Anti-Obesity Pharmacotherapy: Sparks from the Pipeline

November 03, 2023

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Yale Psychiatry Grand Rounds: November 3, 2023

Ania Jastreboff, MD, PhD, Associate Professor of Medicine (Endocrinology), Yale School of Medicine; Director, Yale Obesity Research Center

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00:00Regita, that was an amazing introduction and
00:06and again I've I've enjoyed working with you
00:10for so many years in such an incredible way.
00:13So let me just get this started and
00:16and we will, there we go. All right,
00:20hopefully everyone can see my slides.
00:22So I'll be speaking with you about anti
00:25obesity medications just as Regita said.
00:27And I decided that I would actually
00:30start with my thank you slide because
00:32often times this is the the,
00:34the final slide and there
00:36isn't sufficient time.
00:37And I wanted to highlight the fact
00:41that none of us get here alone.
00:43And I've been at Yale for over 17 years
00:48and my initial mentor was Bob Sherwin.
00:51And Bob introduced me to Rajita.
00:54And I can honestly say that I would
00:57not be here today and I would not be
01:00doing the work that I'm doing if it was
01:02not for her help and her support and
01:04her guidance every step along the way.
01:06And I can say this with true transparency.
01:10Rajita is the one who enabled me to
01:14see patients with obesity without
01:16any other weight related diseases in
01:19the Yale stress center years ago.
01:21And she inspired me to take chances and
01:25to do the work that I was interested
01:27in doing and supported me every,
01:30every step of the way.
01:31So I'm incredibly grateful.
01:32So thank you for that introduction
01:34and thank you for all of your help
01:36across the years now.
01:37Additionally,
01:38as I was putting the slide together,
01:40I also wanted to highlight all the
01:42work that I do with many of you
01:45here in this department.
01:46And so I started highlighting some
01:49of the funding sources and some of
01:51the P is that I share work with.
01:53And I decided to go to to the
01:56website just to see all the different
01:59individuals and faculty I've worked
02:01with over the years here at Yale.
02:03And two things came to light.
02:05One, your department is very large.
02:07And two,
02:08it's just amazing how many of you I've
02:11worked with, whether it's on a paper,
02:14a grant,
02:15whether it got funded or not on
02:19committees and various other things.
02:20So thank you so much.
02:21And I really do think it takes a village
02:24and I'm an endocrinologist and within
02:26psychiatry you have also been my village.
02:29So thank you.
02:30So now let's get on with our talk.
02:33So these are my disclosures and
02:35they are all related to the
02:37exciting field of obesity medicine.
02:38You should know that I do consult
02:40for many of the companies that make
02:42these medications and I will also
02:44be discussing some off label use of
02:46medications and that's important for
02:48you to know because this is a CME talk.
02:52So let's start with an astonishing
02:54and very sad fact.
02:57So currently there are over 760 million
03:02people living with obesity by 20-30.
03:05It's projected that globally the
03:08prevalence of obesity is expected to
03:11reach 1 billion in America by 20-30.
03:14More than half of us are
03:16anticipated to have obesity.
03:18So obesity really touches every one of us,
03:22whether it is ourselves or our loved ones,
03:26but no one is spared.
03:28So when we think about obesity,
03:30often times we think about
03:32the many sequelae of obesity,
03:34the 200 other obesity related diseases.
03:37And often times this focus is on
03:40metabolic health and functional health.
03:42But it's really important to remember that
03:46obesity is also Co occurring with depression,
03:50anxiety and many other
03:52aspects of mental health.
03:56But right now,
03:56we are in the midst of an
03:58incredible transformation and that
04:00transformation is brought on by the
04:03introduction of these new highly
04:05effective anti obesity medications,
04:07many of which you've probably
04:09heard about in the news.
04:11And to illustrate this and to
04:13really bring it back to the patient,
04:15because really that's why we're all here.
04:17It's for the patient.
04:18I'm going to show you 2 examples of patients,
04:21one who was taking medications which
04:24were previously used and older
04:26medications and they're still used,
04:29they are still FDA approved and we
04:31still use them and one with a newer
04:34medication in within a clinical trial.
04:36So the first patient was on these previous
04:39older medications and is still taking them.
