COMMENTARY

Once-Weekly 'Centennial Insulin': Will It Live Up to the Promise?

Harpreet S. Bajaj, MD, MPH

Disclosures

September 24, 2020

What would you say to a basal insulin that doesn't need to be injected daily but just once a week? We are approaching a new frontier in diabetes management that can be considered one of the greatest leaps in innovation since the discovery of insulin in 1921. A once-weekly "centennial insulin" seems an apt way to mark the 100th anniversary of the life-saving protein.

The 2020 European Association for the Study of Diabetes (EASD) virtual congress presented results from three phase 2 trials on icodec, a novel insulin analog in clinical development that has a half-life of 196 hours.

The pivotal trial of icodec randomized 247 insulin-naive participants with type 2 diabetes to weekly icodec vs daily glargine U100 in a double-blind, double-dummy, treat-to-target study design. Participants who received icodec had a statistically comparable A1c reduction (from a baseline mean of 8.1% to 6.7% at 26 weeks), along with a similar incidence of combined level 2 (clinically significant hypoglycemia defined as < 54 mg/dL) and level 3 (severe) hypoglycemia compared with the glargine U100 arm. Level 1 hypoglycemia (alert level hypoglycemia, between 54 and 70 mg/dL) was slightly higher with icodec.

Results of a second trial with icodec seem to suggest that a less intensive titration algorithm (ie, slower weekly increments titrated to a less stringent target of 80-130 mg/dL) may reduce the risk for hypoglycemia while maintaining adequate glycemic control. In addition, adopting a slightly relaxed titration regimen for these new insulin analogs that have a half-life of more than a week may be necessary in real-life scenarios to reduce the potential for over-insulinization with acute changes in diet (eg, fasting), exercise, illness, or in preparation for surgery.

Transitioning to this weekly insulin from a daily insulin requires a loading dose that is double the first calculated weekly dose, according to results of a third phase 2 trial presented at EASD. The group receiving icodec without a loading dose experienced an initial transient, mild worsening of fasting self-monitored blood glucose values compared with those who received the loading dose or who were on glargine U100. This may relate to the 3-4 weeks required to reach steady state for icodec because of its long half-life.

What Are the Next Steps?

To further bolster its clinical utility, we will need to see at least comparable glycemic efficacy and safety in larger and longer phase 3 trials that include participants with a wide variety of background antihyperglycemic regimens, and compare the novel once-weekly insulin analogs against the currently available "ultra-long-acting" once-daily options.

For people with type 2 diabetes, there is also the exciting possibility of combining a weekly GLP-1 receptor agonist with the weekly insulin in the same injection. This has the potential to further reduce injection burden while improving acceptability, tolerability, and adherence.

For people with type 1 diabetes, latent autoimmune diabetes of adults, or type 2 diabetes who are currently dependent on a basal-bolus insulin regimen, this may reduce injection frequency to once per week (from 28 per week) if an inhaled or oral bolus insulin were to become available for widespread use in the future.

Issues around day-to-day and week-to-week glucose variability with a weekly basal insulin will need to be carefully examined, as these problems are especially relevant to those with insulin sensitivity (eg, the majority of people with type 1 diabetes).

Another once-weekly insulin in development, code-named LY3209590, recently completed at least one phase 1 and phase 2 study, with results expected imminently.

The results we've seen so far from the first phase 2 trials with a once-weekly insulin are encouraging. Let's hope that the remaining phase 2 and 3 studies — planned for both type 1 and type 2 diabetes — continue to live up to that promise.

Harpreet S. Bajaj, MD, MPH, is a community endocrinologist in Brampton, Ontario, Canada, and vice chair of the Diabetes Canada Guidelines. His clinical and research interests are the prevention and management of diabetes and its related complications. He is the founder of STOP Diabetes Foundation and volunteers with numerous community public health organizations to raise awareness of diabetes prevention and treatment.

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