Sarah Pinkley, PharmD, Geritom Medical
Background
Initiating basal insulin in adults with type 2 diabetes mellitus (DM) is often delayed due to therapeutic inertia—often driven by regimen complexity, fear of hypoglycemia, and the burden of daily injections and frequent dose adjustments. Such barriers contribute to prolonged periods of suboptimal glycemic control. Once-weekly basal insulin formulations, such as insulin efsitora alfa, have been developed to simplify treatment initiation and intensification. Efsitora has a long half-life and flat pharmacokinetic profile, making it suitable for fixed-dose, once-weekly administration and may improve patient adherence.
Objective
In this trial, researchers assessed whether once-weekly, fixed-dose insulin efsitora is noninferior to once-daily insulin glargine U100 (Lantus®) in reducing A1c in adults with type 2 DM without previous insulin use.
Study Design
This was a 52-week, multicenter, open-label, randomized controlled trial conducted at 71 sites across the U.S., Argentina, and Mexico. Adults ≥18 years with type 2 DM, A1c 7–10%, body mass index (BMI) ≤45 kg/m², and on stable therapy with one to three noninsulin antihyperglycemic agents were eligible. Participants (N=795) were randomized 1:1 to receive either: Once-weekly insulin efsitora (starting at 100 units (U) with 4-week interval titrations to fixed doses of 150, 250, or 400 U) or once-daily insulin glargine U100 (initiated at 10 U/day with weekly titration per standard protocol).
The primary endpoint was the change in A1c from baseline to week 52, evaluated for noninferiority (margin 0.4%). Secondary endpoints included hypoglycemia incidence, change in body weight, adverse events, and adjudicated deaths and major cardiovascular events.
Results
A1c decreased from 8.20% to 7.05% with efsitora and from 8.28% to 7.08% with glargine at 52 weeks, yielding a between-group difference of −0.03% (95% CI, −0.18 to 0.12; P=0.68), confirming noninferiority. Rates of clinically significant or severe hypoglycemia were lower with efsitora (0.50 vs 0.88 events/participant-year; rate ratio, 0.57; 95% CI, 0.39 to 0.84). Mean weekly insulin doses were 289.1 U with efsitora and 332.8 U with glargine (difference, −43.7 U; 95% CI, −62.4 to −25.0), with fewer median dose adjustments (2 vs 8). More participants on efsitora achieved A1c <7.0% without significant hypoglycemia (41% vs 33%), and weight gain was modestly higher (3.9 kg vs 3.3 kg). The study did not demonstrate superiority of efsitora over glargine on multiplicity-adjusted secondary endpoints, a context that tempers interpretation of the secondary outcome findings.
Conclusions
In insulin-naive adults with type 2 DM, once-weekly insulin efsitora in a fixed-dose regimen was noninferior to once-daily glargine in achieving glycemic control over 52 weeks. Efsitora required fewer dose adjustments and was associated with significantly lower rates of hypoglycemia, supporting its potential role as a simplified, lower-burden alternative to daily regimens. However, several limitations must be acknowledged, including the open-label design, the absence of continuous glucose monitoring (CGM), and the lack of re-escalation dosing of efsitora. Furthermore, while outcomes were clinically favorable, superiority was not demonstrated on adjusted secondary endpoints. Overall, efsitora represents a promising strategy to reduce therapeutic inertia and treatment burden in type 2 DM, but longer-term studies with broader monitoring approaches are warranted to confirm its long-term safety and effectiveness.
Published on November 17, 2025.
Reference
- Rosenstock J, Bailey T, Connery L, et al. Weekly fixed-dose insulin efsitora in type 2 diabetes without previous insulin therapy. New England Journal of Medicine. 2025;393(4):325-335. doi:10.1056/NEJMoa2502796