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Diabetes Core Update
Special Edition: What's Next—Once-Weekly Insulins—Mechanisms and Practical Considerations
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- [00:04]
A
Welcome to this special edition of Diabetes Core Update where we will discuss weekly insulin. This is an exciting time, just as it was exciting way back in April of 2000 when daily insulin, and that was specifically insulin Glargine, was first approved by the fda. It is now exciting that we will have weekly insulin available. Available back then. Daily insulin revolutionized insulin management and made it easier for clinicians to prescribe and for patients to use insulin. Over the last few years, we've become used to weekly injectable medicines. It's amazing to those of us who've been practicing for a while, and it is true. And we've become used to that through our experience with weekly GLP1 receptor agonists. On March 26th of this year, the first weekly insulin insulin Icodec, was approved by the FDA. And another weekly insulin, insulin FCITURA is currently under review at the fda. Today we're going to discuss the mechanisms of weakly insulin. We're going to discuss practical considerations as well for patient selection, dosing and some challenges that we may face. I'm your host, Dr. Neal Skolnick, professor of Family and Community Medicine and at the Sidney Kimmel Medical College of Thomas Jefferson University. This special series of Diabetes Core Update is sponsored by Novo. Joining us to discuss today's topic is Dr. Aaron King. Dr. King is a family doctor in San Antonio, Texas who specializes in diabetes. He trained with the United States Navy and Family Medicine, followed that by opening an outpatient diabetes practice in San Antonio and for the last 15 years has provided full scope teen and adult medical care while focusing on diabetes and metabolic health, and is currently certified by the American College of Diabetology. Aaron, we've had a chance to work together a number of times. This is the first time we've had a chance to be on a podcast together. And thank you so much for joining us.
- [02:29]
B
Thank you, Neil. Certainly an honor to be on today with you. And I look forward to our discussion.
- [02:35]
A
So, Aaron, before we begin, can you share with our listeners what made you decide to specialize in diabetes?
- [02:43]
B
Yeah, so I had a unique opportunity when leaving the United States Navy in opening an outpatient diabetes center. And that was, you know, the mid-2000s when we really started to see a proliferation of all the different agents that we now use. And really the uptake of things like CGM and other technology was booming at that time as well. And so I just fell in love with the disease state. I fell in love with the ability to use all these tools to really help improve outcomes, save lives, save limbs. And now it's become a passion of mine to make sure that we bring this to the primary care setting.
- [03:19]
A
That's fantastic. And I think that's why a lot of endocrinologists and primary care really enjoy taking care of people with diabetes because there's a of lot, a lot we can do. There's so many new medicines. It's been such an exciting area to be involved in and how you take care of people makes a real difference. So, speaking about new medicines, let's move on now to our topic for today, which is weekly insulin, something that just a few years ago we would not have imagined. There's a lot of excitement around it. Can you share your perspective on the value of that weekly basal insulin brings to patients above and beyond the value brought by daily basal insulin?
- [04:04]
B
Yeah, I think that's a great question. And you know, what I would say is that our paradigm, if you will, has shifted a lot with these longer acting GLP1s in particular. 10 years ago I felt like the idea of daily dosing was very commonplace and we didn't think anything of asking patients to do that. And now that we have these powerful GLP1s that are weekly, I think the expectation really around our patients and our providers has changed. And I think it's really fortuitous that these insulins are coming out to mimic the paradigm that the GLP1 shifts have done.
- [04:37]
A
Yeah, you know, it's almost like in sports that once you hit a five minute mile, you aim for four, when you hit a four, et cetera, that, that there's this saying, a phrase in a poem, Tennyson's Ulysses, that all experiences an arch where through gleams that untraveled world whose margins fade forever and ever as move. And once we accomplished one thing, we set our sights on the next and we're no longer satisfied with where we have been. And that's how it should be. Aaron, can you describe for us the mechanisms of the weekly insulins and how the formulation of the compounds allow for basal coverage with once weekly injections?
