Type 2 Diabetes Podcast

Future Type 2 Diabetes Drugs: Exciting and a Little Scary

Silvio Inzucchi, MD; Joshua Neumiller, PharmD


July 12, 2022

This transcript has been edited for clarity.

Silvio Inzucchi, MD: Welcome to Medscape InDiscussion. I'm Dr Silvio Inzucchi. This is episode number 6, and we've saved the best for last. We'll be talking about newer therapies for type 2 diabetes. Earlier episodes covered treatment guidelines, effects on cardiovascular and renal outcomes with diabetes medications, obesity, and culturally competent care for minority populations. Today we're shifting the lens to look at promising future treatments. With me today to talk about this interesting topic is Dr Joshua Neumiller. He is vice chair and professor of pharmacotherapy at the College of Pharmacy and Pharmaceutical Sciences at the Washington State University in Spokane, Washington. Josh is past chief editor of the ADA's Diabetes Spectrum journal, as well as past chair of the ADA's Professional Practice Committee, which is the committee that updates the American Diabetes Association's Standards of Medical Care in Diabetes each year. Josh is a clinical pharmacist and diabetes educator and works clinically in the home health setting. Welcome, Josh.

Joshua Neumiller, PharmD: Thanks for having me, Silvio. It's a real pleasure.

Inzucchi: I'm really looking forward to our discussion. The topic today is newer type 2 diabetes treatments. Not that we need any newer treatments. I mean, last time I looked, there were 12 individual drug classes to manage type 2 diabetes. When I started out, Josh, we had two. We had sulfonylureas and insulin, and metformin was just getting on the market. And the progress in this space has been dizzying over the past couple of decades. But here we are, and I don't think there is any less interest in developing newer and better therapies to pharmacologically manage diabetes. Before we begin our discussion, can you tell our audience how you became interested in diabetes and what you find most interesting about the pharmacology of diabetes?

Neumiller: When I graduated pharmacy school, I actually thought I wanted to be a basic scientist, and I was on a path of trying to become an immunologist and work in drug development. And about a year into my postgraduate, post-PharmD training, I fell ill and was diagnosed with type 1 diabetes, and it shifted my perspective going through that experience and realizing how overwhelming that was. Even as a trained healthcare professional, it really opened my eyes to the need for diabetes education and educating people about how best to manage their condition. So it's been quite the opportunity. It's really been amazing how many new agents are coming out all the time and all the new data. Certainly the topics we're going to be discussing today are quite exciting as a pharmacist just because of the unique pharmacology of these medications. Another area that's really fascinating is something you've talked about in previous sessions, and that's the shift from glucose-centric management to complications management.

Inzucchi: It's a radical shift in how we've approached this condition. Well, let's start. I want to talk about insulins, two ends of the spectrum: ultra rapid and ultra slow. They're newer formulations of insulin, the first having a very rapid onset of action targeted at mealtime control of hyperglycemia, and the second being a new weekly — yes, weekly — insulin that's called icodec. And then we'll finish up with the so-called twincretin, which is a compound called tirzepatide. There are some new and very interesting data from that perspective as well.

Inzucchi: Let's start with the ultra-rapid insulins. Can you speak to the need for this? I thought we had this down pat; insulin lispro, insulin aspart, which have been out for more than a decade now, were fast enough. Is there a need for even faster-acting insulins?

Neumiller: I guess we're always striving for matching normal physiology the best we can, and that's where these insulins come in. They've taken rapid-acting insulins and made some changes to the formulation to try to further speed up their absorption. And I think there may be some individuals who gain advantages, but I tend to agree with you, Silvio, that far and away, most individuals with type 2 diabetes may not receive a ton of added benefit from some of these ultra-rapid agents, but there may be some people who could benefit.

Inzucchi: I think the time course of action is maybe 5 or 10 minutes earlier. And so in a physiologic study, if you're using clamps on study participants, you can discern a quicker effect, but in the clinics and in real-world practice, it's not clear to me if that earlier time course of action is going to translate to anything significant. Certainly in the studies there does not seem to be any beneficial effect on Hgb A1c.

