QWINT: Once-weekly insulin tied to similar HbA1c reduction as insulin degludec
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Key takeaways:
- Insulin efsitora alfa conferred noninferior HbA1c reductions vs. insulin degludec in two phase 3 trials.
- Level two and level three hypoglycemia rates were higher with efsitora than degludec in the QWINT-5 trial.
Once-weekly insulin efsitora alfa provided similar reductions in HbA1c as once-daily insulin degludec among insulin-naive adults with type 2 diabetes and adults with type 1 diabetes previously receiving a basal and bolus insulin analog.
During a symposium at the European Association for the Study of Diabetes annual meeting, researchers presented data from two phase 3 trials in the QWINT trial program funded by Eli Lilly. The QWINT-2 trial compared insulin efsitora alfa (Eli Lilly) with insulin degludec (Novo Nordisk) for adults with type 2 diabetes who had not previously used insulin, while the QWINT-5 trial enrolled adults with type 1 diabetes who were receiving multiple daily insulin therapy with a basal-bolus insulin analog prior to enrollment.
Stefano Del Prato, MD, affiliate professor of medicine at the Interdisciplinary Research Center Health Science of the Sant'Anna School of Advanced Studies in Pisa, Italy, said about one-third of people with diabetes do not adhere to insulin therapy and 93% would like to have good glycemic control without receiving daily insulin injections. He said he believes a once-weekly insulin could provide several advantages for people with diabetes, including better medication adherence, improved quality of life and a less overwhelming sense of treatment.
“With daily basal insulin, you have 365 injections per year that can be reduced dramatically to a number of 52 injections per year if you provide that weekly injection interval,” Del Prato said during a presentation.
Efsitora in type 2 diabetes
The QWINT-2 trial, simultaneously published in The New England Journal of Medicine, enrolled 928 adults aged 18 years or older with type 2 diabetes who did not previously use insulin, had an HbA1c of 7% to 10.5% at baseline, had a BMI of 45 kg/m2 or less and had stable diabetes treatment with one to three non-insulin glucose-lowering drugs for at least 3 months prior to baseline (58.8% men; mean age, 57.4 years). The study group was randomly assigned to receive once-weekly insulin efsitora alfa or once-daily insulin degludec for 1 year. The primary outcome was HbA1c change from baseline to 1 year.
Efsitora was noninferior to degludec for change in HbA1c. In the treatment-regimen estimand, adults receiving efsitora had an HbA1c decline of 1.26 percentage points from baseline to 1 year compared with a decrease of 1.17 percentage points for the degludec group. Of the participants, 60.9% receiving efsitora and 59.2% receiving degludec achieved an HbA1c of less than 7% at 1 year.
“Efsitora was as efficacious as degludec in participants using and not using GLP-1 receptor agonists,” Carol H. Wysham, MD, FACP, FACE, clinical professor of medicine at the University of Washington and a Healio | Endocrine Today Editorial Board member, said during the presentation.
Total weekly insulin dose at 1 year was 314.7 U per week with efsitora and 334.4 U per week with degludec. Body weight change was similar between the efsitora and degludec groups.
No episodes of severe hypoglycemia occurred with efsitora and six occurred with degludec. Combined rates of level 2 or level 3 hypoglycemia were similar between the two groups. Adverse events were reported by 72.5% in the efsitora group and 73.8% in the degludec group. Serious adverse events occurred among 8.8% of adults receiving efsitora and 8.2% receiving degludec. There were two deaths in the efsitora group and one in the degludec group, none of which were deemed related to the study treatment.
“Efsitora demonstrated acceptable tolerability, and the safety profile is consistent with expectations for a basal insulin,” Wysham said.
Once-weekly insulin for type 1 diabetes
The QWINT-5 trial enrolled adults aged 18 years and older with type 1 diabetes who previously received treatment with basal and bolus insulin analog multiple daily injection therapy for 90 days prior to screening, had an HbA1c between 7% and 10% and had a BMI of 35 kg/m2 or less at baseline.
Investigators randomly assigned 692 adults (55% men, mean age; 44 years), to receive once-weekly insulin efsitora alfa or once-daily insulin degludec for 1 year. Change in HbA1c from baseline to 26 weeks was the primary outcome of the trial. The QWINT-5 findings were simultaneously published in The Lancet.
Efsitora was noninferior to degludec for change in HbA1c at 26 weeks. In the treatment-regimen estimand, the efsitora group had a 0.51 percentage point decline in HbA1c from baseline to 26 weeks compared with a 0.56 percentage point decrease for the degludec group (estimated treatment difference, 0.052%; 95% CI, –0.077 to 0.181). At 52 weeks, the HbA1c reduction was 0.38 percentage points with efsitora compared with a 0.4 percentage point drop with degludec.
Weekly basal insulin dose was similar in the efsitora and degludec groups at weeks 26 and 52. Weekly bolus insulin and total insulin doses were lower for adults receiving efsitora vs. degludec at 26 and 52 weeks.
