Transforming Type 2 Diabetes Treatment: Key Findings from the QWINT-2 (once-weekly insulin therapy) Trial
Tanmaya Phanda, PharmD
5 minutes
Transforming Type 2 Diabetes Treatment: Key Findings from the QWINT-2 (once-weekly insulin therapy) Trial
Written by Tanmaya Phanda, PharmD, InpharmD Team
This blog will provide an overview of type 2 diabetes, explore key insights from the QWINT-2 trial, and discuss the potential impact of once-weekly insulin in clinical practice.
Introduction
Diabetes is a significant health concern that affects more than 38 million Americans. Of these individuals, 90-95% have type 2 diabetes, meaning that approximately 1 in 10 Americans live with this condition.2
Type 2 diabetes occurs when the body becomes insulin resistant or doesn’t produce enough insulin, resulting in elevated blood glucose levels. A formal diagnosis is made with two fasting blood glucose tests of ≥126 mg/dL. Also, a glycated hemoglobin (HbA1c) test of ≥6.5% indicates a diabetes diagnosis. In 2021 alone, 1.2 million people in the United States were diagnosed with type 2 diabetes. Key risk factors are overweight (body mass index [BMI] = 25-29.9 kg/m2) or obesity (BMI ≥30 kg/m2), lack of physical activity, ≥45 years or older, and a family history.2-3
Signs and symptoms may include persistent thirst/urination, fatigue, blurry vision, and unexplained weight loss.4 Uncontrolled type 2 diabetes can lead to serious complications such as cardiovascular diseases, renal disease, neuropathy, and retinopathy.5 According to the Centers for Disease Control and Prevention (CDC), diabetes is the eighth leading cause of death in the United States, with a death rate of 30.4 deaths per 100,000 people.6
Currently, there is no cure for diabetes, but there are many effective treatment options to help achieve and maintain glycemic control. According to the 2024 American Diabetes Association (ADA) guidelines, metformin is the first-line treatment for patients with type 2 diabetes. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors and certain dual gastric inhibitory polypeptide (GIP) and glucagon‐like peptide‐1 (GLP-1) receptor agonists are preferred agents for diabetic patients at high risk for cardiorenal disease. Dual GIP and GLP-1 receptor agonists also aid in weight loss management for diabetic patients. In addition, dipeptidyl peptidase-4 (DPP-4) inhibitors, sulfonylureas, and thiazolidinediones are other alternative therapies to manage blood glucose levels.3
The ADA guidelines advise initiating insulin in patients with catabolism, HbA1c > 10%, or blood glucose levels ≥300 mg/dL (can be combined with other glucose-lowering agents unless contraindicated or not tolerated). The starting basal insulin dose is 10 U or 0.1-0.2 units/kg, which can be titrated as needed but requires close monitoring due to the risk of hypoglycemia. Treatment can be further escalated as basal insulin can also be used in combination with dual GIP/GLP-1 receptor agonist or prandial insulin.3
Table 1. Type 2 Diabetes Treatment Goals (2024 ADA Guidelines)
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Fasting Blood Glucose (mg/dL)
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80-130
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|
Post-meal Blood Glucose (mg/dL)
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≤180
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|
HbA1c (%)
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≤7
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Concerns about weight gain, hypoglycemia, treatment complexity, and injection frequency, can delay insulin initiation and reduce adherence. A new basal insulin called efsitora alfa (efsitora) offers a promising solution because of its flat pharmacokinetic profile (low peak-to-trough ratio) and long half-life, allowing for once-weekly administration. If efsitora gains FDA approval, it could help reduce the daily injection burden and improve glycemic outcomes.
In a phase 2 study, once-weekly efsitora demonstrated similar glycemic control and safety profile compared to once-daily insulin degludec in insulin-naive type 2 diabetic adult patients. After 26 weeks of treatment, efsitora showed a non-inferior HbA1c change from baseline versus degludec, with a treatment difference of 0.06% (90% Confidence Interval [CI] −0.11, 0.24; P = 0.56).7
Methods
The QWINT phase 3 program, a series of five randomized clinical trials, evaluated efsitora compared to degludec and glargine U100 across various diabetic adult patient populations. QWINT-2, a multi-center, parallel-design, open-label, treat-to-target, randomized, controlled trial, compared the safety and efficacy of efsitora with degludec, both in combination with noninsulin glucose-lowering medications. The trial consisted of a 3-week screening and lead-in period, a 52-week treatment period, and a 5-week follow-up period. The study was done on type 2 diabetic adult patients who had not previously received insulin, had an HbA1c between 7.0-10.5%, and had a body mass index (BMI) ≤ 45 kg/m2. Patients were eligible if they had received stable treatment with one to three noninsulin glucose-lowering agents for at least 3 months before screening.
