Transforming therapy with weekly insulins
Two weekly insulins are well into clinical development, with trials showing promising results so far. An expert panel at the American Diabetes Association’s 83rd Scientific Sessions discussed how these new medications might ease the diabetes burden, particularly for those with type 2 diabetes. Dr Susan Aldridge reports.
The prospect of a daily insulin injection may delay intensification of treatment in type 2 diabetes, as well as adding to diabetes burden. Weekly insulin may alleviate these issues, so promising results from trials with insulin icodec and insulin efsitora have generated excitement in the diabetes community. “Weekly insulin has been shown to improve health-related quality of life,” said Dr Juan Frias, Managing Director of Velocity Clinical Research. “It has the potential to improve persistence and adherence, and hopefully this will translate into improved short- and long-term outcomes.”
The pharmacokinetic profile of a weekly insulin is flat, meaning fewer hypos, and it can also be co-formulated with a GLP-1 receptor agonist, which has a complementary mode of action. The development of weekly insulins relies on extending the half-life of the insulin molecule which, as a peptide, has a short half-life, requiring continuous infusion or frequent injection. Drug delivery systems can overcome this by creating lipid particle or polymeric systems containing insulin, which allow for slower absorption from subcutaneous tissues.
Efsitora is a fusion protein with two single chain insulin molecules and the Fc region of an immunoglobulin G molecule, with a molecular weight of 50 kilodaltons. Meanwhile, icodec (the other weekly insulin in clinical development) is strongly – but reversibly – bound to albumin, creating a subcutaneous insulin reservoir. Efsitora has been developed by Eli Lilly and is in Phase 3 clinical trials with the QWINT programme, while Novo Nordisk’s icodec is in Phase 3 trials with the ONWARD programme.
“Efsitora has a half-life of 17 days because of its slow absorption from the subcutaneous space,” explained Dr Frias. “It also has reduced insulin receptor affinity and reduced renal clearance – this leads to a recycling effect, which is important in the prolongation of its action. It achieves a dose-dependent decrease in fasting blood glucose with a nadir between days four and six in type 2 diabetes.”
Meanwhile, icodec has three amino-acid substitutions in its insulin chain, which reduces enzymatic degradation. It also has lower insulin receptor-binding affinity, which slows insulin receptor-mediated clearance, as well as improved solubility, allowing for a U700 formulation, which is good for weekly administration.
In summary, molecular modifications and methodologies confer biological properties, including those relating to pharmacokinetics and pharmacodynamics, on these weekly insulins making them suitable for once-weekly dosing.
Clinical trials update
Ildiko Lingvay, Professor of Medicine at the University of Texas Southwestern Medical Center, reviewed the clinical trials on the two weekly insulins. There have been three Phase 2 trials in the QWINT programme, all involving people with type 2 diabetes, who were either insulin naïve or switching from another basal insulin, with efsitora against glargine as comparator.
There has also been a trial involving people with type 1 diabetes on multiple daily injections (MDI). Meanwhile, the ONWARDS Phase 3 programme with icodec has also involved people with type 2 diabetes, except for ONWARDS 6, which includes those with type 1 diabetes, and has similarly looked at those who are insulin naïve and switching from another basal insulin against insulin glargine or insulin degludec. Professor Lingvay went on to review the data so far via a series of questions.
First and foremost, do the weekly insulins lower glucose as you would expect for a basal insulin? “In each of the Phase 2 trials, HbA1c lowering matches – or is even lower than – that of the comparator, and there is the same finding for the Phase 3 programme where we have results,” said Professor Lingvay. “So, yes, absolutely they do.” What about hypos? “Looking at insulin-naïve patients with level 2 or 3 hypos, there were very few, but there is a more mixed picture for insulin-experienced patients making the switch, with a very small absolute increase,” she said. In addition, there was no difference in duration of a hypo between the weekly insulins and their comparators.
For Time in Range and Time below Range, there was very little difference between the weekly insulin and comparator, save for a statistically significant difference in favour of icodec in the ONWARDS 1 trial where Time in Range was better, Time above Range less and Time below Range about the same.
Since the insulin dose in a weekly insulin is so large, there have naturally been concerns over the impact of accidentally taking an extra dose. There has been a separate study on this, which shows that comparable numbers got clinical hypoglycaemia with an extra dose between the weekly insulin and insulin glargine. “So you might get a low, but it’s not going to be any worse than taking an extra dose of a daily insulin,” said Professor Lingvay. There is also no difference in response whether you inject the insulin in the thigh, abdomen or upper arm. Finally, Professor Lingvay’s analysis of 11 studies shows that people do gain weight when they start the insulin, but this is related more to HbA1c levels than the type of insulin.
She also referred to the IcoSema Phase 3 trial programme, with a combination of icodec and semaglutide, and hopes results will be ready for next year’s ADA meeting.
“From my patients’ point of view, the biggest benefit is only having to take one shot of insulin instead of seven in the week,” Professor Lingvay concluded. “Everything else is similar. The weekly insulins are expected to reduce barriers to treatment, reduce treatment burden and improve quality of life. All of these are important features for our patients.”
Patient and provider perspectives
Chantal Mathieu, Professor of Medicine at KU Leuven, Belgium, and President of the EASD, began by sharing some statements from participants in the weekly insulin trials, such as, “Why are you even asking me whether I would prefer to administer one injection a day or one a week?”.
“One participant in the ONWARD 4 study, who had been on MDI for five years said, at the end of the trial, ‘You need to keep giving me the weekly insulin,’” said Professor Mathieu. “I replied, ‘But what is the difference because you need your daily mealtime insulin anyway’. Her response was, ‘Every injection I can avoid is a plus. What a relief it was that I did not have to give my basal insulin every day during the trial’. I was even more surprised that this participant was so angry with me that I couldn’t keep giving her the weekly insulin. So I saw great enthusiasm for weekly insulins among patients.”