Neumiller: In those trials, in both type 1 and type 2 diabetes with both of the ultra-rapid insulins, there was really no difference observed in A1c. Maybe where there is some potential advantage is when they had different dosing strategies — where they compared it with the original rapid-acting insulin, whether insulin aspart or insulin lispro, where they dosed both products at the beginning of the meal and then had another arm where they allowed people to dose within 20 minutes after they started eating. I work a lot with older adults who maybe sit down to eat a plate of food, and if they are on rapid-acting insulins and they're dosing before a meal, sometimes their nutritional intake might be less predictable. And for those individuals, those are the few cases where I might recommend some of these agents where they can dose at post-meal.

These so-called closed-loop systems, for our listeners who don't recognize that terminology, are insulin pumps that have been out for decades now; they're married to glucose sensors, which have been out for probably about 10 years now or maybe more. The sensor is feeding glucose data to the pump and the pump is determining the actual basal rate to provide to the patient. They tell me that the quicker the insulin action in those closed-loop systems, the more physiologic the system works. In other words, the better the control might be. Because obviously you're dealing with two devices and getting the pump to provide insulin rapidly in response to the glycemic excursions as determined by the sensor. To me that makes sense that you want as rapid an insulin as possible. It would mean less in terms of the typical number of injections that many of our patients are still using. Would you agree that that may be the niche, shall we say, for these types of insulins?

Neumiller: I totally agree, Silvio. Individuals on CGMs (continuous glucose monitoring) tend to be where I hear patients asking the question as they're seeing a little bit of a postprandial spike and their time in [normoglycemic] range may not be quite where they want it to be. We are thinking about adding these agents to see if they can move the needle a little bit. In those trials they did see some benefit on postprandial blood sugars, but as you mentioned, it's 10-20 mg/dL, depending on the trials.

Inzucchi: I do have a couple of patients that really swear by them, saying that they get better postprandial control. There are two, I believe, on the market now. The first is a faster form of insulin aspart and that's marketed as something called Fiasp, which, I believe, has niacinamide in it. Is that like a vasodilator?

Neumiller: It is. It's a vasodilator they added in with insulin aspart and it helps expedite that absorption to get that small increased rate of absorption for that insulin.

Inzucchi: And the second is lispro known as "[lispro-aabc]." I'm totally unfamiliar with those four letters. What do they mean?

Neumiller: Because we have all these new insulins coming out and now we have, additionally, follow-on insulins and biosimilars, this is a new nomenclature that the FDA has added for biologic agents. About 2017 is when they proposed this nomenclature, that agents approved after that point in time have to have this four-letter suffix that basically identifies it as a specific product. And that's going to hopefully allow for pharmacovigilance, questions about immunogenicity with some of the biosimilars. They're making sure they can follow and appropriately attribute any postmarketing reports to the correct insulin.

Inzucchi: Yeah, that's being marketed as Lyumjev, I believe, and that's a combination of lispro and treprostinil and sodium citrate. Again, are these vasodilators?

Neumiller: Yes — so vasodilation with the treprostinil, which is a prostacyclin analog, and then the citrate increases local vascular permeability to help speed absorption.

Inzucchi: All right, let's switch to the other end of the spectrum: icodec. This is still investigational. The ultra rapids are actually marketed now. Icodec insulin is a weekly insulin. A weekly insulin, Josh. How can that be?

Neumiller: That's incredible.

Inzucchi: I understand that the dose is seven times the normal daily dose. So if somebody were taking, for instance, insulin glargine, 30 units per day or at night, that would translate to 7 x 30. In that circumstance it would be 210 units. That seems like an awfully big dose to start a patient on.

Neumiller: I know the first time I heard about this, it definitely widened my eyes thinking about some of the implications for providers coming on board with this particular approach. It's such a different paradigm in high doses, compared to what we're thinking about giving people in a single injection.

Inzucchi: This is obviously very slowly absorbed. The pharmacokinetic profile allows it to be given once a week. And there was a study in The New England Journal of Medicine about 2 years ago that compared it to glargine. The glargine was started at 10 units at night, and this is in a group of patients with type 2 diabetes that was suboptimally controlled, and then the comparator would be the icodec at 70 units to start. The meds were titrated as we normally would titrate. They had a specific protocol to do that. Surprisingly, the blood glucose data, the Hgb A1c, was almost identical, wasn't it?

