Predicting human half-life for insulin analogs: An inter-drug approach.

An inter-drug approach, applying pharmacokinetic information for insulin analogs in different animal species, rat, dog and pig, performed better compared to allometric scaling for human translation of intra-venous half-life and only required data from a single animal species for reliable predictions. Average fold error (AFE) between 1.2-1.7 were determined for all species and for multispecies allometric scaling AFE was 1.9. A slightly larger prediction error for human half-life was determined from in vitro human insulin receptor affinity data (AFE on 2.3-2.6). The requirements for the inter-drug approach were shown to be a span of at least 2 orders of magnitude in half-life for the included drugs and a shared clearance mechanism. The insulin analogs in this study were the five fatty acid protracted analogs: Insulin degludec, insulin icodec, insulin 320, insulin 338 and insulin 362, as well as the non-acylated analog insulin aspart.

Comparation of fixed-ratio (IDegLira and iGlarLixi) versus free combination of basal insulin and glucagon-like peptide-1 receptor agonist for uncontrolled type 2 diabetes: A systematic review and network meta-analysis.

OBJECTIVE: This study aimed to evaluate the safety and efficacy of the fixed-ratio combination (FRC) and free combination of basal insulin and glucagon-like peptide-1 receptor agonist (GLP-1RA) in patients with type 2 diabetes mellitus (T2DM). METHODS: PubMed, Web of Science, Embase, The Cochrane Library, and four Chinese databases were searched for relevant studies from inception to April 13, 2023. Phase III clinical trials involving FRC or free combination in patients with uncontrolled T2DM were included. A network meta-analysis (NMA) was used to evaluate the effects of FRC and free combination. The Cochrane Collaboration's tool was used to evaluate the risk-of-bias. The primary outcomes were changes in hemoglobin A1c (HbA1c), body weight, and incident hypoglycemia. Secondary outcomes included changes in systolic blood pressure (SBP) and diastolic blood pressure (DBP). This study was registered with PROSPERO (CRD42023409585). RESULTS: Forty-two trials with 23,619 patients were included in the NMA, and treatments were categorized as FRC, free combination and NOINSGLP (neither FRC nor free combination). The forest plots revealed comparable HbA1c control (mean difference (MD) = 0.07%, 95% confidence interval (CI): -0.17 to -0.30) between free combination and FRC. However, there were significant differences in the body weight (MD = -2.06 kg; 95% CI: -3.34 to -0.77), SBP (MD = -1.22 mmHg; 95% CI: -2.41 to -0.04), and DBP (MD = -1.09 mmHg; 95% CI: -1.94 to -0.24) between the two groups. CONCLUSIONS: In patients with uncontrolled T2DM, the safety and efficacy of FRC and free combination therapy were comparable. The use of FRC is justifiable in patients requiring free combination.

Treatment intensification following glucagon-like peptide-1 receptor agonist in type 2 diabetes: Comparative effectiveness analyses between free vs. fixed combination of GLP-1 RA and basal insulin. RESTORE-G real-world study.

BACKGROUND AND AIMS: Add-on of basal insulin (BI) to intensify the ongoing therapy with glucagon-like peptide 1 receptor agonist (GLP-1 RA) is recommended, but it is unclear if free or fixed combination of BI and GLP-1 RA produce similar outcomes. A retrospective comparative effectiveness analysis of the add-on of glargine 300 U/mL (Gla-300) to ongoing GLP-1 RA vs. switch to fixed ratio combination of degludec and liraglutide (iDegLira) was performed. METHODS AND RESULTS: Real-world data collected in electronic medical records by 32 Italian diabetes clinics. Propensity score (PS) adjustment was applied to assess changes in glycated hemoglobin (HbA1c), fasting blood glucose (FBG), body weight, and BI dose after 6 months from Gla-300 or iDegLira initiation. Compared to iDegLira group (N = 260), Gla-300+GLP-1 RA group (N = 255) had older age and higher levels of HbA1c (9.1 vs. 8.9%). After 6 months, statistically significant greater FBG improvement [estimated mean difference and 95% confidence intervals: -24.05 mg/dl (-37.04; -11.06; p = 0.0003) and BI dose increase [+0.03 U/kg (95%CI 0.00; 0.06); p = 0.009] were found in the free vs. fixed combination group, although low doses of BI (0.2 U/kg) were reached in both groups. Trends of larger HbA1c and body weight reductions with the free combination were also found, without reaching the statistical significance. CONCLUSION: Although inertia in insulin initiation and titration was documented in both groups, higher benefit on FBG control was obtained with free vs. fixed combination, likely due to a better titration of BI and GLP-1 RA.

