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- [00:04]
A
Welcome to this special edition of Diabetes Core Update where we are going to discuss weekly insulin. Yes, I said weekly insulin. This is exciting. It seems like just yesterday that. Okay, it doesn't seem like yesterday. It was a long time ago. But I still remember the difference it made when long acting Once daily Insulin Glargine was approved in the early 2000s. It was April 2000, and it completely changed the experience of using insulin both for patients and for us as clinicians. It made it easy to titrate, easy to initiate, and simpler for all of us. But science doesn't stand still. Over the last few years, we've seen studies and now the first FDA approval of a weekly insulin. I'm Dr. Neal Skolnick, professor of Family and Community Medicine at the Sidney Kimmel Medical College of Thomas Jefferson University. This special what's Next edition of Diabetes Core Update is sponsored by Lilly. Joining us to discuss weekly insulin is Dr. Athena Phyllis Tamikis. Dr. Tamikis is a board certified endocrinologist and corporate vice president of the Scripps Whitaker Diabetes Institute and Diabetes Care Line at Scripps Health in San Diego, California. She creates programs, conducts research and delivers diabetes services across five Scripps hospitals, 30 outpatient facilities, and the community. She is also director of community Engaged Research for the Scripps Research Translational Institute's national center for For Advancing Translational Sciences. That is a lot. Athena, welcome to our podcast.
- [02:02]
B
Thank you, Neil. Happy to be here.
- [02:05]
A
This is pretty amazing stuff. Before we talk about the weekly insulins, can you help us understand the conceptual benefits of weekly insulin? So daily insulin, we talked about revolutionized insulin management 25 years ago, but there's still gaps in care. Can you help us understand what some of those gaps may be and therefore why weekly insulin may fill some of those gaps?
- [02:32]
B
Yeah, absolutely, Neil. You know, I think I had the same sort of surprised thoughts as you did when I first heard this. And I loved daily insulin when it first came out. And our biggest fear was, oh my God, it's going to cause hypoglycemia. And it didn't. And I think we have the same questions with once weekly. But the gaps that I think about, and probably you do too, when we start patients on insulin, how many times do they maybe miss a dose in a week if they're taking daily insulin? It happens. And if you miss even a couple of daily doses, that's enough for the A1C to start going up. So missed doses is one. Patients have lives that they want to get around to. They might be Traveling, they might be doing other things. And if we can make it easier for them, I think that's all the better. And maybe the last thing is we now have injectables that very commonly are used once a week. Just think about the GLP1s that went from once daily to once a week for people that might need to pair these up, or just the concept of a once weekly injection is there. Being able to do that with insulin would be valuable as well.
- [03:45]
A
Yeah, you know, it's interesting. I never used to think that there'd be an advantage to a weekly until the GLP1s came on. It makes a big difference for patients. Patients. And the difference between the once dailies and the weeklies is a lot. So, having established the potential benefits of weekly insulin, can you explain to us at a high level about the two weekly insulins that have been developed?
- [04:12]
B
I will, sure. There's actually more than two, to tell you the truth, but coming down the pipe, we probably have another 3, 4, 5. But the two that have made it the furthest along and have completed phase 3 clinical trials are Epsilora Alpha from Lilly and Ikodec from Novo. And those very successfully completed their phase three trials. They have slightly different mechanisms of action. The epsiltura acts, it's a very large molecule and it's a little bit slower to attach to the insulin receptor, which allows it to have a longer half life, but once attached, has exactly the same mechanism of action for stimulating that triggering that insulin receptor to work. There's also a little recycling process from the intracellular space back out to the cell surface. And that allows it to continue to work for a longer period of time, about 17, 18 days. So long half life. And you can definitely inject it once weekly. The Ichodec molecule attaches to albumin. And this is the same mechanism we've seen from other daily insulins in the past, very slowly released from the albumin. And that's how it then has its very long mechanism of action. Again, once attaching to that insulin receptor, exactly the same mechanism. So acts exactly as you would expect insulin, but again over a longer period of time, and this time about seven to eight days. So it also allows a once weekly injection.
- [05:51]
A
And that's actually a big deal because if I remember correctly, Glargine, for instance, which we think of as a daily insulin, doesn't always last 24 hours. Is that right?
- [06:05]
B
That's exactly right. And that's a really good way to think about it. And especially in type 2 diabetes, you know, if It's a little bit longer, a little bit shorter. It doesn't make that much of a difference. It really gives you that insulin that you need in the background.
- [06:17]
A
Yeah. And so you have that kind of very steady amount of basal insulin that is there. Now. I don't want to be comparing and contrasting the two weekly insulins, but I want to make sure our listeners are familiar with at least some of the evidence supporting the use of weekly insulin. And when it comes to medicines, the important focus is, you know, two main things is efficacy and safety. So let's look at those two in turn, starting with efficacy. How well do they work?
