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[00:03]
A
Welcome to this special edition of Diabetes Core Update where we are going to discuss today an incredibly exciting topic and that is medications in the cardiometabolic pipeline. That is medicines in the pipeline now for obesity, for diabetes and for other cardiometabolic related diseases. This is an area that has truly become hard to keep up with and it is more exciting than it ever has has been. And it lets us, from a practical point of view, begin to understand the many ways that our abilities to help patients will continue to grow. I'm Dr. Neal Skolnik, professor of Family and Community Medicine at the Sidney Kimmel Medical College of Thomas Jefferson University. And this special edition of Diabetes Core Update is sponsored by by Lilly. Joining us to discuss medicines in the pipeline, we are really privileged to have Dr. Juan Frias. Dr. Frias is the medical director and principal investigator at the Los Angeles Institute for Metabolic Research. He's been involved in diabetes, obesity, metabolic, liver disease and other metabolic related research for over 25 years now and has really authored an incredible number of studies, including being first author on the Surpass 2 trial in the New England Journal of medicine, the phase 2 study of orphaglipron in the Lancet, the phase 2 trial of CAG resem in the Lancet, other articles he's been authors on in the New England Journal of Medicine, Lancet, Lancet, Diabetes and endocrinology. Diabetes, diabetes care, cell metabolism. I could keep going, but I won't because we want to make sure we have time to discuss our topic today. If you get it, if you read the obesity and diabetes literature, you have seen his name a lot. Juan, welcome back to our podcast. It's such a pleasure to have seen you last week at the ADA Scientific sessions and to be doing this podcast.
[02:14]
B
No, absolutely, my pleasure. Really appreciate you having me back and great to see you also last week. Neil.
[02:20]
A
Juan, you've been in this field for a long time. Before dive into the information, can you share with our audience just how you got interested in clinical research?
[02:30]
B
Yeah, absolutely. I think like so many other things, it's people you meet, mentors you have over time. And I can remember even going back to medical school at Vanderbilt, you know, a million years ago or 40 years ago or whatever it was my mentor there was an endocrinologist during my residency as well, an endocrinologist. So I just had a lot of people around me that were interested in metabolic disease and endocrinology and then I was very fortunate to go to ucsd. My mentor there was Jerry Olefsky who's A big researcher and I started with clinical research in my fellowship and have continued it now for, for over 30 years. So I think it's the, the people I was around and a lot of interest in a growing field that is fantastic.
[03:15]
A
Let's jump now into the pipeline and we're going to really emphasize distinguishing characteristics of each medicine from each other. And we'll start with the multi agonists and let's first start with retatrutide, for which the data was announced actually last week at the ADA scientific sessions. Juan, tell us a little bit about it.
[03:37]
B
Absolutely. So, you know, we went from selective GLP1 receptor agonists like dulaglutide and semaglutide to then tirzepatide, which is a dual GIP and GLP1 agonist, and now retrotrutide sort of takes it a step further. And this is a triagonist, so a triple agonist. It's a so called unimolecular multiagonist. So it's one molecule, but it's been engineered to bind to and stimulate or agonize the GIP receptor, the GLP1 receptor and also the glucagon receptor. And as you mentioned, there were some studies, a couple of studies that were presented last week in New Orleans at the American Diabetes association scientific sessions and really quite startling data. I can go through just the highlights of, for example, Triumph 1. So the Triumph program is the program looking at weight management, so people who are overweight and obese. And Triumph one was a study in people without diabetes, so without type 2 diabetes, who were treated for 80 weeks. And then there was an extension, a 24 week extension. So overall this was 104 week study which looked at body weight, but not only the change in body weight, but also there were what they call baskets or sub studies within the trial looking at people with osteoarthritis of the knees and with obstructive sleep apnea. And what we saw really was the most significant weight loss that has been seen with any agent to date. So at 104 weeks, about an average average with the highest dose, which was a 12 milligram once weekly dose, 30% reduction in body weight, with very large numbers achieving very clinically relevant reductions in body weight, you know, up to 45 or so percent, having over 30% body weight reduction, and then also improvements in pain, so knee pain, significant improvement and significant improvements, as you can imagine, in obstructive sleep apnea and the apnea hypopnea index, which is the measure. So really Quite startling results with retrotrutide, that really is.
[05:58]
A
Now, I know we could talk probably for our whole 30 minutes about any one of the medicines we have on our list today, but we're gonna jump now into our next up, which is maritide. Can you tell us a bit about.
[06:13]
B
Yes, a little about maritide. I don't think there was anything at the ADA, but Maritide is actually a GLP1 agonist and a GIP antagonist. So sort of, you know, Tirzepatide is a GLP1 and GIP agonist. So this has GIP antagonism and it has a very long half life. So it has been studied. And phase two was presented last year, this was in a New England Journal paper, again for weight management. And the distinction here, not only the fact that it's a GIP agonist or antagonist, I should say, is that it is once monthly, so very long half life. And this provides a more potentially convenient dosing regimen for the patient. So again, very robust reductions in body weight with this in phase two, and now it's in phase three. So it'll give us another opportunity, again with a different dosing regimen in this.
[07:14]
A
Fascinating. And we don't have time to discuss the nuances today of why one medicine with GIP agonism works well and the other with antagonism works well. But we'll leave that as a teaser for our audience to at some point we'll try to come back to and talk about next up. Cervotide.
[07:38]
B
Yeah, so cervidutide is an interesting molecule and there are others like this, also a unimolecular multiagonist, but now it's GLP1 Agonism with glucagon receptor agonist. So a dual agonist, which is GLP1 and glucagon. And there were trials presented at the ADA, the synchronized one study, which was an obesity study, and the Synchronized Mastle study, which was looking at metabolic liver disease. And in these trials, about on average, 12 to 15% reduction in body weight over time. So very robust with body weight reduction. But the glucagon receptor agonist is very specific to the liver. So the liver, I mean, glucagon receptors are highly expressed on hepatocytes and it has some very interesting effects in people and positive effects in people with metabolic liver disease as well as the weight gain. So probably that the improvement you see in liver fat and potentially in fibrosis as well, is sort of disproportionate to the amount of weight loss and this is indicating that this glucagon agonism is having a real effect on the liver.