The Effect of Various Degrees of Renal or Hepatic Impairment on the Pharmacokinetic Properties of Once-Weekly Insulin Icodec.

BACKGROUND AND OBJECTIVE: Icodec is a once-weekly insulin being developed to provide basal insulin coverage in diabetes mellitus. This study evaluated the effects of renal or hepatic impairment on icodec pharmacokinetics. METHODS: Two open-label, parallel-group, single-dose (1.5 U/kg subcutaneously) trials were conducted. In a renal impairment trial, 58 individuals were allocated to normal renal function (measured glomerular filtration rate ≥ 90 mL/min), mild (60 to < 90 mL/min), moderate (30 to < 60 mL/min) or severe (< 30 mL/min) renal impairment or end-stage renal disease. In a hepatic impairment trial, 25 individuals were allocated to normal hepatic function or mild (Child-Pugh Classification grade A), moderate (grade B) or severe (grade C) hepatic impairment. Blood was sampled frequently for a pharmacokinetic analysis until 35 days post-dose. RESULTS: The shape of the icodec pharmacokinetic profile was not affected by renal or hepatic impairment. Total icodec exposure was greater for mild (estimated ratio [95% confidence interval]: 1.12 [1.01; 1.24]), moderate (1.24 [1.12; 1.37]) and severe (1.28 [1.16; 1.42]) renal impairment, and for end-stage renal disease (1.14 [1.03; 1.28]), compared with normal renal function. It was also greater for mild (1.13 [1.00; 1.28]) and moderate (1.15 [1.02; 1.29]) hepatic impairment versus normal hepatic function. There was no statistically significant difference between severe hepatic impairment and normal hepatic function. Serum albumin levels (range 2.7-5.1 g/dL) did not statistically significantly influence icodec exposure. CONCLUSIONS: The clinical relevance of the slightly higher icodec exposure with renal or hepatic impairment is limited as icodec should be dosed according to individual need. No specific icodec dose adjustment is required in renal or hepatic impairment. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT03723785 and NCT04597697.

Association Between Treatment Adherence and Continuous Glucose Monitoring Outcomes in People With Diabetes Using Smart Insulin Pens in a Real-World Setting.

OBJECTIVE: To evaluate the association of insulin injection adherence, smart insulin pen engagement, and glycemic control using real-world data from 16 countries from adults self-administering basal insulin degludec and bolus insulin with a smart insulin pen (NovoPen 6 or NovoPen Echo Plus) alongside continuous glucose monitoring (CGM). RESEARCH DESIGN AND METHODS: Data were aggregated over 14-day periods. Treatment adherence was defined according to the number of missed basal and missed bolus insulin doses and smart pen engagement according to the number of days with data uploads. RESULTS: Data from 3,945 adults, including 25,157 14-day periods with ≥70% CGM coverage, were analyzed. On average, 0.2 basal and 6.0 bolus insulin doses were missed over 14 days. The estimated probability of missing at least one basal insulin dose over a 14-day period was 17.6% (95% CI 16.5, 18.7). Missing one basal or bolus insulin dose per 14 days was associated with a significant decrease in percentage of time with glucose levels in range (TIR) (3.9-10.0 mmol/L), of -2.8% (95% CI -3.7, -1.8) and -1.7% (-1.8, -1.6), respectively; therefore, missing two basal or four bolus doses would decrease TIR by >5%. Smart pen engagement was associated positively with glycemic outcomes. CONCLUSIONS: This combined analysis of real-world smart pen and CGM data showed that missing two basal or four bolus insulin doses over a 14-day period would be associated with a clinically relevant decrease in TIR. Smart insulin pens provide valuable insights into treatment injection behaviors.

Combined intake of caffeine and low-dose glucose to reduce exercise-related hypoglycaemia in individuals with type 1 diabetes on ultra-long-acting insulin degludec: A randomized, controlled, double-blind, cross-over trial.

