October 26, 2026 • 27 mins
We are entering an era of choice in terms of diabetes and obesity therapies. Choice is good, but having a keen understanding of each medication is crucial to avoid being overwhelmed. In this special episode of DOC Updates, host Dr. Neil Skolnik explores the latest amylin-based therapies.
This special episode is sponsored with support from Novo Nordisk.
Presented by:
Neil Skolnik, MD, Professor of Family and Community Medicine, Sidney Kimmel Medical College, Thomas Jefferson University; Associate Director, Family Medicine Residency Program, Abington Jefferson Health
Juan Pablo Frias, MD, Medical Director and Principal Investigator, Los Angeles Institute for Metabolic Research, Adjunct Professor of Medicine at Charles Drew University of Medicine and Science
Selected References:
Garvey, et al. "Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity," N Engl J Med 2025;393:635-647 doi.org/10.1056/NEJMoa2502081
Aroda V, Buzzetti R, Dalskov S et al. "Efficacy and safety of once-weekly cagrilintide–semaglutide (CagriSema) in adults with type 2 diabetes inadequately controlled on diet and exercise (REIMAGINE 1): a randomised, double-blind, placebo-controlled, phase 3a study," The Lancet Diabetes & Endocrinology, 2026; 14, 649-661 doi.org/10.1016/S2213-8587(26)00126-9
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(00:03):
Welcome to the special edition of theAmerican Diabetes Association's Diabetes
Obesity and Cardiometabolic Podcast,
where we will be discussing AMLI-basedtherapies.
I'm your host, Dr. Neil Skolnick,
Professor of Family and Community Medicineat the Sidney Kimmel Medical College
of Thomas Jefferson University.
(00:23):
This special edition is sponsored by Novo.
Joining us today to discuss thiscritically important topic is
Is one of the most prominent clinicaltrialists in diabetes and obesity,
Dr. Juan Pablo Frias.
Dr. Frias is the medical director andprincipal investigator at
(00:46):
the Los Angeles Institute for MetabolicResearch and is an adjunct professor
of medicine at Charles Drew University ofMedicine and Science.
In Los Angeles, California. He hasauthored numerous publications,
including first author publications.
In the boy, there's a long list here:
(01:06):
New England Journal of Medicine,
Lancet, Lancet Diabetes and Endocrinology,
Diabetes, Diabetes, Care and CellMetabolism.
If you read the Diabetes, Obesity,
and Metabolic Literature.
You know Dr. Frias' name. He's also beeninvolved in research on Amlin
for over five years and was first authorof the phase two trial
(01:30):
on Cagrissema that was published in TheLancet.
Juan, I remember the first time that Iheard about Amlin was at a meeting where
you told me about Amlin-based therapies,
and that was over five years ago.
And I remember still your excitement aboutit.
On welcome back to ADA's podcast.
(01:52):
Hey, thanks Neil. Great great to be here.
Appreciate you having me.
You know, it's interesting. AMLI is not afamiliar hormone to many
of the clinicians in our audience,
but it's gonna be important to them tobecome familiar with.
So today I'd like to first cover thephysiology of AMLIN,
what it is, then some of the clinicaltrial data with emphasis on trials that will
(02:18):
soon be relevant to us as practicingclinicians,
since there is a GLP1 AMLI combination.
that is currently being evaluated by theFDA.
We'll talk about those trials in a littlebit,
but first, help us understand AMLIN whatit is and what it does.
(02:38):
Absolutely. So I'll tell you what,
I mean, it's been actually probably 20 ormaybe even 25 years since
I started studying amylen because there isan amylin analog which
was actually ~ launched and andcommercialized called Pramlintide,
or the trade name was Simolin,
(02:59):
in 2005.
And it is short acting. It's given threetimes a day,
but was quite potent and was involved inthose clinical trials early on.
But what we're seeing now are newformulations that are longer acting.
So cagrillantide, which is an amyleneanalog we'll be discussing,
is once weekly. But let's go back to theactual hormone amylene.
(03:22):
So this is a hormone that's produced andsecreted by the pancreatic beta cells.
So the same cells that
Produces and secretes insulin.
So it's co-secreted with insulin by thebeta cell when someone eats.
And it really plays a very important rolein nutrient metabolism.
And three sort of key mechanisms.
(03:44):
One, it binds to receptors in the brain,
which reduce appetite and very importantlyalso increase satiety,
so the sense of fullness.
It has effects on gastric emptying.
So it modulates gastric emptying.
So it improves or or I would say modulatespostprandial glucose,
(04:06):
so the rate at which glucose empties astomach.
And it also has a very important effect onthe pancreatic alpha cell,
which produces and secretes glucagon.
So in the postprandial state, or aftersomeone eats,
it reduces glucagon. And that's what youwant to see.
So
Central effects to improve satiety andreduce appetite,
(04:27):
effects on gastric emptying, which sort ofslow or modulate the release
of food after a meal, and improvements inpostpranial glucagon concentrations,
which you want to see low after a meal.
So those are the main actions of thehormone amelin.
So th that's interesting. So some of thoseactions seem to overlap with
(04:50):
the GLP ones, but not all of them.
~ and I know you were involved in theearly clinical trials,
as you said. So given AMLIN's effects,
what was the thinking about how it mightwork in a complementary way with
the GLP one?
So that's important. And actually,
you mentioned something super important isthat these are distinct receptors.
So it's not, when we talk about incretinsor GLP1 medicines,
(05:14):
amylen is a different gut hormone.
So it's not an incritin, and it does nothave the so-called increotin effect,
which GLP1 based medicines have,
which is to augment nutrient stimulatedinsulin secretion.