[08:47]
A
That's fascinating. So completely different mechanism with really a very different target organ than we've seen in other medicines we have. Then next up, as we continue rolling on cagrycema.
[09:06]
B
Okay, so cagrycema. So this now is not what we would call a unimolecular multi agonist. So one molecule with multi agonist activity. This is two separate medications in one dual chamber pen. So this is semaglutide, which we know as Ozempic or Wegovy. So semaglutide with cogrillentide. So cogrillentide is an amylin receptor agonist. So amylin is also a nutrient stimulated hormone. It's secreted along with insulin from the pancreatic beta cell. It has some very interesting central effects to increase satiety. It also slows gastric emptying. It reduces postprandial glucagon concentrations. The bottom line is it has some very important metabolic effects to lower body weight and also improve glycemia and probably some other effects. So now this is a combination of these two. And there were several phase three trials that were reported at the American Diabetes association, and these were called the reimagined studies in type 2 diabetes. So very robust improvements in GLUC, those A1C reductions, you know, in the 1.9 to 2.3% range, and very good weight reduction, particularly in patients with type 2 diabetes that tend to lose less body weight. So, you know, up to 14, 12, 14% average weight reduction in these studies. So, and I will mention one other thing, that there was a study which is the reimagine. I think it's a reimagined 2 study. It is reimagined 2 which compared actually CAGRY, SEMA, 2 semaglutide and 2 cagrillantide given separately, showing that the CAGRY SEMA, so having this combination was more potent than semaglutide alone with respect to glucose lowering and with respect to weight loss. You have something a bit more potent by adding these complementary mechanisms of the amylin analog with the GLP1 receptor agonist, semaglutide, in this case.
[11:15]
A
That is fascinating. You know, Juan, I can feel the anxiety rising in our listeners as they are thinking, you know, I just got used to treating and talking to people about obesity and metabolic disease to begin with. How am I gonna accommodate learning all of these new medicines? Which is why we're talking about it, and to Our listeners, we're not done yet. We got plenty more to still discuss today. So let's go on now to Zanaglamide.
[11:49]
B
Oh yeah, so, so there, there is, there is also a combination that is a unimolecular. So it is a single molecule that is GLP1 and amylin. So this amocretin, it's also called again in clinical development and there is an injectable form and also very interesting, an oral form as well. So this has been studied in obesity, in type 2 diabetes and I think will be another potential oral option and injectable for patients. So unlike cagrisoma, which are two separate medications given in one injection, this is actually a single molecule that is an agonist at GLP1 and is also an agonist at amylin receptors. And again a subcutaneous form and an oral form in clinical development, I have to say. So, you know, we have to wait and see what happens with all of these medications. But like you mentioned, there's going to be a lot of them relatively soon.
[12:51]
A
Yeah, and that's interesting. And you mentioned oral and we'll talk a little more later about other orals in development but that's certainly something that many patients like the idea of. Now we'll go on to talk about some single agonists and let's start with the single agonist from a new class and I'm not even sure I'll pronounce this one correctly, so I'll probably need your help here. Barobenetide.
[13:21]
B
Yes, barabenatide. This is an ultra long acting GLP1 receptor agonist. So this is a selective GLP1 receptor agonist, but it is ultra long acting. So ultimately we'll be given or if the trials work out, it'll be given once monthly. And there have been data, phase two data. It's now in a program, it's called Vesper, which is a phase three program looking at this for weight management. Again as with maritide, it's a different molecule clearly, but convenience of once monthly dosing. So I think those will be very interesting data. But that's again in phase three. So there's still some time. But we're seeing this move from, you know, when we started, Neil, you remember this. Well in 2005 it was twice daily, then we went once daily, then we went to once weekly and now we're looking at maybe once every two weeks or once.
[14:16]
A
It's really amazing, Juan, because it just seems that with there's so much innovation and complicated science essentially on the back end that allows us at the front lines to increasingly have medicines that frankly become easy to use. Much easier than, as you said, this evolution from twice a day medicines to once daily to once weekly. And now we're even looking at once monthly, making things easier for us at the front lines in primary care and endocrinology as well as of course our patients who are the ones that are taking the medicines and benefiting from them.
[15:01]
B
Yeah, I would say absolutely. So not only a range of different modalities of administration and regimens, but I would say also a range of different efficacy, safety and tolerability as well. And maybe targeting other parts of this whole cardiorenal metabolic syndrome. So I think it will be more personalized and we'll be able to say, hey, this person with, you know, really a lot of burden of metabolic liver disease may be better with this drug. This patient who Maybe doesn't need 30% weight loss and has had issues with tolerability may need this drug. And this patient who really will only take an oral agent will have the other drug. So I think it'll help us to have all of this to be able to personalize and probably won't be that difficult. I think once, once they're out there and we learn how to use these.
[15:56]
A
Yeah, that's really fascinating and so promising. Let's go on now and discuss a few other medicines in the pipeline. And let's go to the single agonists that are in a new class of medicines. You mentioned Amlin before. In the context of Cagrecema. There are now single amylin agonists. And remind us what amylin does because for most of us, amylin is this molecule that we remember hearing about at some point but don't necessarily know about it.
[16:30]
B
