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Weekly insulins on trial

26th April 2023

Many people with diabetes would like to reduce the number of insulin injections they need, which is why the development of weekly insulins has been watched with great interest. Findings from recent clinical trials and the opportunities and challenges presented by weekly insulins were discussed at the recent Advanced Technologies & Treatments for Diabetes (ATTD) conference. Dr Susan Aldridge reports. 

Much of the clinical development work with weekly basal insulin has been done with efsitora (formerly known as BIF), which is an insulin receptor agonist combining a single chain variant of insulin with a human immunoglobulin G2 Fc domain. Its half-life is 17 days because the sheer size of the molecule allows for slow absorption from the subcutaneous space after injection, which makes it suitable for weekly use. 

Efsitora (owned by Lilly) also has a very stable pharmacokinetic profile in the week after dosing, with a low peak-to-trough ratio, so giving a sustained dose-dependent, glucose-lowering effect with a nadir at four to six days in type 2 diabetes.

Steve Edelman, Professor Emeritus at the University of California, San Diego, is founder and director of Taking Control of your Diabetes and has been living with type 1 diabetes since the age of 15. “We have seen incredible advances in type 1 diabetes,” he said, citing rapid-acting insulins, four different continuous glucose monitor (CGM) models, four different hybrid closed loop systems, smart pens and now an FDA-approved agent (teplizumab) to delay the onset of type 1 diabetes in those at risk. “But there are still unmet needs, as I see it, such as unpredictable glucose swings, not enough time in range[TIR], reaching your goals without hypos, preventing and controlling weight gain and reducing risk factors for heart disease. And the last thing, which really relates to weekly basal control, is to reduce the emotional and treatment burden of type 1 diabetes.”

He went on to describe a phase 2 study of efsitora versus insulin degludec in type 1 diabetes where the primary outcome was reduction in HbA1c and secondary outcomes were fasting plasma glucose, hypoglycaemia and adverse effects. The outcomes in this trial were similar to those found in other studies, with efsitora demonstrating non-inferiority. “This was the first large phase 2 trial of a once-weekly basal insulin and the findings support continued development into phase 3,” said Professor Edelman. 

Meanwhile, Novo Nordisk’s phase 3a ONWARD 6 trial of its weekly insulin icodec in type 1 diabetes versus insulin degludec also met the primary outcome of non-inferiority. ONWARD is a set of six phase 3 trials in people with type 1 and type 2 diabetes, which has begun to report its findings.  

Opportunities and challenges

“Weekly insulin seems safe and effective compared with daily basal insulins in the clinical trial setting,” said Professor Edelman. “It is more convenient and reduces the burden of self-management by reducing seven daily injections to an injection once a week, which may improve adherence.”  

Easing the diabetes burden will improve quality of life. And weekly insulins may be an easier option for those who require assistance with their self-care. They may also be a useful alternative for those people with type 1 diabetes who cannot manage, or haven’t got access to, a hybrid closed loop system. 

However, there are also challenges around introducing weekly insulins. Healthcare professionals and people with diabetes will have to learn about dose equivalents when switching from a daily to weekly basal insulin. Treatment protocols around initiation and titration will have to be developed and care must be taken to monitor and account for any weekly changes in peaks and troughs that may affect glucose management. 

And then there will be the issue of cost, access and acceptance by payers. “Education will be key,” said Professor Edelman. “We’re going to have to educate everybody – people with diabetes, healthcare professionals and payers. But, in the end, I can add this to the list of incredible advances in type 1 diabetes – once-weekly basal insulin for those who want it.”  

Weekly insulin for type 2 diabetes

People with type 2 diabetes are often reluctant to start on insulin when intensification of therapy is recommended and it’s usually because they don’t want to do the daily injections. A weekly insulin may therefore be more acceptable, so it was encouraging to hear some positive findings for efsitora in type 2 diabetes from Dr Juan Frias, Medical Director and Principal Investigator at Velocity Clinical Research, Los Angeles. He has been involved in efsitora research for the past five years and focused here on two completed phase 2 studies comparing efsitora with insulin degludec in type 2 diabetes. 

In the first study, participants had previously been treated with basal insulin. In the trial, they were treated with two different efsitora dosing regimens and different target glucose levels – 7.8 mmol/l and 6.7 mmol/l, with 5.6 mmol/l being the target in the insulin degludec control group. 

This was a 32-week study and all participants showed significant reduction in HbA1c and fasting glucose by the end and efsitora was, accordingly, declared non-inferior to insulin degludec. All participants wore unblinded CGM, which revealed no significant differences between TIR, time below range and time above range. “There was also significantly lower glucose variability during the day and night with efsitora compared with insulin degludec, which may be a function of the very flat profile of efsitora seen during the week,” said Dr Frias. “There was also less hypoglycaemia, especially at night.” 

In the second trial, the participants were insulin-naïve and on metformin, and some were also on a DPP-4 inhibitor. All had the same target glucose and wore a blinded Libre CGM. Both efsitora and insulin degludec groups showed a significant improvement by the end of the trial, and efsitora was again declared non-inferior to insulin degludec. 

Similar proportions of participants reached an HbA1c of less than 7% (53 mmol/mol) – 62.3% versus 68.6% – and decreases in fasting glucose were also similar. At week 26, both had a similar TIR of more than 75% with low incidence of participant-reported hypoglycaemia and no severe hypos or severe adverse events.

Meanwhile, the efsitora phase 3 programme is known as QWINT and consists of five programmes across a range of diabetes populations and background treatments – it’s expected to report later this year. “I think weekly insulin could be the way of the future for type 2 diabetes,” concluded Dr Frias. “There will need to be a lot of education, though. There are some concerns, unfounded I believe, about these large doses of insulin, but I think this will be a very important therapy for our patients with type 2 diabetes.” 

To learn more about insulin, explore our film series Insulin@100:

Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.