Ania Jastreboff, MD, PhD - The Time is Now, Y-Weight!

March 07, 2024

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00:00OK. The time is now. Why wait?
00:05These are my disclosures.
00:09So let me ask you a question.
00:13Why are we all here today?
00:16Whether you're a scientist,
00:19a physician, a provider, a trainee,
00:23we're all here with one common
00:25goal and that is to help our
00:28patients lead healthier lives.
00:30And within the context of obesity,
00:32that's why we're here today.
00:34And let's think about the fact that
00:37if we can effectively treat obesity,
00:40we can treat, mitigate and potentially
00:44prevent hundreds of other diseases.
00:47And so here we are in
00:50this transformative time,
00:51a time that is transformational because
00:54of the introduction of these new highly
00:57effective anti obesity medications.
00:59And I would argue that this is a
01:02moment in medical history akin to
01:04discoveries such as the discovery of
01:07insulin or the discovery of penicillin.
01:12Honestly treating this one disease
01:14can change the face of medicine and
01:17all of you here in this room and
01:19online are part of that history.
01:22So to illustrate this transformation,
01:24I'm going to show you two patients,
01:26one treated with the older anti obesity
01:29medications and one with the new.
01:32So this is an 18 year old who
01:34I saw her BMI was 57.
01:35She already had obesity related diseases
01:38and had considered bariatric surgery
01:40but had encountered some barriers.
01:42She came to me to see other options.
01:45So what did I do over the next
01:46three to four years?
01:48Well, I used four different medications
01:50and her response was remarkable.
01:53She lost nearly 140 lbs over
01:55those three to four years,
01:57with her BMI decreasing to
01:5931 and her A1C normalizing.
02:01And so with these previous
02:03medications for agents,
02:0445% total body weight loss.
02:06This was possible.
02:07Now let's look at our next patient,
02:11a 49 year old who came to
02:13see me when her BMI was 34.
02:15She had successfully lost weight multiple
02:18times in her life and had regained it,
02:21so losing weight was not the issue,
02:23It's maintaining that weight reduction.
02:25She also had some obesity related diseases.
02:28So what did she do?
02:30Well,
02:30we enrolled her in our surmount one
02:33trial with tirzepatide and this is what
02:36happened over the course of the year.
02:42She lost over 90 lbs,
02:45nearly £100 in the course of this
02:49trial and completely transformed
02:50her health and her life.
02:53So next generation medications,
02:55one agent maybe 45%.
02:56Of course she was a super responder
02:58but this is what we're talking about
03:01when we talk about these new agents.
03:03So we're clearly at this watershed brought
03:05on by the introduction of these highly
03:08effective anti obesity medications.
03:10The older medications it was possible
03:12to achieve this type of obesity
03:14treatment but now with Somagletite
03:16and Tirzepatite really bringing
03:17forward the development of all of
03:19these new anti obesity medications.
03:21Now the ones that we're focusing in
03:23on right now are nutrient stimulated
03:25hormone based therapies or Nushes.
03:27But please know this is only one class
03:30of medications for obesity treatment.
03:32There's active and receptor inhibitors
03:34that can potentially increase lean
03:36mass while decreasing fat mass.
03:38There's an MC4 agonist for monogenic
03:40obesity and there are many
03:42other mechanisms being explored.
03:43So this is just one class.
03:46So in terms of these nutrients,
03:47stimulated hormones, what are they?
03:49Well,
03:50they're hormones that are stimulated
03:51when we eat food and they signal
03:53to various tissues in our body and
03:55our brain about energy homeostasis,
03:57about satiety and potentially
03:59about energy expenditure.
04:01Now,
04:01the one that we're the most
04:02familiar with is GLP one,
04:03because GLP one receptor agonists
04:05have been used for the treatment
04:07of diabetes for nearly two decades.
04:09But there are so many others,
04:11*** Oxintomodulin,
04:11Amylin and right now what's being
04:14explored are dual and triple agonists.
04:17But please know that there are
04:19monotherapies in development as well,
04:21for example with PYY and Amylin.
04:23And this is just the beginning
04:25for this class of medications.