So it's secreted along with insulin andhas those effects that I mentioned.
(05:34):
Four. But it does have distinct receptorsthat are central.
So, you know, you have GLP1 hitting GLP1receptor centrally to reduce appetites.
You have amylin hitting amylene receptorscentrally.
So sort of some overlapping effects there.
Both of them actually reduce glucagonconcentrations.
(05:58):
Both GLP1 and AMILINE.
slow or modulate gastric emptying.
So again, these are distinct receptors.
Some of the actions overlap, but some aredistinct.
And and that's why they're they arecomplementary when when combined.
And that's what we've shown in theclinical trials,
(06:18):
both in the phase two and now in phasethree.
So Juan, can you share with us a bit aboutthe early clinical data and
how you felt about it as the data emergedfor for both obesity and diabetes?
Yeah, absolutely. So we conducted,
and I was the the lead investigator on ona phase two study,
(06:39):
and this was in people with type twodiabetes.
And as I recall, they were treated withwith mecformin,
SGLT2 inhibitors, with or without asulfonyl urea as well.
A1C a little over eight percent ofbaseline.
But the bottom line is that we studied thecombination of cagrillantite,
so the long acting amylen analog andsemaglutide.
(07:01):
well-known GLP1 receptor Agnes,
both at a dose of 2.4 milligrams onceweekly.
So we slowly escalated to that,
those doses. But importantly we comparedit to the so-called monocomponents.
So there was one arm which was CAGRECEMA,
one arm which was just semaglutide,
(07:21):
and then one arm that was justcagrillentide.
So now we were comparing the combinationto the individual components.
And it was double blind
not placebo controlled, it was the thesewere all active medications.
And we studied these patients for 32weeks.
And again, this was injected once weekly,
subcutaneously. And we actually sawgreater A1C reduction.
(07:45):
This was numerically greater withCAGRISEMA.
I mean, very robust A1C reduction from8.2,
there was a 2.2% ~ reduction in hemoglobinA1C.
As I recall, it was 1.8% with semaglutide.
And close to 1% with cagrillantide alone.
But we got better effect with thecombination compared to the individual components.
(08:09):
And particularly for weight loss,
I mean the weight loss was quiteimpressive.
For 32 weeks, we saw with CAGRI SEMA,
the combination, 16% average weightreduction with
the combination compared to 5% withsemaglutide and 8%.
With cagrillentide. And at 32 weeks,
(08:30):
I mean, in in actually in all of the arms,
it was still reductions that were ongoingin in body weight,
because usually that plateaus at about ayear on average.
So again, these were, you know,
it was about 90 or so participants.
So some you know, smallish phase twostudy,
but gave us a very good indication thatthe combination,
again, because of these complementaryactions,
(08:52):
was likely better.
with respect to weight and maybe toglucose lowering than the individual components,
a semaglutide alone or cagrillantitealone.
So I think they sort of helped prove thisthis hy or beginning
to prove the hypothesis. And certainly itwas it was evidence that we should move
(09:12):
on to to phase three and look at this bothfor diabetes and for weight management.
Yeah, that that must have been veryexciting.
How'd you feel when you saw those results?
'Cause those are impressive results.
You know, I I wouldn't say I was shocked,
but I was, you know, pleasantly surprised.
~ I have to say that I was somewhatsurprised that the sumaglutide
(09:34):
did not do better. And that happenssometimes in small studies
and because we've seen in people withdiabetes greater weight loss with semaglutide
alone at 2.4 milligrams, somewhere in the10% range.
But again, it was only 32 weeks.
You don't know what happens beyond that.
And in each of the three arms,
there was still reduction ongoing.
(09:55):
I I thought the results with cagrillantitealone were very impressive
to have an eight percent weight reductionon average of 32 weeks.
So I I think that was very good sort ofproof of concept that an amelin analog,
even on its own, could have some very niceeffects.
And I and I would say something else aboutthe phase two studies,
(10:16):
it was really well tolerated.
~ so the typical effects, side effectsthat you see with with increin-based
therapies, ~ you see with amylin as well.
So GI side effects are the most common.
But there were ~ and they tend to occurduring escalation and then most mild
or moderate in severity and tend todissipate or reduce over time.
(10:40):
So you need to start low and go slow withthe escalation.
But I recall that with CAGRICEMA,
there were
No patients that discontinued the trialdue to GI side effects during
the entire 32 weeks, which was,
I think, a very good signal that it was itwas being tolerated well.
So you weren't getting sort of an additiveeffect of potential side effects.
(11:01):
So I think that's we we always have tobalance obviously the tolerability with
the efficacy.
Yeah, that that's a really good point.
Let's move on to the more recent clinicaltrial data.
There's the redefined studies and thereimagined trials.
Can you go over some of the phase threedata that we now have?
(11:23):
Yeah, absolutely. So very robust phasethree.
So after the phase two study, the decisionwas made by NOVA to move into phase
three, both for weight management andspecifically for type two diabetes.
So the reimagined program is a largeprogram in type two diabetes.
And then the redefined program,
(11:44):
a program with the primary endpoint beingbody weight.
And most of these studies are in peoplewithout diabetes.
But from a regulatory perspective,
and certainly from what we want to see asclinicians,
it was also a study. It was ~ it wasredefined two,
which was specifically in patients withtype two diabetes with
the primary endpoint of weight loss.
(12:05):
So these were longer-term studies,
68 weeks in general. So now you'regetting,
you know, is there where does the theweight loss or the A1C reduction plateau?
