Switching to once-weekly insulin icodec versus once-daily insulin degludec in individuals with basal insulin-treated type 2 diabetes (ONWARDS 2): a phase 3a, randomised, open label, multicentre, treat-to-target trial

Philis‐Tsimikas, Athena; Asong, Marisse; Franek, Edward; Jia, Ting; Rosenstock, Julio; Stachlewska, Karolina; Watada, Hirotaka; Kellerer, Monika

doi:10.1016/s2213-8587(23)00093-1

Cited by 47 publications

(65 citation statements)

References 28 publications

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“…Concern over injection site reactions has not been raised in other icodec trials to date, and this finding remains unexplained. [3][4][5][6]8,9 Additionally, although the occurrence of diabetic retinopa-thy was higher with icodec than degludec, the absolute numerical difference was small. No difference in retinopathy events between groups has been observed in other icodec trials to date.…”

Section: Discussionmentioning

confidence: 97%

“…The number of injection site reactions was numerically higher with icodec than degludec. Concern over injection site reactions has not been raised in other icodec trials to date, and this finding remains unexplained . Additionally, although the occurrence of diabetic retinopathy was higher with icodec than degludec, the absolute numerical difference was small.…”

Section: Discussionmentioning

confidence: 99%

“…ONWARDS is a phase 3a clinical trial program that comprises 6 trials investigating the efficacy and safety of icodec in various clinical scenarios . In the ONWARDS 4 and ONWARDS 2 trials, among participants with insulin-treated type 2 diabetes, hemoglobin A 1c (HbA 1c ) reductions were similar or better with icodec than once-daily insulin glargine U100 or insulin degludec, with no statistically significant differences in level 2 or 3 hypoglycemia rates …”

Section: Introductionmentioning

confidence: 99%

“…7 In the ONWARDS 4 and ONWARDS 2 trials, among participants with insulintreated type 2 diabetes, hemoglobin A 1c (HbA 1c ) reductions were similar or better with icodec than once-daily insulin glargine U100 or insulin degludec, with no statistically significant differences in level 2 or 3 hypoglycemia rates. 8,9 This study reports the results of the ONWARDS 3 trial, which assessed the efficacy and safety of once-weekly icodec vs oncedaily degludec in people with insulin-naive type 2 diabetes.…”

mentioning

confidence: 99%

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Once-Weekly Insulin Icodec vs Once-Daily Insulin Degludec in Adults With Insulin-Naive Type 2 Diabetes

Lingvay

Asong

Desouza

et al. 2023

JAMA

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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 &lt;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 &lt; .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

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Once-Weekly Insulin Icodec vs Once-Daily Insulin Degludec in Adults With Insulin-Naive Type 2 Diabetes

Lingvay

Asong

Desouza

et al. 2023

JAMA

Self Cite

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“…Finally, this meta-analysis included 7 randomized controlled trials involving 2391 patients. [10,11,[17][18][19][20][21] A PRISMA flow chart describing study identification and selection is shown in Figure 1. Three trials included insulin-naive patients with T2D, [17,19,20] while 4 trials included basal insulin-treated patients with T2D.…”

Section: Study Identification and Characteristicsmentioning

confidence: 99%

Efficacy and safety of once-weekly basal insulin versus once-daily basal insulin in patients with type 2 diabetes: A systematic review and meta-analysis

Wang,

Xiao,

Liang

et al. 2023

Medicine

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Background: Once-weekly insulin is expected to improve treatment compliance and durability and lead to better glycemic control. Several clinical trials on once-weekly insulin have recently been published. We conducted a systematic review and meta-analysis to investigate the efficacy and safety of once-weekly insulin versus once-daily insulin in type 2 diabetes (T2D). Methods: The following databases were searched for studies: PubMed, EMBASE, and Cochrane library (From January 1, 1946 to May 9, 2023). All randomized trials comparing weekly versus daily insulin in T2D were eligible for inclusion. Data analysis was performed using STATA 17.0 software (Stata Corporation, College Station, TX). The main outcomes and indexes included reduction in Hemoglobin A1c (HbA1c), fasting plasma glucose and bodyweight, proportion of patients achieving HbA1c < 7%, time-in-range 70 to 180 mg/dL and adverse events. Results: This systematic review and meta-analysis included 7 randomized controlled studies involving 2391 patients (1347 receiving 1-week insulin and 1044 receiving 1-day insulin). Once-weekly insulin was not inferior to once-daily insulin in HbA1c change [estimated treatment difference (ETD) = −0.05; 95% confidence intervals (CI): −0.14 to 0.04), HbA1c < 7% (odds ratio = 1.14; 95% CI: 0.87–1.50), fasting plasma glucose (ETD = 0.09; 95% CI: −0.19 to 0.36) and body weight loss (ETD = 0.27; 95% CI: −0.36 to 0.91). In terms of time-in-range 70 to 180 mg/dL, weekly insulin was superior to daily insulin (MTD = 3.84; 95% CI: 1.55–6.08). Icodec was associated with higher incidence of all adverse events (odds ratio = 1.20; 95% CI: 1.03–1.48; P = .024), but did not result in high risk of serious and severe adverse events. Moreover, icodec and Basal Insulin Fc did not result in higher incidence of hypoglycemia compared with insulin daily. Conclusion: Our meta-analysis found that insulin weekly was well tolerated and effective for glycemic control. Once-weekly insulin was not inferior to once-daily insulin in both efficacy and safety in T2D.

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

An¹,

Wang

et al. 2023

Clinical Pharm in Drug Dev

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

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Switching to once-weekly insulin icodec versus once-daily insulin degludec in individuals with basal insulin-treated type 2 diabetes (ONWARDS 2): a phase 3a, randomised, open label, multicentre, treat-to-target trial

Cited by 47 publications

References 28 publications

Once-Weekly Insulin Icodec vs Once-Daily Insulin Degludec in Adults With Insulin-Naive Type 2 Diabetes

Once-Weekly Insulin Icodec vs Once-Daily Insulin Degludec in Adults With Insulin-Naive Type 2 Diabetes

Efficacy and safety of once-weekly basal insulin versus once-daily basal insulin in patients with type 2 diabetes: A systematic review and meta-analysis

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

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