AIM: To evaluate whether caffeine combined with a moderate amount of glucose reduces the risk for exercise-related hypoglycaemia compared with glucose alone or control in adult people with type 1 diabetes using ultra-long-acting insulin degludec. MATERIALS AND METHODS: Sixteen participants conducted three aerobic exercise sessions (maximum 75 min) in a randomized, double-blind, cross-over design. Thirty minutes before exercise, participants ingested a drink containing either 250 mg of caffeine + 10 g of glucose + aspartame (CAF), 10 g of glucose + aspartame (GLU), or aspartame alone (ASP). The primary outcome was time to hypoglycaemia. RESULTS: There was a significant effect of the condition on time to hypoglycaemia (χ2 = 7.674, p = .0216). Pairwise comparisons revealed an 85.7% risk reduction of hypoglycaemia for CAF compared with ASP (p = .044). No difference was observed between GLU and ASP (p = .104) or between CAF and GLU (p = .77). While CAF increased glucose levels during exercise compared with GLU and ASP (8.3 ± 1.9 mmol/L vs. 7.7 ± 2.2 mmol/L vs. 5.8 ± 1.4 mmol/L; p < .001), peak plasma glucose levels during exercise did not differ between CAF and GLU (9.3 ± 1.4 mmol/L and 9.1 ± 1.6 mmol/L, p = .80), but were higher than in ASP (6.6 ± 1.1 mmol/L; p < .001). The difference in glucose levels between CAF and GLU was largest during the last 15 min of exercise (p = .002). Compared with GLU, CAF lowered perceived exertion (p = .023). CONCLUSIONS: Pre-exercise caffeine ingestion combined with a low dose of glucose reduced exercise-related hypoglycaemia compared with control while avoiding hyperglycaemia.

Once-weekly insulin efsitora alfa: Design and rationale for the QWINT phase 3 clinical development programme.

AIMS: Insulin efsitora alfa (efsitora) is a once-weekly basal insulin. This review describes the study design and rationale of the efsitora phase 3 Once Weekly (QW) Insulin Therapy (QWINT) clinical development programme, including the five trials, QWINT-1 through QWINT-5. MATERIALS AND METHODS: The five trials included insulin-naïve adults (QWINT-1 and -2) with type 2 diabetes (T2D), adults with T2D previously treated with basal insulin (QWINT-3 and -4), and QWINT-5 in adults with type 1 diabetes. All five trials were designed as multicentre, randomized, controlled, open-label, treat-to-target studies to investigate the efficacy and safety of efsitora versus active once-daily basal insulin comparators (insulin glargine U100 or insulin degludec U100). The primary objective of each trial is to compare the change in HbA1c from baseline to week 26 or 52 between efsitora and the active comparator. The key secondary objectives include change in fasting glucose, insulin dose and continuous glucose monitoring variables, and patient-reported outcome questionnaires. CONCLUSIONS: The QWINT development programme includes a racially and geographically diverse population to provide important information regarding the efficacy and safety of efsitora and its clinical management of people with diabetes.

You may delay, but time will not. Beta cells lost are never found again: a case for timely initiation of basal insulin in type 2 diabetes.

Since its first use just over a century ago, insulin treatment has evolved dramatically, such that the molecules are physiologic in nature, and treatment can now closely resemble the natural hormone response over 24 hours. Newer, longer-acting basal insulin analogs have provided insulin therapies with improved characteristics and, therefore, ease of use, and can readily be incorporated as part of routine treatment for type 2 diabetes (T2D), but evidence suggests that insulin remains underused in people with T2D. We review the barriers to initiation of basal insulin and the education needed to address these barriers, and we provide practical pointers, supported by evidence, for primary care physicians and advanced practice providers to facilitate timely initiation of basal insulin in the people with T2D who will benefit from such treatment.

Type 2 diabetes is a complex disease. It causes increased amounts of sugar in the blood, which can cause damage to the body. Medications are given to people with type 2 diabetes to keep their blood sugar at normal levels. Unfortunately, type 2 diabetes worsens over time, so regular adjustments to medications are needed to keep blood sugar levels controlled.Basal insulin, which is a type of insulin that works over the entire day, is a key treatment for type 2 diabetes. It works best if it is started as soon as other medications (tablets or non-insulin injections) are not working to control blood sugar levels. Unfortunately, delays in starting basal insulin are common. Some healthcare professionals and people with type 2 diabetes believe insulin is difficult to use. False information on insulin is common; for example, some people with diabetes believe that their symptoms are caused by insulin treatment rather than high blood sugar.This review summarizes key information to encourage effective conversations between healthcare professionals and people with type 2 diabetes about starting basal insulin. Proactive, positive, early discussion of the benefits of basal insulin can help to: 1) address concerns, 2) set appropriate, individual treatment targets, and 3) provide practical information and training to help with injecting insulin. This will give people living with type 2 diabetes the knowledge and confidence to take an active part in managing their diabetes and overcome any barriers to using basal insulin.