04:41When I first saw her,
04:42she was 18 and her BMI was 57.
04:44She was considering bariatric surgery and
04:46wanted to see what her other options were.
04:49She had developed obesity at a young
04:52age and already had some of the obesity
04:55related diseases that we we know coexist.
04:58So this is her course.
04:59Over about four years,
05:01we started several medications,
05:03metformin,
05:04laraglatide,
05:04the combination naltrexone,
05:06bupropion.
05:07And over the course of that time
05:10period she lost about 140 pounds,
05:12which was about a 45% total body weight
05:16reduction over the years and her BMI
05:18decreased to 31 and her A1C normalized.
05:21So with these previous medications,
05:23it took about four agents,
05:25several years to reach that degree of weight
05:28reduction and improvement in her health.
05:30Now this is the second patient.
05:32When I saw her,
05:33she was 49 years old,
05:35her BMI was 34.
05:36And you can see her trajectory of weight
05:39over the years before she came to see me.
05:41And every time you see a dip,
05:43that is her employing her prefrontal
05:46cortex and doing everything that
05:48she can in terms of improving her,
05:50her healthy eating and her exercise.
05:52And she was very successful at that,
05:54but unfortunately always regained the weight.
05:56She had already developed some
05:58of the obesity related diseases
06:00that we spoke about earlier.
06:02So her BMI was 34 and we enrolled
06:04her in one of our clinical trials
06:06of one of these new agents.
06:08And what you can see is that over
06:10the course of a year she lost a
06:13significant amount of weight and
06:15her BMI decreased to about 20.
06:17She lost over 90 pounds with a total
06:20body weight reduction of about 45%.
06:23So next generation medication,
06:25one agent over a course of a
06:27year and about
06:2845% weight reduction.
06:29So again you can see that this
06:32was possible before and it is now
06:35possible and potentially will be
06:37significantly easier to attain.
06:40But obesity remains vastly under treated
06:42and we're going to talk about some of
06:45the barriers of and why that may be.
06:47So let's look at these numbers.
06:49So there's about about 45 or 46% of
06:54adults in the United States or almost
06:57half that meet the recommendations for
06:59treatment with anti obesity pharmacotherapy.
07:02So that's ABMI of greater than 30
07:04or greater than 27 with a weight
07:06related disease.
07:07So it's about half.
07:08So now let's see how many individuals
07:11in the United States receive
07:14appropriate pharmacotherapy for
07:15their obesity treatment and it is 2%.
07:22And so when I initially saw this statistic,
07:24I thought, Oh my goodness, 2%,
07:26is it OK to treat 2% of patients
07:29with diabetes or 2% of patients
07:32with hypertension or 2% of
07:34patients with depression?
07:35And I thought to myself,
07:37for any other disease,
07:38we would not treat 2% of patients.
07:41And yet that's what we're doing
07:43with our patients with obesity.
07:45And for bariatric surgery,
07:46it's even less,
07:47It's less than 1% of individuals who
07:50qualify for bariatric surgery who
07:52receive surgery for their obesity.
07:54Now as a comparison,
07:55here's type 2 diabetes and we're
07:57treating about 86% of individuals
08:00with appropriate pharmacotherapy.
08:02So we're not perfect, but we're
08:04certainly better than the abysmal 2%.
08:07So we have medications,
08:09we have surgery,
08:10We have lifestyle interventions.
08:12What are some of the barriers
08:14that can be causing this?
08:16And to illustrate this,
08:17I'm going to talk about a patient
08:20at the beginning here and then come
08:21back to him through the course of the
08:24discussion and end with how he did.
08:26And this patient when I saw him
08:28was 59 and actually I saw this
08:31patient at the Yale Stress Center.
08:33He had come to the Yale Stress
08:36Center specifically for his anxiety,
08:38which he did not actually report to me.
08:40What he did tell me about was
08:41his Type 2 diabetes,
08:42his hypertension and his hyperlipidemia.
08:45And what he asked me is basically he said,
08:48Doc, I'm a walking time bomb.
08:50It's only a matter of time
08:51before I have a heart attack.
08:52Can you help me? I need to lose weight.