- [06:51]
B
Yeah, so these were looked at in people that were starting insulin, insulin naive. You know, they've been given all their oral medicines or even the GLP1 injections. They aren't at goal. This is the population that was studied for insulin starts. And first time out, you give them now once weekly insulin compared to several of the daily insulins. Because we have, you know, we have Degludec, we have Glargine, as you mentioned, they could have been on any one of those. In the trials, they were all completed with non inferiority outcomes, equal in efficacy and in some cases even superiority. Overall, though we saw a drop of over 1% in all those trials that was insulin naive. They also examined them in insulin experience. So people that were already taking insulin, already on a basal dose daily, switching them over and then doing that comparison in an rct, once again, non inferiority was proven. It didn't make a difference which one you took. You had equal, lowering and in some cases even slight superiority.
- [08:03]
A
So we can really, those criteria that you had laid out in the beginning that, you know, if someone misses a dose, it's easy, easier to live with. We like the weekly, we can have a lot of certainty that the efficacy is just as good as those typical basal insulins that are given daily that we're used to. Let's now look at the safety side of things.
- [08:27]
B
That's right, you're right. So we're always thinking about the safety and I think that's where you and I probably have the biggest fear. Oh, can you really do this and give it safely? And the answer was, once again, because these were RCTs, they, they had equal levels of hypoglycemia between the two groups and they, they used both finger stick glucoses to look at this. And in several of the studies, continuous glucose monitoring, where really you can look at the overnight period, you can look at the initiation period, all these different periods, and they still had equivalent levels of hypoglycemia between the two. Not only that, the overall amounts of hypoglycemia that occurred were very low, less than 1% in the majority of the studies, which when you think about it, is much below what the American Diabetes association says. For less than severe, the level threes, you want them definitely less than 1%, even level 2 hypoglycemia, less than 4%. And this fell well below that. Maybe just one little caveat. The only time it came, it went above was in the basal bolus group that was taking bolus. And the thought was that in those it was mostly because of the bolus that the hypos were occurring. And again, it was equal in both groups. So it wasn't that the once weekly had any excess hypoglycemia over the daily basals.
- [09:59]
A
Now, something that I've heard when I've casually discussed weekly insulin with some colleagues is people say, okay, that makes sense in a randomized trial. But in real life, when my patients get something like a flu or gastroenteritis, if they're on a basal insulin, that's a daily basal inside, tell them hold it for the day, perhaps take regular. Are people at risk? What are your thoughts about that? And what should our colleagues be thinking and understanding about the safety of weekly insulin in a real world setting where people sometimes get sick and don't eat as much on one day as another day?
- [10:44]
B
Right. I think we need to think about this. Similar with the daily basils, if you are taking too much of a daily basil, that concept that we call over basal, right. And if you enter the hospital and you've had too much, or if you have a day where you're not eating, you may dip down, Right? But if you're on the right amount of basil, even if you have no food for that day, you should stay rock solid. That's exactly what basil is supposed to do. And it works exactly the same way in the once weekly. So the important thing is, look at how you're titrating it up. You don't want to over basalize someone. You don't want to compensate for meals with this. What you want is to ensure that it allows you to stay, stay flat and even and give you just that amount of background insulin that you need.
- [11:32]
A
That makes a lot of sense. So we've talked about efficacy, we've talked about safety. And let me ask you a question about something that I've actually never thought about before. And I'll say I've thought about emotion a lot, but I've never thought about emotion in relationship to dosing. And when I've talked to again to colleagues about dosing here, people get scared, which is an emotion. They get a little anxious because the starting doses are higher than the starting doses that are we're used to when we titrate up a little bit. If you can address titration doses as well, because they're once weekly, you know, the math is there, they're about sevenfold higher than what we're used to. And that feels like a lot of insulin. How do you address this with colleagues when you're teaching them about weekly insulins?
- [12:36]
B
Yeah, you know, that is going to be a little bit of practice and getting used to because you are right. It's not going to feel comfortable, at least to us as physicians maybe who know and are very familiar. But just think about someone starting out insulin for the first time. They're not going to know the difference. So if you start them on 70 or 100 units or something for the first time, they're going to say, okay, that's what I take. We have to do that mental math and understand and remember it's seven times approximately what we used to give as a daily dose and that the studies did show that it was safe and to be careful with the titration, as you say, and the titration. This is a pen, just like we're used to up and down. And you can go up by about 20 units at a time. And when you think about that over one week, that's about two to three units a day or so if you were to go up or down, which is what we had learned how to do with daily. So it will be a little bit of an adjustment and I'm sure that there will be aids to help all of us on that titration as we go up and down. Watching whether you use a continuous glucose monitor or daily finger sticks, watching where those blood glucose, whether it's the fasting number or the overnights, looking at those and ensuring that they stay stable aren't dipping down.