The Short-Term Cost-Effectiveness of a Fixed-Ratio Combination of Insulin Degludec and Aspart: A Cost of Control Analysis in Australia and India.

OBJECTIVES: The real-world ARISE study demonstrated initiation of fixed-ratio combination insulin degludec and aspart (IDegAsp) led to improvements in people achieving key glycemic control targets compared with prior therapies in Australia and India. This study evaluated the short-term cost-effectiveness of IDegAsp in these countries, in terms of the cost per patient achieving these targets. METHODS: A model was developed to evaluate the cost of control (treatment costs divided by the proportion of patients achieving each target) of IDegAsp versus prior therapies received in ARISE for 2 endpoints: glycated hemoglobin (HbA1c) <7.0%, and HbA1c less than a predefined individual treatment target. Costs, expressed from a healthcare payer perspective, were captured in 2022 Australian dollars (AUD) and 2022 Indian rupees (INR). RESULTS: The number of patients needed to treat to bring one to endpoints of HbA1c <7.0% and less than an individualized target with IDegAsp was 51% and 87% lower, respectively, than with prior therapies in Australia, and 52% and 66% lower, respectively, versus prior therapies in India. Cost of control was AUD 2449 higher and AUD 64 863 lower with IDegAsp versus prior therapies for endpoints of HbA1c <7.0% and less than an individualized target, respectively, in Australia and INR 211 142 and INR 537 490 lower with IDegAsp compared with prior therapies in India. CONCLUSIONS: IDegAsp was estimated to be cost-effective versus prior therapies when considering an individualized HbA1c target in Australia, and when considering an individualized HbA1c target and HbA1c <7.0% in India.

The Basis for Weekly Insulin Therapy: Evolving Evidence With Insulin Icodec and Insulin Efsitora Alfa.

Basal insulin continues to be a vital part of therapy for many people with diabetes. First attempts to prolong the duration of insulin formulations were through the development of suspensions that required homogenization prior to injection. These insulins, which required once- or twice-daily injections, introduced wide variations in insulin exposure contributing to unpredictable effects on glycemia. Advances over the last 2 decades have resulted in long-acting, soluble basal insulin analogues with prolonged and less variable pharmacokinetic exposure, improving their efficacy and safety, notably by reducing nocturnal hypoglycemia. However, adherence and persistence with once-daily basal insulin treatment remains low for many reasons including hypoglycemia concerns and treatment burden. A soluble basal insulin with a longer and flatter exposure profile could reduce pharmacodynamic variability, potentially reducing hypoglycemia, have similar efficacy to once-daily basal insulins, simplify dosing regimens, and improve treatment adherence. Insulin icodec (Novo Nordisk) and insulin efsitora alfa (basal insulin Fc [BIF], Eli Lilly and Company) are 2 such insulins designed for once-weekly administration, which have the potential to provide a further advance in basal insulin replacement. Icodec and efsitora phase 2 clinical trials, as well as data from the phase 3 icodec program indicate that once-weekly insulins provide comparable glycemic control to once-daily analogues, with a similar risk of hypoglycemia. This manuscript details the technology used in the development of once-weekly basal insulins. It highlights the clinical rationale and potential benefits of these weekly insulins while also discussing the limitations and challenges these molecules could pose in clinical practice.

Once-Weekly Insulin Icodec vs Once-Daily Insulin Degludec in Adults With Insulin-Naive Type 2 Diabetes: The ONWARDS 3 Randomized Clinical Trial.