And ~ in redefined one.
was this this was in people with obesitywithout type two diabetes
(12:25):
was was ~ it was an important study itcompared cagrillantite
to ~ to to cagricema and semaglutide soquite similar to what we
did in phase two but this was in peoplewithout diabetes now we were looking
at the combination versus the individualcomponents and here again
(12:47):
You know, we saw very impressive weightloss with the combination,
which was greater than the individualcomponents.
I mean, depending on which estimate waslooked at with the hypothetical
or efficacy estimate, it was approximately23% weight reduction with
the combination compared to around 16%with semaglutide,
(13:08):
which is what we'd seen in semaglutide inpeople without diabetes in the past,
and about 12% with cagrillantite,
so very good weight.
With cadrillantite as well, and kind of asimilar side effect profile.
I think, I think quite manageable,
but again, we don't want to minimize thiswith GI side effects being
the most important, but both mild tomoderate and severity.
(13:30):
So I think we sort of, you know,
although the phase two study was in peoplewith type two diabetes,
and this study, which is redefined one,
was in people without diabetes,
we saw sort of similar, directionallysimilar results with quite impressive weight
reduction.
The combination, you know, as high astwenty three percent on average
in the efficacy estimate.
(13:52):
Interesting. And ~ you just never knowuntil you study it whether these individual
components are gonna have a greater effecttogether or are gonna have greater side
effects and it's fortunate they don't havegreater side effects together.
No, that's a good point. I mean,
you don't know till you study,
even though you see, you know,
you've got the mechanism of action,
(14:12):
you certainly have, you know, a breadth ofdata for many years with semaglutide,
and you think based on the mechanisms inearlier trials that these are
the types of results you get, you don'tknow until you do it.
And you mentioned, I mean, I think veryimportantly,
you don't know what the side effectprofile is going to be.
And thankfully, you know, it was it wassomething that
(14:32):
That I think, and this is my opinion,
once this is launched and in clinicalpractice will be will be very manageable just
as we manage GLP one medicines today.
Yeah, and can you also ~ talk about thediabetes trials with Cagri Semin?
Yeah, so the diabetes trials were the theso-called reimagined trials,
(14:53):
and there are a number of these of thesestudies.
So in reimagined one versus placebo,
there was significantly greater A1Creduction with CAGRECEMA you you would expect.
I mean, almost a 2% point reduction inhemoglobin A1C,
and also very robust weight loss.
Though in these type two diabetes trials,
the primary end point is A1C. We sawsomewhere around 15% weight loss.
(15:19):
In people with type 2 diabetes,
which is very, very robust for thatpopulation.
But then Reimagine 2 actually looked atpeople already
on anti-hyperglycemic agents, so metforminwith or without SGLT2 inhibitor.
And as with the phase two study,
looked at CAGRICEMA versus semaglutidealone,
(15:41):
2.4 milligrams versus cagrillentide.
And we saw
greater reduction in body weight andhemoglobin A one C with
the combination compared to the individualcomponents.
So it looks like and and again,
similar from a safety perspective,
quite comparable safety profile as well.
(16:01):
So I think very encouraging data.
Yeah, for both diabetes and obesity.
Now, whenever we treat either one ofthese,
it's not just about weight, it's not justabout blood sugar,
it's also about the broader set ofcardiometabolic parameters.
Can you touch on that? 'Cause I saw arecent trial on blood pressure with CAGRECEMA.
(16:25):
Yeah, no, no, absolutely. And that's socritical.
I mean, we're we're treating, you know,
we're not treating just to reduce weight.
I mean, we want to improve health.
And most of these patients haveobesity-related complications or will develop these
complications, whether they're metaboliccomplications like prediabetes
or diabetes or hypertension ordyslipidemia,
(16:47):
~ or biomechanical complications likeosteoarthritis or obstructive sleep apnea,
and we can't
you know, discount the the psychologicalcomplications as well.
But if we look specifically at thecardiovascular risk factors,
and there was a a recent analysis or oradditional data from redefined one.
(17:08):
So redefined one again was ~ these werewere patients without diabetes that were
treated ~ with CAGRECEMA or cagrillentide.
But the bottom the bottom line is we sawvery robust improvement
improvements in in blood pressure in inthat trial.
So up to in systolic blood pressure,
(17:30):
up to an average of slightly over 10millimeters of mercury,
with about 40% of the patients that weretreated with antihypertensive agents
actually stopping those antihypertensives.
So from a clinical perspective issomething that with these medications
and with weight loss
You know, it's important to know that wemay need to make adjustments,
(17:51):
particularly in blood pressuremedications,
as we're escalating these and patients areare losing weight.
Mm-hmm. That that's important.
And effect on lipids.
Yeah, improvements in in lipid parametersas well,
primarily triglycerides, but alsoincreases in in HDL,
cholesterol. I would say improvementsalso.
(18:13):
I mean, very large. I I think it wassomewhere around,
you know, 65-ish percent, maybe slightlymore improvements in
in highly sensitive CRP. So ~ improvementsin inflammatory markers as well.
And then there have been, you know,
looks also at body composition.
So
A real improvement, not only just in insort of a more kind of
(18:36):
I wouldn't say primitive gross measure ofbody composition,
which would be waist circumference,
but you're getting it looks like most ofthis fat is being lost,
or the weight is being lost as fat fromvisceral adiposity,
which is where we want to lose it.
But this has been shown also with with MRIstub studies as well.
So I think you know the the weight lossseems to be coming from the right place.
(19:00):
And then we're getting these improvementsthat have been shown in these studies
in cardiometabolic or cardiovascular riskfactors as well.
