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Clinical Trial
. 2025 Jul;68(7):1416-1422.
doi: 10.1007/s00125-025-06414-6. Epub 2025 Apr 5.

The effect of once-weekly insulin icodec vs once-daily basal insulin on physical activity-attributed hypoglycaemia in type 2 diabetes: a post hoc analysis of ONWARDS 1-5

Michael C Riddell  1 , Simon Heller  2 , Lisbeth Carstensen  3 , Thaís M Pagliaro Rocha  3 , Sara Kehlet Watt  3 , Vincent C Woo  4
Affiliations
Clinical Trial

The effect of once-weekly insulin icodec vs once-daily basal insulin on physical activity-attributed hypoglycaemia in type 2 diabetes: a post hoc analysis of ONWARDS 1-5

Michael C Riddell et al. Diabetologia. 2025 Jul.

Abstract

Aims/hypothesis: Physical activity increases the risk of hypoglycaemia in individuals with type 2 diabetes when basal or basal-bolus insulin therapy is administered. Once-weekly basal insulins may elevate the risk of physical activity-attributed hypoglycaemia compared with other basal insulins because the administered levels cannot be reduced in anticipation of increased physical activity. This post hoc analysis of five separate randomised trials (ONWARDS 1-5) aimed to examine physical activity-attributed hypoglycaemic episodes in adults with type 2 diabetes receiving either once-weekly basal insulin icodec (herein referred to as 'icodec') or once-daily basal insulins.

Methods: The ONWARDS 1-5 Phase 3a randomised controlled trials compared the efficacy and safety of once-weekly basal icodec vs once-daily basal insulin in insulin-naive (ONWARDS 1, 3 and 5) and insulin-experienced (ONWARDS 2 and 4) adults with type 2 diabetes. Participants self-monitored their blood glucose levels using a blood glucose meter and a digital diary. In each trial, suspected hypoglycaemia symptoms triggered additional self-measured blood glucose readings, and values indicative of hypoglycaemia were recorded in the participants' digital diary. Participants who experienced hypoglycaemic episodes were instructed to note any relation of each episode to physical activity. Hypoglycaemic episodes were classified as alert value (level 1: blood glucose <3.9 but ≥3.0 mmol/l), clinically significant (level 2: blood glucose <3.0 mmol/l) or severe (level 3: cognitive impairment requiring external assistance). The proportions of hypoglycaemic episodes that were attributed to physical activity and the ORs of having a physical activity-attributed hypoglycaemic episode were calculated for the two basal insulin types (once-weekly vs once-daily) for each of the five trials.

Results: Across all trials, there were no consistent differences between icodec and the once-daily insulin comparators in the proportions of hypoglycaemic episodes that were attributed to physical activity; these episodes were mainly alert value or clinically significant hypoglycaemic episodes. In both insulin-naive and insulin-experienced participants, the incidence of physical activity-attributed clinically significant or severe hypoglycaemic episodes was consistently ≤3.0% in ONWARDS 1, 2, 3 and 5. In ONWARDS 4, the incidence of physical activity-attributed hypoglycaemic episodes was numerically higher in both treatment groups (18.6% [icodec] vs 17.9% [insulin glargine U100]), which was expected given the basal-bolus insulin regimen. Across all trials, there were no statistically significant differences in the odds of experiencing a physical activity-attributed clinically significant or severe hypoglycaemic episode with icodec vs once-daily insulin comparators. The frequency of recurrent clinically significant or severe hypoglycaemic episodes in the 24 h after a physical activity-attributed clinically significant or severe hypoglycaemic episode was low, with no such episodes in ONWARDS 1, 3 and 5. In contrast, in ONWARDS 2 and 4, the frequency of recurrent clinically significant hypoglycaemic episodes in the 24 h after a physical activity-attributed clinically significant or severe hypoglycaemic episode was numerically higher with icodec vs the once-daily insulin comparators, whilst no additional severe episodes were reported in any participants across the trials.

Conclusions/interpretation: These findings do not suggest that there is an additional increase in hypoglycaemia risk attributed to physical activity with once-weekly basal icodec vs once-daily basal insulins in adults with type 2 diabetes.

Trial registration: ClinicalTrials.gov NCT04460885 (ONWARDS 1), NCT04770532 (ONWARDS 2), NCT04795531 (ONWARDS 3), NCT04880850 (ONWARDS 4) and NCT04760626 (ONWARDS 5).

Keywords: Exercise; Hypoglycaemia; Insulin icodec; Once-weekly basal insulin; Physical activity; Type 2 diabetes.