- [05:26]
B
Well, yes, to your point exactly. I think, you know, our pharmaceutical partners have done an amazing job of continuing to move forward these expectations. So really we have these two different molecules we're going to mainly focus on today. Ikodec and Esatora. So and those mechanisms are a little bit unique to each other. So with the Ikodec molecule, this is a concept that I think many of our listeners will be familiar with. There's been basically the addition to the insulin molecule and of a long 20 carbon fatty acid moiety. And that moiety allows that molecule to bind to albumin, which kind of hides it from degradation and extends the half life. This concept is not new. We've used it in basal insulins like Dedemir and also in Degladec. And then we've also used this same concept with GLP1 therapies like liraglutide or semaglutide. And so in the same way, we've had some modifications here to extend this half life out to around, you know, seven days or so, seven to eight days. And that concept works really well with this ikodec molecule. Now, efsatura is different and a little bit unique. So a pathway maybe some of our listeners are not familiar with is around the preservation of immunoglobulins. So if you haven't thought about it, you know, immunoglobulins circulate in the body and they're not readily degraded rapidly by our different cellular mechanisms. And so what we do here is we take an insulin molecule and attach it to an IGG2FC portion. And what that does is it kind of hides the insulin molecule from degradation. And so this molecule can now be taken up into the cell, it can hide from degradation and reach basically a long steady state where it's recirculated back into the serum where it can take its effects at the insulin receptor. And, and so this relatively complicated and novel mechanism allows for an extremely long half life of about 14 to 17 days. And so each of these two different molecules achieves this very nice steady state in two different ways.
- [07:32]
A
So that's fascinating. They have a little bit different half lives. Can you talk about time to steady state with each of them? Because that's important for us to understand clinically because that it takes till then to have the essentially maximum effect.
- [07:48]
B
Yes, that's right. And so as many of us remember, you know, it usually takes about four to five half lives to reach steady state for any molecule. And so with the numbers I'd mentioned, roughly seven days, let's call it for I could act, you're looking at about one month, about four weeks to reach steady state. And then with Esatora, because we're more at about the 14 to 17 day mark, you're looking at about two months, roughly or eight weeks for steady state with that molecule.
- [08:16]
A
That's helpful. So let's now go to our clinical trial data and if you can give us an overview of efficacy as well as safety with the weekly insulins.
- [08:27]
B
Yeah. So again with Icodec. First there's a series of trials known as the onwards trials in which they looked at both type 1 and type 2 patients. And in those trials they began with both insulin naive patients and then also patients that were on existing basal insulin and switching them over. And then we compared that to a basal insulin, typically glargine or sometimes Deglodec. And so what we generally see in the trials in summation was that there was equivalent or non inferiority with the new molecule with Echodec. And really we had very low rates of hypoglycemia as well. So basically we achieved a similar effect but got the convenience of the once weekly dosing when it comes to efsatora. Again, very similar story here. We had a similar series of trials called the Quint trials and those again compare type 1 and type 2 insulin naive and folks that were already on basal insulin, again with similar comparators. And we again saw non inferiority with efficacy and in some cases some improvements in hypoglycemia, particularly at night, but overall generally very well tolerated. And so we achieved, I think, the outcomes in these trials that we were hoping for.
- [09:44]
A
And that's so important to see. And that of course those are the things that the FDA looks at for registration. We'll talk about in a little while, hypoglycemia, because that's an area of course of a lot of interest. And I think that in primary care and general endocrinology, when we think about the weekly insulins, that's the thing that we want to make sure our patients are good with out there. And it's incredibly reassuring to see the low incidence in the trials. So one of the challenges with weekly insulins are going to be getting used to how they differ in dosing from what we're used to with daily insulin. Can you give us a sense of the initial dosing of the two weekly insulins? One, of course is going to be dosing that's in the product label FDA approved. The other dosing from the phase three trials because it's not at this point FDA approved.
- [10:47]
B
So when we look at the two different insulins, the dosing initiation and titrations are slightly different. So with ICADEC we typically start with what is equivalent to 10 units per day, as is going to be familiar with most of our providers, but we do that over seven days. So that's a 70 unit dose. So you start at 70 units and then you can up titrate based on fasting glucoses as early as every once a week. And we do want to make sure we wait that full week because of that long half life. That way we don't stack too much insulin on top of itself. And over titrate. Now with Fctora, which is still pending FDA review, the Quint1 study had a unique approach where they used fixed dosing. And so they started out with a hundred units per week and then after four weeks went up to 150, followed by four weeks later at 250 and then as needed up to 400. And so that trial was a little bit different with those fixed dosing combinations.
- [11:49]
A
So that's really helpful for us to understand because in both cases, one of the challenges I suspect in this large world out there of clinicians who take a while to get used to things is going to be seeing these large doses of insulin and initially perhaps being afraid. And it's really important for people to understand what you said, Aaron, which is we're used to starting with 10 units a day. This really isn't different than that because it's a long half life being given once a week. So that when we hear that large dose just in our minds to translate it to what would that look like daily? Now what are the how about for people transitioning who are currently on daily basal insulin?
