Once-Weekly Insulin Looks Good in T2D, but Risk Seen in T1D

MADRID — Eli Lilly’s investigational once-weekly basal insulin analog efsitora alfa continues to show noninferiority to once-daily insulin in people with type 2 diabetes. However, in those with type 1 diabetes, there was an increased risk for hypoglycemia. 
The data come from Lilly’s QWINT global phase 3 clinical trial program for efsitora alfa, which enrolled a total of more than 4000 adults with type 2 or type 1 diabetes across five trials. The latest data — from QWINT-2, in insulin-naive adults with type 2 diabetes, and QWINT-5, in adults with type 1 diabetes — were presented on September 10, 2024, at the annual meeting of the European Association for the Study of Diabetes (EASD) and simultaneously published in The New England Journal of Medicine and The Lancet, respectively. 
On September 5, 2024, Eli Lilly released top-line results from two other trials: QWINT-1, in insulin-naive patients with type 2 diabetes who were using a fixed-dose titration regimen, and QWINT-3, evaluating efsitora alfa vs daily insulin degludec in adults who were already using basal insulin. 
These follow the release in May 2024 of top-line results for QWINT-2 and also QWINT-4, which showed noninferiority to daily insulin glargine in adults with type 2 diabetes who require multiple daily injections. 
Asked to comment, session moderator Rory McCrimmon, professor of medicine at the University of Dundee, Scotland, and lead clinician for the Scottish Diabetes Research Network in the UK, told Medscape Medical News, “It’s a very exciting time and the data are intriguing. There can be no doubt that one of the major issues we face in type 2 diabetes is around persistence and adherence to therapy and a failure of the population to titrate. Therefore, new insulins such as these once weekly that reduce the requirement for injections, and possibly don’t necessarily need the same sort of titration algorithms, are going to be useful for a lot of people with type 2 diabetes.”
However, McCrimmon also noted, “We’ve seen the clinical trial data, but we’ll have to see what happens in the real world when we start to use these agents. There’s a big educational component here, because you’re having to get healthcare professionals used to an entirely different way of delivering and titrating, and I think that’s going to be a big challenge.”
The overall data for efsitora alfa resemble those for Novo Nordisk’s once-weekly basal insulin analog icodec (Awiqli). Awiqli has been authorized for use in the European Union but not in the United States, where the US Food and Drug Administration (FDA) requested additional information from the company. In May, an FDA advisory panel voted against approval owing to hypoglycemia concerns in people with type 1 diabetes.
McCrimmon noted, “The data so far suggest there are small differences between the compounds, particularly in peak-to-trough ratios and longer half-life, which favor efsitora…. We’re going to have to wait and see.”
In a commentary during the EASD session, Cornelis J. Tack, professor of internal medicine and head of the diabetes section at Radboud University Medical College, Nijmegen, the Netherlands, called QWINT-2 and QWINT-5 “high-quality clinical studies in relevant populations providing important scientific information. Once-weekly insulin efsitora performs equal to once-daily insulin in insulin-naive people with type 2 diabetes. But once-weekly insulin efsitora is probably not a good idea in people with type 1 diabetes.”
He also noted that efsitora’s longer half-life compared with icodec means less variability throughout the week, but it also complicates the switch from once-daily administration. 
After the session, Tack spoke to Medscape Medical News about the hypoglycemia risk in type 1 diabetes. “I think if you do it appropriately with [continuous glucose monitoring] from the start with careful titration, then you can use it in type 1, but it wouldn’t be the first choice…. I don’t think it’s enough to really say stop the whole program, but I think they need to do more (research) on how to use it safely in type 1.” Automated insulin delivery is the preferred choice in type 1 diabetes, he noted. 
But for people with type 2 diabetes, Tack said there is a definite convenience advantage. 