Neumiller: Yes. The A1c reduction was very comparable over the course of the trial — after titration, of course. I went straight to the safety section of the paper to look at the rates of hypoglycemia; there were really no increases in level 2 or level 3 hypoglycemia. Even the level 1 blood sugar [less than 70, but above 54] was not as big of an increase as you might fear with such a long-acting insulin.

Inzucchi: One of my concerns is, what do you do when patients are sick and are not eating? They may be predisposed to both hyperglycemia, depending on the nature of the illness, but also hypoglycemia — if they're not eating. What do you do when patients have surgery or are hospitalized? What do you think is going to happen?

Neumiller: Gosh, I think that's going to be a huge question. There's going to be a lot of work that needs to be done in the real-world setting to think about strategies for those individuals.

Neumiller: Another interesting aspect of this, Silvio, is that there was also a paper looking at switching insulin with this particular agent. And that one really was interesting because when they switched them from U100 insulin to this once-weekly, they basically gave them a loading dose also, 100% loading dose for that first dose. So if it's 70 units, they're converting, they gave them an initial 140-unit dose. Because this has such a long half-life, about a week, it takes a while for that to get to steady state. I think there will be some early adopters for this once-weekly insulin, but I think there will be people who will need some convincing, too.

Inzucchi: It'll be interesting to see what develops. But again, that's still investigational, not yet marketed. Let's switch tracks, Josh. I wanted to talk about tirzepatide. Now we've all become very familiar with the GLP-1 agonists. They've been out for a number of years now and are showing exciting data in regard to their cardiovascular benefits. And these are mostly injectables, although there is one oral formulation of semaglutide. These agents reduce glucose by stimulating insulin secretion in a glucose-dependent fashion, but they also slow gastric emptying. They may suppress glucagon and also have an effect on appetite. So there are at least three, if not four, different effects. They're powerfully effective glucose-lowering agents without significant increases in hypoglycemia and maybe cardiovascular benefits. This tirzepatide molecule is very interesting. It is known as a twincretin, as I alluded to before. Can you tell us a little bit about it?

Neumiller: As you said, this is a dual-incretin agent. It activates both GLP-1 receptors, which we're all familiar with. We have a lot of products on the market that are GLP-1 receptor agonists. This one's a little bit different because it hits one of our other incretin hormones and activates its receptors. That's a GIP, or glucose-dependent insulinotropic polypeptide.

I think there are some questions as to what this mixed effect is doing pharmacologically. Both incretin hormones, GLP-1 and GIP, stimulate insulin in a glucose-dependent fashion, as you mentioned. GIP may also have some effects on lipid metabolism and some other factors that may play into its effects. But this particular agent, tirzepatide, is actually structured based on the GIP backbone. This is a peptide-based agent that will be injectable and have a once-weekly administration.

Inzucchi: And some feel that it's really a very powerful GLP-1 agonist, that most of the efficacy data we're going to be talking about in just a few minutes may be related to how powerful a GLP-1 agonist it is — that the GIP may be coming along for the ride, but how much that is playing a role in terms of the glucose reduction and the weight reduction is not entirely clear.

Neumiller: Yeah, definitely some questions here mechanistically, but the data look really amazing.

Inzucchi: Quite impressive.

Inzucchi: There are a couple of studies I wanted to touch upon. The first was published in The Lancet last year, in 2021. It's known as the SURPASS-1 study. This is their foundational study in the clinic, phase 3 tirzepatide vs placebo, given to almost 500 patients with type 2 diabetes. Their Hgb A1c at baseline was about 8%, and they demonstrated powerful reductions in both A1c as well as in body weight. I think at the 15-mg dose, the mean reduction was over 2%, wasn't it? For Hgb A1c?

Neumiller: It was, it was.

Inzucchi: And the weight effect was about 10 kg. Now, we're talking significant reductions in body weight of more than 20 lb. I'm not sure about you, but I've had a lot of trouble getting patients with type 2 diabetes to lose weight, and they do tend to respond less well to weight-reducing medications than patients with simple obesity without type 2 diabetes.