So we talk primarily about CAGRI SEMAbecause that is the one that is closest
to FDA approval, but it's not the onlyAmlin agonist out there.
Can you just touch on some of the others?
(19:21):
Because there there are some others thatare in the pipeline,
is that correct?
Yeah, no, no, no, absolutely. LR alantiteis an in also a long acting amylin
analog that's it's in clinical developmentnow in phase three.
And ~ and that is it's a lily drug,
(19:41):
again, investigational and and beingstudied along coglantide as well,
being studied sort of as monotherapy aswell for for weight management.
So there's petrolantide, which is anotherone that's that now just recently
in Milan, actually at the EASD,
the European Diabetes Meeting,
there was phase two data and peoplelooking at weight management
(20:04):
and people without diabetes. And this is aRoche drug,
and they've completed a trial now,
Roche in Zealand, I should say,
completed a trial of phase two and typetwo diabetes as well.
That hasn't been
Published yet, but it's been, you know,
released. The top line data have beenreleased.
So the bottom line is that there are otherlong-acting ambient analogs that are,
(20:27):
and there are others as well, but ~ thatare in either phase two
or now several starting phase threeclinical trials ~ and and look look quite
promising.
Particularly from a tolerabilityperspective.
It looks and we'll need to see the dataobviously,
you know, in greater detail in the phasethree trials,
(20:47):
but certainly looks like it may be bettertolerated than GLP
one medicines in general.
that's interesting and that it's soimportant clinically because ~ one,
these are challenging medicines for a lotof patients and there also
are patients who are just unable to doseescalate.
We've all ~ seen that and a ~ more easilytolerated medicine certainly would
(21:12):
be very attractive.
I agree. And I and it gives you at the endof the day that that,
you know, theoretically could give youbetter persistence.
And you know, even if and and I would say,
you know, in general, when we look at thedegree of weight loss,
and we've seen this in the CAGRI semaversus cagrillantite alone,
and we've seen this with some of the theother long-acting amylin,
(21:34):
the the weight reduction is not on theorder of what you get with semaglutide
or trzepatite you know retrotrutide,
but not everyone needs.
twenty, thirty percent weight loss.
I mean, people may need less or may nottolerate other medications
and and persistence may end up improving ~effectiveness in the real world as well.
(21:56):
So I think it's nice to have theseoptions.
I I agree with you. I think that ~ one ofthe things we've learned
is that obesity is in a way the soil outof which all these other cardiometabolic
problems, hypertension, cholesterol,
mash, ~ HEFPEF grow.
And to have something where we can feelmore comfortable treating people
(22:21):
at lower levels of obesity. I believe nowthe average
BMI at which people are treated issomewhere above 35.
And and that's not what we should need towait for.
Yeah, I would agree. I mean we need to bewe need to be treating this earlier
if we're seeing the trajectory going we'rereally preventing,
(22:42):
preventing at the end of the day andpreventing these obesity related complications.
So CAGRICEME is the ~ amlin agonistcombined with
s semiglutide that is most advanced now.
It's at the FDA, it it they will ~ declarewhatever they declare probably
(23:05):
by the end of the year. Where do you seethis fitting in
to our now more expansive set of choices?
That is a great question. I think,
you know, based on the degree of weightloss,
I mean, I would start with saying peoplethat need to lose significant weight.
(23:26):
I mean, if someone, you know, just needs alittle weight loss,
there may be other options for them.
There may be oral options, there may be,
you know, less potent medications,
or maybe this at a lower dose.
But I think someone who really wouldbenefit from significant weight loss.
I would also say that, you know,
it it could be someone who's who'stransitioning already on a medication
(23:51):
and maybe has plateaued and is,
you know, would like additional weightloss and is at the highest dose
of whatever weight management medicationthey're on.
This could be sort of a a a step up,
if you will.
also for for patients. So that's sort ofyou know big picture where I would
see this this being used. But certainly Ithink there's utility with a
(24:13):
lot of these very potent medications,
potentially at lower doses.
That's interesting. Yeah. Yeah.
We don't we often don't think about that,
but I I think you're right. We'll at somepoint be talking about other potent
medicines, ~ where, you know, we now havean option of lower doses which might
be better tolerated. Right.
(24:34):
and i it's gonna be this balance.
We like choices, but choices can also leadto ~ inertia when
you can't decide among
The choices. And I think that particularlyfor our broad group
of primary care clinicians out there,
we are entering an era of choice withregard to medicines
(24:57):
for treating obesity, GLP 1 basedmedicines for treating diabetes.
And choice is always good and bad,
right? You you you need to know yourscience.
You need to know the medicines to not beimpeded by an overwhelming
Amount of choices. Juan, we're about outof time.
(25:18):
Any final thoughts you want to share forour listeners?
Yeah, well, I you made a great point.
I think at the end of the day,
you know, we need to, to the extentpossible,
avoid clinical inertia, realize that thisis a disease that has many,
many very important complications that weneed to either improve or prevent.
(25:39):
So we need to get comfortable with thesemedications and and use them.
And you know, quite frankly, I think it'snice to have all of these choices.
This is such a complex disease.
That for people to have different sort ofpathways,
if you will, that are mitigated or thatare addressed,
I think will be important for many,
(25:59):
many people to have both the GLP1 with theAMLIN,
for example. So that's really where we'reheaded with this.
And the last thing I would say is,
you know, the weight reduction is clearlyimportant.
Patients need to be patient and they needto realize that at the lower doses,
they may not lose that much, but we startlow to improve tolerability,
but at the end of the day.
(26:20):
I like to show my patients, look what yourlipids are doing,
look what your ALT and AST is doing.