Yes, actually, I mean, amylin is very interesting. So it is a hormone again that's produced and secreted by the pancreatic beta cell. When we secrete insulin, we secrete Amylon as well. It's got central actions which really control energy balance or food intake and satiety, slows gastric emptying of well or regulates gastric empty and to regulate postprandial glucose and lipids. It reduces glucagon concentrations. And in fact the first amylin analog, which was Pramlintide or Simlin, was approved in 2005 for use in people with diabetes. But it was a three times daily injection in combination with or in conjunction with insulin therapy. So now we have these once weekly amylin analogs. You know, we mentioned craglantide in the context of cagrecema. But cragolantide on its own is also being studied for overweight and obesity, as is Petralentide, which is one that there was actually a phase two study presented at the ADA. So we're seeing 10 plus percent reduction in body weight with these, you know, just with the amyl and analog and a distinction, probably one of the important distinctions clinically is very well tolerated. So you're seeing tolerability profiles at almost a mirroring placebo. There's slightly more nausea generally during escalation, but withdrawal rates or stopping of the drug in these studies very comparable to what's seen with placebo. So amylin analogs are very well tolerated and you're getting some very robust weight reduction, not retrotrutide weight reduction, but very, very good weight reduction with these medicines as well. And there's several in clinical development.
[18:17]
A
Wow, that's amazing. And that really is, I mean, boy, would that be welcome, because that's the big issue for a lot of patients and many patients just can't tolerate the GI side effects of GLP1.
[18:31]
B
Yeah, absolutely. So even on its own in some cases, but then again in combination like cagrecema. And there are other combinations now with dual agonists as well that are in clinical development because the actions of an amylin analog and a GLP1 or GLP1 Gipsy are complementary and used together, they might even get more powerful weight reduction for those patients who need it.
[18:57]
A
Yeah. And you know, as we're talking about all these different mechanisms, it also reminds me that there are some patients, when we talk about means, those are always means, but that means there are some patients that either are non responders to a given medicine or don't respond as well as a lot of other people. And these we'll see as this continues, whether or not these different mechanisms might work better for that group than the traditional GLP1 or GLP1 GIP dual agonist.
[19:31]
B
You know, that's a great point. I always say, you know, in these trials, the mean is usually the median. Like you say, you got some super responders, some that respond less, some that are, you know, around the mean. But when we're in practice, sort of each patient is a clinical trial of n equals 1, and we need to individualize, see how they do. And it may be to your point that people who are not responding well may respond to a different drug. And in time we'll learn more about that. But a lot of this just don't know, at this point, but it's nice to have other options to switch them to if they're not responding.
[20:02]
A
Yeah. So talking about individual preferences, let's now talk about oral agents.
[20:08]
B
Yeah. So oral agents, we've got oral semaglutide, but sort of what we're seeing, or the latest kid on the block, if you will, is small molecule oral GLP1 receptor agonists. And there's one that is approved, which is orphoglypron, and it's approved now for weight management either in people without diabetes or with diabetes. So this has the advantage that it could be taken with or without food, with no water restrictions any time of day, because it's a small molecule, not a peptide. And there are a couple of studies for weight management that supported the registration and ARPA Bush, a study called Attain 1 in people without diabetes, Attain 2 in people with diabetes and very again robust weight reduction in Attain 1, for example, and at the highest dose, which in the studies was 36 milligrams, commercially it's a different formulation that's equivalent, but it's 17.2 milligrams. There was an about 11% average reduction in body weight with about 55 or so percent of the patients achieving greater than 10% weight reduction. Again, very robust. And all of these, I should mention, you know, seems like the tolerability profile for the amylan analog is better than the GLP1 receptor. Okay. And we also have oral semaglutide as well that's been studied and approved for type 2 diabetes and also for weight management and very robust weight reduction and now at higher doses for overweight and obesity. So 25 milligrams and still a 14 milligram dose for diabetes. And here seeing very robust reductions in body weight that are over 10% on average. So very important oral agents and then other oral small molecules that are in clinical development as well.
[22:06]
A
Juan, this is. I don't know many people that could have given this type of overview in this amount of time. We're about out of time now. Do you have any final thoughts to the thousands of clinicians that have been really listening carefully to this and are feeling perhaps a sense of both excitement but maybe also a little overwhelmed. Any final thoughts?
[22:33]
B
No, I think, you know, it would be sort of a very overarching thought that obesity is a chronic disease. Most patients with the disease are not on medication or anti obesity medications. So I think having all of these options is going to be important to be able to individualize therapy for patients to get patients on these agents. And I would also say it's not just about the degree of weight loss, but it's the improvement we see with all of these drugs that have been seen kind of across the board with respect to improvements in lipids, in blood pressure and inflammatory markers in quality of life as well. So we're trying to really improve function, improve quality of life, improve cardiometabolic risk factors, and we're doing it with these medications at lower body weight. So I think it's an exciting time and it's great to have agents available, and I think it'll all sort itself out. But I think we need to be really focusing on treating these patients.
[23:36]
A
I think that's such a good point, that overarching issue that right now, less than 1 in 10 people who are eligible for these medicines are actually treated critically. Important. I'm looking forward to all these new choices, and I know all of our listeners and I as well learned a lot from our discussion today. Dr. Juan Frias, thank you so much for joining us.
[23:59]
B
Thank you, Neil.
[24:01]
A
And most of all, of course, as always, thanks to our listeners. Thank you for joining us on this special, special edition of Diabetes Core Update, where we discussed more in the pipeline than I think most of us had any idea was coming, that is there as a result of incredible scientific research and innovation that'll provide medicines eventually for our patients that will make their lives better. This special edition of Diabetes Core Update is sponsored by 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.