A total of 928 patients were randomized 1:1, with 466 assigned to the efsitora group and 462 to the degludec group. In the efsitora group, patients were subcutaneously administered a one-time starting dose of 300 U in the first week, and then given a 100 U weekly dose thereafter. In the degludec group, patients received 10 U daily. In both groups, dose assessments were completed weekly until week 12 and every four weeks thereafter. Doses were adjusted based on the median of the three most recent fasting blood glucose values to achieve a target of 80 to 120 mg/dL.
The demographics and baseline characteristics were similar in both treatment groups, with the mean age 57.4±10.8 years, the mean duration of diabetes being 11.60±7.26 years, the mean HbA1c being 8.22±0.96%, and the mean BMI 30.58±5.87 kg/m2. —Table 2.
Table 2. Patient Baseline Characteristics
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Baseline Characteristic
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Efsitora
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Degludec
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Total
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Mean Age (years)
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57.6±10.6
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57.3±11.0
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57.4±10.8
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Mean Duration of Type 2 Diabetes (years)
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11.78±7.54
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11.42±6.97
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11.60±7.26
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Mean HbA1c (%)
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8.21±0.96
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8.23±0.96
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8.22±0.96
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Mean BMI ( kg/m2)
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30.44±5.85
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30.72±5.90
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30.58±5.87
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Along with the treatment arm regimen, patients continued to use noninsulin glucose-lowering agents. The most common agents were metformin (779 patients [83.9%]), GLP-1 receptor agonists (464 patients [50.0%]), SGLT2-inhibitors (328 patients [35.3%], and sulfonylurea (304 patients [32.8%].—Figure 1.
Figure 1. Most Common Non-insulin Diabetic Medications Co-Administered with Treatment Arms
Results
The primary efficacy endpoint was the noninferiority of efsitora to degludec measured by the change in the HbA1c from baseline to week 52.
The mean HbA1c decreased from 8.21% at baseline to 6.97% at week 52 with efsitora (least-squares mean [LSM] change, −1.26 percentage points) and from 8.24% to 7.05% with degludec (LSM change, −1.17 percentage points). An estimated treatment difference in the HbA1c of -0.09 percentage points (95% CI, -0.22 to 0.04), showing efistora non-inferior to degludec (P-value = 0.19).—Table 3.
At the end of the 52-week treatment period, both groups had similar percentages of patients achieving HbA1c <7% (60.9% in the efsitora group and 59.2% in the degludec group)
Figure 3*. Primary Efficacy Endpoints
| |
Efsitora
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Degludec
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Estimated Treatment Difference (95% CI)
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Baseline HbA1c (%)
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8.21
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8.24
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-0.09 percentage points (-0.22 to 0.04), P value = 0.19
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Week 52 HbA1c (%)
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6.97
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7.05
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LSM Change (percentage points)
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-1.26
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-1.17
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*LSM values from the treatment-regimen estimand
The secondary efficacy endpoints were designed to evaluate further the effects of efsitora compared to degludec.—Table 4.