Even if you don't have, you know,
significant metabolic liver disease.
We're seeing improvements in so manymarkers that I think that helps patients stay
on the medications as well. They theyreally can see that their entire sort
of their health is improving.
(26:41):
Well, those are such good points,
Juan. This has been a great discussion.
Doctor Juan Pablofrias, thank you so muchfor joining us.
Thank you. Thanks for having me,
Neil.
And to our listeners, thank you forjoining us on this special edition
of ADA's Diabetes, Obesity, andCardiometabolic Podcast.
This special edition is sponsored by Novofor the American Diabetes Association.
(27:05):
I'm Dr. Neil Skolnick. Till next time,
stay safe and keep learning.
Welcome to the special edition of theAmerican Diabetes Association's Diabetes
Obesity and Cardiometabolic Podcast,
where we will be discussing AMLI-basedtherapies.
I'm your host, Dr. Neil Skolnick,
Professor of Family and Community Medicineat the Sidney Kimmel Medical College
of Thomas Jefferson University.
(00:23):
This special edition is sponsored by Novo.
Joining us today to discuss thiscritically important topic is
Is one of the most prominent clinicaltrialists in diabetes and obesity,
Dr. Juan Pablo Frias.
Dr. Frias is the medical director andprincipal investigator at
(00:46):
the Los Angeles Institute for MetabolicResearch and is an adjunct professor
of medicine at Charles Drew University ofMedicine and Science.
In Los Angeles, California. He hasauthored numerous publications,
including first author publications.
In the boy, there's a long list here:
(01:06):
New England Journal of Medicine,
Lancet, Lancet Diabetes and Endocrinology,
Diabetes, Diabetes, Care and CellMetabolism.
If you read the Diabetes, Obesity,
and Metabolic Literature.
You know Dr. Frias' name. He's also beeninvolved in research on Amlin
for over five years and was first authorof the phase two trial
(01:30):
on Cagrissema that was published in TheLancet.
Juan, I remember the first time that Iheard about Amlin was at a meeting where
you told me about Amlin-based therapies,
and that was over five years ago.
And I remember still your excitement aboutit.
On welcome back to ADA's podcast.
(01:52):
Hey, thanks Neil. Great great to be here.
Appreciate you having me.
You know, it's interesting. AMLI is not afamiliar hormone to many
of the clinicians in our audience,
but it's gonna be important to them tobecome familiar with.
So today I'd like to first cover thephysiology of AMLIN,
what it is, then some of the clinicaltrial data with emphasis on trials that will
(02:18):
soon be relevant to us as practicingclinicians,
since there is a GLP1 AMLI combination.
that is currently being evaluated by theFDA.
We'll talk about those trials in a littlebit,
but first, help us understand AMLIN whatit is and what it does.
(02:38):
Absolutely. So I'll tell you what,
I mean, it's been actually probably 20 ormaybe even 25 years since
I started studying amylen because there isan amylin analog which
was actually ~ launched and andcommercialized called Pramlintide,
or the trade name was Simolin,
(02:59):
in 2005.
And it is short acting. It's given threetimes a day,
but was quite potent and was involved inthose clinical trials early on.
But what we're seeing now are newformulations that are longer acting.
So cagrillantide, which is an amyleneanalog we'll be discussing,
is once weekly. But let's go back to theactual hormone amylene.
(03:22):
So this is a hormone that's produced andsecreted by the pancreatic beta cells.
So the same cells that
Produces and secretes insulin.
So it's co-secreted with insulin by thebeta cell when someone eats.
And it really plays a very important rolein nutrient metabolism.
And three sort of key mechanisms.
(03:44):
One, it binds to receptors in the brain,
which reduce appetite and very importantlyalso increase satiety,
so the sense of fullness.
It has effects on gastric emptying.
So it modulates gastric emptying.
So it improves or or I would say modulatespostprandial glucose,
(04:06):
so the rate at which glucose empties astomach.
And it also has a very important effect onthe pancreatic alpha cell,
which produces and secretes glucagon.
So in the postprandial state, or aftersomeone eats,
it reduces glucagon. And that's what youwant to see.
So
Central effects to improve satiety andreduce appetite,
(04:27):
effects on gastric emptying, which sort ofslow or modulate the release
of food after a meal, and improvements inpostpranial glucagon concentrations,
which you want to see low after a meal.
So those are the main actions of thehormone amelin.
So th that's interesting. So some of thoseactions seem to overlap with
(04:50):
the GLP ones, but not all of them.
~ and I know you were involved in theearly clinical trials,
as you said. So given AMLIN's effects,
what was the thinking about how it mightwork in a complementary way with
the GLP one?
So that's important. And actually,
you mentioned something super important isthat these are distinct receptors.
So it's not, when we talk about incretinsor GLP1 medicines,
(05:14):
amylen is a different gut hormone.
So it's not an incritin, and it does nothave the so-called increotin effect,
which GLP1 based medicines have,
which is to augment nutrient stimulatedinsulin secretion.
So it's secreted along with insulin andhas those effects that I mentioned.
(05:34):
Four. But it does have distinct receptorsthat are central.
So, you know, you have GLP1 hitting GLP1receptor centrally to reduce appetites.
You have amylin hitting amylene receptorscentrally.
So sort of some overlapping effects there.
Both of them actually reduce glucagonconcentrations.
(05:58):
Both GLP1 and AMILINE.
slow or modulate gastric emptying.
So again, these are distinct receptors.
Some of the actions overlap, but some aredistinct.
And and that's why they're they arecomplementary when when combined.
And that's what we've shown in theclinical trials,
(06:18):
both in the phase two and now in phasethree.
