Weekly insulin efsitora alfa ‘noninferior’ to daily degludec for type 1 diabetes HbA1c reduction

medwireNews: Weekly treatment with insulin efsitora alfa is noninferior to daily insulin degludec for the reduction of glycated hemoglobin (HbA1c) in adults with type 1 diabetes, the QWINT-5 trial investigators have found. However, the phase 3 study indicated that efsitora was associated with higher rates of level 2 and 3 hypoglycemia and severe hypoglycemia compared with degludec, the researchers reported at EASD 2024 in Madrid, Spain. Writing in a simultaneous publication in The Lancet, Richard Bergenstal (International Diabetes Center, HealthPartners Institute, Minneapolis, Minnesota, USA) and team say that their findings “might suggest the need for additional evaluation of efsitora dose initiation and optimisation in people with type 1 diabetes.” Nevertheless, the investigators believe their study “highlights the possibility of a once-weekly basal insulin that could reduce patient burden and improve treatment adherence.” The study participants were 692 patients with type 1 diabetes and a glycated hemoglobin of 7.0–10.0% (53.0–85.8 mmol/mol) who had been using basal and bolus insulin analog given in multiple daily injections for at least 90 days. The patients were aged an average of 44 years, 55% were men, and 75% were White. The patients were randomly assigned to receive open-label, treat-to-target efsitora 500 units/mL (n=343) or degludec 100 units/mL (n=349), with both treatments given alongside bolus insulin lispro and a carbohydrate counting plan using an insulin-to-carbohydrate ratio or a fixed-dose plan. The first dose of efsitora was calculated using the person’s regular daily basal dose times seven to cover the week, multiplied by three, while the second injection was calculated using daily basal dose times seven. Patients whose baseline fasting blood glucose was above 140 g/dL (7.8 mmol/L), were recommended to receive an incremental dose increase of 10–20% for a fasting blood glucose of 141–160 mg/dL (7.8–8.9 mmol/L) or 20–30% for a level above 160 mg/dL (8.9 mmol/L). Overall, 90% of participants completed the study. The mean HbA1c in efsitora-treated patients fell from a mean 7.88% (62.7 mmol/mol) at baseline to 7.41% (57.5 mmol/mol) at week 26, while the degludec-treated controls had a decrease from 7.94% (63.3 mmol/mol) to 7.36% (56.9 mmol/mol). Thus, the primary endpoint of the change in HbA1c between baseline and week 26 was estimated to be –0.51% with efsitora and –0.56% with degludec, giving a nonsignificant treatment difference of 0.05% that was within the prespecified noninferiority margin of 0.40%. In weeks 22–26 of treatment, the percentage of time spent in the target range of 70–180 mg/dL (3.9–10.0 mmol/mol) was 53% for both the efsitora and degludec treatment groups. But the combined rate of level 2 hypoglycemia (patient-reported blood glucose <54 mg/dL; 3.0 mmol/L) or level 3 severe hypoglycemia (altered mental or physical stature requiring assistance) in the first 26 weeks was significantly higher with efsitora than degludec (17.19 vs 14.06 events per patient year of exposure [PYE]) and this trend continued to week 52 (14.03 vs 11.59 events per PYE), with estimated rate ratios (ERRs) of 1.22 and 1.21, respectively. The peak rate of level 2–3 hypoglycemia occurred in the first 12 weeks, the researchers say. Further analysis showed that there was no significant difference in the nocturnal rate of level 2 or 3 hypoglycemia between the efsitora and degludec groups over 52 weeks (1.99 vs 1.96 events per PYE), whereas non-nocturnal events were significantly more common (11.81 vs 9.43 events per PYE, ERR=1.26). Overall, 10% of patients given efsitora experienced severe hypoglycemia over the year versus 3% of controls. Bergenstal et al note that the findings are in agreement with those of the earlier ONWARDS 6 phase 3 study that showed weekly insulin with icodec was noninferior to degludec and was associated with an increased rate of level 2–3 hypoglycemia, which included nocturnal hypoglycemia. “Findings in people living with type 1 diabetes who use closed loop insulin delivery systems show highly variable basal insulin needs that could explain the increased risk of hypoglycaemia in people with type 1 diabetes randomly assigned to once-weekly insulins in both weekly insulin studies,” the researchers postulate. “Additional guidance on how to leverage 24-h glucose profiles and other continuous glucose monitoring metrics, rather than focusing on fasting glucose, could further optimise basal insulin titration,” they suggest. Noting that efsitora-treated participants had “significantly greater overall treatment satisfaction” at week 26 than those given degludec, the team concludes that “for some people living with type 1 diabetes who struggle with administering daily basal insulins, weekly insulin treatment could offer a valuable therapeutic alternative.” medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2024 Springer Healthcare Ltd, part of the Springer Nature Group EASD 2024; Madrid, Spain: 9–13 September Lancet 2024; doi:10.1016/S0140-6736(24)01804-X

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Weekly insulin efsitora alfa ‘noninferior’ to daily degludec for type 1 diabetes HbA1c reduction

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