08:55He was very anxious and did
08:58not want surgery and again was
09:00interested in other options.
09:01His history was similar
09:02to many of our patients,
09:04He had gained weight slowly over time.
09:06He had tried everything and
09:08every time he was successful.
09:10In fact,
09:10with meal replacement he lost £60.00.
09:12But the issue was he always
09:14regained the weight as is the
09:15case with many of our patients.
09:17As I said,
09:18he reported to me that he
09:19already had type 2 diabetes,
09:21Hypertension,
09:21hyperlipidemia was taking a bunch
09:24of medications and his A1C was 8.5,
09:27so his his diabetes was not well controlled.
09:30So I noticed OK,
09:32he was taking two medicines for his diabetes,
09:342 medicines for his blood pressure,
09:36a statin for his hyperlipidemia.
09:38And I thought to myself,
09:40when we care for this patient with obesity,
09:42why are all these other diseases
09:44being addressed but not obesity,
09:46not the disease that is likely
09:48causing if not at least contributing
09:51to all of these other diseases.
09:54And so the question was well,
09:55do we have medications to treat obesity.
09:58And as I showed you with the
10:00example of the first patient we do,
10:01there are several FDA approved
10:03anti obesity medications.
10:04There's also another one
10:06specifically for monogenic obesity.
10:08Additionally,
10:09we have many medications that we
10:11can use and these are off label use
10:13and some of these are components
10:15of the FDA approved medications
10:17because oftentimes these FDA
10:19approved medications are not
10:21covered by our patient's insurance.
10:23If the patient has type 2 diabetes,
10:25we may even have additional options and
10:27they're highlighted here in purple.
10:29And many of these medications also lead
10:31to weight reduction and we're going
10:33to focus in on some of these today.
10:36Again,
10:36the indication for using these
10:38medications is ABMI of greater than 30,
10:40greater than or equal to 30 or greater
10:42than equal to 27 with a weight related
10:45disease such as type 2 diabetes,
10:46hypertension or hyperlipidemia.
10:48Now we have these medications,
10:52we've had them for quite some time.
10:54And so the question is you know
10:55what are some of the challenges
10:57and barriers to treating our
10:58patients with these medications?
11:00Well,
11:00there's the perception that obesity is
11:02not a disease and I'm going to focus
11:05in on this specific barrier today.
11:07I think it's actually the most
11:08important one and I also think there
11:10are so many parallels in terms of
11:13obesity not being viewed as a disease
11:15for so long and and mental health
11:18issues like depression not being
11:20viewed as a disease and now it is.
11:22And what can we learn from the way
11:25that all of you manage this and
11:26brought forward mental health issues?
11:28What can we learn in the obesity space
11:31to really bring forward that obesity is
11:33a disease and needs to be treated as such?
11:37There's also the fear of
11:38causing dangerous side effects.
11:39We'll talk about this the perception
11:40that the medicines are not effective,
11:42which is rapidly changing.
11:44There's cost to consider and scalability
11:47and these are really huge barriers
11:49that we are facing now since so many
11:53patients have obesity and the cost issue.
11:55The question here is why is there
11:58this tenfold increase in cost in the
12:00United States where many of these new
12:03medications are are available at a
12:05fraction of the cost at in other countries?
12:09OK.
12:09So let's focus in on this first
12:11barrier and spend some time on this.
12:13So why is it important to understand
12:15that obesity is a disease and
12:16how does it affect the way that
12:18we use these medications?
12:19And again,
12:20I think this comes back to the fact
12:22really understanding the biology
12:24of obesity and what we're really
12:26trying to to obtain with treatment.
12:28So back to our patient,
12:31what did he teach me?
12:32Well, he taught me that he was
12:34highly motivated and he tried
12:36every method under the sun that he
12:38had access to caloric reduction,
12:40meal replacement, Mediterranean diet,
12:42improving the quality of his food.
12:45And yet he always regained the weight.
12:47And so the question with him was
12:48why is it so difficult to lose
12:51weight and maintain weight loss?
12:52Well, it turns out that our body
12:55has this beautiful system that it
12:57it's evolved over over centuries.
12:59And basically there are hormones
13:01which are signals which tell our
13:03brain about energy homeostasis.