So Juan, can you share with us a bit aboutthe early clinical data and
how you felt about it as the data emergedfor for both obesity and diabetes?
Yeah, absolutely. So we conducted,
and I was the the lead investigator on ona phase two study,
(06:39):
and this was in people with type twodiabetes.
And as I recall, they were treated withwith mecformin,
SGLT2 inhibitors, with or without asulfonyl urea as well.
A1C a little over eight percent ofbaseline.
But the bottom line is that we studied thecombination of cagrillantite,
so the long acting amylen analog andsemaglutide.
(07:01):
well-known GLP1 receptor Agnes,
both at a dose of 2.4 milligrams onceweekly.
So we slowly escalated to that,
those doses. But importantly we comparedit to the so-called monocomponents.
So there was one arm which was CAGRECEMA,
one arm which was just semaglutide,
(07:21):
and then one arm that was justcagrillentide.
So now we were comparing the combinationto the individual components.
And it was double blind
not placebo controlled, it was the thesewere all active medications.
And we studied these patients for 32weeks.
And again, this was injected once weekly,
subcutaneously. And we actually sawgreater A1C reduction.
(07:45):
This was numerically greater withCAGRISEMA.
I mean, very robust A1C reduction from8.2,
there was a 2.2% ~ reduction in hemoglobinA1C.
As I recall, it was 1.8% with semaglutide.
And close to 1% with cagrillantide alone.
But we got better effect with thecombination compared to the individual components.
(08:09):
And particularly for weight loss,
I mean the weight loss was quiteimpressive.
For 32 weeks, we saw with CAGRI SEMA,
the combination, 16% average weightreduction with
the combination compared to 5% withsemaglutide and 8%.
With cagrillentide. And at 32 weeks,
(08:30):
I mean, in in actually in all of the arms,
it was still reductions that were ongoingin in body weight,
because usually that plateaus at about ayear on average.
So again, these were, you know,
it was about 90 or so participants.
So some you know, smallish phase twostudy,
but gave us a very good indication thatthe combination,
again, because of these complementaryactions,
(08:52):
was likely better.
with respect to weight and maybe toglucose lowering than the individual components,
a semaglutide alone or cagrillantitealone.
So I think they sort of helped prove thisthis hy or beginning
to prove the hypothesis. And certainly itwas it was evidence that we should move
(09:12):
on to to phase three and look at this bothfor diabetes and for weight management.
Yeah, that that must have been veryexciting.
How'd you feel when you saw those results?
'Cause those are impressive results.
You know, I I wouldn't say I was shocked,
but I was, you know, pleasantly surprised.
~ I have to say that I was somewhatsurprised that the sumaglutide
(09:34):
did not do better. And that happenssometimes in small studies
and because we've seen in people withdiabetes greater weight loss with semaglutide
alone at 2.4 milligrams, somewhere in the10% range.
But again, it was only 32 weeks.
You don't know what happens beyond that.
And in each of the three arms,
there was still reduction ongoing.
(09:55):
I I thought the results with cagrillantitealone were very impressive
to have an eight percent weight reductionon average of 32 weeks.
So I I think that was very good sort ofproof of concept that an amelin analog,
even on its own, could have some very niceeffects.
And I and I would say something else aboutthe phase two studies,
(10:16):
it was really well tolerated.
~ so the typical effects, side effectsthat you see with with increin-based
therapies, ~ you see with amylin as well.
So GI side effects are the most common.
But there were ~ and they tend to occurduring escalation and then most mild
or moderate in severity and tend todissipate or reduce over time.
(10:40):
So you need to start low and go slow withthe escalation.
But I recall that with CAGRICEMA,
there were
No patients that discontinued the trialdue to GI side effects during
the entire 32 weeks, which was,
I think, a very good signal that it was itwas being tolerated well.
So you weren't getting sort of an additiveeffect of potential side effects.
(11:01):
So I think that's we we always have tobalance obviously the tolerability with
the efficacy.
Yeah, that that's a really good point.
Let's move on to the more recent clinicaltrial data.
There's the redefined studies and thereimagined trials.
Can you go over some of the phase threedata that we now have?
(11:23):
Yeah, absolutely. So very robust phasethree.
So after the phase two study, the decisionwas made by NOVA to move into phase
three, both for weight management andspecifically for type two diabetes.
So the reimagined program is a largeprogram in type two diabetes.
And then the redefined program,
(11:44):
a program with the primary endpoint beingbody weight.
And most of these studies are in peoplewithout diabetes.
But from a regulatory perspective,
and certainly from what we want to see asclinicians,
it was also a study. It was ~ it wasredefined two,
which was specifically in patients withtype two diabetes with
the primary endpoint of weight loss.
(12:05):
So these were longer-term studies,
68 weeks in general. So now you'regetting,
you know, is there where does the theweight loss or the A1C reduction plateau?
And ~ in redefined one.
was this this was in people with obesitywithout type two diabetes
(12:25):
was was ~ it was an important study itcompared cagrillantite
to ~ to to cagricema and semaglutide soquite similar to what we
did in phase two but this was in peoplewithout diabetes now we were looking
at the combination versus the individualcomponents and here again
(12:47):
You know, we saw very impressive weightloss with the combination,
which was greater than the individualcomponents.
I mean, depending on which estimate waslooked at with the hypothetical
or efficacy estimate, it was approximately23% weight reduction with
the combination compared to around 16%with semaglutide,
(13:08):
which is what we'd seen in semaglutide inpeople without diabetes in the past,
and about 12% with cagrillantite,
so very good weight.