Summary5 min read

Podcast Summary: Diabetes Core Update

Special Edition: Medications in the Pipeline for Cardiometabolic Disease

Release Date: June 25, 2026
Host: Dr. Neil Skolnik (A)
Guest: Dr. Juan Frias (B), Medical Director and Principal Investigator, Los Angeles Institute for Metabolic Research

Episode Overview

This special edition focuses on emerging medications in the cardiometabolic pipeline, highlighting innovations for obesity, diabetes, and related conditions. Dr. Neil Skolnik and expert guest Dr. Juan Frias discuss pivotal clinical trials, distinct mechanisms of action, and the future of individualized cardiometabolic care. The conversation is rich with clinical nuances, comparison of drug classes, and a peek into practical implementation for healthcare providers.

Key Discussion Points & Insights

Introduction and Dr. Frias’ Research Background

[00:02–03:15]

Dr. Skolnik introduces Dr. Juan Frias, emphasizing his key role in pivotal trials (e.g., Surpass 2, Cagrisema, Orforglipron).
Dr. Frias shares that mentorship and exposure to endocrinology sparked his research interest.
- Quote:
  "It's people you meet, mentors you have over time... a lot of interest in a growing field that is fantastic." — Dr. Juan Frias [02:29]

Multi-Agonists in the Pipeline

1. Retatrutide (Triagonist)

[03:37–05:57]

Triple agonist: GIP, GLP-1, and glucagon receptors.
ADA 2026 presented “startling” results, especially in the TRIUMPH-1 study:
- 30% average weight reduction at 104 weeks at the top dose (12 mg).
- About 45% of subjects lost ≥30% body weight.
- Positive effects on knee osteoarthritis pain and sleep apnea.
- Quote:
  "Really quite startling data ... the most significant weight loss that has been seen with any agent to date." — Dr. Juan Frias [03:37]

2. Maritide (GLP-1 Agonist, GIP Antagonist)

[06:13–07:13]

Distinct for its antagonism at GIP (vs. Tirzepatide's agonism).
Once-monthly dosing with robust weight loss in Phase 2; now in Phase 3.
Notable for its potentially improved convenience.

3. Cervedutide (GLP-1 and Glucagon Dual Agonist)

[07:37–08:47]

Dual agonist, focusing on GLP-1 and glucagon receptors.
ADA trials (“SYNCHRONIZE-1” and “SYNCHRONIZE-MASTLE”) for obesity and metabolic liver disease.
12-15% average weight loss. Particularly effective in improving liver fat and fibrosis, disproportionate to weight loss.

4. Cagrisema (Semaglutide + Cagrilintide Combo)

[09:05–11:14]

Fixed-dose dual therapy: semaglutide (GLP-1 RA) + cagrilintide (amylin RA) in a dual-chamber pen, not a unimolecular.
"REIMAGINE" studies in type 2 diabetes:
- HbA1c reductions of 1.9–2.3%, weight loss up to 14%.
- Cagrisema outperformed semaglutide alone in glycemic and weight endpoints.
- Quote:
  "More potent by adding these complementary mechanisms of the amylin analog with the GLP1 receptor agonist." — Dr. Juan Frias [10:37]

5. Zanamcreotide (GLP-1 and Amylin Agonist)

[11:49–12:50]

Unimolecular agonist at both GLP-1 and amylin receptors (vs. two-drug cagrilintide combo).
Both oral and injectable forms under development for diabetes and obesity.

