X2 insulin pump with Control-IQ 1.5 technology in children, teenagers, and adults living with type 1 diabetes (T1D). Methods: At 14 U.S. diabetes centers, youth and adults with T1D completed a 16-day lead-in period using lispro in a t:slim X2 insulin pump with Control-IQ 1.5 technology, followed by a 13-week period in which URLi insulin was used in the pump. Results: The trial included 179 individuals with T1D (age 6-75 years). With URLi, 1.7% (3 participants) had a severe hypoglycemia event over 13 weeks attributed to override boluses or a missed meal. No diabetic ketoacidosis events occurred. Two participants stopped URLi use because of infusion-site discomfort, and one stopped after developing a rash. Mean time 70-180 mg/dL increased from 65% ± 15% with lispro to 67% ± 13% with URLi (P = 0.004). Mean insulin treatment satisfaction questionnaire score improved from 75 ± 13 at screening to 80 ± 11 after 13 weeks of URLi use (mean difference = 6; 95% confidence interval 4-8; P < 0.001), with the greatest improvement reported for confidence avoiding symptoms of high blood sugar. Mean treatment-related impact measure-diabetes score improved from 74 ± 12 to 80 ± 12 (P < 0.001), and mean TRIM-Diabetes Device (score improved from 82 ± 11 to 86 ± 12 (P < 0.001). Conclusions: URLi use in the Tandem t:slim X2 insulin pump with Control-IQ 1.5 technology was safe for adult and pediatric participants with T1D, with quality-of-life benefits of URLi use perceived by the study participants. Clinicaltrials.gov registration: NCT05403502.

Insulin enhances drone semen quality after cryopreservation

The main objective of this study was to investigate the effect of insulin on drone semen quality after cryopreservation. Semen samples were obtained from sexually mature drones. The semen samples were pooled and diluted with varying concentrations of insulin lispro, specifically 5 IU (I-5), 10 IU (I-10), 15 IU (I-15), and 20 IU (I-20), as well as a control. The assessment of motility, plasma membrane integrity and DNA integrity was conducted using microscopy. Flow cytometry was used to assess acrosome integrity, mitochondrial membrane potential, and nitric oxide level. The preservation of motility, plasma membrane functional integrity, and acrosome integrity was significantly superior in the I-5 group compared to the control group. However, increasing levels of insulin had a detrimental impact on the integrity of the acrosome in both the I-15 and I-20 groups. The mitochondrial membrane potential was significantly elevated in the I-5 and I-10 groups compared to the control group. However, a statistically significant decrease was observed in both the I-15 and I-20 groups. We observed a significant decrease in nitric oxide levels in both the I-5 and I-10 groups as compared to the control group. The preservation of DNA integrity was significantly higher in the insulin containing groups compared to the control group. The study findings revealed that the inclusion of insulin lispro in drone semen extenders yielded beneficial outcomes for drone semen.

Review of data on comparative pharmacokinetics, pharmacodynamics, efficacy and safety of the superfast insulin drug lispro

Diabetes mellitus remains one of the main socially significant health problems worldwide. Glycemic control plays a key role in the prevention of all complications of diabetes mellitus. One of the most important factors in the overall control of glycemia in patients with both type 1 and type 2 diabetes mellitus is postprandial glucose levels, as a leading risk factor for delayed vascular complications. Modern possibilities for controlling postprandial glycemia include the use of not only ultrashort insulin preparations, but also ultrafast action. One of the superfast insulin preparations available today is the drug Lumzhev ® (inLisFast), which contains lyspro insulin as an active ingredient. A number of studies on the comparative pharmacokinetics and pharmacodynamics of inLisFast compared with insulin lispro consistently demonstrate a shift in the pharmacokinetic and pharmacodynamic profile to the left, which indicates faster absorption, an increase in early insulin exposure and a decrease in late insulin exposure. inLisFast provides flexibility in the regulation of food intake, which can play a significant role in optimizing glycemic control and improving the quality of life of patients with diabetes.

Ultra rapid lispro improves postprandial glucose control versus lispro in combination with basal insulin: a study based on CGM in type 2 diabetes in China.