With cadrillantite as well, and kind of asimilar side effect profile.
I think, I think quite manageable,
but again, we don't want to minimize thiswith GI side effects being
the most important, but both mild tomoderate and severity.
(13:30):
So I think we sort of, you know,
although the phase two study was in peoplewith type two diabetes,
and this study, which is redefined one,
was in people without diabetes,
we saw sort of similar, directionallysimilar results with quite impressive weight
reduction.
The combination, you know, as high astwenty three percent on average
in the efficacy estimate.
(13:52):
Interesting. And ~ you just never knowuntil you study it whether these individual
components are gonna have a greater effecttogether or are gonna have greater side
effects and it's fortunate they don't havegreater side effects together.
No, that's a good point. I mean,
you don't know till you study,
even though you see, you know,
you've got the mechanism of action,
(14:12):
you certainly have, you know, a breadth ofdata for many years with semaglutide,
and you think based on the mechanisms inearlier trials that these are
the types of results you get, you don'tknow until you do it.
And you mentioned, I mean, I think veryimportantly,
you don't know what the side effectprofile is going to be.
And thankfully, you know, it was it wassomething that
(14:32):
That I think, and this is my opinion,
once this is launched and in clinicalpractice will be will be very manageable just
as we manage GLP one medicines today.
Yeah, and can you also ~ talk about thediabetes trials with Cagri Semin?
Yeah, so the diabetes trials were the theso-called reimagined trials,
(14:53):
and there are a number of these of thesestudies.
So in reimagined one versus placebo,
there was significantly greater A1Creduction with CAGRECEMA you you would expect.
I mean, almost a 2% point reduction inhemoglobin A1C,
and also very robust weight loss.
Though in these type two diabetes trials,
the primary end point is A1C. We sawsomewhere around 15% weight loss.
(15:19):
In people with type 2 diabetes,
which is very, very robust for thatpopulation.
But then Reimagine 2 actually looked atpeople already
on anti-hyperglycemic agents, so metforminwith or without SGLT2 inhibitor.
And as with the phase two study,
looked at CAGRICEMA versus semaglutidealone,
(15:41):
2.4 milligrams versus cagrillentide.
And we saw
greater reduction in body weight andhemoglobin A one C with
the combination compared to the individualcomponents.
So it looks like and and again,
similar from a safety perspective,
quite comparable safety profile as well.
(16:01):
So I think very encouraging data.
Yeah, for both diabetes and obesity.
Now, whenever we treat either one ofthese,
it's not just about weight, it's not justabout blood sugar,
it's also about the broader set ofcardiometabolic parameters.
Can you touch on that? 'Cause I saw arecent trial on blood pressure with CAGRECEMA.
(16:25):
Yeah, no, no, absolutely. And that's socritical.
I mean, we're we're treating, you know,
we're not treating just to reduce weight.
I mean, we want to improve health.
And most of these patients haveobesity-related complications or will develop these
complications, whether they're metaboliccomplications like prediabetes
or diabetes or hypertension ordyslipidemia,
(16:47):
~ or biomechanical complications likeosteoarthritis or obstructive sleep apnea,
and we can't
you know, discount the the psychologicalcomplications as well.
But if we look specifically at thecardiovascular risk factors,
and there was a a recent analysis or oradditional data from redefined one.
(17:08):
So redefined one again was ~ these werewere patients without diabetes that were
treated ~ with CAGRECEMA or cagrillentide.
But the bottom the bottom line is we sawvery robust improvement
improvements in in blood pressure in inthat trial.
So up to in systolic blood pressure,
(17:30):
up to an average of slightly over 10millimeters of mercury,
with about 40% of the patients that weretreated with antihypertensive agents
actually stopping those antihypertensives.
So from a clinical perspective issomething that with these medications
and with weight loss
You know, it's important to know that wemay need to make adjustments,
(17:51):
particularly in blood pressuremedications,
as we're escalating these and patients areare losing weight.
Mm-hmm. That that's important.
And effect on lipids.
Yeah, improvements in in lipid parametersas well,
primarily triglycerides, but alsoincreases in in HDL,
cholesterol. I would say improvementsalso.
(18:13):
I mean, very large. I I think it wassomewhere around,
you know, 65-ish percent, maybe slightlymore improvements in
in highly sensitive CRP. So ~ improvementsin inflammatory markers as well.
And then there have been, you know,
looks also at body composition.
So
A real improvement, not only just in insort of a more kind of
(18:36):
I wouldn't say primitive gross measure ofbody composition,
which would be waist circumference,
but you're getting it looks like most ofthis fat is being lost,
or the weight is being lost as fat fromvisceral adiposity,
which is where we want to lose it.
But this has been shown also with with MRIstub studies as well.
So I think you know the the weight lossseems to be coming from the right place.
(19:00):
And then we're getting these improvementsthat have been shown in these studies
in cardiometabolic or cardiovascular riskfactors as well.
So we talk primarily about CAGRI SEMAbecause that is the one that is closest
to FDA approval, but it's not the onlyAmlin agonist out there.
Can you just touch on some of the others?
(19:21):
Because there there are some others thatare in the pipeline,
is that correct?
Yeah, no, no, no, absolutely. LR alantiteis an in also a long acting amylin
analog that's it's in clinical developmentnow in phase three.
And ~ and that is it's a lily drug,
(19:41):
again, investigational and and beingstudied along coglantide as well,
being studied sort of as monotherapy aswell for for weight management.