Single-Agonists & New Modalities

Barabenatide (Ultra-Long Acting GLP-1 RA)

[13:20–14:16]

Selective GLP-1 RA with ultra-long action; could offer once-monthly dosing (currently in Phase 3 Vesper program).
Represents a continued evolution in patient convenience.
- Quote:
  "We went from twice daily...once daily...once weekly, and now we're looking at maybe once every two weeks or once monthly." — Dr. Juan Frias [14:02]

Amylin Agonists as Standalone Therapy

[15:56–18:56]

Amylin: Hormone coreleased with insulin, centrally increases satiety, slows gastric emptying, and lowers postprandial glucagon.
New long-acting amylin analogs (e.g., cagrilintide, petrelintide) show 10%+ weight loss and are very well tolerated, with minimal GI side effects compared to GLP-1 RAs.
Potential synergy when combined with GLP-1s or dual agonists.
- Quote:
  "Amylin analogs are very well tolerated and you're getting some very robust weight reduction, not retatrutide weight reduction, but very, very good weight reduction with these medicines as well." — Dr. Juan Frias [17:35]
- Quote:
  "Each patient is a clinical trial of n equals 1, and we need to individualize, see how they do." — Dr. Juan Frias [19:31]

Oral Agents in Development

[20:08–22:06]

In addition to oral semaglutide, Orforglipron is a small-molecule oral GLP-1 RA:
- No food/water restrictions; flexible dosing.
- Robust efficacy (11% average weight loss at high dose, >50% with ≥10% weight loss).
High-dose oral semaglutide (25 mg for obesity) also shows over 10% average weight loss.
Other oral agents are in pre-marketing development, expanding options for patients preferring non-injectables.

Final Thoughts and Overarching Messages

[22:06–23:59]

Less than 1 in 10 eligible patients are currently on anti-obesity medications.
Emphasis should be on treating obesity as a chronic disease, improving not just weight but also other cardiometabolic risk factors and quality of life.
- Quote:
  "It's not just about the degree of weight loss, but it's the improvement we see with all of these drugs... in lipids, in blood pressure and inflammatory markers in quality of life." — Dr. Juan Frias [22:32]
The rapidly expanding choices will make it possible to individualize therapy and improve access, adherence, and clinical outcomes.
Dr. Skolnik and Dr. Frias highlight the excitement and optimism for providers and patients, noting the need for education and adaptability as the medication landscape evolves.

Notable Quotes & Memorable Moments

"Really quite startling data ... the most significant weight loss that has been seen with any agent to date." — Dr. Juan Frias (on retatrutide) [03:37]
"This person with, you know, really a lot of burden of metabolic liver disease may be better with this drug...It'll help us to have all of this to be able to personalize." — Dr. Juan Frias [15:01]
"Each patient is a clinical trial of n equals 1." — Dr. Juan Frias [19:31]
"Less than 1 in 10 people who are eligible for these medicines are actually treated." — Dr. Neil Skolnik [23:35]
"It's not just about the degree of weight loss, but it's the improvement we see... with respect to improvements in lipids, in blood pressure and inflammatory markers in quality of life as well." — Dr. Juan Frias [22:32]

Key Timestamps for Major Segments

Introduction and Dr. Frias' background: [00:02–03:15]
Retatrutide, TRIUMPH-1 data: [03:37–05:57]
Maritide: [06:13–07:13]
Cervedutide: [07:37–08:47]
Cagrisema: [09:05–11:14]
Zanamcreotide: [11:49–12:50]
Barabenatide & convenience evolution: [13:20–14:16]
Standalone amylin agonists: [15:56–18:56]
Oral agents (Orforglipron, semaglutide): [20:08–22:06]
Overarching messages and clinical application: [22:06–23:59]

Clinical Takeaways

The future of cardiometabolic medicine features a rapidly diversifying array of therapies targeting distinct mechanisms as monotherapies and combinations.
Expanding options will support personalized, patient-centered care with choices across injectables, oral agents, and drugs tailored to specific comorbidities.
Most novel candidates show robust efficacy, and several offer improved tolerability or convenience.
The challenge ahead focuses on education and adapting to incorporate these advances into practice, ensuring more patients benefit from new low-barrier treatments.

Hosted by the American Diabetes Association. For further information, visit www.diabetesjournals.org.

Note: Advertisements, intros, and outros are omitted from this summary.