13:05And it turns out that our bodies
13:07and our brain have this concerted
13:10interest in carrying fuel,
13:11and it carries that fuel as fat.
13:14And so our body,
13:15and specifically our brain,
13:16defends a certain amount of fat mass.
13:19We don't want to starve if there's
13:21no food available.
13:22We also don't want to carry so much fat
13:24or so much energy that we can't carry
13:27out the activities of daily living.
13:29Now, one might ask,
13:30well,
13:31if our if our body and our brain
13:32has this beautiful system where
13:34we're going to carry exactly
13:36the appropriate amount of fuel,
13:38then why are so many people
13:41developing obesity?
13:42Well, it turns out our environment,
13:44which is filled with highly palatable,
13:47highly processed foods,
13:48lack of sleep, increased stress,
13:50lack of physical activity,
13:52all of these things impact how our
13:56brain and how our body decides to
13:59defend that that fat mass at that point
14:02and how much fat it wants to carry.
14:04And so this actually brought me to
14:07some of the earlier work that I started
14:10to do during my doctoral thesis.
14:11And Dr.
14:12Sinha was my primary mentor with Doctor
14:16Bob Sherwin for my doctoral thesis.
14:19And this started a range of
14:21work over over many years,
14:23kind of leading us to address
14:25some of these questions.
14:27So looking at how food cues may impact us,
14:31well,
14:31of course there are neural responses that
14:34occur that then result in eating behavior.
14:36So biology informs behavior.
14:38There are hormones that impact these
14:41neural responses and these hormones
14:43and metabolic factors are potentially
14:45changed in the setting of obesity,
14:47for example by insulin resistance.
14:50Now when we think about how this may then
14:52alter all of these downstream effects,
14:55so the neural responses,
14:56the eating behavior,
14:57this can all result in weight gain.
14:59And where anti obesity medications
15:01can intervene is in the brain
15:04specifically as well as changing
15:06these different things that that
15:08are perturbations of obesity that
15:10can then result in weight loss.
15:12And we're going to focus in and talk
15:14about how this may all be happening.
15:16Now, how do we study this and
15:18how did we start to study this?
15:20Well,
15:20we conducted studies in
15:22both adolescents and adults.
15:23We used F MRI to look at this,
15:26and we used a food snack
15:28test developed at the
15:30Yale Stress Center by Doctor Sinha to
15:32look at some of the changes that may
15:35occur in terms of eating behavior.
15:37And then of course,
15:38we assess hormones and metabolic
15:40factors as we're doing these studies.
15:43And so as an endocrinologist,
15:45I may have thought and maybe
15:46I did in the beginning,
15:48that everything that was important in
15:50terms of eating began and ended in
15:53the hypothalamus because it is the
15:55hunger and satiety center of the brain.
15:57But little did I know at the time that
15:59there were so many other regions of
16:01the brain that are so critical to this,
16:03so striatal regions,
16:04limbic regions and cortical regions.
16:06And of course speaking with this audience,
16:08you know all of this so much better than I.
16:11So when we were doing these studies,
16:13we were giving patients different
16:15types of cues.
16:16So food stories,
16:17food pictures and even ingestion,
16:19ingestion of macro nutrients
16:21such as glucose and fructose.
16:23We would expose participants to these
16:25various cues and then conduct MRI
16:28studies to to ascertain their response.
16:31So I'm just going to highlight
16:33a few studies that we did.
16:34And so if we wanted to look at
16:37neural responses to visual food
16:38cues in adolescence with obesity to
16:40see if they responded differently
16:42than adolescents who were lean.
16:44So we exposed them to food pictures,
16:47conducted scans and assessed
16:49hormonal responses.
16:50And so in this first study
16:52that I'm sharing with you,
16:53we looked at the the difference in
16:56terms of BOLD signal activation in
16:58terms of the response to high calorie
17:01foods versus non non food pictures.
17:04And this is in individuals with obesity
17:06versus individuals who are lean.
17:08And what we found was that adolescents
17:10with obesity had increased activation
17:12and reward motivation regions in
17:14response to high calorie food pictures.