QWINT-2: Efsitora Noninferior to Daily Basal in Type 2 Diabetes 
QWINT-2 was a 52-week open-label trial of 928 insulin-naive adults assigned in a 1:1 ratio to receive once-weekly efsitora or daily degludec. The primary endpoint, change in A1c from baseline to week 52, was from 8.21% to 6.97% with efsitora and from 8.24% to 7.05% with degludec — a statistically insignificant difference of 0.09% demonstrating noninferiority (margin, 0.4%). 
Efsitora was also noninferior in subgroups using and not using glucagon-like peptide 1 receptor agonists, and in the time spent in target range of 70-180 mg/dL (64.3% vs 61.2%), respectively, at weeks 48-52.
Rates of combined clinically significant and severe hypoglycemia were 0.58 vs 0.45 events per participant-year of exposure with efsitora and degludec, respectively, a nonsignificant difference. No severe hypoglycemia was reported with efsitora, whereas six episodes were reported with degludec. The incidence of other adverse events was similar in the two groups.
QWINT-5: More Hypoglycemia Seen With Efsitora in Type 1 Diabetes 
This randomized, 52-week open-label trial randomly assigned 692 adults with type 1 diabetes to receive once-weekly efsitora or once-daily degludec. Participants also used insulin lispro for meals. The mean A1c decreased from 7.88% at baseline to 7.41% at week 26 with efsitora and from 7.94% to 7.36% with degludec, with a nonsignificant estimated treatment difference of 0.052% (P = .43) confirming noninferiority. 
However, rates of combined level 2 (< 54 mg/dL [3.0 mmol/L]) or level 3 severe hypoglycemia were higher with efsitora compared with degludec, at 14.03 vs 11.59 events per patient-year of exposure during weeks 0-52 (rate ratio, 1.21; P =.016), with the highest rates occurring during weeks 0-12. Rates of severe hypoglycemia were also higher with efsitora than degludec, at 10% vs 3% during weeks 0-52 (rate ratio, 3.44; P = .0011).
Rates of other adverse events were similar. There was one death in the degludec group, deemed not related to study treatment.
QWINT-1 and QWINT-3 Topline: All Positive in Type 2 Diabetes 
In QWINT-1, insulin-naive adults were randomly assigned to receive either efsitora titrated across four fixed doses at 4-week intervals as needed for blood glucose control or insulin glargine. Efsitora reduced A1c by 1.31% vs 1.27% with glargine, resulting in A1c levels of 6.92% and 6.96%, respectively — a nonsignificant difference meeting noninferiority criteria. 
QWINT-3 compared once-weekly efsitora vs once-daily degludec in 78 weeks in adults with type 2 diabetes currently treated with basal insulin, this time with a 2:1 randomization. The primary noninferiority endpoint was met at week 26, with A1c reductions of 0.86% and 0.75%, respectively, down to 6.93% and 7.03%. Time spent in target glucose range during weeks 22-26 was also similar between the two groups: 62.8% for efsitora and 61.3% for degludec. 
Safety profiles were similar between efsitora and the daily basal insulins in both trials. In QWINT-1, estimated combined rates of severe or clinically significant hypoglycemic events (blood glucose < 54 mg/dL) per patient-year of exposure from weeks 0-52 were 0.50 with efsitora vs 0.88 with glargine — that is, approximately 40% lower with efsitora than glargine.
In QWINT-3, estimated combined rates of severe or clinically significant hypoglycemic events per patient-year of exposure during weeks 0-78 were 0.84 with efsitora vs. 0.74 with degludec. 
Detailed results for QWINT-1 and QWINT-3 will be presented at a later conference and published in a peer-reviewed journal, according to a Lilly statement. 
McCrimmon has served on advisory boards and/or received lecture fees and/or research support from Sanofi and Novo Nordisk, but not within the past year. Tack has received consulting and/or lecture fees from Novo Nordisk, Boehringer Ingelheim, Lilly, and Insulet. 
Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape, with other work appearing in The Washington Post, NPR’s Shots blog, and Diatribe. She is on X (formerly Twitter) @MiriamETucker.
 
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