- [12:48]
B
Right. So we're going to kind of think about this the same way and do it almost in reverse. So if somebody is on a fixed dose of a daily dose, we're going to multiply that dose by seven and that's going to be our maintenance dose. But then what we do need to do is we do need to give a one time initiating bolus and that is at 50% higher. So simply put, you would multiply the maintenance dose by 1.5 and that's so that we can give a larger bolus up front because remember, it's going to take some time for this molecule to work and that's going to need to kind of replace the lack of, of the daily basal. So the day after the daily basal is stopped, you would do 1.5 times the maintenance dose and then after that weekly, you would go back to your maintenance doses of seven times the original daily basal dose.
- [13:42]
A
And that's so helpful. And I'm just going to say the units out loud because I do want people to understand what we're talking about. So if someone is on, for instance, 30 units of basal insulin daily, when we transition to weekly, that would be 30 times 7 is 210 plus 50% of that approximately brings us to 300 units on their first weekly shot, is that correct?
- [14:12]
B
That's right. So 300 on that first shot and then going back to 210 weekly. And to your point, Neil, that's exactly what we need to get comfortable with. I think we need to trust the data in these trials and these low hypoglycemia rates that were done this way. And then as our experience teaches us, I think we'll begin to get more comfortable with these larger numbers.
- [14:33]
A
I do think so. And I think we have to remind ourselves, as you said, one, the studies were rock solid low, low rates of hypos, and two, the benefit that this brings to patients. Can you talk about over basalization and how that fits into things?
- [14:51]
B
That's a really important point. You know, I think it took us a while to get comfortable titrating basal insul and I think at times we can get too aggressive with that. And you know, there are several studies validating that usually you do not need more than about 0.5 units per kilo per day of basal insulin. And if you get above that, you're probably really treating the wrong problem. You're not controlling the postprandial hyperglycemia and you're driving down the fastings potentially dangerous. So I think when we're doing these switches from existing patients to weekly basal, we do need to be careful and make sure that the patient isn't over basal when doing that conversion. And my suggestion might be that if you feel the patient is getting too much basal, you back that down in the calculation to somewhere around that 0.5 units per kilo per day or less.
- [15:45]
A
That's really important. Let me ask you now some practical questions. It's clear in the studies the incidence of hypos is low. How do you manage sick day management? We see people who might have a gastroenteritis or really decrease their food intake for any reason. Perhaps there's six day management, there's people in the hospital, there's someone going for a procedure. How do you handle that?
- [16:13]
B
Yeah, well, I think that's a really important question. And to be honest, it's one that hasn't been fully flushed out in the literature yet. And so to some degree I think we're going to have to rely on our clinical experience here. It does remind me a little bit of when the weekly GLP1s were first developed. There was concern that they would have long term nausea and other GI related side effects because of the long half life. And we didn't really see that clinically for the most part. And so I think here again, we have to trust that those kinds of things probably did happen in some of these trials. And yet we still see the hypoglycemia rates are fairly low. So my general advice would just be that at this point we don't have official guidance from the companies and so we would want to support that glucose with rapid acting glucose if possible, if needed, if they were to develop symptoms of hypoglycemia during any of those events you mentioned.
- [17:06]
A
Yeah, that's a good point. That safety net of just making sure you're checking your sugars more often is never a bad approach. Any advice on missed doses?
- [17:17]
B
Yeah, so with the missed doses, the general advice is if you can do your dose within four days, go ahead and do that. That. But then when you resume dosing, resume it at a weekly time frame. So in other words, you would just add seven days from the day that you restarted that dose. Now if you go beyond four days from your missed dose, just go ahead and wait until the next scheduled dose and then you can keep that as well.
- [17:43]
A
That makes sense. Let's think for a couple of minutes, Aaron, about patient selection. So as this is now new, are there any patients who you think really fit best early on for use with weekly insulin?
- [18:02]
B
Yeah, so we mentioned earlier, you know how to switch patients over how to do the calculation and to be careful not to over basalize these patients. So I think for practitioners getting comfortable, it makes a lot of sense to me that if you have a patient on non insulin therapy and they're new to insulin, that may be one of the simplest ways to start off a patient. And that way we can start at a low number number and move cautiously and make sure that everyone is comfortable with that. So in particular those patients on weekly GLP1 therapy, this seems to be a good fit for somebody maybe who needs further control and needs to progress to weekly insulin.
- [18:43]
A
Couldn't agree with you more. Which brings us to GLP1. A lot of our patients with type 2 diabetes are on GLP1s, both for management of their blood sugar as well as management of for weight. It started very early. Now, in our algorithm, for many people, how does weekly insulin work along with or in addition to GLP1s when someone still has those elevated blood Sugars on their GLP1?