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Transcript31 lines

[00:03]
A
Welcome to this special edition of Diabetes Core Update where we are going to discuss today an incredibly exciting topic and that is medications in the cardiometabolic pipeline. That is medicines in the pipeline now for obesity, for diabetes and for other cardiometabolic related diseases. This is an area that has truly become hard to keep up with and it is more exciting than it ever has has been. And it lets us, from a practical point of view, begin to understand the many ways that our abilities to help patients will continue to grow. I'm Dr. Neal Skolnik, professor of Family and Community Medicine at the Sidney Kimmel Medical College of Thomas Jefferson University. And this special edition of Diabetes Core Update is sponsored by by Lilly. Joining us to discuss medicines in the pipeline, we are really privileged to have Dr. Juan Frias. Dr. Frias is the medical director and principal investigator at the Los Angeles Institute for Metabolic Research. He's been involved in diabetes, obesity, metabolic, liver disease and other metabolic related research for over 25 years now and has really authored an incredible number of studies, including being first author on the Surpass 2 trial in the New England Journal of medicine, the phase 2 study of orphaglipron in the Lancet, the phase 2 trial of CAG resem in the Lancet, other articles he's been authors on in the New England Journal of Medicine, Lancet, Lancet, Diabetes and endocrinology. Diabetes, diabetes care, cell metabolism. I could keep going, but I won't because we want to make sure we have time to discuss our topic today. If you get it, if you read the obesity and diabetes literature, you have seen his name a lot. Juan, welcome back to our podcast. It's such a pleasure to have seen you last week at the ADA Scientific sessions and to be doing this podcast.
[02:14]
B
No, absolutely, my pleasure. Really appreciate you having me back and great to see you also last week. Neil.
[02:20]
A
Juan, you've been in this field for a long time. Before dive into the information, can you share with our audience just how you got interested in clinical research?
[02:30]
B
Yeah, absolutely. I think like so many other things, it's people you meet, mentors you have over time. And I can remember even going back to medical school at Vanderbilt, you know, a million years ago or 40 years ago or whatever it was my mentor there was an endocrinologist during my residency as well, an endocrinologist. So I just had a lot of people around me that were interested in metabolic disease and endocrinology and then I was very fortunate to go to ucsd. My mentor there was Jerry Olefsky who's A big researcher and I started with clinical research in my fellowship and have continued it now for, for over 30 years. So I think it's the, the people I was around and a lot of interest in a growing field that is fantastic.
[03:15]
A
Let's jump now into the pipeline and we're going to really emphasize distinguishing characteristics of each medicine from each other. And we'll start with the multi agonists and let's first start with retatrutide, for which the data was announced actually last week at the ADA scientific sessions. Juan, tell us a little bit about it.
[03:37]
B
Absolutely. So, you know, we went from selective GLP1 receptor agonists like dulaglutide and semaglutide to then tirzepatide, which is a dual GIP and GLP1 agonist, and now retrotrutide sort of takes it a step further. And this is a triagonist, so a triple agonist. It's a so called unimolecular multiagonist. So it's one molecule, but it's been engineered to bind to and stimulate or agonize the GIP receptor, the GLP1 receptor and also the glucagon receptor. And as you mentioned, there were some studies, a couple of studies that were presented last week in New Orleans at the American Diabetes association scientific sessions and really quite startling data. I can go through just the highlights of, for example, Triumph 1. So the Triumph program is the program looking at weight management, so people who are overweight and obese. And Triumph one was a study in people without diabetes, so without type 2 diabetes, who were treated for 80 weeks. And then there was an extension, a 24 week extension. So overall this was 104 week study which looked at body weight, but not only the change in body weight, but also there were what they call baskets or sub studies within the trial looking at people with osteoarthritis of the knees and with obstructive sleep apnea. And what we saw really was the most significant weight loss that has been seen with any agent to date. So at 104 weeks, about an average average with the highest dose, which was a 12 milligram once weekly dose, 30% reduction in body weight, with very large numbers achieving very clinically relevant reductions in body weight, you know, up to 45 or so percent, having over 30% body weight reduction, and then also improvements in pain, so knee pain, significant improvement and significant improvements, as you can imagine, in obstructive sleep apnea and the apnea hypopnea index, which is the measure. So really Quite startling results with retrotrutide, that really is.
[05:58]
A
Now, I know we could talk probably for our whole 30 minutes about any one of the medicines we have on our list today, but we're gonna jump now into our next up, which is maritide. Can you tell us a bit about.
[06:13]
B
Yes, a little about maritide. I don't think there was anything at the ADA, but Maritide is actually a GLP1 agonist and a GIP antagonist. So sort of, you know, Tirzepatide is a GLP1 and GIP agonist. So this has GIP antagonism and it has a very long half life. So it has been studied. And phase two was presented last year, this was in a New England Journal paper, again for weight management. And the distinction here, not only the fact that it's a GIP agonist or antagonist, I should say, is that it is once monthly, so very long half life. And this provides a more potentially convenient dosing regimen for the patient. So again, very robust reductions in body weight with this in phase two, and now it's in phase three. So it'll give us another opportunity, again with a different dosing regimen in this.
[07:14]
A
Fascinating. And we don't have time to discuss the nuances today of why one medicine with GIP agonism works well and the other with antagonism works well. But we'll leave that as a teaser for our audience to at some point we'll try to come back to and talk about next up. Cervotide.
[07:38]
B
Yeah, so cervidutide is an interesting molecule and there are others like this, also a unimolecular multiagonist, but now it's GLP1 Agonism with glucagon receptor agonist. So a dual agonist, which is GLP1 and glucagon. And there were trials presented at the ADA, the synchronized one study, which was an obesity study, and the Synchronized Mastle study, which was looking at metabolic liver disease. And in these trials, about on average, 12 to 15% reduction in body weight over time. So very robust with body weight reduction. But the glucagon receptor agonist is very specific to the liver. So the liver, I mean, glucagon receptors are highly expressed on hepatocytes and it has some very interesting effects in people and positive effects in people with metabolic liver disease as well as the weight gain. So probably that the improvement you see in liver fat and potentially in fibrosis as well, is sort of disproportionate to the amount of weight loss and this is indicating that this glucagon agonism is having a real effect on the liver.
