CHICAGO, 2025-06-22
Once-Weekly Insulin Efsitora Shows Noninferiority
Efsitora offers a simplified approach to managing type 2 diabetes.
- Insulin efsitora demonstrated noninferior blood sugar control compared to daily insulins in three trials.
- Efsitora did not increase the risk of significant hypoglycemia.
- The convenience of weekly dosing may improve adherence for some patients.
The QWINT trials revealed that once-weekly insulin efsitora achieved similar HbA1c levels compared to once-daily insulins in adults with type 2 diabetes, whether they were new to insulin or had prior experience.
New data presented at the American Diabetes Association Scientific Sessions in Chicago highlights the potential of once-weekly insulin efsitora (Eli Lilly) in managing type 2 diabetes. The QWINT-1, QWINT-3, and QWINT-4 trials explored efsitora’s effectiveness across different patient groups, comparing it to once-daily insulin glargine in QWINT-1 and QWINT-4, and to once-daily insulin degludec (Novo Nordisk) in QWINT-3. The results indicated that efsitora successfully met the primary endpoint in all three trials, achieving noninferior HbA1c reductions relative to the daily insulins, with a noninferiority margin set at an HbA1c difference of 0.4 percentage points or less.
Findings from three QWINT trials showed once-weekly insulin efsitora was noninferior to once-daily insulins in adults with type 2 diabetes.
Julio Rosenstock, MD, FACE, senior scientific advisor for Velocity Clinical Research, director of Velocity’s site at Medical City Dallas and clinical professor of medicine at the University of Texas Southwestern Medical Center, pointed out the challenges patients face when titrating daily insulin, possibly leading to poor adherence or delayed treatment initiation. He suggested that insulin efsitora could simplify the process of starting and managing insulin therapy.
Did you know? Simplifying insulin regimens may improve patient compliance and overall blood sugar control.
“We’re very familiar with the single fixed dosing that has been widely used, accepted and increasingly utilized very successfully with [incretin-based] therapies,” Rosenstock said during a press conference. “You can imagine that if we can do the same with weekly insulin, that may become a real game changer.”
QWINT-1: insulin-Naive Patients
The QWINT-1 trial involved 795 adults with type 2 diabetes who had never used insulin before (49.9% women; mean age, 56.3 years). participants were randomized in a 1:1 ratio to receive either once-weekly insulin efsitora or daily 100 U insulin glargine for a duration of 1 year. The efsitora group commenced with a weekly dose of 100 U, with subsequent dose adjustments aimed at maintaining a fasting blood glucose level between 80 mg/dL and 130 mg/dL. Those whose glucose levels remained above 130 mg/dL after reaching a fixed dose of 400 U insulin efsitora were switched to variable dosing.
At the end of the year,the insulin efsitora group experienced a decrease in HbA1c from a baseline of 8.2% to 7.05%, while the insulin glargine group saw a decrease from 8.28% to 7.08%. The reduction in HbA1c with insulin efsitora was deemed noninferior to that of glargine (estimated treatment difference, -0.03 percentage points; 95% CI, -0.18 to 0.12; P for noninferiority =.68).
After a year, 57% of the insulin efsitora group and 52% of the insulin glargine group achieved an HbA1c of less than 7%. The mean fasting glucose levels were 127.7 mg/dL and 126.7 mg/dL, respectively. Notably, the insulin efsitora group required a lower mean total weekly insulin dose at 1 year (289.1 U/week vs.332.8 U/week).
The efsitora group also showed lower rates of level 2 hypoglycemia (glucose less than 54 mg/dL) and level 3 hypoglycemia (requiring assistance for treatment) compared to the glargine group (estimated RR = 0.57; 95% CI, 0.39-0.84). Furthermore, 41% of the efsitora group and 33% of the glargine group achieved an HbA1c of less than 7% without experiencing a level 2 or level 3 hypoglycemic event.
Adverse events were observed in 59.9% of the insulin efsitora group and 65.1% of the insulin glargine group, while severe adverse events were reported in 6.5% and 5.3%, respectively.
Rosenstock emphasized the reassuring finding that the once-weekly insulin did not result in higher rates of hypoglycemia when compared to the once-daily therapy.
“In terms of the adverse event profile, we didn’t see any signal, nothing to be concerned about,” Rosenstock said.
Rosenstock also noted that 76% of adults in the insulin efsitora group were able to maintain glycemic control on a fixed dose by the trial’s end.
“I think this can substantially facilitate and simplify initiating and escalating insulin therapy, potentially changing the management paradigm in type 2 diabetes,” Rosenstock said.
