Hypoglycaemia frequency and physiological response after double or triple doses of once-weekly insulin icodec vs once-daily insulin glargine U100 in type 2 diabetes: a randomised crossover trial.
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SUBMITTER: Pieber TR
PROVIDER: S-EPMC10317887 | biostudies-literature | 2023 Aug
REPOSITORIES: biostudies-literature
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Hypoglycaemia frequency and physiological response after double or triple doses of once-weekly insulin icodec vs once-daily insulin glargine U100 in type 2 diabetes: a randomised crossover trial.
Pieber Thomas R TR Arfelt Kristine N KN Cailleteau Roman R Hart Marlies M Kar Soumitra S Mursic Ines I Svehlikova Eva E Urschitz Martina M Haahr Hanne H
Diabetologia 20230613 8
<h4>Aims/hypothesis</h4>This study compared the frequency of hypoglycaemia, time to hypoglycaemia and recovery from hypoglycaemia after double or triple doses of once-weekly insulin icodec vs once-daily insulin glargine U100. Furthermore, the symptomatic and counterregulatory responses to hypoglycaemia were compared between icodec and glargine U100 treatment.<h4>Methods</h4>In a randomised, single-centre (Department of Internal Medicine, Division of Endocrinology and Diabetology, Medical Univers ...[more]
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Project description:ObjectiveInsulin icodec is a novel once-weekly basal insulin analog. This trial investigated the efficacy and safety of icodec using different once-weekly titration algorithms.Research design and methodsThis was a phase 2, randomized, open-label, 16-week, treat-to-target study. Insulin-naive adults (n = 205) with type 2 diabetes and HbA1c 7-10% while treated with oral glucose-lowering medications initiated once-weekly icodec titrations A (prebreakfast self-measured blood glucose target 80-130 mg/dL; adjustment ±21 units/week; n = 51), B (80-130 mg/dL; ±28 units/week; n = 51), or C (70-108 mg/dL; ±28 units/week; n = 52), or once-daily insulin glargine 100 units/mL (IGlar U100) (80-130 mg/dL; ±4 units/day; n = 51), all titrated weekly. Percentage of time in range (TIR) (70-180 mg/dL) during weeks 15 and 16 was measured using continuous glucose monitoring.ResultsTIR improved from baseline (means: A, 57.0%; B, 55.2%; C, 51.0%; IGlar U100, 55.3%) to weeks 15 and 16 (estimated mean: A, 76.6%; B, 83.0%; C, 80.9%; IGlar U100, 75.9%). TIR was greater for titration B than for IGlar U100 (estimated treatment difference 7.08%-points; 95% CI 2.12 to 12.04; P = 0.005). No unexpected safety signals were observed. Level 2 hypoglycemia (<54 mg/dL) was low in all groups (0.05, 0.15, 0.38, 0.00 events per patient-year of exposure for icodec titrations A, B, and C and IGlar U100, respectively), with no episodes of severe hypoglycemia.ConclusionsOnce-weekly icodec was efficacious and well tolerated across all three titration algorithms investigated. The results for icodec titration A (80-130 mg/dL; ±21 units/week) displayed the best balance between glycemic control and risk of hypoglycemia.
| S-EPMC8323172 | biostudies-literature
Project description:ObjectiveInsulin icodec (icodec) is a novel once-weekly basal insulin analog. This trial investigated two approaches for switching to icodec versus once-daily insulin glargine 100 units/mL (IGlar U100) in people with type 2 diabetes receiving daily basal insulin and one or more oral glucose-lowering medications.Research design and methodsThis multicenter, open-label, treat-to-target phase 2 trial randomized (1:1:1) eligible basal insulin-treated (total daily dose 10-50 units) people with type 2 diabetes (HbA1c 7.0-10.0% [53.0-85.8 mmol/mol]) to icodec with an initial 100% loading dose (in which only the first dose was doubled [icodec LD]), icodec with no loading dose (icodec NLD), or IGlar U100 for 16 weeks. Primary end point was percent time in range (TIR; 3.9-10.0 mmol/L [70-180 mg/dL]) during weeks 15 and 16, measured using continuous glucose monitoring. Key secondary end points included HbA1c, adverse events (AEs), and hypoglycemia.ResultsEstimated mean TIR during weeks 15 and 16 was 72.9% (icodec LD; n = 54), 66.0% (icodec NLD; n = 50), and 65.0% (IGlar U100; n = 50), with a statistically significant difference favoring icodec LD versus IGlar U100 (7.9%-points [95% CI 1.8-13.9]). Mean HbA1c reduced from 7.9% (62.8 mmol/mol) at baseline to 7.1% (54.4 mmol/mol icodec LD) and 7.4% (57.6 mmol/mol icodec NLD and IGlar U100); incidences and rates of AEs and hypoglycemic episodes were comparable.ConclusionsSwitching from daily basal insulin to once-weekly icodec was well tolerated and provided effective glycemic control. Loading dose use when switching to once-weekly icodec significantly increased percent TIR during weeks 15 and 16 versus once-daily IGlar U100, without increasing hypoglycemia risk.