Importance: Once-weekly insulin icodec could provide a simpler dosing alternative to daily basal insulin in people with type 2 diabetes. Objective: To evaluate the efficacy and safety of once-weekly icodec vs once-daily insulin degludec in people with insulin-naive type 2 diabetes. Design, Setting, and Participants: Randomized, double-masked, noninferiority, treat-to-target, phase 3a trial conducted from March 2021 to June 2022 at 92 sites in 11 countries in adults with type 2 diabetes treated with any noninsulin glucose-lowering agents with hemoglobin A1c (HbA1c) of 7%-11% (53-97 mmol/mol). Interventions: Participants were randomly assigned in a 1:1 ratio to receive either once-weekly icodec and once-daily placebo (icodec group; n = 294) or once-daily degludec and once-weekly placebo (degludec group; n = 294). Main Outcomes and Measures: The primary end point was change in HbA1c from baseline to week 26 (noninferiority margin, 0.3% percentage points). Secondary end points included change in fasting plasma glucose from baseline to week 26, mean weekly insulin dose during the last 2 weeks of treatment, body weight change from baseline to week 26, and number of level 2 (clinically significant; glucose level <54 mg/dL) and level 3 (severe; requiring external assistance for recovery) hypoglycemic episodes. Results: Among 588 randomized participants (mean [SD] age, 58 [10] years; 219 [37%] women), 564 (96%) completed the trial. Mean HbA1c level decreased from 8.6% (observed) to 7.0% (estimated) at 26 weeks in the icodec group and from 8.5% (observed) to 7.2% (estimated) in the degludec group (estimated treatment difference [ETD], -0.2 [95% CI, -0.3 to -0.1] percentage points), confirming noninferiority (P < .001) and superiority (P = .002). There were no significant differences between the icodec and degludec groups for fasting plasma glucose change from baseline to week 26 (ETD, 0 [95% CI, -6 to 5] mg/dL; P = .90), mean weekly insulin dose during the last 2 weeks of treatment, or body weight change from baseline to week 26 (2.8 kg vs 2.3 kg; ETD, 0.46 [95% CI, -0.19 to 1.10] kg; P = .17). Combined level 2 or 3 hypoglycemia rates were numerically higher in the icodec group than the degludec group from week 0 to 31 (0.31 vs 0.15 events per patient-year exposure; P = .11) and statistically higher in the icodec group from week 0 to 26 (0.35 vs 0.12 events per patient-year exposure; P = .01). Conclusions and Relevance: Among people with insulin-naive type 2 diabetes, once-weekly icodec demonstrated superior HbA1c reduction to once-daily degludec after 26 weeks of treatment, with no difference in weight change and a higher rate of combined level 2 or 3 hypoglycemic events in the context of less than 1 event per patient-year exposure in both groups. Trial Registration: ClinicalTrials.gov Identifier: NCT04795531.

Weekly Icodec versus Daily Glargine U100 in Type 2 Diabetes without Previous Insulin.

BACKGROUND: Insulin icodec is an investigational once-weekly basal insulin analogue for diabetes management. METHODS: We conducted a 78-week randomized, open-label, treat-to-target phase 3a trial (including a 52-week main phase and a 26-week extension phase, plus a 5-week follow-up period) involving adults with type 2 diabetes (glycated hemoglobin level, 7 to 11%) who had not previously received insulin. Participants were randomly assigned in a 1:1 ratio to receive once-weekly insulin icodec or once-daily insulin glargine U100. The primary end point was the change in the glycated hemoglobin level from baseline to week 52; the confirmatory secondary end point was the percentage of time spent in the glycemic range of 70 to 180 mg per deciliter (3.9 to 10.0 mmol per liter) in weeks 48 to 52. Hypoglycemic episodes (from baseline to weeks 52 and 83) were recorded. RESULTS: Each group included 492 participants. Baseline characteristics were similar in the two groups. The mean reduction in the glycated hemoglobin level at 52 weeks was greater with icodec than with glargine U100 (from 8.50% to 6.93% with icodec [mean change, -1.55 percentage points] and from 8.44% to 7.12% with glargine U100 [mean change, -1.35 percentage points]); the estimated between-group difference (-0.19 percentage points; 95% confidence interval [CI], -0.36 to -0.03) confirmed the noninferiority (P<0.001) and superiority (P = 0.02) of icodec. The percentage of time spent in the glycemic range of 70 to 180 mg per deciliter was significantly higher with icodec than with glargine U100 (71.9% vs. 66.9%; estimated between-group difference, 4.27 percentage points [95% CI, 1.92 to 6.62]; P<0.001), which confirmed superiority. Rates of combined clinically significant or severe hypoglycemia were 0.30 events per person-year of exposure with icodec and 0.16 events per person-year of exposure with glargine U100 at week 52 (estimated rate ratio, 1.64; 95% CI, 0.98 to 2.75) and 0.30 and 0.16 events per person-year of exposure, respectively, at week 83 (estimated rate ratio, 1.63; 95% CI, 1.02 to 2.61). No new safety signals were identified, and incidences of adverse events were similar in the two groups. CONCLUSIONS: Glycemic control was significantly better with once-weekly insulin icodec than with once-daily insulin glargine U100. (Funded by Novo Nordisk; ONWARDS 1 ClinicalTrials.gov number, NCT04460885.).