QWINT-3: Patients on Basal Insulin
QWINT-3 involved 986 adults with type 2 diabetes who were already using basal insulin and up to three glucose-lowering drugs (but not prandial insulin) at baseline (median age,62 years; 44% women). The participants were randomized in a 2:1 ratio to receive either once-weekly insulin efsitora or once-daily insulin degludec for 78 weeks. The primary endpoint was to determine noninferiority in HbA1c levels between the two groups at 26 weeks.
Analyzing the treatment-regimen estimand, HbA1c levels decreased from 7.8% at baseline to 6.99% at 26 weeks for adults in the insulin efsitora group. The insulin degludec group experienced a decrease from 7.79% at baseline to 7.08% at 26 weeks.The insulin efsitora group exhibited a 0.09 percentage point greater decline in HbA1c compared to the insulin degludec group, thus meeting the study’s noninferiority margin of 0.4 percentage points.
at 52 weeks, the insulin efsitora group demonstrated a larger HbA1c decrease compared to the insulin degludec group (estimated treatment difference; -0.19 percentage points, 95% CI, -0.3 to -0.07; P = .0014). Though, both groups showed a similar change in HbA1c at 78 weeks.
Changes in fasting blood glucose (FBG) were comparable between the two groups at 26 weeks. In the 4 weeks leading up to week 26, both groups also showed similar time in range as measured by continuous glucose monitoring, with 62.8% time in range for the efsitora group and 61.3% for the degludec group. Time above range did not differ significantly. However, adults receiving insulin efsitora had a 0.14 percentage point higher time below range compared to those receiving insulin glargine (P = .04).
The rates of level 2 and level 3 hypoglycemia did not differ significantly between the two groups, with 41% of adults in the efsitora group and 37% in the degludec group experiencing such events. Nocturnal level 2 and level 3 hypoglycemia rates were low, with 0.11 events per patient-year in the efsitora group and 0.1 events per patient-year in the degludec group. At 78 weeks, level 1 hypoglycemia occurred more frequently with insulin efsitora compared to insulin glargine (8.34 events per patient-year vs. 6.05 events per patient-year).
Treatment-emergent adverse events were more common in the efsitora group compared to the degludec group (75% vs. 66%). The proportion of adults with serious adverse events was similar.
Athena Philis-Tsimikas, MD, corporate vice president of Scripps Whittier Diabetes Institute in San Diego, noted that the insulin efsitora group reported significantly higher treatment satisfaction scores at 26, 52, and 78 weeks compared to the insulin degludec group.
“We have an amazing number of new medications, but insulin will always remain relevant,” Philis-Tsimikas said during a presentation. “We will need it for our patients. So,I’m very happy that we continue to have innovations in the types of insulin that can be offered.”
QWINT-4: Patients on Basal and Prandial Insulin
The QWINT-4 study included 730 adults with type 2 diabetes previously treated with basal insulin who also received at least two prandial insulin injections per day at baseline (51% women; mean age, 58.9 years). Participants were randomized in a 1:1 ratio to receive either insulin efsitora or 100 U once-daily insulin glargine for 26 weeks.
Analyzing the treatment-regimen estimand, both groups had a baseline HbA1c of 8.18%. At 26 weeks, the efsitora group had a mean HbA1c of 7.17% compared to 7.18% in the glargine group (estimated treatment difference; -0.01 percentage points; 95% CI,-0.14 to 0.12),meeting the trial’s noninferiority endpoint. There was no difference in the percentage of adults achieving an HbA1c of less than 7% without level 2 or level 3 hypoglycemia.
time in range was similar between the two groups. From 6 a.m. to midnight, the efsitora group had a higher time in range than the glargine group.
Total weekly insulin dose was lower with efsitora (592.9 U/week vs. 666.4 U/week; P < .0001). Basal weekly insulin dose was also lower with efsitora (391.6 U/week vs. 426.6 U/week; P =.0008).
Level 2 and level 3 hypoglycemia occurred in 56% of participants in each group.Five severe hypoglycemia episodes were reported in each group. adults receiving efsitora had a higher rate of level 1 hypoglycemia than the glargine group (estimated RR= 1.33; 95% CI, 1.13-1.55). Nocturnal level 1 hypoglycemia rates were lower with efsitora than glargine (estimated RR = 0.75; 95% CI,0.57-0.98).
“The incidence of hypoglycemia in all of these different categories [combined] was similar between the two [groups],” Thomas Blevins, MD, FACE, a clinical endocrinologist at Texas Diabetes and Endocrinology in Austin, said during the presentation.
Adverse events occurred in 54% of the efsitora group and 52% of the glargine group. Nasopharyngitis and urinary tract infection were the two most common treatment-emergent adverse events in both groups. No cases of diabetic ketoacidosis were reported.
