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An investigational once-weekly insulin was noninferior to a daily option for patients with type 2 diabetes, but proved risky for those with type 1 diabetes, the phase III QWINT-2 and -5 trials showed.

In insulin-naive patients with type 2 diabetes enrolled in QWINT-2, average HbA1c levels decreased from 8.21% at baseline to 6.97% at week 52 with once-weekly insulin efsitora, and from 8.24% to 7.05% with once-daily insulin degludec (estimated treatment difference -0.09 percentage points, 95% CI -0.22 to 0.04), reported Carol Wysham, MD, of the MultiCare Rockwood Center for Diabetes and Endocrinology in Spokane, Washington, at the European Association for the Study of Diabetes (EASD) annual meeting in Madrid.

In addition, time in target range was slightly higher with the once-weekly option. The efsitora group spent 64.3% of time with a glucose level between 70 and 180 mg/dL compared with 61.2% of time for those in the degludec group (estimated treatment difference 3.1 percentage points, 95% CI 0.1-6.1), according to the study that was simultaneously published in the .

Efsitora is a basal insulin comprised of a fusion protein that combines a novel single-chain variant of insulin with a human IgG2 Fc domain designed to provide stable glucose levels over 7 days.

"Traditionally, basal insulins are dosed once a day -- a treatment schedule that can make compliance difficult for a significant portion of people living with type 2 diabetes," said Wysham. "Efsitora has the potential to address treatment burden and improve adherence, all while lowering A1C."

Melanie Davies, MD, of the University of Leicester in England, noted that "patients liked this insulin," referencing the significant improvement in Treatment-Related Impact Measure-Diabetes total score with efsitora over degludec.

There were no severe hypoglycemia events reported with insulin efsitora compared with six episodes reported with degludec. The rate of combined clinically significant or severe hypoglycemia was 0.58 events per participant-year of exposure with efsitora versus 0.45 events per participant-year of exposure with degludec (estimated rate ratio 1.30, 95% CI 0.94-1.78).

Currently, all basal insulin products on the market are designed for daily dosing. Safety concerns with a once-weekly formulation, particularly hypoglycemia, have historically been a barrier to their adoption, though this is a greater concern for type 1 diabetes.

"It was important that efsitora did not induce an excess of clinically significant hypoglycemia episodes, given the recent report from the involving persons with type 1 diabetes that another once-weekly insulin, icodec, resulted in disproportionate rates of hypoglycemia as compared with degludec," wrote Irwin Brodsky, MD, MPH, of the MaineHealth Endocrinology and Diabetes Center in Scarborough, in an .

In May, an FDA advisory committee voted against approval of investigational once-weekly icodec for patients with type 1 diabetes due to risks of hypoglycemia. (The product is still under review for adults with type 2 diabetes.)

QWINT-5 tested efsitora in patients with type 1 diabetes, showing noninferiority to degludec, with average HbA1c levels dropping from 7.88% at baseline to 7.41% at week 26 with efsitora and from 7.94% to 7.36% with degludec (estimated treatment difference 0.052%, 95% CI -0.077 to 0.181, P=0.43), reported Richard Bergenstal, MD, of the University of Minnesota in Minneapolis, at EASD and in .

However, like with icodec, safety was a concern. Rates of combined level 2 (<54 mg/dL) and level 3 (severe) hypoglycemia were higher with efsitora compared with degludec: 14.03 versus 11.59 events per patient-year of exposure over 52 weeks. This was mainly driven by a higher risk for severe hypoglycemia (estimated relative rate 3.44, 95% CI 1.64-7.19, P=0.0011).

Rates were highest during the first 12 weeks of treatment. Nocturnal hypoglycemia didn't differ between the groups.

"Once-weekly insulin efsitora is probably not a good idea in people with type 1 diabetes," commented Cees Tack, MD, PhD, of Radboud University Medical Center in the Netherlands, who wasn't involved with the study.

"There may have been an excess of insulin in those initial weeks of treatment," said Bergenstal. "I think we work to optimize the initiation ... the starting [dose] and titration because people with type 1 diabetes really liked this insulin and want to take a weekly insulin, but we have to figure out the sweet spot."

Davies agreed, noting that the researchers "need to reflect if [they] got this right with the starting dose."

Study Details

In QWINT-2, a total of 928 participants with type 2 diabetes were randomized from June 2022 to April 2024 at 121 sites in 10 countries: 466 to efsitora 500 U/mL and 462 to degludec 100 U/mL. All participants were naive to insulin. Mean age was 57.4, 58.8% were men, 50.4% were white, and 35.2% were Asian.

Half were on a GLP-1 receptor agonist at baseline. When participants were split according to GLP-1 use, efsitora was still noninferior to degludec for changes in HbA1c levels at 52 weeks:

• Using a GLP: 8.17% to 6.96% with efsitora versus 8.26% to 7.02% with degludec
• Not using a GLP: 8.25% to 6.97% with efsitora versus 8.21% to 7.08% with degludec

The incidence of adverse events was similar in the two groups.

For QWINT-5, a total of 692 participants with type 1 diabetes were randomized from August 2022 to May 2024 at 82 healthcare centers in Argentina, Japan, Poland, Slovakia, Taiwan, and the U.S.: 343 to efsitora 500 U/mL and 349 to degludec 100 U/mL, both in combination with bolus insulin lispro. Mean age was 44, 55% were men, 75% were white, and 21% were Asian.

For the first injection only, participants in the efsitora group received a one-time loading dose calculated as their usual daily basal dose multiplied by 7, and then multiplied by 3 to reach efficacious levels quicker.

One death unrelated to study treatment occurred in the degludec group, and the overall incidence of treatment-emergent adverse events was similar across treatment groups.