To evaluate the efficacy and safety of URLi (ultra rapid lispro insulin) compared to insulin lispro as bolus insulin with basal insulin using CGM in the individuals with type 2 diabetes(T2D) in China. This was a double-blind, randomized, parallel, prospective, phase 3 study. Subjects with uncontrolled T2D were recruited and randomized 1:2 into the insulin lispro and URLi groups. Subjects received a consistent basal insulin regimen during the study and self-administered insulin lispro or URLi before each meal throughout the treatment period. Subjects underwent a 3-day continuous glucose monitoring (CGM) at the baseline and endpoint respectively, and then CGM data were analyzed. The primary endpoint was to compare the difference in postprandial glucose (PPG) control using CGM between the two groups. A total of 57 subjects with T2D completed the study. Our CGM data showed that postprandial glucose excursions after breakfast (BPPGE) in the URLi group was lower than that in the insulin lispro group (1.59 ± 1.57 mmol/L vs 2.51 ± 1.73 mmol/L, p = 0.046). 1-hour PPG was observed to decrease more in the URLi group than that in the insulin lispro group (-1.37 ± 3.28 mmol/L vs 0.24 ± 2.58 mmol/L, p = 0.047). 2-hour PPG was observed to decrease more in the URLi group than that in the insulin lispro group (-1.12 ± 4.00 mmol/L vs 1.22 ± 2.90 mmol/L, p = 0.021). The mean HbA1c level decreased by 1.1% in the URLi group and 0.99% in the insulin lispro group, with no treatment difference (p = 0.642). In the CGM profile, TBR was not significantly different between the two groups (p = 0.743). The weight gain also did not differ between the two groups (p = 0.303). URLi can control breakfast PPG better than insulin lispro in adults with T2D in China, while it is non-inferior in improving HbA1c. The incidence of hypoglycemic and weight gain were similar between the two groups.

4S-fluorination of ProB29 in insulin lispro slows fibril formation

Recombinant insulin is a life-saving therapeutic for millions of patients affected by diabetes mellitus. Standard mutagenesis has led to insulin variants with improved control of blood glucose; for instance, the fast-acting insulin lispro contains two point mutations that suppress dimer formation and expedite absorption. However, insulins undergo irreversible denaturation, a process accelerated for the insulin monomer. Here we replace ProB29 of insulin lispro with 4R-fluoroproline, 4S-fluoroproline, and 4,4-difluoroproline. All three fluorinated lispro variants reduce blood glucose in diabetic mice, exhibit similar secondary structure as measured by circular dichroism, and rapidly dissociate from the zinc- and resorcinol-bound hexamer upon dilution. Notably, however, we find that 4S-fluorination of ProB29 delays the formation of undesired insulin fibrils that can accumulate at the injection site in vivo, and can complicate insulin production and storage. These results demonstrate how subtle molecular changes achieved through non-canonical amino acid mutagenesis can improve the stability of protein therapeutics.

Efficacy and safety of basal insulins in people with type 2 diabetes mellitus: a systematic review and network meta-analysis of randomized clinical trials.

The comparative effectiveness of basal insulins has been examined in several studies. However, current treatment algorithms provide a list of options with no clear differentiation between different basal insulins as the optimal choice for initiation. A comprehensive search of MEDLINE, Embase, Cochrane Library, ISI, and Scopus, and a reference list of retrieved studies and reviews were performed up to November 2023. We identified phase III randomized controlled trials (RCTs) comparing the efficacy and safety of basal insulin regimens. The primary outcomes evaluated were HbA1c reduction, weight change, and hypoglycemic events. The revised Cochrane ROB-2 tool was used to assess the methodological quality of the included studies. A random-effects frequentist network meta-analysis was used to estimate the pooled weighted mean difference (WMD) and odds ratio (OR) with 95% confidence intervals considering the critical assumptions in the networks. The certainty of the evidence and confidence in the rankings was assessed using the GRADE minimally contextualized approach. Of 20,817 retrieved studies, 44 RCTs (23,699 participants) were eligible for inclusion in our network meta-analysis. We found no significant difference among various basal insulins (including Neutral Protamine Hagedorn (NPH), ILPS, insulin glargine, detemir, and degludec) in reducing HbA1c. Insulin glargine, 300 U/mL (IGlar-300) was significantly associated with less weight gain (mean difference ranged from 2.9 kg to 4.1 kg) compared to other basal insulins, namely thrice-weekly insulin degludec (IDeg-3TW), insulin degludec, 100 U/mL (IDeg-100), insulin degludec, 200 U/mL (IDeg-200), NPH, and insulin detemir (IDet), but with low to very low certainty regarding most comparisons. IDeg-100, IDeg-200, IDet, and IGlar-300 were associated with significantly lower odds of overall, nocturnal, and severe hypoglycemic events than NPH and insulin lispro protamine (ILPS) (moderate to high certainty evidence). NPH was associated with the highest odds of overall and nocturnal hypoglycemia compared to others. Network meta-analysis models were robust, and findings were consistent in sensitivity analyses. The efficacy of various basal insulin regimens is comparable. However, they have different safety profiles. IGlar-300 may be the best choice when weight gain is a concern. In contrast, IDeg-100, IDeg-200, IDet, and IGlar-300 may be preferred when hypoglycemia is the primary concern.