[08:47]
A
That's fascinating. So completely different mechanism with really a very different target organ than we've seen in other medicines we have. Then next up, as we continue rolling on cagrycema.
[09:06]
B
Okay, so cagrycema. So this now is not what we would call a unimolecular multi agonist. So one molecule with multi agonist activity. This is two separate medications in one dual chamber pen. So this is semaglutide, which we know as Ozempic or Wegovy. So semaglutide with cogrillentide. So cogrillentide is an amylin receptor agonist. So amylin is also a nutrient stimulated hormone. It's secreted along with insulin from the pancreatic beta cell. It has some very interesting central effects to increase satiety. It also slows gastric emptying. It reduces postprandial glucagon concentrations. The bottom line is it has some very important metabolic effects to lower body weight and also improve glycemia and probably some other effects. So now this is a combination of these two. And there were several phase three trials that were reported at the American Diabetes association, and these were called the reimagined studies in type 2 diabetes. So very robust improvements in GLUC, those A1C reductions, you know, in the 1.9 to 2.3% range, and very good weight reduction, particularly in patients with type 2 diabetes that tend to lose less body weight. So, you know, up to 14, 12, 14% average weight reduction in these studies. So, and I will mention one other thing, that there was a study which is the reimagine. I think it's a reimagined 2 study. It is reimagined 2 which compared actually CAGRY, SEMA, 2 semaglutide and 2 cagrillantide given separately, showing that the CAGRY SEMA, so having this combination was more potent than semaglutide alone with respect to glucose lowering and with respect to weight loss. You have something a bit more potent by adding these complementary mechanisms of the amylin analog with the GLP1 receptor agonist, semaglutide, in this case.
[11:15]
A
That is fascinating. You know, Juan, I can feel the anxiety rising in our listeners as they are thinking, you know, I just got used to treating and talking to people about obesity and metabolic disease to begin with. How am I gonna accommodate learning all of these new medicines? Which is why we're talking about it, and to Our listeners, we're not done yet. We got plenty more to still discuss today. So let's go on now to Zanaglamide.
[11:49]
B
Oh yeah, so, so there, there is, there is also a combination that is a unimolecular. So it is a single molecule that is GLP1 and amylin. So this amocretin, it's also called again in clinical development and there is an injectable form and also very interesting, an oral form as well. So this has been studied in obesity, in type 2 diabetes and I think will be another potential oral option and injectable for patients. So unlike cagrisoma, which are two separate medications given in one injection, this is actually a single molecule that is an agonist at GLP1 and is also an agonist at amylin receptors. And again a subcutaneous form and an oral form in clinical development, I have to say. So, you know, we have to wait and see what happens with all of these medications. But like you mentioned, there's going to be a lot of them relatively soon.
[12:51]
A
Yeah, and that's interesting. And you mentioned oral and we'll talk a little more later about other orals in development but that's certainly something that many patients like the idea of. Now we'll go on to talk about some single agonists and let's start with the single agonist from a new class and I'm not even sure I'll pronounce this one correctly, so I'll probably need your help here. Barobenetide.
[13:21]
B
Yes, barabenatide. This is an ultra long acting GLP1 receptor agonist. So this is a selective GLP1 receptor agonist, but it is ultra long acting. So ultimately we'll be given or if the trials work out, it'll be given once monthly. And there have been data, phase two data. It's now in a program, it's called Vesper, which is a phase three program looking at this for weight management. Again as with maritide, it's a different molecule clearly, but convenience of once monthly dosing. So I think those will be very interesting data. But that's again in phase three. So there's still some time. But we're seeing this move from, you know, when we started, Neil, you remember this. Well in 2005 it was twice daily, then we went once daily, then we went to once weekly and now we're looking at maybe once every two weeks or once.
[14:16]
A
It's really amazing, Juan, because it just seems that with there's so much innovation and complicated science essentially on the back end that allows us at the front lines to increasingly have medicines that frankly become easy to use. Much easier than, as you said, this evolution from twice a day medicines to once daily to once weekly. And now we're even looking at once monthly, making things easier for us at the front lines in primary care and endocrinology as well as of course our patients who are the ones that are taking the medicines and benefiting from them.
[15:01]
B
Yeah, I would say absolutely. So not only a range of different modalities of administration and regimens, but I would say also a range of different efficacy, safety and tolerability as well. And maybe targeting other parts of this whole cardiorenal metabolic syndrome. So I think it will be more personalized and we'll be able to say, hey, this person with, you know, really a lot of burden of metabolic liver disease may be better with this drug. This patient who Maybe doesn't need 30% weight loss and has had issues with tolerability may need this drug. And this patient who really will only take an oral agent will have the other drug. So I think it'll help us to have all of this to be able to personalize and probably won't be that difficult. I think once, once they're out there and we learn how to use these.
[15:56]
A
Yeah, that's really fascinating and so promising. Let's go on now and discuss a few other medicines in the pipeline. And let's go to the single agonists that are in a new class of medicines. You mentioned Amlin before. In the context of Cagrecema. There are now single amylin agonists. And remind us what amylin does because for most of us, amylin is this molecule that we remember hearing about at some point but don't necessarily know about it.
[16:30]
B
