Abstract 133: Hypoglycaemia frequency and physiological response to double or triple doses of once-weekly insulin Icodec vs. once-daily insulin glargine in T2D

Background: Insulin icodec is a basal insulin in development for once weekly (OW) dosing. Insulinicodec has a half-life suited for once weekly dosing, which could potentially improve treatment adherence, persistence, and clinical outcomes. Insulin icodec has an efficacy and safety profile similar to insulin glargine U100 as demonstrated in phase 2 clinical trials2,3,4 - phase 3a (ONWARDS) trials are ongoing. Objective: Was to compare the hypoglycaemia frequency and response after icodec vs. insulin glargine U100 (IGlar) overdosing. Methods: In a randomized, open-label, two-period crossover trial, 43 individuals with T2D on basal insulin ± metformin (mean ± SD age 56 ± 9 yrs, HbA1c 7.2 ± 0.7%) received OW icodec for 6 weeks and once-daily IGlar for 12 days at equimolar total weekly doses based on the individual daily run-in IGlar dose (mean 30 ± 14 U) titrated to a fasting SMPG target of 80-130 mg/dL. Once at steady state, double (DD) and triple (TD) doses of icodec and IGlar were followed by hypoglycaemia induction 44 h (icodec) or 7 h (IGlar) post-dose (expected time of maximum glucose-lowering effect): First, euglycemia was maintained at 100 mg/dL by variable i.v. glucose. Then, PG was allowed to decrease to a nadir of no less than 45 mg/dL maintained for 15 min. Euglycemia was restored by constant i.v. glucose. Hypoglycaemia symptom score (HSS) and counterregulatory hormones were assessed at PG 100 mg/dL and at predefined PG levels until nadir PG. Results: For DD Clinically significant hypoglycaemia (PG < 54 mg/dL) occurred in 40 vs. 36% of subjects for icodec vs. IGlar (odds ratio 1.28; p = 0.63). For TD Clinically significant hypoglycaemia occurred in 53 vs. 70% of subjects (odds ratio 0.48; p = 0.14), mean nadir PG was 56 vs. 52 mg/dL (treatment ratio 1.07; p < 0.001), change in HSS at nadir PG was comparable for icodec vs. IGlar (treatment difference 0.46; p = 0.77), responses in adrenaline, noradrenaline and cortisol during hypoglycaemia development were greater for icodec vs. IGlar, while glucagon and growth hormone levels increased similarly. Conclusion: A DD or TD of once-weekly insulin icodec does not lead to increased risk of hypoglycaemia compared to once-daily IGlar. During hypoglycaemia, a comparable symptomatic response and a moderately greater endocrine response were seen for icodec vs. IGlar.