04:27So this is a slide that I update
04:29almost daily because of the
04:31frenetic pace of development of
04:32these new anti obesity medications.
04:35And I'm just highly highlighting
04:36for you here those in phase two
04:39and three of development And so
04:41we have all these new medications
04:43we need to study them and that
04:45was the impetus for Huawei,
04:47the Yale Obesity Research Center
04:48really at its inception to
04:50focus on investigation of these
04:52anti obesity medications,
04:54looking at clinical obesity
04:55research in three areas.
04:57So clinical Physiology,
04:58So not just looking at whether
05:01or how these medications work,
05:03but also using the medications as
05:06probes to better understand obesity,
05:09pathophysiology,
05:10clinical trials to understand if these
05:12medications are safe and effective and if so,
05:15for whom.
05:15And of course,
05:16patient outcomes,
05:17because we need to know how these
05:19medications work in the real world.
05:21Now additionally,
05:22there are 4 themes within Y Wait
05:24collaboration with translational and
05:26basic science, because of course,
05:28we'd have none of these medications
05:29if it wasn't for our basic colleagues,
05:31mentorship of investigators and physicians,
05:35scientists again, to take this forward,
05:37This is going to take many generations
05:39to figure out education of academic
05:42leaders in obesity medicine,
05:43really educating in terms of
05:45the biology of obesity and
05:47understanding obesity is a disease.
05:49And then integration with clinical care,
05:51which we're going to hear about today.
05:53And for all this we really need to build
05:55community which is a really important
05:57facet for all of this and there's amazing
05:59research already ongoing at Yale and
06:01how do we help bring this together.
06:03So there's many researchers looking
06:05at obesity and obesity treatment
06:08and Sonia Caprio,
06:09I'm going to highlight some,
06:10some several of them for you here.
06:11So Sonia Caprio has been leading the
06:14charge in terms of pediatric obesity
06:16research for decades now and now she's
06:18embarking on looking at some magnetite
06:21specifically for youth with obesity
06:22and pre diabetes as well as type 2
06:25and Maffold and she just started
06:27enrolling this summer for this study.
06:29So we anxiously await those results.
06:31There are many other physician
06:33investigators in pediatric obesity and
06:35you'll hear from Michelle Van name today.
06:38What about bariatric surgery and
06:40using these medications before
06:41and after surgical interventions?
06:43Willpower at Yale,
06:45led by Carlos Grillo has been looking
06:47at binge eating and more recently
06:49looking at naltrexone bupropion
06:51after bariatric surgery to look at
06:53whether it can impact loss of control
06:55eating as well as weight regain.
06:57And it's great because the power at Yale
07:00partners with clinician educators to
07:02involve them in this type of research.
07:05The adolescent bariatric surgery program
07:08incredibly robust and now prospectively
07:10looking at mitigating weight regain with
07:13somagletite in their young patients.
07:15And then John Morton partnering
07:17with the Yale Specialty Pharmacy,
07:19looking at implementing medication pathways
07:23before and after surgery at the Yale
07:26Stress Center directed by Rigita Sinha,
07:29who I've just had the incredible pleasure
07:31of working with for so many years,
07:32first as a mentor, now as a collaborator.
07:35We have an RO one looking at somagletite,
07:37basically the impact of Somagletite
07:39on metabolic and stress responses,
07:41predicting weight outcomes,
07:42looking at craving, hunger,
07:44food consumption and of course
07:46we're doing an observed eating task.
07:49And this type of study that is so
07:51involved really requires A-Team.
07:53And at the Yale Stress Center,
07:54we're doing this study as well as several
07:57others looking at obesity treatment.
07:59Now obesity is a neuro metabolic
08:01disease and this is actually
08:03where I started my research.
08:04And now the question is how can we
08:06begin to look at this in terms of
08:08the impact of these medications and
08:09how they are working in the brain?
08:11There's some pilot studies and
08:13smaller studies, some of which we did,
08:15but there's an incredible powerhouse of
08:18investigators at the Yale MRC and the
08:20Pet Center where we can really utilize
08:23these tools to better understand this.
08:25And you're going to hear from
08:26one of these investigators today,
08:27Murray Cirilli.