| S-EPMC8323191 | biostudies-literature
Project description:Insulin icodec* (icodec) is a novel once-weekly basal insulin analog in development. This post hoc analysis explored hypoglycemia duration using double-blinded CGM (Dexcom G6®) data from 2 phase 2, randomized, open-label, treat-to-target 16-week trials. One trial compared 3 titration algorithms of icodec vs. insulin glargine U100 (IGlar U100) in 205 insulin-naïve patients with T2D (NCT03951805), the other assessed 154 basal insulin-treated patients with T2D switching from any daily basal insulin to icodec with or without a 100% loading dose vs. IGlar U100 (NCT03922750). In line with ATTD guidelines, a hypoglycemic episode was defined as a CGM period of interstitial glucose (IG) <70 mg/dL for at least 15 min, ending when IG ≥70 mg/dL for at least 15 min. In the titration trial, hypoglycemia duration was similar across all arms: median overall hypoglycemic episode duration (IQR) was 35.0 (20.0, 70.0) min for icodec titrations A (SMBG 80-130 mg/dL ±21 U/wk) and B (80-130 mg/dL ±28 U/wk) and for IGlar U100 (80-130 mg/dL ±4 U/day), and 39.0 (24.0, 70.0) min for icodec titration C (70-108 mg/dL ±28 U/wk). The distribution pattern of hypoglycemic episodes by duration was similar across all treatment arms. Results were similar for nocturnal hypoglycemic episodes. Similarly, in the switch trial, the duration of hypoglycemia was similar between arms, irrespective of loading dose use: median overall hypoglycemic episode duration (IQR) was 40.0 (20.0, 75.0) min for icodec with loading dose, 40.0 (25.0, 80.0) min for icodec without loading dose, and 35.0 (20.0, 60.0) min for IGlar U100. The distribution pattern of hypoglycemic episodes by duration was similar across treatment arms. Similar results were seen for the nocturnal period. In conclusion, CGM-derived hypoglycemic episode duration was similar with icodec vs. IGlar U100 in insulin-naïve and insulin-experienced patients with T2D, regardless of titration algorithm or initial loading dose use. *Proposed INN.
| S-EPMC9067734 | biostudies-literature
Project description:IntroductionONWARDS 5 evaluated the effectiveness and safety of insulin icodec (icodec) titrated with a dosing guide app (icodec with app) versus once-daily insulin analogs in insulin-naive adults with type 2 diabetes. The insulin glargine U300 (glargine U300) stratum was too small to enable a robust post hoc efficacy comparison. Augmentation methodology was applied to increase the glargine U300 group size using real-world data (RWD), to facilitate efficacy comparisons of icodec with app versus glargine U300, and to demonstrate the potential of the augmentation methodology to strengthen underpowered treatment comparisons (AUGMENT study).MethodsONWARDS 5 data were augmented with RWD collected from the US Ambulatory Electronic Medical Records database. Randomized and augmented comparisons (propensity-score-matched) between icodec with app and glargine U300 were weighted to provide a fully augmented estimate of the primary outcome (change in glycated hemoglobin [HbA1c] after 52 weeks). Data were adjusted for trial effects. Sensitivity analyses were conducted.ResultsThe nonaugmented randomized estimated treatment difference (ETD; 95% CI) between icodec with app and glargine U300 (trial stratum) for change in HbA1c was - 0.21 (- 0.70 to 0.28) percentage points. After adjusting for trial effects, the overall fully augmented ETD (95% CI) was - 0.33 (- 0.68 to 0.01) percentage points numerically in favor of icodec with app, although not statistically significant. Sensitivity analyses supported the findings.ConclusionsUsing augmented data, the precision of the change in HbA1c estimate was increased compared with the trial stratum analysis alone. These findings help to validate the principle of utilizing augmentation to strengthen trial outcomes.Trial registration numberThe ONWARDS 5 trial is registered with ClinicalTrials.gov (NCT04760626).