Basal weekly insulins: the way of the future!

Basal insulin treatment is indispensable for patients with type 1 diabetes and often required by many with type 2 diabetes. Incremental advances lengthening the duration of action of insulin analogs and reducing pharmacodynamic variability have resulted in truly once-daily, long-acting basal insulin analogs. In the quest for better basal insulins to facilitate improvements in glycemic control and long-term outcomes, the driving need is to remove barriers delaying timely initiation of basal insulin, to maximize treatment adherence and persistence and reduce treatment burden without increasing risk of hypoglycemia. We review the range of investigational once-weekly insulins and their molecular strategies and profiles. Currently, the two most advanced clinical development programs are: (1) basal insulin icodec, an insulin analog acylated with a C20 fatty diacid (icosanedioic acid) side chain (Novo Nordisk) and (2) basal insulin Fc, a fusion protein that combines a single-chain insulin variant with a human immunoglobulin G fragment crystallizable domain (Eli Lilly). Available phase 2 data for these two once-weekly agents show comparable glycemic control to existing once-daily insulin analogs, with no greater risk of hypoglycemia. While phase 3 data are awaited to confirm efficacy and safety, we provide future clinical perspectives on practical considerations for the potential use of once-weekly insulins.

A fully artificial pancreas versus a hybrid artificial pancreas for type 1 diabetes: a single-centre, open-label, randomised controlled, crossover, non-inferiority trial.

BACKGROUND: For people with type 1 diabetes, there is currently no automated insulin delivery system that does not require meal input. We aimed to assess the efficacy of a novel faster-acting insulin aspart (Fiasp) plus pramlintide fully closed-loop system that does not require meal input. METHODS: In this open-label, randomised controlled, crossover, non-inferiority trial we compared the Fiasp (Novo Nordisk, Bagsværd, Denmark) plus pramlintide closed-loop system with no meal input (fully artificial pancreas) and the Fiasp-alone closed-loop system with precise carbohydrate counting (hybrid artificial pancreas). Adults (≥18 years) who had a clinical diagnosis of type 1 diabetes for at least 12 months, had glycated haemoglobin 12% or lower, and had been on insulin pump therapy for at least 6 months were enrolled at McGill University Health Centre, Montreal, QC, Canada. The Fiasp plus pramlintide fully closed-loop system delivered pramlintide in a basal-bolus manner with a fixed ratio of 10 µg:U relative to insulin. A research staff member counted the carbohydrate content of meals to input in the hybrid closed-loop system. Participants completed the two full-day crossover interventions in a random order allocated by a computer-generated code implementing a blocked randomisation (block size of four). The primary outcome was the percentage of time spent within the glucose target range (3·9-10·0 mmol/L), with a 6% non-inferiority margin, assessed in all participants who completed both interventions. This trial is registered with ClinicalTrials.gov, NCT03800875. FINDINGS: Between Feb 8, 2019, and Sept 19, 2020, we enrolled 28 adults, of whom 24 completed both interventions and were included in analyses. The percentage of time spent in the target range was 74·3% (IQR 61·5-82·8) with the fully closed-loop system versus 78·1% (66·3-87·5) with the hybrid Fiasp-alone closed-loop system (paired difference 2·6%, 95% CI -2·4 to 12·2; non-inferiority p=0·28). Eight (33%) participants had at least one hypoglycaemia event (<3·3 mmol/L) with the fully closed-loop system compared with 14 (58%) participants with the hybrid closed-loop system (2200-2200 h). Non-mild nausea was reported by three (13%) participants and non-mild bloating by one (4%) participant with the fully closed-loop system compared with zero participants with the hybrid closed-loop system. INTERPRETATION: The Fiasp plus pramlintide fully closed-loop system was not non-inferior to the Fiasp-alone hybrid closed-loop system for the overall percentage of time in the glucose target range. However, participants still spent a high percentage of time within the target range with the fully-closed loop system. Outpatient studies comparing the fully closed-loop hybrid systems with patient-estimated, rather than precise, carbohydrate counting are warranted. FUNDING: Diabetes Canada.