Biorelevant subcutaneous in vitro test predicts the release of human and fast acting insulin formulations

The administration of insulins by subcutaneous injection is nowadays widely prevalent. The injection site is located below the dermis and composed of cells and the extracellular matrix formed of a network of macromolecules such as hyaluronic acid and collagen. Following an injection, the insulins from the formulated products are timely released as drug molecules from the injection site into systemic circulation. In this publication, we show the development of an in vitro setup utilizing a hydrogel composed of a special collagen-hyaluronic acid mixture that mimics the extracellular matrix. Another setup was used for differentiation of the commercially available and research insulin formulations by determining the in vitro permeation characteristics with the results that were correlated with the human in vivo data. Significant differentiation was achieved at 90 % confidence level between the permeation curves of insulin glulisine containing formulations (U100 and a concentrated research formulation), while in case of the insulin lispro containing formulations (U100 and U200) the permeation curves showed similarity. These results demonstrated that the in vitro setup may be used as a tool for formulation development and drug candidate profiling as it is able to differentiate or show similarities between the agglomeration states and concentration of the active pharmaceutical ingredients.

Postprandial Glucose Excursions with Ultra-Rapid Insulin Analogs in Hybrid Closed-Loop Therapy for Adults with Type 1 Diabetes.

Objective: To evaluate postprandial glucose control when applying (1) faster-acting insulin aspart (Fiasp) compared to insulin aspart and (2) ultra-rapid insulin lispro (Lyumjev) compared to insulin lispro using the CamAPS FX hybrid closed-loop algorithm. Research Design and Methods: We undertook a secondary analysis of postprandial glucose excursions from two double-blind, randomized, crossover hybrid closed-loop studies contrasting Fiasp to standard insulin aspart, and Lyumjev to standard insulin lispro. Endpoints included incremental area under curve (iAUC)-2h, iAUC-4h, 4 h postprandial time in target range, time above range, and time below range. It was approved by independent research ethics committees. Results: Two trials with 8 weeks of data from 51 adults with type 1 diabetes were analyzed and 7137 eligible meals were included. During Lyumjev compared with insulin lispro, iAUC-2h and iAUC-4h were significantly decreased following breakfast (mean difference 92 mmol/L per 2 h (95% confidence interval [CI]: 56 to 127); P < 0.001 and 151 mmol/L per 4 h (95% CI: 74 to 229); P < 0.001, respectively) and the evening meal (P < 0.001 and P = 0.011, respectively). Mean time in target range (3.9-10.0 mmol/L) for 4 h postprandially significantly increased during Lyumjev with a mean difference of 6.7 percentage points (95% CI: 3.3 to 10) and 5.7 percentage points (95% CI: 1.4 to 9.9) for breakfast and evening meal, respectively. In contrast, there were no significant differences in iAUC-2h, iAUC-4h, and the other measures of postprandial glucose control between insulin aspart and Fiasp during breakfast, lunch, and evening meal (P > 0.05). Conclusion: The use of Lyumjev with CamAPS FX closed-loop system improved postprandial glucose excursions compared with insulin lispro, while the use of Fiasp did not provide any advantage compared with insulin aspart. Clinical Trial Registration numbers: NCT04055480, NCT05257460.

Is Tirzepatide the New Game Changer in Type 2 Diabetes?