What does this mean for clinical care?
efsitora isn’t the only once-weekly insulin in the pipeline. As previously reported, once-weekly insulin icodec (Novo Nordisk) also demonstrated long-term HbA1c reduction for adults with type 2 diabetes in the ONWARDS 1 trial.
Chantal Mathieu, MD, PhD, professor of medicine and chair of endocrinology at the University Hospital Gasthuisberg Leuven in Belgium, emphasized the importance of healthcare professionals understanding the profiles of both once-weekly insulins should they receive FDA approval.
“icodec has a half-life of 8 days and… there is some variation at the end of the injection,” Mathieu said during the presentation. “Efsitora has a half-life of 19 days with a more flat profile. These very long half-lives also mean when you initiate these insulins,they take some time to reach the plateau.”
Mathieu anticipates that once-weekly insulins will bring about a paradigm shift in how type 2 diabetes is managed.
“It is obvious that we are now living in exciting times with all of these therapies that we have for people with type 2 diabetes,” Mathieu said.”But insulin is still there.”
Perspective on Weekly Insulin for Diabetes
What is the potential impact of weekly insulin on diabetes management?
According to Rodica Pop-Busui, MD, PhD, weekly insulin is “quite exciting and particularly relevant for patients with type 2 diabetes.”
Pop-Busui adds, “For type 1 diabetes, the technologies that we have managed to develop, with automated insulin delivery that is precise, a very small patient population with type 1 diabetes will be candidates for weekly insulin. But for people with type 2 diabetes who cannot achieve glucose control with other agents, the ease of combining, for instance, a GLP-1, with weekly insulin, is probably extremely rare, Quality of life for our patients, glucose control, less weight gain are all crucial components, especially if the risk for hypoglycemia is also mitigated. I think that for type 2 diabetes, it has a very high relevance and impact for care at large.”
In the context of ongoing innovation in diabetes management, the potential impact of weekly insulin extends beyond just convenience and efficacy. The shift to less frequent dosing schedules could profoundly influence patient behavior and the overall approach to diabetes care. This is particularly relevant given the complexities of daily insulin regimens, wich often involve multiple injections, dose adjustments, and the persistent risk of both hyperglycemia and hypoglycemia.
One critical aspect to consider is the psychological burden associated with managing a chronic condition. The need for frequent self-monitoring, meticulous dose calculations, and the constant vigilance against complications can lead to ‘diabetes distress,’ a state of emotional exhaustion and overwhelm. Weekly insulin, by reducing the frequency of injections, could perhaps alleviate some of this stress, thereby improving patients’ mental well-being and their overall quality of life. This could translate to better adherence to treatment plans and, ultimately, improved glycemic control.
Another notable advantage is the potential for simplifying insulin initiation and titration, as pointed out by Dr. Rosenstock. Historically, initiating insulin therapy has been a complex process, requiring patients to learn new skills and often navigate an intricate dose-adjustment process. Weekly insulins with their pre-persistent dosing, especially with fixed-dose options as seen in the QWINT trials, may streamline this process, making it easier for both patients and healthcare providers.Simplified regimens may lessen the hesitations some patients have about starting insulin, potentially leading to earlier intervention and better long-term outcomes.
Moreover,the unique pharmacokinetic profiles of diffrent weekly insulins can play a crucial role in patient outcomes. As noted by Dr.Mathieu, efsitora’s longer half-life and flatter profile, compared to other weekly insulins like icodec, can offer distinct benefits, such as a more stable basal insulin effect throughout the week with potentially fewer fluctuations. However,the elongated time required to reach a steady therapeutic state may also present challenges,which requires consideration in individual patient treatment planning. The choice of the best insulin for any given patient would depend on their specifics, including their individual health status, current treatment, and treatment goals and also the various medications themselves.
The integration of weekly insulin into the existing clinical landscape also presents opportunities for improved integrated care. The fact that these medications can combine well with other therapies such as GLP-1 receptor agonists as mentioned by Dr. Pop-busui,indicates how they might work synergistically with other therapies to offer greater degrees of success. Furthermore, the simplicity of weekly dosing could simplify the work of clinicians, giving them space to address other aspects of diabetes care, such as lifestyle changes, and help their patients realize their own treatment goals.
Beyond the immediate benefits for patients, the adoption of weekly insulin could influence how healthcare systems allocate resources. Simplified treatment regimens can reduce the need for frequent office visits and may reduce the burden on healthcare providers, potentially freeing up resources for other aspects of diabetes care and patient education.The financial impact must also be factored in, as the cost-effectiveness of weekly insulin relative to daily regimens will play a critical role in its widespread adoption. In the context of rising healthcare costs, demonstrating cost-effectiveness for treatments helps to support better long-term outcomes and sustainability of modern healthcare solutions.
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