Table 4. Secondary Efficacy Endpointsa
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Secondary Efficacy Endpoint
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Efsitora
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Degludec
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Estimated Treatment Difference (95% CI)
|
|
Change in the HbA1c from baseline to week 52 in patients using GLP-1 receptor agonists
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−1.26%
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−1.19%
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−0.06 % ( −0.26 to 0.13)
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Change in the HbA1c from baseline to week 52 in patients not using GLP-1 receptor agonists
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−1.26%
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−1.15%
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−0.11% −0.28 to 0.07)
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Percentage of time that the glucose level was in the target range (70 to 180 mg/dL), as measured by continuous glucose monitoring, in weeks 48 through 52
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64.3%
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61.2%
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3.1 percentage points (0.1 to 0.7)
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Change from baseline to week 52 in the fasting blood glucose level (measured by patient-monitored blood glucose tests)
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−64.5 mg/dL
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−63.7 mg/dL
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−0.74 mg/dL (−4.29 to 2.82)
|
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Insulin dose at week 52
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314.7 U per week (45.0 U per day)
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334.4 U per week (47.8 U per day)
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−19.7 U per week (−37.0 to −2.4)
|
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Change from baseline to week 52 in the TRIM-Db total score
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8.82 points
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6.81 points
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2.00 points (0.57 to 3.44)
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a)LSM values from the treatment-regimen estimand
b)TRIM-D: Treatment-Related Impact Measure–Diabetes (on a scale from 0 to 100, with higher scores indicating better functioning and greater well-being)
All efficacy endpoints demonstrated noninferiority for all comparisons (P-value < 0.001).
Safety was assessed by:
Table 5. Safety Endpoints
|
Safety Endpoint
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Efsitora
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Degludec
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Estimated Treatment Difference (95% CI)
|
|
Incidence and rate of overall hypoglycemia*
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0.58 events per participant-year of exposure
|
0.45 events per participant-year of exposure
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1.30 (0.94 to 1.78)
|
|
Incidence and rate of nocturnal hypoglycemia*
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0.08 events per participant-year of exposure
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0.08 events per participant-year of exposure
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1.01 (0.53 to 1.89)
|
|
Change in body weight from baseline to week 52
|
3.6 kg
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3.5 kg
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0.1 (−0.4 to 0.5)
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*Hypoglycemia defined as clinically significant (level 2; glucose level, <54 mg/dL) or severe (level 3)
There were no episodes of severe hypoglycemia in the efsitora group and six in the degludec group. (Five of these six participants were using sulfonylureas). A total of 42 participants (9.0%) permanently discontinued efsitora, and 28 (6.1%) permanently discontinued degludec. In the efsitora group, two deaths occurred and one death in the degludec, but none were related to either treatment regimen.
Study Conclusions
The QWINT-2 trial concluded that once-weekly efsitora showed improvement in glycemic control. The efficacy and safety outcomes were consistent with those observed in the earlier phase 2 trial. Efsitora was non-inferior once-daily degludec in the change of HbA1c from baseline to week 52 and subgroups of patients using and not using GLP-1 receptor agonists. Clinically meaningful hypoglycemia and other safety measures were similar in the two treatment groups, without severe hypoglycemia during efsitora treatment.
Despite having a large diverse representative of type 2 diabetic patients and a wide range of noninsulin glucose-lowering agents, the trial had some limitations. Tirzepatide, a dual GIP receptor agonist for diabetes and weight loss, was not approved during the trial enrollment. The study’s open-label design also allows for potential biases. Blinded continuous glucose monitoring prevented making dose adjustments based on the readings which may have further improved blood glucose management and reduced the risk of hypoglycemia.
Clinical Impact
Currently, there is no FDA-approved once-weekly basal insulin for diabetic patients. Yet, Eli Lily’s QWINT trial program with efsitora and Novo Nordisk’s ONWARDS (six phase-3a global clinical trials investigating the efficacy and safety of once-weekly insulin icodec in type 1 and 2 diabetic adult patients) are dedicated to improving diabetes care.8 Notably, Eli Lily has not requested FDA approval for efsitora so far. Despite encouraging results, icodec was rejected by the FDA in May 2024 due to concerns over its manufacturing process and the increased risk of hypoglycemia compared to daily insulin in type 1 diabetic patients. The company plans to address these concerns in 2025. However, icodec is approved in Europe, Canada, Japan, and Australia under the brand name Awiqli™ for type 1 and 2 diabetes, and in China for type 2 diabetes.9 While the path to FDA approval for once-weekly basal insulins remains uncertain, ongoing trials and international approvals suggest a promising future for innovative diabetes treatment.
