Weekly efsitora compared to degludec in type 1 and type 2 diabetes by industry studies
Although two manufacturer trials showed that the weekly insulin efsitora was noninferior to daily degludec, that finding might not be sufficient to justify its use, particularly in patients with type 1 diabetes, an ACP Journal Club commentary said.
Two manufacturer-funded trials of weekly efsitora insulin in patients with type 1 and type 2 diabetes (T1D and T2D) found the new drug to be noninferior to daily degludec. The QWINT-2 trial randomized 928 adults with type 2 diabetes who had not previously received insulin to efsitora or degludec and found that mean HbA1c level decreased from 8.21% at baseline to 6.97% at week 52 with efsitora and from 8.24% to 7.05% with degludec. The QWINT-5 trial randomized 692 patients with type 1 diabetes and HbA1c levels of 7% to 10% to efsitora or degludec, both in combination with insulin lispro, and found that mean HbA1c levels decreased from 7.88% to 7.41% and from 7.94% to 7.36%, respectively, at week 26. Rates of hypoglycemia were higher with efsitora than degludec in that study.
The QWINT-2 study was published by the New England Journal of Medicine on Sept. 10, 2024. The QWINT-5 study was published by The Lancet on Sept. 21, 2024. The following commentary by Felipe Larios, MD; Michael R. Gionfriddo, PharmD, PhD; and Victor M. Montori, MD, MSc, FACP, was published in the ACP Journal Clubsection of Annals of Internal Medicine on Jan. 7.
QWINT-2 and QWINT-5 report the effects of a very-long-acting insulin preparation that requires weekly administration. What therapeutic need do these long-acting insulins meet?
Weekly insulins may have a role in the care of patients with T2D. The QWINT-2 trial found that weekly insulin efsitora and daily insulin degludec had similar effects in patients with insulin-naive T2D, regardless of whether patients were receiving once-weekly glucagon-like peptide-1 (GLP-1) receptor agonists. Thus, patients who receive once-daily insulin may value switching to a once-weekly regimen if they can do so affordably and safely. Clinical guidelines recommend the use of glucose-lowering agents, such as GLP-1 receptor agonists, that have been shown to reduce cardiovascular and renal complications while inducing substantial weight loss and posing minimal to no risk for hypoglycemia. When glycemic control is insufficient with these agents, guidelines recommend combining them with insulin. Therefore, patients may appreciate the convenience of combining these agents into a once-weekly regimen. For patients who need prandial insulin and more physiologic basal insulin administration (e.g., those with more advanced or long-standing T2D with severe insulin deficiency), weekly insulins may not be preferable to daily basal insulin.
The results of QWINT-5 show that weekly basal insulin efsitora also did not reduce HbA1c compared with daily basal insulin degludec in patients with T1D, but it did increase risk for severe hypoglycemia. These results are similar to those of trials comparing another weekly insulin, insulin icodec, with daily insulin.
In patients with T1D who require multiple prandial insulin doses per day, there may not be much value in reducing the frequency of basal insulin administration from daily to weekly. In fact, trial patients reported a trivially small preference for weekly over daily insulin, and this preference did not consider the greater out-of-pocket costs with weekly insulin. Weekly insulin requires a loading dose, and dose adjustment occurs less frequently than with daily insulin, which may limit the ability to achieve and maintain timely glycemic control compared with daily basal insulin. This may be particularly pertinent when compared with sensor-augmented insulin pump therapy, which is increasingly the standard of care. When using an insulin pump, changes to basal insulin occur in nearly real time in response to changes in the patient's situation. Thus, the therapeutic role for a weekly basal insulin in patients with T1D remains unclear.
The real-world comparative safety and efficacy of weekly insulins may differ from the findings of the rigorous QWINT-2 and QWINT-5 trials. In the trials, a loading dose was needed to start weekly insulin, and clinicians, rather than patients, adjusted insulin doses weekly for both daily and weekly insulins. Also, real-world patients may use a different adjustment schedule for each type of insulin (e.g., dose adjustment every 3 to 5 d for daily insulin and every 3 to 5 wk for weekly insulin) than the weekly frequency used in these trials.
Ultimately, noninferiority might not be sufficient to justify the use of efsitora, particularly in patients with T1D. For patients with T2D, who tend to be less dependent on insulin, efsitora might be useful in combination with weekly GLP-1 receptor agonists. Careful discussion and shared decision making are needed so that the resulting regimen benefits and fits patients' lives.