| S-EPMC11794749 | biostudies-literature
Project description:ImportanceOnce-weekly insulin icodec could provide a simpler dosing alternative to daily basal insulin in people with type 2 diabetes.ObjectiveTo 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 participantsRandomized, 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).InterventionsParticipants 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 measuresThe 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.ResultsAmong 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 relevanceAmong 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 registrationClinicalTrials.gov Identifier: NCT04795531.
| S-EPMC10354685 | biostudies-literature
Project description:IntroductionThis post hoc analysis evaluated subgroup data from China (Chinese mainland, n = 100; Taiwan, n = 45) in ONWARDS 3, a 26-week, randomized, double-blind, double-dummy, treat-to-target, phase 3a trial comparing the efficacy and safety of once-weekly insulin icodec (icodec) versus once-daily insulin degludec (degludec) in insulin-naive participants with type 2 diabetes (T2D).MethodsAdults were randomized 1:1 to icodec and once-daily placebo (icodec; n = 72) or degludec and once-weekly placebo (degludec; n = 73). The primary endpoint was change in glycated hemoglobin (HbA1c) (baseline to week 26). Secondary assessments included change in fasting plasma glucose (FPG; baseline to week 26); total weekly insulin dose (weeks 24-26); body weight change (baseline to week 26); and clinically significant or severe hypoglycemia rates (baseline to week 31 [5-week follow-up included]).ResultsAt week 26, from baseline values of 8.22% (icodec) and 8.39% (degludec), estimated mean changes in HbA1c were - 1.38% points and - 1.10% points, respectively (estimated treatment difference [95% confidence interval], - 0.28%-points [- 0.50%-points, - 0.05%-points]; p = 0.0152). For icodec and degludec, estimated mean FPG change (- 2.3 mmol/L vs. - 2.3 mmol/L), estimated mean insulin doses (158 U/week vs. 142 U/week), and estimated body weight change (2.5 kg vs. 2.4 kg) were similar. Combined clinically significant or severe hypoglycemia rates were low (0.10 [icodec] vs. 0.07 [degludec] events per patient-year of exposure), with no statistically significant difference between groups.ConclusionIn insulin-naive Chinese individuals with T2D, once-weekly icodec treatment showed significantly greater HbA1c reductions after 26 weeks than once-daily degludec, with low combined clinically significant or severe hypoglycemia rates across groups.ClinicaltrialsGov identifierNCT04795531.
| S-EPMC11926311 | biostudies-literature
Project description:AimThis post hoc analysis of ONWARDS 1-5 assessed the efficacy and hypoglycaemia outcomes with once-weekly insulin icodec (icodec) versus once-daily basal insulin comparators (degludec, glargine U100 or glargine U300) in insulin-naive (ONWARDS 1, 3 and 5) and insulin-experienced (ONWARDS 2 and 4) adults (aged ≥18 years) with type 2 diabetes (T2D) by kidney function subgroup.Materials and methodsTreatment outcomes were analysed by trial according to kidney function subgroup (estimated glomerular filtration rate [eGFR] ≥90; eGFR 60-<90; eGFR 30-<60; eGFR <30; all mL/min/1.73m2). Severe kidney function impairment (eGFR <30) at screening was an exclusion criterion for ONWARDS 1-4, but not ONWARDS 5.ResultsONWARDS 1-5 included 3765 participants; 3763 were included in this analysis. In ONWARDS 1, 3 and 5, there were no statistically significant treatment interactions by kidney function subgroup for change in glycated haemoglobin (HbA1c) from baseline to end of treatment (EOT); there were statistically significant subgroup interactions in ONWARDS 2 and 4 (both p-interaction <0.05). Change in body weight (baseline to EOT) across kidney function subgroups was comparable between treatment arms. Across trials, there was no consistent trend by kidney function subgroup for mean weekly insulin dose during the last 2 weeks of treatment or rates of combined clinically significant or severe hypoglycaemia. There were no statistically significant treatment interactions by kidney function subgroup for the achievement of HbA1c <7% without clinically significant or severe hypoglycaemia; all p-interaction >0.05.ConclusionsEfficacy and hypoglycaemia outcomes of icodec versus once-daily comparators were generally consistent among adults with T2D, regardless of kidney function.