17:17And specifically these adolescents
17:19demonstrated increased activation in
17:21striatal limbic regions including
17:23the amygdala, hypothalamus, caudate,
17:25putamen, thalamus and insula.
17:28Now,
17:28we also wanted to see whether there
17:30were differences in neural responses
17:32to monosaccharides in these adolescents.
17:34Adolescents take in a lot of sugar.
17:37So what we did is we brought
17:39our adolescents in fasting,
17:43we we did a baseline F MRI,
17:46and then we basically gave them
17:48either glucose or fructose and then
17:50scanned them and then assessed various
17:52metabolic factors during the F MRI scan.
17:56And what we saw in this study was
17:59that adolescents with obesity
18:00in response to drinking glucose
18:02demonstrated decreased perfusion in
18:04decision making regions of the brain,
18:06so various regions like the
18:08prefrontal cortex and the ACC.
18:10And they demonstrated increased
18:12perfusion and reward motivation
18:15regions as you can see here.
18:17And you can see for comparison,
18:19lean adolescence and their response
18:21in the prefrontal cortex and
18:24the ACC was actually increased.
18:26Now we were also interested in looking at,
18:29well,
18:29what was the effect of leptin
18:30on these neural responses.
18:32So leptin is an adipokine or a hormone
18:35that's secreted proportionally to fat mass.
18:37So as we gain weight,
18:39most people increase their leptin levels.
18:41This isn't homogeneous across the population,
18:43but in general leptin is proportionally
18:46increased in terms of the amount of
18:48fat mass that somebody may have.
18:50And indeed this is what we found in
18:52our sample, that the individuals who
18:55had obesity had higher leptin levels.
18:57So what we did is conducted whole
18:59brain correlations with leptin and we
19:01found that higher endogenous leptin
19:03levels correlated with decreased
19:04perfusion in the prefrontal cortex
19:06in adolescence with obesity.
19:08And we thought that perhaps altered
19:11or dysfunctional leptin signaling
19:13there could be leptin resistance.
19:15This may contribute to lower
19:18prefrontal cortical responses in
19:20adolescence with obesity.
19:21And actually this this was congruent
19:24with studies conducted by Sadaf Farooqi,
19:27where she actually gave leptin back to
19:31individuals who have leptin deficiency,
19:33and she demonstrated that those
19:36individuals then had increased
19:38activation in the prefrontal cortex.
19:41OK, so the of course with these
19:42studies that I've shown you,
19:44there are many questions yet to be addressed.
19:47What is the cause and effect?
19:48So what happened first,
19:49the brain changes or the obesity,
19:51What's the timing?
19:52Does it happen during adolescence in utero?
19:55When does obesity really set in and
19:58what is the impact on behavior?
20:00Do we really know?
20:01And and of course these are things
20:03that need to be looked at and
20:05especially reversibility.
20:06So when patients actually undergo
20:09treatment for their obesity,
20:11are these changes potentially reversible?
20:15So back to the question,
20:16why is it so difficult to lose
20:17weight and maintain weight loss?
20:19And again,
20:19let's talk about this defended fat
20:21mass set point and this is a model
20:23that I'm going to tell you about.
20:25We don't know the molecular basis
20:27for it yet until maybe perhaps one
20:29of you can help us figure it out.
20:31So let's talk about the asset point.
20:35So let's talk about a house.
20:37And the house has a thermostat,
20:38and let's say that the thermostat
20:40is set to 70 degrees Fahrenheit.
20:43What happens when it is hot outside?
20:44Well, when it's hot outside,
20:46that thermostat senses, oh, it's 80 degrees.
20:48Let's turn on the air conditioner.
20:50This is not conscious. This just happens.
20:52You don't walk over to the air conditioner,
20:53it just does it itself as long
20:55as it's functioning properly.
20:57The opposite happens when it's cold outside.
21:00The furnace turns on.
21:01And again, this isn't a conscious decision.
21:02It just happens.
21:03Now what happens if it's July or
21:06August and it is incredibly hot?
21:08Well,
21:08sometimes that defended or that
21:10temperature set point is pushed up.
21:12It's really hard to maintain 70 degrees.
21:15You might open the windows and
21:16try different things,
21:17but sometimes that temperature just needs
21:19to be turned up for the system not to fail.