- [19:13]
B
Yeah. As amazing as the GLP1s have been for the treatment of diabetes in the last several years, we know that sometimes it's not enough. And I think the weekly basal insulins fit in really nicely after those medications with other non insulin therapies maybe have not gotten the patient to goal. Another thing to remember too is that, remember our GLP1s work through increasing beta cells production of insulin and decreasing the production of glucagon from the alpha cell. And both of those very nicely target the postprandial state. Remember that basal insulin mainly works in the fasting state, and so this also makes it a nice complementary piece to what the GLP1 is already doing.
- [19:56]
A
That makes a lot of sense. Let me toss a case to you to bring together some of what we've been talking about. So let's say I have a patient who's 57 years old, 12 year history of type 2 diabetes, well controlled hypertension, hyperlipidemia, has obesity with a BMI of 32. He's been on semaglutide 2 milligrams weekly for his diabetes, as well as metformin a thousand twice a day, DAPA, 10 milligrams daily. And his A1Cs for the last few years have been between 6.4 and 6.8. But over the last six months he's now had two readings. The first was an A1C of 7.2, the next one 7.8. Is this someone you would consider starting insulin for at this point? And how would you decide between daily versus weekly?
- [20:55]
B
Yeah, I think this is a perfect scenario that we were talking about and one that we see often in clinic. And it definitely would be somebody that would need to move on to basal insulin. Now one thing to keep in mind is that we might want to try to assess where the control problems are coming from. And I think something like CGM here might be very helpful to make sure that the fasting glucose is the problem and not necessarily just hyperglycemia after meals, because we might treat that postparandal hyperglycemia with a different agent or maybe some mealtime insulin. But with that being said, I think that this kind of patient is who we're thinking about for these weekly basal insulins. And I think we have to remember too that I think the goal here is to increase the adherence over time. If we can introduce them weekly.
- [21:43]
A
Yeah, you know, it's interesting. I think adherence over time clearly a big issue and also therapeutic inertia. If I remember correctly, this is already going back a few years ago, but there was a wonderful study looking at how long does it take to add insulin after someone is already on two oral agents and their blood sugars are not controlled. And that Trial again a little while ago showed that it took up to seven years till insulin was started, regardless of the specific amount of time. And there certainly is this gap between when someone's a 1C rises above goal and when we decide to do that next intervention, often insulin. And do you think that because weekly insulins are more patient friendly, that may help address this issue?
- [22:43]
B
Yeah, I really do. And I think to the number you just mentioned, it makes me wonder, if we did that trial again today, would it be even longer? Because I find, at least clinically, that a lot of patients will push back if I suggest that they go to a daily injectable after they've already been used to weekly injectables of GLP1 type therapy. So, yes, I think this is a good paradigm here. And I would remind everyone too, that our current thought process is that we typically want to maximize those incretin therapies and non insulin therapies and minimize the amount of insulin that we have to administer. And I think that these weekly being separate from the GLP1s, allow for us to just titrate in the amount of insulin that we might want to use most effectively.
- [23:30]
A
Really good points, Aaron. We're about out of time. Do you have any final thoughts for our listeners?
- [23:37]
B
Well, I think most importantly, this is an amazing time to treat patients with diabetes. We have so many tools in our toolbox and I want to applaud everyone for listening and staying on the forefront of diabetes and diabetes technology. It's very hard, especially in the primary care realm, I think, to keep track of everything. And so, as you always say, Neil, you know, keep learning. And I think our patients benefit from that.
- [24:02]
A
I think you're right. I think we live in this amazing time with all these new developments. But who is it? It is the best of times, it is the worst of times, right, that there are all these challenges. And it is the best of times for patients with medicines that make it easier to obtain excellent control of blood sugar, of weight. But maybe the worst of times, I don't know, in that it is really hard to keep up with these changes. It takes a lot of work. And fortunately, there are people like you that help us learn about this and their technologies like podcasts that make it easy for people to tune in and learn. Dr. Aaron King, thank you so much for joining us.
- [24:52]
B
Thank you, Neil. Have a great day.
- [24:54]
A
And most of all, of course, as always, thank you to our listeners for joining us on this special edition of Diabetes Core Update discussing practical considerations about weekly insulin. This special edition of Diabetes Core Update is sponsored by Novo. We thank you for listening. For the American American diabetes association, I'm Dr. Neal Skolnick. Till next time, stay safe and keep learning.