Efficacy, Pharmacokinetics, Biodistribution and Excretion of a Novel Acylated Long-Acting Insulin Analogue INS061 in Rats.

PURPOSE: Long-acting insulin analogues are known to be a major player in the management of glucose levels in type I diabetic patients. However, highly frequent hypo- and hyperglycemic incidences of current long-acting insulins are the important factor to limit stable management of glucose level for clinical benefits. To further optimize the properties for steadily controlling glucose level, a novel long-acting insulin INS061 was designed and its efficacy, pharmacokinetics, biodistribution and excretion profiles were investigated in rats. METHODS: The glucose-lowering effects were evaluated in a streptozocin-induced diabetic rats compared to commercial insulins via subcutaneous administration. The pharmacokinetics, biodistribution, and excretion were examined by validated analytical methods including radioactivity assay and radioactivity assay after the precipitation with TCA and the separation by HPLC. RESULTS: INS061 exhibited favorable blood glucose lowering effects up to 24 h compared to Degludec. Pharmacokinetic study revealed that the concentration-time curves of INS061 between two administration routes were remarkably different. Following intravenous administration, INS061 was quickly distributed to various organs and tissues and slowly eliminated over time with urinary excretion being the major route for elimination, and the maximum plasma concentrations (Cmax) and systemic exposures (AUC) increased in a linear manner. CONCLUSION: The present structural modifications of human insulin possessed a long-acting profile and glucose-lowering function along with favorable in vivo properties in rats, which establish a foundation for further preclinical and clinical evaluation.

Choice of basal insulin therapy is associated with weight and height development in type 1 diabetes: A multicenter analysis from the German/Austrian DPV registry in 10 338 children and adolescents.

BACKGROUND: Available basal insulin regimes differ in pharmacokinetic profiles, which may be related to subsequent changes in anthropometry in patients with type 1 diabetes. This analysis elucidates the standardized height and body mass index development (height and BMI standard deviation score [height-SDS and BMI-SDS]) in pediatric type 1 diabetes patients depending on the choice of basal insulin. METHODS: Longitudinal data of 10 338 German/Austrian patients from the Diabetes Prospective Follow-up (DPV, Diabetes Patienten Verlaufsdokumentation) database were analyzed. Patients aged 5.0 to 16.9 years were treated exclusively with neutral protamine Hagedorn (NPH), insulin detemir (IDet), insulin glargine (IGla), or continuous subcutaneous insulin infusion (CSII) for at least 3 years. Population-based German reference data were used to calculate height-SDS and BMI-SDS. Multiple linear regression was conducted. RESULTS: BMI-SDS increased significantly in all regimes (NPH P = .0365; IDet P = .0003; IGla P < .0001; and CSII P < .0001). Direct comparison of the therapies revealed a favorable association only for NPH vs IGla. A rise in BMI-SDS was observed for all insulins in females, but only for IGla in males. BMI-SDS increment was not observed before 8 years of age. Initially and at the end of the observation period, mean height was above the 50th percentile of the reference population. Across the cohort, height-SDS declined during the observation period, except for CSII. Apart from the 5.0- to 7.9-year-old subgroup, long-acting insulin analogues were associated with a significant loss of height-SDS. CONCLUSIONS: Choice of basal insulin regimen might influence height development. CSII appeared to have a favorable effect on growth trajectories. All therapies were associated with an increase of BMI-SDS, most evident in females.

Comparative clinical outcomes of insulin degludec and insulin glargine 300 U/mL after switching from other basal insulins in real-world patients with type 1 and type 2 diabetes.

AIMS/INTRODUCTION: To evaluate and compare the efficacy of insulin degludec (IDeg) and insulin glargine 300 U/mL (Gla300) 6 months after switching from other basal insulins by assessing the changes in glycated hemoglobin (HbA1c), body mass index (BMI), and insulin doses in patients with type 1 and type 2 diabetes in a real-world clinical setting. MATERIALS AND METHODS: A total of 307 patients with type 1 diabetes and 294 patients with type 2 diabetes with HbA1c >7.0% were studied. Adjusted mean changes in HbA1c, BMI, and insulin doses were compared between IDeg (IDeg group) and Gla300 (Gla300 group) switchers. Multivariable logistic regression analyses were carried out to examine whether the IDeg or Gla300 group was associated with HbA1c or insulin dose reduction and BMI gain. RESULTS: HbA1c was significantly decreased in both the IDeg and Gla300 groups. Adjusted mean changes in HbA1c (approximately -0.3% and -0.5% in type 1 diabetes and type 2 diabetes patients, respectively) and BMI were similar between both groups. The mean change in insulin dose was slightly larger for dose reduction in the IDeg group than in the Gla300 group. Multivariable logistic regression models showed that the IDeg group was significantly associated with insulin dose reduction after adjusting for basal insulin type, insulin dose, and number of basal insulin injections at baseline and other confounding factors. CONCLUSIONS: The current study suggested that IDeg and Gla300 have similar effects in reducing HbA1c and gaining BMI after switching from other basal insulins in Japanese patients with type 1 diabetes and type 2 diabetes. IDeg selection was associated with insulin dose reduction.