21:22And it turns out our body
21:24does this with many functions.
21:26We call this homeostasis and
21:28it does this with fat mass.
21:30And now let's look at our body and let's
21:33see how it does this with fat mass.
21:34So now our brain is the thermostat
21:37and it defends a fat mass set point.
21:39So what happens when we gain weight
21:41or specifically when we gain fat mass?
21:43Well, the signals to our brain via
21:46various hormones that we have gained fat
21:48mass and it should signal us to increase
21:51thermogenesis and decrease appetite.
21:53But what happens when we lose
21:55weight or lose fat mass?
21:56Well, this should signal us to increase
21:59appetite and decrease thermogenesis
22:01and this is what we think is the
22:03defended fat mass or set point model.
22:05But now what happens in our
22:08current obesogenic environment,
22:09this environment filled with highly processed
22:12food that's available all the time,
22:15increased stress, lack of sleep,
22:16lack of physical activity.
22:18Well, this defended fat mass set point
22:20is pushed up on a population level.
22:22We are responding to our environment.
22:26And so when we think about obesity,
22:27really what obesity is and what it
22:30results from is an inappropriate
22:32dysregulation or or setting of that
22:35defended fat mass set point and
22:37what obesity treatment then requires
22:39is resetting or re regulation of
22:42that defended fat mass set point.
22:44And so why is all this important and
22:46why am I talking about it in the
22:48context of anti obesity medications?
22:50That's because any treatment that
22:52we use for obesity,
22:53the goal should be re regulation
22:56of this defended fat mass.
22:58So when we think about anti
23:00obesity medications,
23:00the goal is to decrease
23:02that defended fat mass.
23:03So you have all of these different
23:05things pushing up the defended
23:07fat mass and in our obesogenic
23:10environment and what we want is
23:12anti obesity medications to bring
23:14it back down to re regulate it.
23:17Now the question is how can anti
23:20obesity medications potentially do this?
23:22How can they reset or re regulate
23:24that defended fat mass at that point?
23:26Well,
23:26it turns out a majority of the
23:29medications that we have work in the
23:31brain and it's not surprising because
23:33the brain is what we think sets or
23:35regulates that defended fat mass.
23:37Now the one medication that's not
23:39on here that is FDA approved for
23:41obesity treatment is Orlistat.
23:43We don't think that Orlistat re
23:46regulates that defended fat mass
23:48at that point.
23:49So let's talk about the brain
23:51again a little bit.
23:53So we talked about the brain and
23:55there are different regions that work
23:58together to control eating behavior.
24:00So cognitive executive regions,
24:02hedonic and homeostatic.
24:04And again initially it was thought
24:06that the hypothalamus controlled
24:08most of this in terms of being the
24:11hunger center and the satiety center.
24:13And so initially when looking at how
24:17GLP one receptor agonist may work,
24:20the focus was initially on the hypothalamus.
24:25And if we and again GLP one receptor
24:27agonist just to level set their
24:30medications like somaglitide,
24:31tirzepatide,
24:31the things that you've been
24:33likely reading about in the news.
24:35So the thought is that GLP one directly
24:39activates pump C CART neurons in the
24:42hypothalamus and indirectly inhibits
24:44NPYAGRP neurons and collectively this results
24:47in signaling that reduces food intake.
24:50Of course, we know now that the story
24:52is much more complex and there is
24:54research ongoing actually looking at
24:56how these medications may impact reward
24:58and motivation regions of the brain and
25:00I think this is incredibly interesting.
25:02We were also interested in looking
25:04at this and looking at some of
25:06the the animal studies.
25:09There has been evidence that for example,
25:11some maglitide does act in
25:14the hypothalamus as as well as
25:16various regions in the hind brain.
25:18For us, we had an early pilot study,
25:20it was funded by the ADA and this
25:23was conducted by a pediatric
25:26endocrinology fellow who's now an
25:29assistant professor as well as a a
25:31post grad who is now in medical school.
25:33And we did this work with Regita and
25:36Bob Sherwin where we gave individuals
25:39laraglatide for about 12 weeks
25:42and we assessed various things,
25:44metabolic function or response,
25:46neural response and behavior.