Events of level 2 and level 3 hypoglycemia were higher in the efsitora group (17.19 events per patient-year of exposure [PYE]) vs. the degludec group (14.06 events per PYE). The increased level 2 and level 3 hypoglycemia events with efsitora were observed during non-nocturnal periods (P = .0044). Additionally, 64% of the severe hypoglycemia events in the efsitora group occurred during the dose titration portion in the first 12 weeks of the trial. Bergenstal said the increased hypoglycemia may be due to a change in dose titration from the phase 2 trial to the phase 3 study.
“In the phase 2 study of efsitora when compared to degludec, there was no increase in hypoglycemia compared to degludec, but glucose levels in the efsitora group were up more than in the degludec group from baseline, so it was felt new starting dose strategies were needed,” Richard M. Bergenstal, MD, executive director of the International Diabetes Center, HealthPartners Institute, Minneapolis, told Healio. “The new dose initiation strategies did avoid the fasting glucose from going up, but may have contributed to more early hypoglycemia.”
Treatment-emergent adverse events occurred in 72% of the efsitora group and 67% of the degludec group. Serious adverse events were reported by a higher percentage of adults receiving efsitora compared with degludec (13% vs. 7%).
“Level 3 hypoglycemia [was] counted for serious adverse events,” Bergenstal said during the presentation.
Some groups may benefit from efsitora
In an editorial published in NEJM, Irwin Brodsky, MD, MPH, endocrinologist and internal medicine provider at MaineHealth Endocrinology and Diabetes Center and Maine-Health Institute for Research, said people with disabilities that may struggle with administering daily insulin could benefit from a once-weekly option.
“The burden and complexity of administering insulin injections is particularly severe for persons who have disabilities of dexterity, vision or executive mental functions, such as memory, planning and problem solving,” Brodsky wrote. “Often, persons with such disabilities are unable to inject insulin in a timely way and require the help of caregivers who may not be available for daily injections.”
During a commentary at the presentation, Cees J. Tack, MD, professor in the faculty of medical sciences and chair of internal medicine, diabetology at Radboud University Medical Center in the Netherlands, noted efsitora decreases the barrier to start insulin and treatment burden by reducing the number of injections. However, he noted people with diabetes will still need to monitor their glucose on days they are not receiving insulin and described the once-weekly insulin as something that would “nice to have” for certain patient populations and not necessarily a “must have” for everyone.
Additionally, Tack expressed concerns about the use of the insulin for type 1 diabetes due to the hypoglycemia rates observed in QWINT-5. As Healio previously reported, the FDA rejected once-weekly insulin icodec (Novo Nordisk) due to concerns regarding hypoglycemia risk for adults with type 1 diabetes.
“Once-weekly insulin efsitora is probably not a good idea in people with type 1 diabetes,” Tack said.
Bergenstal said patient treatment satisfactions scores were higher with efsitora than degludec in QWINT-5, showing adults with type 1 diabetes may prefer a once-weekly option. He said additional research into dosing strategies by analyzing continuous glucose monitoring data could lower hypoglycemia rates in the type 1 diabetes population.
“While many individuals with type 1 diabetes are now using automated insulin delivery therapy, there will always be a substantial number who prefer to use multiple daily injections with CGM and not advanced pump and algorithm technology,” Bergenstal told Healio. “Many will want to try once-weekly background insulin if given an opportunity.”
References:
Bergenstal RM, et al. Lancet. 2024;doi:10.1016/S0140-6736(24)01804-X.
Brodsky I. N Engl J Med. 2024;doi:10.1056/NEJMe2410551.
Wysham C, et al. N Engl J Med. 2024;doi:10.1056/NEJMoa2403953.
Perspective
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Steve Edelman, MD
Once-weekly insulin is an incredible advance in the way scientists can manipulate hormones to change their time course of action. Both Lilly and Novo Nordisk have been developing these weekly insulins for type 1 and type 2 diabetes almost in parallel. The phase 3 clinical trials for both are also not dissimilar. For people with type 2 diabetes who were research subjects, both weekly insulins work well and are basically noninferior to the current daily basal insulins.
The issues of ramping up the loading dose, need for initial frequent monitoring when access to medical appointments has never been more difficult, potential higher price point than daily basal formulations and the need for a tremendous education campaign for both providers and patients represents strong headwinds to implementing these weekly insulins successfully. Lastly and perhaps most important, is there an unmet need for weekly insulin? Perhaps in combination with a weekly GLP-1 or dual agonist?
These same issues apply to individuals with type 1 diabetes; however, both Lilly’s and Novo Nordisk’s weekly basal insulins lead to higher rates of hypoglycemia. This is not a small issue, as folks with type 1 diabetes like myself think about hypoglycemia every single day during our waking hours. Perhaps it was the initial dosing schedule, but in any case, with the advancements in hybrid closed-loop systems and the need for frequent adjustments in daily insulin use in multiple daily injection patients, weekly insulin can be of benefit for a subset of individuals as mentioned by my colleagues.
I applaud both Lilly and Novo Nordisk for undertaking this endeavor to make life better living with diabetes.
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De Prato S, et al. S18. Presented at: European Association for the Study of Diabetes Annual Meeting; Sept. 9-13, 2024; Madrid, Spain.
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