The QWINT-2 data highlights efsitora’s advantage of a lower injection burden compared to conventional basal insulin treatments. Studies comparing once-daily GLP-1 receptor agonists with once-weekly dosing have shown that fewer injections lead to improved adherence and glycemic control, indicating that efsitora may provide similar benefits.10-12 A simplified insulin dosing regimen can improve patient quality of life as shown by the secondary endpoint utilizing the TRIM-D scale, in which a greater improvement in total score with efsitora (8.82) was observed compared to degludec (6.81). In addition, insulin therapy can contribute to clinical inertia in diabetes management. Clinical inertia occurs when healthcare providers are reluctant or unable to start or intensify treatment for patients when needed. This level of provider hesitancy often stems from patient resistance, careful monitoring related to the risk of hypoglycemia and weight gain, and healthcare costs. According to studies, in the United States clinical inertia ranged from 35.4% to 85.8% in type 2 diabetic patients.13 Efsitora’s once-weekly administration may mitigate clinical inertia by facilitating earlier treatment initiation and minimizing the challenges of careful monitoring, ultimately reducing clinical inertia and improving diabetes management.
Results from additional trials (QWINT-1 and QWINT-3) within the QWINT program will provide more insight into the safety and efficacy of efsitora for diabetic patients, but, QWINT-2 has already shown promising results of introducing once-weekly insulin into clinical practice.
References:
- Wysham C, Bajaj HS, Del Prato S, et al. Insulin Efsitora versus Degludec in Type 2 Diabetes without Previous Insulin Treatment. N Engl J Med. 2024. doi:https://doi.org/10.1056/nejmoa2403953
- CDC. About Type 2 Diabetes. Diabetes. Published May 31, 2024. https://www.cdc.gov/diabetes/about/about-type-2-diabetes.html#:~:text=Key%20points%201%20About%201%20in%2010%20Americans
- American Diabetes Association. Diabetes Care. American Diabetes Association. Published 2024. https://diabetesjournals.org/care/issue/47/Supplement_1
- CDC. Symptoms of Diabetes. CDC. Published May 15, 2024. https://www.cdc.gov/diabetes/signs-symptoms/index.html
- CDC. Diabetes Complications. Diabetes. Published May 22, 2024. https://www.cdc.gov/diabetes/complications/index.html
- CDC. FastStats - Diabetes. Centers for Disease Control and Prevention. Published April 27, 2024. https://www.cdc.gov/nchs/fastats/diabetes.htm
- Bue-Valleskey JM, Kazda CM, Ma C, et al. Once-weekly basal insulin Fc demonstrated similar glycemic control to once daily insulin degludec in insulin-naive patients with type 2 diabetes: a phase 2 randomized control trial. Diabetes Care. 2023;46:1060-7
- Novo Nordisk. Company announcement. Once-weekly insulin icodec demonstrates superior reduction in HbA1c in combination with a dosing guide app versus once-daily basal insulin in people with type 2 diabetes in ONWARDS 5 phase 3a trial https://www.novonordisk.com/news-and-media/news-and-ir-materials/news-details.html?id=138024. Published October 3, 2024.
- Novo Nordisk. Company announcement. Novo Nordisk receives Complete Response Letter in the US for once-weekly basal insulin icodec. https://www.novonordisk.com/news-and-media/news-and-ir-materials/news-details.html?id=168532. Published July 10, 2024.
- Qiao Q, Ouwens MJ, Grandy S, Johnsson K, Kostev K. Adherence to GLP-1 receptor agonist therapy administered by once-daily or once-weekly injection in patients with type 2 diabetes in Germany. Diabetes Metab Syndr Obes 2016;9:201-5. 11.
- Polonsky WH, Arora R, Faurby M, Fernandes J, Liebl A. Higher rates of persistence and adherence in patients with type 2 diabetes initiating once-weekly vs daily injectable glucagon-like peptide-1 receptor agonists in US clinical practice (STAY study). Diabetes Ther 2022;13:175- 87.
- Mody R, Huang Q, Yu M, et al. Adherence, persistence, glycaemic control and costs among patients with type 2 diabetes initiating dulaglutide compared with liraglutide or exenatide once weekly at 12-month follow-up in a real-world setting in the United States. Diabetes Obes Metab 2019;21:920-9.
- Almigbal TH, Alzarah SA, Aljanoubi FA, et al. Clinical Inertia in the Management of Type 2 Diabetes Mellitus: A Systematic Review. Medicina (Kaunas). 2023;59(1):182. Published 2023 Jan 16. doi:10.3390/medicina59010182
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