25:48And I'll just highlight very briefly
25:50some of the some of the findings
25:53from this pilot that then led to
25:55an RO one that we currently have.
25:58So what we looked at was brain
26:01response again using F MRI and we gave
26:04participants this time these were
26:05young adults, high fructose corn syrup.
26:07It was a small sample,
26:09but what we found and what we looked
26:11at was basically the neural response
26:13after three months of treatment
26:15with loraglitide.
26:16And so this is the difference
26:18between during treatment with
26:20loraglitide versus at baseline.
26:22And the the difference that we
26:23found was in the hypothalamus,
26:25which is an important relay center
26:27in the brain.
26:28Again,
26:28this was a small sample but at least
26:30it gave us a clue that there were some
26:33differences that were ongoing in the brain.
26:35We also adapted the food snack
26:37task which was developed by Regita
26:39and we adapted it because we were
26:42interested in looking at sweet
26:43taste preference at the time.
26:45There was some indication that
26:47potentially GLP one receptor
26:48agonist may impact this and that
26:50was based on some animal work.
26:51So we plate,
26:52we replaced some of the foods with
26:54you can see some 3 sweet foods and
26:57three foods that are carbohydrate and
27:00potentially containing fat but not sweet.
27:03We videotaped participants and they
27:05had the opportunity for 30 minutes
27:07and then we measured the food that
27:10they ate and how much they ate.
27:12And what you'll see on these graphs are
27:15lean individuals are depicted in blue.
27:18Yellow are participants with obesity
27:21before receiving any laraglatide,
27:24then orange are participants
27:26during treatment with laraglatide.
27:28And then the green is the change,
27:30the difference between pre and
27:32post treatment.
27:33So first, in terms of caloric consumption,
27:36what you can see is that individuals
27:38with obesity did eat more than
27:41lean individuals at baseline,
27:43which is not surprising.
27:45Again,
27:45they're trying to defend this
27:47higher defended fat mass and so
27:49they're consuming more calories
27:51to defend that amount of
27:53fat. Then during treatment they ate less
27:54and it was not statistically significant.
27:57Again, this may be because of power
27:59and this is a consistent theme that
28:01you'll see with these findings.
28:02And here you can just see the change
28:04in terms of how much people eat.
28:06Then we looked at the observed
28:07sweet food intake.
28:08That's what I was interested in.
28:11And again, you can see that individuals
28:13with obesity depicted here in yellow
28:15did consume more sweet foods than
28:17those who were lean at baseline.
28:19And then with treatment again we saw
28:21a trend for decreased and sweet food
28:24intake but but not statistically
28:26significant and you can see the
28:28difference here depicted in green.
28:30Now this LED,
28:32this was sufficient pilot data to lead
28:35to an RO one that I have the privilege
28:37of of conducting with Regita as as Co PIS.
28:41And here is some of our wonderful
28:43team who is actually doing all the
28:46work and some of our junior faculty
28:48who are now progressing on into
28:51further ladder track positions.
28:52And this RO one we're looking at
28:56Somagnetide and the effects of food cues,
28:58stress and motivation for highly
29:00palatable food and weight.
29:02And what we're doing is we're
29:04randomizing individuals with obesity to
29:06receive either placebo or Somagnetide.
29:08They received that for 12 weeks and
29:10then we actually also look at a one
29:13month follow up off the medication
29:14to see what happens.
29:16We're looking at weight,
29:17but we're actually what we're really
29:20interested in are the metabolic
29:21responses as well as how individuals
29:23may be consuming food differently
29:25and we're using this validated
29:27food snack test to assess this.
29:30And so we are in year four.
29:32So anticipate those results fairly
29:36soon and hopefully next time
29:38I I present to all of you,
29:40we'll have some data on that.
29:43Now additionally,
29:44let's focus in briefly again on the
29:47hedonic salience regions of the brain
29:48and I think there will be a lot
29:51more work with GLP ones specifically
29:52on these regions of the brain.
29:54But up till now, what has been looked at?
29:56Well, of course,
29:58dopaminergic pathways that are so
30:00important for reward and motivation
30:02as well as serotonergic pathways.
