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Recent clinical trials indicate that once-weekly insulin injections are on the horizon as a treatment for diabetes. Catherine Falls Commercial/Getty Images
  • A year-long phase 3 clinical trial suggests that a once-weekly insulin injection for type 1 diabetes is potentially as effective as daily injections.
  • In a similar phase 3 trial, researchers compared the efficacy of once-weekly and once-daily insulin icodec treatments for type 2 diabetes.
  • They found that once-weekly icodec injections were more effective in lowering blood sugar levels than the standard once-daily injections.
  • Researchers say that once-weekly insulin injections could revolutionize diabetes treatments.

A new, once-weekly insulin treatment could be a game changer for people with diabetes, according to the results of clinical trials.

A recent phase 3 clinical trial, ONWARDS 6, compared the effectiveness and safety of a once-weekly insulin icodec injection with a once-daily insulin degludec shot in adults with type 1 diabetes. Degludec is a long-acting insulin drug that helps regulate blood sugar levels.

The results of the year-long trial, published on October 17 in The Lancet, indicate the once-weekly insulin treatment may work just as well as daily injections.

In another phase 3 clinical trial, ONWARDS 3, researchers compared the efficacy and safety of a once-weekly insulin icodec shot with the standard once-daily injection degludec for treating type 2 diabetes.

They found that once-weekly icodec treatment resulted in greater reductions in blood sugar levels than once-daily degludec after 26 weeks. Those study results were published in June in JAMA.

Moreover, an earlier study published in March 2021 found that icodec injections produce similar glucose-lowering effects as daily insulin injections.

Researchers involved with these studies say that once-weekly insulin injections could revolutionize the future of diabetes care and help millions of people manage their condition.

In the October 2023 study, researchers assigned 582 participants from 12 countries across 99 different sites either insulin icodec (290 subjects) or insulin degludec (292 subjects).

They measured blood glucose levels at week 26, compared them to baseline values, and saw a slight reduction in hemoglobin A1c (HBA1c) levels in both groups.

HBA1c measures average blood sugar levels over the preceding three months. People without diabetes tend to have HBA1c values of less than 5.7%; however, those with diabetes are recommended to maintain levels of 6.5% or below.

Participants who took icodec decreased from an average of 7.59% at baseline to 7.15%. The degludec group decreased from 7.63% to 7.10%.

The researchers estimated the difference between the two treatments was 0.05%, which confirms that icodec is non-inferior to degludec and has a “significantly reduced injection frequency” for managing type 1 diabetes.

Prof. David Russell-Jones, PhD, professor of diabetes and endocrinology at the University of Surrey and a consultant at the Royal Surrey Foundation Trust, said in a press release:

“Many people find managing a long-term condition such as diabetes very difficult and report missing vital insulin injections. Missed injections can affect glycaemic control, and a lack of consistency in the treatment has been linked to increased rates of diabetic ketoacidosis, a serious complication of the condition that can be life-threatening. Reducing insulin injection frequency could lessen the burden of treatment for some people with the condition and improve their glycaemic control.”

For the ONWARDS 3 study, the researchers recruited 588 individuals with an average age of 58 from 11 countries, including the USA, Argentina, and China. All participants were being treated with non-insulin glucose-lowering agents, and just over a third were women.

During the study, they were randomly assigned to receive one of the following treatment regimens for 26 weeks:

  • once-weekly icodec and once-daily placebo
  • once-daily degludec and once-weekly placebo

Ultimately, the researchers found that icodec reduced hemoglobin A1c (HBA1c) levels more than degludec.

After 26 weeks, HBA1c levels among participants in the icodec group decreased from an average of 8.6% to 7%. Meanwhile, HBA1c levels in the degludec group fell from an average of 8.5% to 7.2%.

The researchers noted that fasting glucose and body weight did not significantly differ between participants taking icodec and degludec.

Medical News Today asked Dr. Absalon Gutierrez, associate professor of endocrinology with McGovern Medical School at UTHealth Houston, not involved in this study, what may explain icodec’s superior effects on lowering HBA1c values.

“Though we don’t know for sure, it likely has to do with patient adherence to the medication. Based on the way the study was designed, it was much easier to miss the degludec injections than it was to miss the icodec injections. This is likely the case in real life as well.”

— Dr. Absalon Gutierrez, endocrinologist

In the ONWARDS 6 study, researchers reported 39 serious adverse events in 24 subjects (8%) who took icodec and 25 adverse events in 20 subjects (7%) who took degludec.

One participant died, but researchers say the death was unlikely to be related to the treatment.

In both clinical trials, adverse events included clinically significant to severe hypoglycemia — when blood sugar levels are lower than the standard range.

Researchers involved with the ONWARDS 3 study noted that from the start of the study until week 31, 8.9% of participants in the icodec group and 5.8% of those taking degludec experienced hypoglycemia.