Background: Tirzepatide (TZP) is a once-weekly glucagon-like peptide 1 (GLP-1) and glucose-dependent-insulinotropic-polypeptide (GIP) receptor co-agonist approved for T2D. TZP provides promising evidence in improving glucose control and weight loss in T2D and obesity across preclinical and human studies, including data from the SURPASS program. Aims: The goal of this paper was to review the evidence on TZP in terms of glucose control, body weight, and the progression of chronic diabetes-related complications and comorbidities. Results: The mean change in HbA1c ranged from −1.6% to −2.06% over placebo, from −0.29% to −0.92% over each GLP-1RAs, and from −0.7% to −1.09% over basal insulins. In SURPASS-6, TZP was more effective than insulin lispro U100 added to basal insulin in reducing HbA1c levels at the study end (−2.1% vs. −1.1%, respectively). Compared to placebo, TZP induces a significant weight loss: 7.5 (5 mg/week); 11 (10 mg/week); and 12 kg (15 mg/week). Compared to GLP-1RAs, TZP reduces body weight from −1.68 kg to −7.16 kg depending on the dose (5 to 15 mg, respectively). Compared to basal insulin alone rigorously titrated, TZP added onto basal-insulin results in the best strategy for the composite endpoint of improvement of glucose control and weight loss. In SURPASS-6, TZP compared to insulin lispro U100 in add-on to insulin glargine U100 reduced body weight by 9 kg in mean (versus weight gain in basal-bolus users: +3.2 kg). TZP has pleiotropic effects potentially dampening the individual cardiovascular risk, including a reduction in systolic arterial pressure by 4 to 6 mmHg and total cholesterol by 4–6% compared to baseline. A post hoc analysis of SURPASS-4 revealed that TZP, compared to glargine U100, delayed the rate of glomerular filtration decline (−1.4 mL/min vs. −3.6 mL/min, respectively), reduced the rate of urinary albumin excretion (−6.8% vs. +36.9%, respectively), and was associated with a lower occurrence of the composite renal endpoint (HR 0.58 [0.43; 0.80]). Conclusions: Consistent evidence indicates that TZP dramatically changes the clinical course of T2D in different clinical scenarios. The efficacy and safety of TZP on chronic diabetes-related comorbidities and complications seem promising, but ongoing trials will clarify the real benefits.

Undetected Exogenous Insulin Administration in a Child: Assessment of Assay Limitations and Impact on the Practice of Laboratory Medicine

Abstract Introduction/Objective The development of new synthetic insulin analogues over the past few decades has significantly impacted the management of hypoglycemia. However, accurately measuring these analogues presents challenges due to variable cross-reactivity with many insulin assays. Failure to consider cross-reactivity may lead to the misdiagnosis of exogenous insulin administration. Methods/Case Report A 13-year-old female with a history of type 1 DM was presented to an outside hospital emergency department with symptoms indicative of hypoglycemia. Multiple child protective services (CPS) referrals are noted. The patient had experienced several episodes of hypoglycemia over the prior week with blood glucose in the 30-40 mg/dL range. There were no associated symptoms of diarrhea, emesis, or fatigue. The patient was transferred to a pediatric hospital were preliminary investigations indicated abnormally low blood glucose levels with low insulin and C-peptide levels. Further evaluation was initiated to determine the underlying cause of these episodes and to ensure appropriate adjustments in insulin dosing and regimen. Initially, the Elecsys insulin assay (Roche Diagnostics) was utilized to quantify insulin levels which shows a low cross-reactivity for insulin lispro and glargine. To validate the hypothesis of an undetected exogenous insulin overdose, blood samples were sent to another laboratory employing The Advia Centaur insulin assay (Siemens) which exhibits a higher cross-reactivity for insulin lispro and glargine (89%-143%, respectively), indicating a higher recognition and measurement sensitivity for these insulin analogues. The analysis using this assay revealed significantly elevated insulin levels, corroborating the presence of an insulin overdose. The sample at the time of presentation at the outside hospital was confirmed to be 434.1 mU/L. A sample collected 17 hours later had an insulin level of 23.5 mU/L. Results (if a Case Study enter NA) NA Conclusion This case study highlights the critical issue of undetected insulin overdose in a child and emphasizes the limitations of the initial insulin assay employed. Improving assay sensitivity and reliability will enhance patient care and safety. This case study reminds clinicians and laboratory professionals of the need for ongoing quality assurance and vigilance in their practices.