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Conflict of interest statement

Acknowledgements: Medical writing support was provided by S. Bestall of Oxford PharmaGenesis, Oxford, UK, with funding from Novo Nordisk. Some of the data included in this manuscript were presented as an abstract at the American Diabetes Association 84th Scientific Sessions in 2024 and at the 60th Annual Meeting of the European Association for the Study of Diabetes in 2024. Data availability: Individual participant data will be shared in datasets in a de-identified or anonymised format. Shared data will include datasets from clinical research sponsored by Novo Nordisk and completed after 2001 for product indications approved in the EU and the USA. The study protocol and redacted clinical study report will be made available according to Novo Nordisk’s data-sharing commitments. These data will be available permanently after research completion and after approval of product and product use in both the EU and the USA (no end date). Data will be shared with bona fide researchers submitting a research proposal requesting access to data for use as approved by the Independent Review Board (IRB) according to the IRB charter (see www.novonordisk-trials.com ). These data can be accessed via an access request proposal form; the access criteria can be found at www.novonordisk-trials.com . The data will be made available on a specialised SAS data platform. Funding: This study was funded by Novo Nordisk. Representatives of Novo Nordisk had a role in the study design; analysis and interpretation of the data; and in the preparation, review and approval of the manuscript. Novo Nordisk did not have the right to veto publication or to control the decision regarding which journal the manuscript was submitted to; these decisions were made by the authors. Authors’ relationships and activities: MCR reports consulting fees from Eli Lilly, the Jaeb Center for Health Research, Zealand Pharma and Zucara Therapeutics; speaker fees from Dexcom Canada, Eli Lilly, Novo Nordisk and Sanofi Diabetes; and stock options from Supersapiens and Zucara Therapeutics. SH reports consultancy fees from Zealand Pharma and Zucara Therapeutics; fees for speaker panel involvement with Novo Nordisk; data monitoring and safety board participation with Eli Lilly; and research support from Dexcom. LC, TMPR and SKW are employees and shareholders of Novo Nordisk. VCW reports speaker fees and advisory board meeting involvement for Boehringer Ingelheim, Eli Lilly and Novo Nordisk. Contribution statement: All authors had full access to the data associated with this study and contributed to interpreting the data and drafting the manuscript. LC, TMPR and SKW analysed, accessed and verified the data. The authors jointly decided to submit the manuscript, approved it before submission and took full responsibility for its content. MCR is the guarantor for this work.

Figures

Fig. 1
Fig. 1
Proportion of hypoglycaemic episodes that were attributed to physical activity during the on-treatment period of ONWARDS 1–5. The on-treatment period was defined as the onset date on or after the first dose of the trial product and no later than the first date of either the follow-up visit, the last date on trial product +5 weeks for once-daily insulin and +6 weeks for once-weekly insulin, or the end date for the in-trial period (defined as the time from randomisation to whichever occurred first of the last direct participant–site contact, withdrawal of informed consent, the last participant–investigator contact before loss to follow-up, or death). Hypoglycaemia alert value was defined as a blood glucose value <3.9 mmol/l but ≥3.0 mmol/l, confirmed by a blood glucose meter; clinically significant hypoglycaemia was defined as a blood glucose value <3.0 mmol/l, confirmed by a blood glucose meter; severe hypoglycaemia was defined as hypoglycaemia with severe cognitive impairment requiring external assistance for recovery. aThe choice of the once-daily insulin analogue (insulin degludec, insulin glargine U100 or insulin glargine U300) was made at the discretion of the investigator. Aspart, insulin aspart; degludec, insulin degludec; glargine U100, insulin glargine U100; glargine U300, insulin glargine U300; icodec, insulin icodec; OD, once-daily
Fig. 2
Fig. 2
Observed incidence of physical activity-attributed clinically significant or severe hypoglycaemia with icodec vs once-daily insulin comparators during the on-treatment period of ONWARDS 1–5. The table presents the number of participants in each treatment arm that were included in the analyses that are presented in the bar graph. The on-treatment period was defined as the onset date on or after the first dose of trial product and no later than the first date of either the follow-up visit, the last date on trial product +5 weeks for once-daily insulin and +6 weeks for once-weekly insulin, or the end date for the in-trial period (defined as the time from randomisation to whichever occurred first of the last direct participant–site contact, withdrawal of informed consent, the last participant–investigator contact before loss to follow-up, or death). The incidence of hypoglycaemia was analysed using a binary logistic regression model, with treatment, geographical region, sulfonylurea/glinide use (ONWARDS 3) and personal continuous glucose monitoring device use (ONWARDS 2 and 4) as fixed factors. Missing data were imputed using multiple imputations. Clinically significant hypoglycaemia was defined as a blood glucose value <3.0 mmol/l, confirmed by a blood glucose meter; severe hypoglycaemia was defined as hypoglycaemia with severe cognitive impairment requiring external assistance for recovery. ORs (icodec/once-daily insulin comparator) are shown; there were no statistically significant differences between treatment arms in each trial (two-sided p values for the test of no treatment difference [with no correction for multiplicity] were p=0.1607, p=0.1103 and p=0.4640 for ONWARDS 1, ONWARDS 3 and ONWARDS 5, respectively, and p=0.8621 and p=0.7250 for ONWARDS 2 and ONWARDS 4, respectively). aThe choice of the once-daily insulin analogue (degludec, glargine U100 or glargine U300) was made at the discretion of the investigator. Aspart, insulin aspart; degludec, insulin degludec; glargine U100, insulin glargine U100; glargine U300, insulin glargine U300; icodec, insulin icodec; OD, once-daily
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