Furthermore, over the course of the trial, 177 (60.4%) patients in the icodec group and 167 (56.8%) of those receiving degludec experienced adverse events. The researchers wrote that 60 events in the icodec group and 46 in the degludec group were possibly linked to insulin treatments.

They noted, however, that most of the events were mild and included COVID-19, influenza, and diabetic retinopathy, an eye condition that can cause vision loss in patients with diabetes.

While 5.1% of patients in the icodec group compared to 2% of those on degludec developed diabetic retinopathy, they noted that the absolute numerical difference was small, and that the observed differences had not been recorded in previous icodec trials.

The researchers involved with both phase 3 clinical trials noted the limitations of their studies.

In the ONWARDS 6 trial, the researchers cited the study’s open-label design and use of self-measured blood sugar monitoring as limitations that have a potential risk of bias.

“Our findings are very promising, but further analysis of continuous glucose monitoring data and real-world studies are needed,” Prof. Russell-Jones said.

The researchers also note the exclusion of comorbidities or lack of subject awareness of existing hypoglycemia as further limitations that could limit the findings to wider type 1 diabetes populations.

The researchers of the ONWARDS 3 trial noted that the 26-week study duration means that longer-term effects remain unknown.

Similar to ONWARD 6, the ONWARDS 3 trial did not collect continuous glucose monitoring data or data on patient-reported outcomes.

“Though icodec performed slightly superior in lowering HBA1c, it also showed more hypoglycemia,” Dr. Gutierrez noted. “This would be expected, since it can’t be titrated as frequently. Also, based on the study design, the degludec titrations were not optimal.”

MNT also spoke with Dr. Lushun Wang, the senior consultant orthopedic surgeon and medical director of Arete Orthopaedic Clinic in Singapore, who was not involved in the ONWARDS 3 study, about its limitations:

“The duration of the studies can be further lengthened to ensure reliable long-term efficacy and safety. Rigorous and more in-depth testing should be done to better understand icodec,” Dr. Wang said.

“Data on continuous glucose monitoring may ensure a more robust insight into the control of blood glucose as well as its impact on the patient’s quality of life. Other than that, the trial was designed with a larger quantity of injections of icodec compared to the daily regimen, which does not accurately reflect real-world use and any potential benefits in terms of treatment adherence.”

— Dr. Lushun Wang, orthopedic surgeon

Over 37 million people in the United States have diabetes. Between 90–95% of these people have type 2 diabetes.

Insulin is a hormone made by the pancreas that allows cells to use glucose as energy. Type 2 diabetes occurs when cells no longer respond properly to insulin, which leads to increased blood sugar levels.

Over time, high blood sugar can damage several organs, including the eyes, kidneys, and heart. Treatment is thus necessary either by lifestyle modifications or non-insulin glucose-lowering agents.

Current guidelines recommend insulin-based drugs to lower blood sugar levels in people with type 2 diabetes when non-insulin medications are ineffective.

Currently, insulin-based drugs for type 2 diabetes require daily injections. Daily injections, however, can be cumbersome for patients, leading to poor adherence rates.

Research suggests that weekly injections improve adherence. One study found that patients taking once-weekly insulin treatments adhere to treatment regimens for an average of 333 days, compared to 269 days for those receiving daily injections.

Lack of adherence to insulin therapy can have severe consequences. Research indicates that poor adherence to insulin therapy in patients with diabetes is linked to a higher risk of death and hospitalization.

Increasing adherence rates is thus key to improving health outcomes and quality of life among people with diabetes.

The ONWARDS 3 researchers noted that icodec might improve treatment adherence and convenience among patients with type 2 diabetes by reducing injections from 365 to 52 per year.

Regarding the results of ONWARDS 6, Prof. Russell-Jones noted:

“What we have found is that once-weekly icodec injections showed non inferiority to once-daily injections of degludec in reducing HbA1C after 26 weeks. Although there is a slightly higher rate of hypoglycaemia under this regime, we found this could be easily managed. We’ve concluded this new insulin may have a role in reducing the burden of daily basal injections for patients managing type 1 diabetes.”

ONWARDS 3 researchers said that the small added glycemic benefit and convenience of once-weekly administration should outweigh the “small absolute risk of hypoglycemia.”

“Conveniently designed, icodec can allow daily injections to be replaced by this once-weekly option,” Dr. Wang said. “Its primary advantage is hedged on its ability to provide a stable and continuous release of insulin over the course of a week, helping to reduce fluctuations in blood glucose levels. This ability of icodec can lead to the better overall control of blood glucose, as demonstrated in the superior HbA1c reduction observed in the trials.”

Dr. Guitierrez agreed that icodec insulin may be a good option for people who have difficulty adhering to once-daily basal insulin. He noted, however, that further studies are needed to better understand the hypoglycemia risk of taking icodec relative to once-daily insulin injections.