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

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).

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