08:30Now what about cancer?
08:31So cancer is another area that we
08:34are fast moving into looking at the
08:36primary and secondary prevention
08:37with anti obesity medications.
08:40There are thirteen types of
08:41obesity related cancers and one
08:43of them endometrial cancer,
08:45There's a sevenfold increase if
08:47somebody has severe obesity.
08:49And Claire Flannery has been looking
08:51at this since fellowship when she
08:53had a patient with endometrial
08:55hyperplasia who is very young.
08:57And now she's moving forward with
08:59her research looking at obesity
09:00driven endometrial hyperplasia to
09:02potentially use these medications and
09:04look at outcomes in those patients.
09:06She's partnering with Sonia Caprio with
09:09the patients that Sonia so eloquently
09:12or elegantly phenotyped when they
09:14were children looking at the Yale
09:17longitudinal reproductive and obesity cohort.
09:19There are many,
09:20many other avenues to take with
09:23these obesity related cancers and
09:24we look forward to that as well.
09:27Now what about health outcomes
09:28and anti obesity medication.
09:30So you're going to hear an entire
09:32talk about this from Harlan Krumholtz.
09:34Today.
09:34It's so important to look at
09:36different populations, for example,
09:37outcomes in older individuals,
09:39cardiovascular outcomes and beyond.
09:41Now moving into the clinical space,
09:45so you're going to hear a talk about
09:46this not particular to obesity,
09:48but the overall system.
09:50But how can we begin to engage
09:52patients to be partners in studies
09:55with us and invite them to,
09:57to engage in our protocols.
09:58This of course, will take all of us,
10:01the whole team of us,
10:01clinicians,
10:02scientists,
10:02everyone within our programs that
10:04are existing such as the pediatric
10:06program and newer programs like
10:08the Center for Weight management.
10:10I'd also like to highlight that at 8 Devine,
10:12we do have research space and that is
10:15being led by Boo Boo Benini and Diana Rivera.
10:18And and again,
10:19there's so many other opportunities
10:21within the clinical space.
10:23And so here we are.
10:24Why wait?
10:25These are our goals and now into
10:27our workshop.
10:29So we really intend today to take you
10:31from the bench to bedside and beyond.
10:33And so we should do this in order.
10:35But since I'm standing here right now,
10:37I'm going to address briefly some of
10:39the clinical trials that we've done.
10:41Then you're going to hear two
10:43talks that focus on Physiology,
10:45basic Physiology of obesity and
10:47then two clinical Physiology talks.
10:50Then you'll hear a talk about
10:52patient outcomes or health outcomes
10:54and then integration with clinical
10:56care from Doctor McGovern.
10:58OK.
10:58So let's start with clinical
10:59trials and I'm going to start this
11:01section by giving a big thank you,
11:03a huge thank you to YCCI because
11:05all of our clinical trials have
11:07been done at the CSRU with the
11:09staff who's sitting right here
11:11supporting us through all of these
11:13trials and especially Margo and Kim,
11:15who are the research coordinators
11:17that I work with that truly
11:18make all of this possible.
11:20So thank you so much.
11:21We really look forward to
11:22engaging with you and why wait
11:25in in future trials as well.
11:26So here we are in terms of these medications,
11:29let me highlight a few of them and where
11:31we are and how we have participated in
11:33the development of these medications.
11:35So Samaglatide was FDA approved
11:37initially for diabetes and then for
11:40obesity in 2021 and it was really
11:42the first agent that demonstrated
11:44double digit weight reduction.
11:46Now we were part of the select
11:48cardiovascular outcomes trial which
11:50was the first trial that really looked
11:52at patients with obesity without type
11:542 diabetes over 17,000 participants
11:56and what was demonstrated was a
11:5920% reduction in three-point Mace.
12:01So we've been waiting to see
12:03does treating obesity with these
12:05medications improve health outcomes
12:06and the answer is clearly yes.
12:09And now we're seeing these outcomes with HEF,
12:10PEF just released yesterday evidence
12:12of in terms of kidney benefit.