Views among providers were different, though. Endocrinologists feared major stacking of insulin with weekly injections and thus prolonged hypoglycaemia, which would be impossible to manage. Diabetes educators said that with so much insulin on board, people will gain a lot of weight. Primary care providers, on the other hand, were more positive saying: “Oh, this is nice. So we can now give insulin in the same way as we give GLP-1 receptor agonists”.
“There are some diverse opinions out there,” said Professor Mathieu, “but Ildiko showed the benefits of weekly insulins very nicely in her talk – convenience, improved health-related quality of life and a less overwhelming sense of treatment burden.”
Who should get weekly insulin?
Professor Mathieu turned to an issue that will be of major concern to providers. Which patients do we want to use weekly insulins? “Hypoglycaemia was my biggest fear,” she admitted. “But the clinical data show only a slight increase and this was the biggest surprise. And it was mainly induced by mealtime insulin rather than basal. I do think the jury is still out on the place of weekly insulins in those with type 1 diabetes, but I would give money to have a once-weekly insulin in some of my adolescent patients. However, we will use personalised medicine and decide who with type 1 diabetes can benefit because, in the trials, there was an increase in hypos in those who started with a very nice HbA1c.”
Turning to efsitora, this increase in hypos in participants with type 1 diabetes wasn’t seen as in ONWARDS 6 with icodec, but Time in Range was only in the 50% range, which is a concern. “So when considering a weekly insulin in type 1 diabetes, I think it depends upon baseline HbA1c,” said Professor Mathieu.
Clinicians will also want advice on initiating a weekly insulin. From the Phase 3 trials on icodec, Professor Mathieu would advise that you do as you would when initiating an insulin-naïve individual on glargine and so a one-time 50% loading dose, then titrate 20U up or down depending on glucose measurements. With efsitora, which is earlier in clinical development, initiating is more of an exploratory process where starting doses are still being evaluated and it is hoped there will be firmer guidance by next year.
What about people on MDI? The ONWARDS 4 trial showed some very interesting data. If you have a weekly insulin on board, you need less mealtime insulin. “This was quite spectacular,” said ProfessorMathieu. “There was almost no titration needed of the mealtime insulin. As clinicians we will have to take this on and bring the mealtime insulin down. It opens up new perspectives for us. Perhaps with once-weekly insulins, we will have fewer people needing MDI. Maybe, if we combine it with a GLP-1 receptor agonist, we can get rid of mealtime insulin, making the burden of insulin treatment in type 2 diabetes a lot less.”
So, in summary, weekly insulins will first and foremost be for people with type 2 diabetes in need of a basal insulin and for some with type 1 diabetes as well. We know that people like weekly insulins as the ONWARDS trials have Patient Reported Outcomes that mention treatment satisfaction, convenience and flexibility. Of course, questions remain and some of the knowledge gaps are about the impact of exercise, intercurrent illness, fasting and hospitalisation. We also need more information about weekly insulins in pregnancy, the elderly and in children. “So we will need communication and education, in particular for primary care, nurses, diabetes educators, dietitians, surgeons, internists, paediatricians and patients,” concluded Professor Mathieu.
Future outlook for weekly insulins
Dr Ronald Goldenberg of LMC Diabetes & Endocrinology, Toronto, said,“There have been incredible innovations in the half-life of insulins and we’ll probably be able to prescribe icodec sometime in 2024 and efsitora in 2025.” This is because the efficacy and safety data in type 2 diabetes is very encouraging, as is that on therapeutic inertia, adherence and treatment satisfaction. “In fact, efficacy and safety in the ONWARDS trials show superiority for the weekly insulin over the daily comparator.” he said. “So if you have a choice for insulin-naïve patients, I think clinicians will favour the once-weekly. In the type 2 diabetes space, there is good efficacy and safety. The data on efsitora is encouraging too, but we need to wait for the Phase 3 trial results.”
The ability to prescribe a once-weekly basal insulin really helps in type 2 diabetes. “We know that initiation of insulin is often delayed and 30% of patients decline it, then 38% of the decliners eventually start on insulin, with mean time to initiation of more than two years,” said Dr Goldenberg. Even then, uptitration is slow and insufficient in the six months after initiation. In the trials, the insulin-naïve patients had diabetes duration of 10 to 12 years. The availability of weekly insulin will allow earlier initiation and titration.
However, Dr Goldenberg sounded some cautions. “There will need to be some education around the fear of high doses. There is also some complexity around different regimes for insulin-naïve patients and those who are switching from another insulin when it comes to initiation and titration, but this can be addressed with apps and smart pens.”
Then there is the issue of cost and access. “Banting would roll over in his grave if he saw what was happening with the cost of insulin in recent years,” said Dr Goldenberg. “Things are getting better in the US, with various programmes to reduce the cost, but the big question is will weekly insulins be accessible and affordable?”.
And then there is type 1 diabetes, where the go-ahead for weekly insulins is currently at a red light. “We need more information before we can go forward with this,” he said. “We need a deeper dive into the hypos seen in the ONWARDS 6 trial. Who were the patients most affected, what were their characteristics and so on?”.
So, in conclusion, Dr Goldenberg agreed with Professor Mathieu that initiating weekly insulins in type 2 diabetes is a ‘no brainer’ and he thinks that for some patients in the future, the combination of a weekly basal insulin and a GLP-1 receptor agonist could well be the way forward.
To learn more, enrol on the EASD e-Learning course ‘Management of hyperglycaemia in type 2 diabetes’.
Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.