| S-EPMC11885089 | biostudies-literature
Project description:Insulin icodec is a once-weekly insulin analogue that has a long half-life of approximately 7 days, making it suitable for once weekly dosing. The Insulin icodec molecule was developed based on the hypothesis that lowering insulin receptor affinity and introducing a strong albumin-binding moiety would result in a long insulin half-life, provided that non-receptor-mediated clearance is diminished. Here, we report an insulin clearance mechanism, resulting in the splitting of insulin molecules into its A-chain and B-chain by a thiol-disulphide exchange reaction. Even though the substitutions in insulin icodec significantly stabilise insulin against such degradation, some free B-chain is observed in plasma samples from minipigs and people with type 2 diabetes. In summary, we identify thiol-disulphide exchange reactions to be an important insulin clearance mechanism and find that stabilising insulin icodec towards this reaction significantly contributes to its long pharmacokinetic/pharmacodynamic profile.
| S-EPMC11271312 | biostudies-literature
Project description:Background//objectiveDiabetes affects millions of people globally, despite treatment options, adherence and other factors pose obstacles. Once-weekly Insulin Icodec, a novel basal Insulin analog with a week-long half-life, offers potential benefits, enhancing convenience, adherence, and quality of life for improved glycemic control. This systematic review and meta-analysis aimed to assess the efficacy and safety of once-weekly Insulin Icodec compared to once-daily Insulin Glargine U-100 in individuals with type II diabetes (T2D).MethodsA comprehensive literature search was conducted using PubMed, and Cochrane Library databases before September 2023 to identify relevant Randomized control trials (RCTs) with no language restrictions following PRISMA guidelines. The Cochrane risk-of-bias tool was used for quality assessment. All statistical analyses were conducted using RevMan (version 5.4; Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014).ResultFour RCTs published from 2020 to 2023 with a cumulative sample size of 1035 were included. The pooled mean difference (MD) revealed a 4.68% longer TIR (%) with Insulin Icodec compared to Insulin Glargine U-100 [{95% CI (0.69, 8.68), p = 0.02}], the estimated mean changes in HbA1c (%) and FPG (mg%) were found to be insignificant between the two groups [MD = - 0.12 {95% CI (- 0.26, 0.01), p = 0.07}] and [MD = - 2.59 {95% CI (- 6.95, 1.78), p = 0.25}], respectively. The overall OR for hypoglycemia was also nonsignificant between the two regimens 1.04 [{95% CI (0.71, 1.52), p = 0.84}]. Other safety parameters were similar between the two groups.ConclusionsSwitching from daily Insulin Glargine U-100 to weekly Insulin Icodec showed longer TIR (%) as well as similar blood glycemic control and safety profile. Hence, it may be a good alternate option for management of longstanding T2D.
| S-EPMC10988795 | biostudies-literature
Project description:IntroductionInsulin icodec is a basal insulin designed for once-weekly administration. This study assessed the pharmacological properties of icodec in Japanese individuals with type 1 diabetes (T1D).Materials and methodsIn a randomized, open-label, crossover study, 24 Japanese individuals with T1D (20-64 years; glycated hemoglobin ≤9.0%) received once-weekly icodec for 8 weeks and once-daily insulin glargine U100 for 14 days at individual constant equimolar doses per week together with bolus insulin aspart. Individual doses were determined during run-in with glargine U100 titrated to prebreakfast self-measured plasma glucose (SMPG) of 4.4-7.2 mmol/L. Blood samples for icodec pharmacokinetics were taken from the first icodec dose until 35 days after last dose. The steady-state glucose-lowering effect was measured in glucose clamps (target 6.7 mmol/L) during 24-48 h and 150-168 h after last icodec dose and 0-24 h after last glargine U100 dose. One-week glucose-lowering effect of icodec was simulated using a pharmacokinetic/pharmacodynamic model. Hypoglycemia was identified from SMPG during the treatment periods.ResultsIcodec pharmacokinetic steady state was achieved on average after 2-3 weeks of treatment. Model-derived daily glucose-lowering effect during the weekly dosing interval averaged 14.6%, 18.0%, 16.6%, 14.9%, 13.3%, 11.9%, and 10.7%, respectively. Rates of level 2 hypoglycemia (PG <3.0 mmol/L) were 37.3 vs 30.6 episodes per patient-year of exposure for icodec vs glargine U100.DiscussionIcodec pharmacological properties in Japanese individuals with T1D in this study support the potential of icodec to provide basal insulin coverage with once-weekly dosing in Japanese individuals with diabetes.
| S-EPMC11871391 | biostudies-literature