So there's petrolantide, which is anotherone that's that now just recently
in Milan, actually at the EASD,
the European Diabetes Meeting,
there was phase two data and peoplelooking at weight management
(20:04):
and people without diabetes. And this is aRoche drug,
and they've completed a trial now,
Roche in Zealand, I should say,
completed a trial of phase two and typetwo diabetes as well.
That hasn't been
Published yet, but it's been, you know,
released. The top line data have beenreleased.
So the bottom line is that there are otherlong-acting ambient analogs that are,
(20:27):
and there are others as well, but ~ thatare in either phase two
or now several starting phase threeclinical trials ~ and and look look quite
promising.
Particularly from a tolerabilityperspective.
It looks and we'll need to see the dataobviously,
you know, in greater detail in the phasethree trials,
(20:47):
but certainly looks like it may be bettertolerated than GLP
one medicines in general.
that's interesting and that it's soimportant clinically because ~ one,
these are challenging medicines for a lotof patients and there also
are patients who are just unable to doseescalate.
We've all ~ seen that and a ~ more easilytolerated medicine certainly would
(21:12):
be very attractive.
I agree. And I and it gives you at the endof the day that that,
you know, theoretically could give youbetter persistence.
And you know, even if and and I would say,
you know, in general, when we look at thedegree of weight loss,
and we've seen this in the CAGRI semaversus cagrillantite alone,
and we've seen this with some of the theother long-acting amylin,
(21:34):
the the weight reduction is not on theorder of what you get with semaglutide
or trzepatite you know retrotrutide,
but not everyone needs.
twenty, thirty percent weight loss.
I mean, people may need less or may nottolerate other medications
and and persistence may end up improving ~effectiveness in the real world as well.
(21:56):
So I think it's nice to have theseoptions.
I I agree with you. I think that ~ one ofthe things we've learned
is that obesity is in a way the soil outof which all these other cardiometabolic
problems, hypertension, cholesterol,
mash, ~ HEFPEF grow.
And to have something where we can feelmore comfortable treating people
(22:21):
at lower levels of obesity. I believe nowthe average
BMI at which people are treated issomewhere above 35.
And and that's not what we should need towait for.
Yeah, I would agree. I mean we need to bewe need to be treating this earlier
if we're seeing the trajectory going we'rereally preventing,
(22:42):
preventing at the end of the day andpreventing these obesity related complications.
So CAGRICEME is the ~ amlin agonistcombined with
s semiglutide that is most advanced now.
It's at the FDA, it it they will ~ declarewhatever they declare probably
(23:05):
by the end of the year. Where do you seethis fitting in
to our now more expansive set of choices?
That is a great question. I think,
you know, based on the degree of weightloss,
I mean, I would start with saying peoplethat need to lose significant weight.
(23:26):
I mean, if someone, you know, just needs alittle weight loss,
there may be other options for them.
There may be oral options, there may be,
you know, less potent medications,
or maybe this at a lower dose.
But I think someone who really wouldbenefit from significant weight loss.
I would also say that, you know,
it it could be someone who's who'stransitioning already on a medication
(23:51):
and maybe has plateaued and is,
you know, would like additional weightloss and is at the highest dose
of whatever weight management medicationthey're on.
This could be sort of a a a step up,
if you will.
also for for patients. So that's sort ofyou know big picture where I would
see this this being used. But certainly Ithink there's utility with a
(24:13):
lot of these very potent medications,
potentially at lower doses.
That's interesting. Yeah. Yeah.
We don't we often don't think about that,
but I I think you're right. We'll at somepoint be talking about other potent
medicines, ~ where, you know, we now havean option of lower doses which might
be better tolerated. Right.
(24:34):
and i it's gonna be this balance.
We like choices, but choices can also leadto ~ inertia when
you can't decide among
The choices. And I think that particularlyfor our broad group
of primary care clinicians out there,
we are entering an era of choice withregard to medicines
(24:57):
for treating obesity, GLP 1 basedmedicines for treating diabetes.
And choice is always good and bad,
right? You you you need to know yourscience.
You need to know the medicines to not beimpeded by an overwhelming
Amount of choices. Juan, we're about outof time.
(25:18):
Any final thoughts you want to share forour listeners?
Yeah, well, I you made a great point.
I think at the end of the day,
you know, we need to, to the extentpossible,
avoid clinical inertia, realize that thisis a disease that has many,
many very important complications that weneed to either improve or prevent.
(25:39):
So we need to get comfortable with thesemedications and and use them.
And you know, quite frankly, I think it'snice to have all of these choices.
This is such a complex disease.
That for people to have different sort ofpathways,
if you will, that are mitigated or thatare addressed,
I think will be important for many,
(25:59):
many people to have both the GLP1 with theAMLIN,
for example. So that's really where we'reheaded with this.
And the last thing I would say is,
you know, the weight reduction is clearlyimportant.
Patients need to be patient and they needto realize that at the lower doses,
they may not lose that much, but we startlow to improve tolerability,
but at the end of the day.
(26:20):
I like to show my patients, look what yourlipids are doing,
look what your ALT and AST is doing.
Even if you don't have, you know,
significant metabolic liver disease.
We're seeing improvements in so manymarkers that I think that helps patients stay
on the medications as well. They theyreally can see that their entire sort
of their health is improving.
(26:41):
Well, those are such good points,
Juan. This has been a great discussion.
Doctor Juan Pablofrias, thank you so muchfor joining us.
Thank you. Thanks for having me,
Neil.
And to our listeners, thank you forjoining us on this special edition
of ADA's Diabetes, Obesity, andCardiometabolic Podcast.
This special edition is sponsored by Novofor the American Diabetes Association.
(27:05):
I'm Dr. Neil Skolnick. Till next time,
stay safe and keep learning.
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