12:15So this is all coming full force Now
12:18we're also part of the step young
12:21trial looking at children aged 6 and
12:23above for treatment with somagotite now
12:25before you think well six years old,
12:28six years old and weighing 160
12:30lbs or 70 kilograms.
12:32So this is severe obesity and we have to
12:35develop options for these young patients.
12:38And so we look forward to that trial.
12:40We're almost fully enrolled at our
12:42site now In terms of tirzepatide,
12:44this was originally FDA approved
12:46for diabetes and then FDA approved
12:48for obesity in 2023 and we were so
12:51honored to be a part of that process.
12:53So I was the lead Pi on the surmount
12:571 tirzepatide trial.
12:59And in this trial,
13:00we demonstrated that with the
13:02highest dose of tirzepatide,
13:03participants on average lost
13:0622.5% of their body weight,
13:07which translated to 52 lbs in just
13:1072 weeks and 40% of individuals
13:13lost over 1/4 of their body weight.
13:15So this is really, truly amazing.
13:17We're moving forward with additional studies.
13:19Now a cohort here about 40% had pre diabetes.
13:23So look out for those outcomes
13:25in the months to come.
13:27And and we're also moving
13:29forward with the surmount MMO,
13:30the cardiovascular outcomes trial and I'm
13:33on the steering committee for that as well.
13:35Now what about CAGRI SEMA,
13:38So this is an Amylin analog with a GL,
13:41P1 receptor agonist also showing
13:43impressive weight reduction.
13:45And I'm on the steering committee for this
13:48cardiovascular outcomes trial as well.
13:50What about Glucagon GLP,
13:52one receptor agonist?
13:54So there's several in development.
13:56The one that's farthest along is cerutatide.
13:59Again,
13:59impressive weight reduction results
14:01with this agent and we're also part
14:04of this phase three trial here now.
14:08Next we have a triple hormone receptor
14:10agonist and I'm going to spend a few
14:14slides speaking about retitrutide.
14:15So I was also the lead Pi on this
14:18trial and retitrutide is a GIPGL
14:21P1 Glucagon receptor agonist.
14:23And we were incredibly impressed
14:25to see that the weight reduction
14:28with this agent was 24.2% at just
14:30eleven months and that translated
14:32to an average weight reduction
14:35of £58 in the short time frame.
14:38And Please note that all the
14:40participants were still actively
14:41losing weight at the time that the
14:43trial product was discontinued.
14:45So this will have to wait for the
14:47phase three to see the full efficacy,
14:48but eleven months this was very impressive.
14:51Now with this agent and with
14:53all agents we look
14:54at the the threshold that the
14:56percentage of people reaching
14:58the weight reduction threshold.
15:00So we often use 5% as that threshold
15:03because the FDA uses this in
15:05terms of its decision making of
15:07approval for these medications.
15:09And so with redditruitide,
15:10this triple hormone receptor agonist,
15:12what we saw was that 100% of
15:16individuals taking this medication
15:18lost at least 5% of their body weight.
15:21I don't think I'll probably ever be
15:23able to say that again in clinical
15:25research of any kind, 100% of anything,
15:27but this was a phase two trial
15:29and now we're doing phase three.
15:31Now what about the loftier weight
15:34reduction threshold targets, 10/15/2020?
15:36Five well with the highest dose.
15:39Many individuals also reach this target.
15:411/4 of participants lost more
15:44than 30% of their body weight,
15:46which is has never been seen before.
15:49And again, this is just in 11 months.
15:50This is not the full efficacy of this agent.
15:53Now if we look at Reditruitite
15:55a little bit more closely,
15:56as with any treatment for obesity,
15:58there's great variability in
16:00terms of response.
16:01So whether it's bariatric surgery,
16:03medications or anything,
16:04you'll have this variability.
16:06And if I can draw your attention
16:08just to the 8 milligram dose,
16:09you can see that some participants lost 10%,
16:12other participants lost more than 45%.
16:14And the question is why do we see
16:16this type of variability And we
16:18have to understand this better.
16:19We genetics is really important to look at.
16:22We also look at clinical factors.
16:24And one of the things that we saw here
16:26was that sex actually made a difference.