- [13:57]
A
That's the important thing that makes sense. I guess it'll take some getting used to. But we have to realize that when we go up by as you said, that 20 units, it's not 20 units that are suddenly dumping into the bloodstream. There's a fairly flat pharmacokinet of the insulin. And so there would be. Am I correct in understanding there would be kind of a slow increase in the amount of insulin when you go
- [14:26]
B
up on the dose, that is exactly right. And they have done both direct studies as well as modeling looking at that because it does have such a long half life, you double and even triple the doses, results in very little increase over an extended period of time. And they also looked at the hypoglycemia rates, did not result in any difference in hypoglycemia whether you were giving double triple dose of a daily basal versus the weekly basal. So, yes, I think we can feel confident that if we're titrating according to what's recommended, that it's safe.
- [15:08]
A
Yeah. And I've seen those pharmacokinetic curves that we're all used to seeing for regular insulin, the different basal insulins. And when you look at the weekly insulin curve, it is immensely reassuring when new medicines come out. Often we don't start everyone on the new medicine. We pick and choose which patients are, are really good candidates for the new medicine as we get used to and comfortable with using it. Are there any types of patients who you feel would be the, the best type of patient to start using weekly insulin on?
- [15:47]
B
Yeah, that's so funny because I just saw a patient today and she's someone that had been, she's on oral, she's on a little bit of SGLT2 inhibitor, some metformin, she's on a GLP1 once weekly and that A1C is hanging out at 7.5, 7.6. And we talked about it, we said, you know, maybe this would be perfect for someone to start on a once weekly insulin. So I suggested it to her, I said, you know, let's think about it. When, you know, if the time comes, she'll adjust a little bit of her breakfast to see if things can't get a little bit better. You know, we work together with patients. Right. But if the time comes, just think that offering a once weekly injection, something she's already used to, instead of adding a daily injection, I just think it'll make it much easier. As one thought.
- [16:39]
A
Yeah, that makes a lot of sense. And you know, you mentioned the GLP1 and GLP1s are particularly good at taking care of those postprandial blood sugars. And a lot of people do, no matter what, end up needing insulin along the way. And that does seem like an ideal patient to start that on and likely will help a lot bringing that A1C back down to that goal range.
- [17:08]
B
Yeah, Neil, maybe I should just add one more thing because we're all, sometimes we forget this but there's that natural beta cell decline as we age in all of us, whether we end up developing diabetes or not. But a good 20 to 25% of all people with diabetes may end up needing insulin at some point. So we just shouldn't forget that. And instead of delay, delay, delay. If we see that, here's an opportunity to jump on it and try and keep their blood sugars well managed throughout their life.
- [17:42]
A
Now that's such an important point because we've almost become, oh, a little bit insulin phobic again because the GLP1s are so powerful that we forget what you just said, that there's this natural decline in beta function and a lot of people need insulin. And that's an important reminder. We've covered a lot of ground and we're getting close to the end of our podcast. Any additional things that you think are important for our listeners to know?
- [18:16]
B
You know, maybe the only other thing is for people already on insulin, when we do a switch, the studies that we did, we did have to give a loading dose in that first, for that very first dose and then continue on with a regular sort of seven times or approximately seven times dose thereafter. And I think just reminding people it's something to get used to just like that. Oh, do I really want to do the once weekly reminding? If you're going to do the switch, there will be a one time increased dose that could be given. And the whole idea is because of what we talked about earlier, the longer half life, if you want to not have a period of hyperglycemia as you're making, as you're waiting for steady state, you need a little bit of a loading dose. There have been some studies done where they haven't given that and you do get to eventually the right dose, but it just takes a little bit longer so that consideration is in there. But overall, I can tell you the patients we had in our studies really enjoyed being on this. They were all hoping they could stay on it at the end of the study. So they'll be looking forward to being able to being placed on this when these are both available.
- [19:28]
A
I think this is really exciting because it is what patients want. Any final thoughts?
- [19:35]
B
No. Looking forward to innovation. You know, this is, this is what we enjoy in medicine and why research is important. It really gives us new opportunities, gives our patients new opportunities.
- [19:47]
A
Dr. Athena, Phyllis Tamikis, thank you so much for joining us.
- [19:52]
B
Neil, thank you.
- [19:53]
A
And most of all, of course, thanks to our listeners. Thanks for joining us on this special edition of Diabetes Core Update, discussing an exciting advance in the management of diabetes. Weekly insulin. Who'd have thought we would see weekly Insulin? And now we are going to this special edition of Diabetes. Core Update is sponsored by Lilly. We thank you for listening. For the American diabetes association, I'm Dr. Neal Skolnick. Till next time, stay safe and keep learning.
- [20:30]
B
Sam.