The differences between insulin glargine U300 and insulin degludec U100 in impact on the glycaemic variability, arterial stiffness and the lipid profiles in insulin naïve patients suffering from type two diabetes mellitus - outcomes from cross-over open-label randomized trial.

BACKGROUND AND AIMS: Diabetes mellitus type two is one of the major cardiovascular risk factors. Treatment of diabetes can reduce this risk, but the treatment options differ a lot in their risk-reducing capabilities. We compared the impact of insulin degludec (IDeg-100) and insulin glargine U300 (IGlar-300) on cardiovascular risk parameters - glycaemic variability (GV), arterial stiffness and lipid parameters - in insulin naive patients with DMT2. METHODS: To 23 individuals who previously had uncontrolled DMT2 on two or more oral antidiabetic drugs, IGlar-300 and IDeg-100 were applied for 12 weeks and then switched in a cross over design manner. Prior and after of each insulin phase, we analysed biochemical parameters,7-point SMBG profile over three days and arterial stiffness which was assessed indirectly by measuring the augmentation index (AIx) on the principles of applanation tonometry. RESULTS: There were no significant differences between IGlar-300 and IDeg-100 regarding reduction of mean glucose values and coefficient of variation (CV). Both insulins insignificantly reduced AIx for standardised pulse of 75 beats/min and without differences between them. IGlar-300 and IDeg-100 reduced triglycerides and increased HDL with no significant difference between the two insulins. IGlar-300 increased the total cholesterol level and IDeg-100 decreased total cholesterol, but without statistically significant difference. IGlar-300 increased LDL level by 0.508 mmol/L and IDeg-100 decreased LDL by 0.217 mmol/L, with statistically significant difference (p = 0.0215). CONCLUSIONS: This study did not show significant difference between IGlar-300 and IDeg-100 regarding glycaemic parameters and augmentation index using the same dose of 0.2 IU/kg for both insulins, but it has revealed possible differences in impact on lipid profile. TRIAL REGISTRATION: Clinicaltrials.gov, NCT04692415 . Retrospectively registered on December 31th 2020.

Insulin doses requirements in patients with type 1 diabetes using glargine U300 or degludec in routine clinical practice.

There are not many real-world studies evaluating daily insulin doses requirements (DIDR) in patients with type 1 diabetes (T1D) using second-generation basal insulin analogs, and such comparison is necessary. The aim of this study was to compare DIDR in individuals with T1D using glargine 300 UI/mL (IGlar-300) or degludec (IDeg) in real clinical practice. An observational, retrospective study was designed in 412 patients with T1D (males: 52%; median age 37.0±13.4 years, diabetes duration: 18.7±12.3 years) using IDeg and IGla-300 ≥6 months to compare DIDR between groups. Patients using IGla-300 (n=187) were more frequently males (59% vs 45.8%; p=0.004) and had lower glycosylated hemoglobin (HbA1c) (7.6±1.2 vs 8.1%±1.5%; p<0.001) than patients using IDeg (n=225). Total (0.77±0.36 unit/kg/day), basal (0.43±0.20 unit/kg/day) and prandial (0.33±0.23 unit/kg/day) DIDR were similar in IGla-300 and IDeg groups. Patients with HbA1c ≤7% (n=113) used significantly lower basal (p=0.045) and total (p=0.024) DIDR, but not prandial insulin (p=0.241), than patients with HbA1c between 7.1% and 8% and >8%. Patients using IGla-300 and IDeg used similar basal, prandial and total DIDR regardless of metabolic control subgroup. No difference in basal, prandial and total DIDR was observed between patients with T1D using IGla-300 or IDeg during at least 6 months in routine clinical practice.