16:28So women lost more weight than men,
16:3328.5% at 11 months.
16:34So even looking at those type of factors
16:36and we need to understand why this is,
16:38is it the distribution of the adipose,
16:41the percent of adipose tissue,
16:42What's different about women and men?
16:45And so now we're in phase three and we're
16:47almost fully enrolled here at Yale.
16:49There's oral agents in development.
16:51For the sake of time,
16:52I'm not going to speak about those.
16:54There's also a monthly agent in
16:56development in case your patients
16:58are not able to take a daily oral
17:00or a weekly injectable.
17:01And so with all these medications,
17:03we know now that we can achieve
17:06fifteen 2025% weight reduction,
17:07but we're really moving beyond
17:09weight reduction.
17:10We're treating obesity and what we
17:12want to do is improve health outcomes.
17:15And so when we think about this,
17:17we want to optimize health when
17:19we're treating obesity.
17:20And in order to do that,
17:21we really need to understand the
17:23biology of obesity and how to target
17:26that pathophysiology to really maximize
17:28those health benefits for our patients.
17:30And so with this,
17:32I'm going to come back to our
17:34patient and tell you what happened
17:36with her after the trial.
17:38So as you remember from
17:40the beginning of my talk,
17:42she had lost over 90 lbs
17:43during the course of the trial.
17:46Now the trial ended and there's
17:48a safety period.
17:49It's about a month And she came to
17:51see me in clinic at 5 weeks and
17:54at that time she had already began
17:56to rapidly regain that weight.
17:59And So what did we do?
18:00Well, I started her on some Maglatite
18:02to try and temper that weight regain,
18:05which was successful.
18:06She did slow down in terms of her
18:09weight regain as we escalated the dose.
18:11We then added naltrexone bupropion
18:13to try and bring her back down
18:16to around a BMI of 2425,
18:18which again we successfully did and
18:21she's done so well with this now,
18:23right now, just as of a few days ago.
18:27Tirzepatide is available to her now.
18:29So we're switching the Samaglatite
18:30for tirzepatite and we'll see if
18:33we'll be able to stop the naltrexone
18:34bupropion as well and switch her
18:36back to what was effective for her.
18:38And what I'd like to highlight
18:41here right now is this is a patient
18:44case on a slide,
18:46but these are our patients and
18:49this patient is here sitting in
18:53the room with you today.
18:55And she has graciously agreed to stand up
18:57when we give her a big round of applause.
19:07So thank you so much, Lena.
19:09And I don't hear people were asking
19:12me if I was so. So I'm happy.
19:16Yes. So thank you so much, Lena.
19:18And thank you to all of you for
19:20your attention in this first talk.
19:23And and we welcome you to check
19:25out our website at Y Wait,
19:26which Lena made for us.
19:28So thank you so much.
19:36And we have a couple of minutes
19:38for questions before we move on
19:40to to the the stars of our show,
19:42our speakers. Any questions?
19:48Oh yes.
19:51So what is the goal of these seven trees?
19:54It's like maybe it's a lot of late time,
19:56but those like mall or is it going to like?
20:03Yeah. So that's a really,
20:04really great question and we're
20:06actually trying to figure that out.
20:08Obesity is a chronic disease.
20:10So what we believe is that
20:11chronic treatment is needed.
20:12Now whether it's with that agent,
20:14whether it's with a lower dose or a
20:16different medication, we don't know.
20:18As you can see from the,
20:19you know, from Lena's case,
20:21there is variability and we can add
20:23in different medications over time,
20:25but we don't know.
20:26We do think that just as there's variability
20:28in terms of response to these medications,
20:30there's also variability
20:31in terms of weight regain.
20:33Some people very quickly gain
20:35back all the weight and others
20:36gain back less of the weight.
20:38But on average,
20:39most people regain the weight.
20:41And again,
20:41it's because we're trying to reset
20:43a defended fat mass or set point,
20:46and that's what we're doing when
20:47we're treating obesity rather than
20:49treating for weight loss per SE.
20:50That's a byproduct of what
20:52we're trying to do.
20:53And I think you're going to
20:55hear more about that today.