Neumiller: Definitely. The weight loss is really quite impressive here. And even beyond the mean, we think of about 5% weight loss as an off-ramp for our antiobesity medications. What was really impressive to me in this trial is that when they looked at the percentage of people who achieved at least a 5% weight loss, depending on the dose it was between 65% and 80% of those participants receiving this agent.

Inzucchi: And many were even achieving 10% weight loss.

Neumiller: Yes, and greater, so it's pretty incredible.

Inzucchi: Now, obviously there are downsides to any pharmacologic agent, and the Achilles heel of the GLP-1 agonist and also the GLP-1/GIP agonist would be GI side effects, right?

Neumiller: Absolutely. We definitely see the same effect with this. And we do have some head-to-head studies where we're really looking at a very similar nausea, vomiting, GI-type side-effect profile that we're accustomed to seeing with some of the more potent GLP-1 receptor agonists.

Inzucchi: Obviously, slow titration is key when using these medications. So, the study you alluded to is SURPASS-2. This was a comparative study between again, those three doses of tirzepatide: 5 mg, 10 mg, and 15 mg vs what many would consider best in class in terms of the GLP-1 agonist, in terms of its efficacy data: semaglutide. It looked like at the highest dose of tirzepatide, again, that dual GLP-1/GIP agonist was stronger than semaglutide at the 1-mg dose.

Neumiller: Yeah, it was; it compared very well. Statistically significant in terms of being a little bit better with the A1c reduction. But I think you made a key specification that it is the semaglutide 1-mg dose. We know that we can use it at higher doses for glucose lowering, up to 2 mg, and also a little bit higher than that: up to 2.4 mg for weight loss. So it is important to contextualize that with the data.

Inzucchi: Obviously the study was designed when 1 mg of semaglutide was the highest dose available, so it made sense to compare it to that. But since this study, SURPASS-2 got underway, as you mentioned, and there are higher doses of semaglutide available and now marketed. The question is, what about a head-to-head study of tirzepatide at the 50-mg dose, the highest vs the optimal doses of semaglutide? It's hard to predict what would happen with that kind of study, but it's quite extraordinary.

I even heard that there were some top-line data released over the weekend in an obese population, a nondiabetic obese population, using tirzepatide, and they were reporting upwards of a 50-lb weight loss as the mean, meaning there are some patients who are probably losing 60 and 70 lbs. That study has not been released yet, but there were some press releases from the company.

This is obviously a very exciting newer injectable agent, still not marketed, still investigational. Hopefully we'll have access to that at some point. And hopefully the rest of the research portfolio for that compound will be relatively safe. Although again, whenever you use these incretin agents, you have to go slow and be careful in terms of GI side effects.

Well, Josh, it looks like we are out of time. We've covered a lot of ground today. We've talked about these newer, ultra-rapid insulins, where their role might be. We discussed this new weekly insulin, which I think we both have a little discomfort with, in terms of how we initially dose this medication, and issues regarding hypoglycemia, although the data looked pretty good. We finished up with a discussion about tirzepatide, this new GLP-1/GIP agonist that is showing some impressive results, both on Hgb A1c in patients with type 2 diabetes and also on body weight reduction, both in type 2 diabetes as well as in obesity. Did you want to pass any final thoughts to our listeners before we wrap up?

Neumiller: I just want to thank you, Silvio, for having me. There are a lot of exciting things happening. All of these medications look very promising. But we've highlighted some questions that will really determine how these are taken up in practice. For me, it really comes down to making sure we're providing very efficient education to the people using these medications to make sure they use them appropriately, especially now that we're looking at once-weekly insulins potentially. And I think not only will the providers maybe have some apprehension, but there's a lot of opportunity for confusion with patients and caregivers, too. So, really thinking about some of those practical aspects of medication management.

Inzucchi: Good point. Well, Dr Joshua Neumiller, vice chair and professor of pharmacotherapy at Washington State University, thanks so much for joining me today.

Neumiller: Thank you, Dr Inzucchi.

Inzucchi: Thanks for listening. I'm Silvio Inzucchi for Medscape InDiscussion.


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FDA Approves Novel, Dual-Targeted Treatment for Type 2 Diabetes

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