Yes, actually, I mean, amylin is very interesting. So it is a hormone again that's produced and secreted by the pancreatic beta cell. When we secrete insulin, we secrete Amylon as well. It's got central actions which really control energy balance or food intake and satiety, slows gastric emptying of well or regulates gastric empty and to regulate postprandial glucose and lipids. It reduces glucagon concentrations. And in fact the first amylin analog, which was Pramlintide or Simlin, was approved in 2005 for use in people with diabetes. But it was a three times daily injection in combination with or in conjunction with insulin therapy. So now we have these once weekly amylin analogs. You know, we mentioned craglantide in the context of cagrecema. But cragolantide on its own is also being studied for overweight and obesity, as is Petralentide, which is one that there was actually a phase two study presented at the ADA. So we're seeing 10 plus percent reduction in body weight with these, you know, just with the amyl and analog and a distinction, probably one of the important distinctions clinically is very well tolerated. So you're seeing tolerability profiles at almost a mirroring placebo. There's slightly more nausea generally during escalation, but withdrawal rates or stopping of the drug in these studies very comparable to what's seen with placebo. So amylin analogs are very well tolerated and you're getting some very robust weight reduction, not retrotrutide weight reduction, but very, very good weight reduction with these medicines as well. And there's several in clinical development.
[18:17]
A
Wow, that's amazing. And that really is, I mean, boy, would that be welcome, because that's the big issue for a lot of patients and many patients just can't tolerate the GI side effects of GLP1.
[18:31]
B
Yeah, absolutely. So even on its own in some cases, but then again in combination like cagrecema. And there are other combinations now with dual agonists as well that are in clinical development because the actions of an amylin analog and a GLP1 or GLP1 Gipsy are complementary and used together, they might even get more powerful weight reduction for those patients who need it.
[18:57]
A
Yeah. And you know, as we're talking about all these different mechanisms, it also reminds me that there are some patients, when we talk about means, those are always means, but that means there are some patients that either are non responders to a given medicine or don't respond as well as a lot of other people. And these we'll see as this continues, whether or not these different mechanisms might work better for that group than the traditional GLP1 or GLP1 GIP dual agonist.
[19:31]
B
You know, that's a great point. I always say, you know, in these trials, the mean is usually the median. Like you say, you got some super responders, some that respond less, some that are, you know, around the mean. But when we're in practice, sort of each patient is a clinical trial of n equals 1, and we need to individualize, see how they do. And it may be to your point that people who are not responding well may respond to a different drug. And in time we'll learn more about that. But a lot of this just don't know, at this point, but it's nice to have other options to switch them to if they're not responding.
[20:02]
A
Yeah. So talking about individual preferences, let's now talk about oral agents.
[20:08]
B
Yeah. So oral agents, we've got oral semaglutide, but sort of what we're seeing, or the latest kid on the block, if you will, is small molecule oral GLP1 receptor agonists. And there's one that is approved, which is orphoglypron, and it's approved now for weight management either in people without diabetes or with diabetes. So this has the advantage that it could be taken with or without food, with no water restrictions any time of day, because it's a small molecule, not a peptide. And there are a couple of studies for weight management that supported the registration and ARPA Bush, a study called Attain 1 in people without diabetes, Attain 2 in people with diabetes and very again robust weight reduction in Attain 1, for example, and at the highest dose, which in the studies was 36 milligrams, commercially it's a different formulation that's equivalent, but it's 17.2 milligrams. There was an about 11% average reduction in body weight with about 55 or so percent of the patients achieving greater than 10% weight reduction. Again, very robust. And all of these, I should mention, you know, seems like the tolerability profile for the amylan analog is better than the GLP1 receptor. Okay. And we also have oral semaglutide as well that's been studied and approved for type 2 diabetes and also for weight management and very robust weight reduction and now at higher doses for overweight and obesity. So 25 milligrams and still a 14 milligram dose for diabetes. And here seeing very robust reductions in body weight that are over 10% on average. So very important oral agents and then other oral small molecules that are in clinical development as well.
[22:06]
A
Juan, this is. I don't know many people that could have given this type of overview in this amount of time. We're about out of time now. Do you have any final thoughts to the thousands of clinicians that have been really listening carefully to this and are feeling perhaps a sense of both excitement but maybe also a little overwhelmed. Any final thoughts?
[22:33]
B
No, I think, you know, it would be sort of a very overarching thought that obesity is a chronic disease. Most patients with the disease are not on medication or anti obesity medications. So I think having all of these options is going to be important to be able to individualize therapy for patients to get patients on these agents. And I would also say it's not just about the degree of weight loss, but it's the improvement we see with all of these drugs that have been seen kind of across the board with respect to improvements in lipids, in blood pressure and inflammatory markers in quality of life as well. So we're trying to really improve function, improve quality of life, improve cardiometabolic risk factors, and we're doing it with these medications at lower body weight. So I think it's an exciting time and it's great to have agents available, and I think it'll all sort itself out. But I think we need to be really focusing on treating these patients.
[23:36]
A
I think that's such a good point, that overarching issue that right now, less than 1 in 10 people who are eligible for these medicines are actually treated critically. Important. I'm looking forward to all these new choices, and I know all of our listeners and I as well learned a lot from our discussion today. Dr. Juan Frias, thank you so much for joining us.
[23:59]
B
Thank you, Neil.
[24:01]
A
And most of all, of course, as always, thanks to our listeners. Thank you for joining us on this special, special edition of Diabetes Core Update, where we discussed more in the pipeline than I think most of us had any idea was coming, that is there as a result of incredible scientific research and innovation that'll provide medicines eventually for our patients that will make their lives better. This special edition of Diabetes Core Update is sponsored by 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.