30:04Now there are medications that have
30:06targeted these different pathways
30:08in the brain.
30:09Lorcasterin is no longer on the market,
30:11but it targeted serotonergic pathways,
30:14bupropion,
30:14phentermine and then naltrexone
30:17and topiramate target different
30:19types of pathways.
30:20And it's just to say again that
30:22these medications target these
30:23different regions of the brain.
30:24And there are investigators like
30:26Carlos Grillo and Valentina Ivisage
30:28who have also had the privilege
30:30of working on various studies,
30:32both in terms of looking at
30:34naltrexone bupropion in the setting
30:36of binge eating disorder,
30:37as well As for loss of control
30:41eating following bariatric surgery.
30:43And now what about cognitive
30:45executive regions of the brain?
30:47For so long,
30:48it was thought that patients could control
30:51every morsel of food that they eat.
30:53For the rest of their lives,
30:54they could simply impart
30:56executive function and decision
30:58making to make these decisions.
31:00But of course we know as as we've
31:02just talked about that the striatum,
31:04the hypothalamus,
31:05all of these brain regions work in
31:07concert and biology is really pushing
31:09us and making it very difficult for
31:11us to make those types of decisions.
31:13It's almost as if we were asking
31:16our patients to hold their breath
31:18indefinitely in the same way we're
31:20asking them to to decide on every
31:22morsel food that they eat for the
31:24rest of their life when their biology
31:26is telling them that they are
31:28incredibly hungry or craving foods.
31:30And of course,
31:31there's many interventions
31:31that can be used for this,
31:33but it does make it very difficult.
31:35So all of these regions of
31:37the brain work together.
31:39They impact food intake as
31:42well as energy homeostasis.
31:45OK.
31:45So we've talked a lot about
31:47this first barrier,
31:48and that's what I really wanted to focus on,
31:50But let's touch on a couple of others
31:52and then return to our patient.
31:55So the next barrier is this fear
31:57of causing dangerous side effects.
31:59This has been something that's come
32:01about from the fact that these
32:03medications that were approved for
32:05obesity treatment have had a sordid history.
32:08And of course many of you I'm
32:11sure remember Romanaband,
32:12but if we look at the second
32:14generation medication, so for example,
32:16phentermine, topiramate, naltrexone,
32:17bupropion,
32:18the components of these medications
32:20have been used for different
32:23indications over many years.
32:24So it's not to say that they
32:26were specifically looked at for
32:28safety and obesity,
32:29but we at least have more information
32:31about them in different contexts now.
32:34Loraglitide and Somaglitide,
32:35which are both FDA approved for
32:37obesity treatment belong to a class
32:40of medications called Glucagon
32:41like peptide receptor agonist,
32:43and they've been used for the treatment
32:45of type 2 diabetes for nearly two decades.
32:47So again,
32:48we have more safety data on these
32:50medications.
32:51Now there are common side effects
32:53of these medications and we
32:54hear about this all the time.
32:56I don't think there's any medicine
32:57for any disease that doesn't
32:58have any side effects,
33:00but certainly these are important to
33:02consider as we counsel our patients.
33:05So most of them are gastrointestinal
33:07side effects, but for example,
33:09topiramate can have mental fogginess or
33:12paresthesias that we have to look out for.
33:14Naltrexone of course can lead to nausea.
33:17So there are other side effects that we
33:20have to counsel our patients about as well.
33:23Now just focusing in on the GI side
33:25effects because these come up quite a bit.
33:27Let's look at nausea and diarrhoea.
33:29These are the most commonly reported
33:31with the newer medications especially.
33:33So this is depicting the observation
33:36or the time during a trial.
33:38It was a trial which was appetite.
33:40And what you can see with nausea
33:41is that in the placebo group
33:43at the start of the trial,
33:44more participants reported
33:45nausea and it that was also the
33:48case with the 10 milligram
33:49dose of tirzepatide and the
33:51incidence of this was higher.
33:53But you can see that after the dose
33:56escalation phase this decreased.
33:57You can see the same trend for
34:00diarrhea with both placebo as well
34:03as with tirzepatide that over time
34:05these side effects began to decrease.
34:08And so we learned from these
34:10trials that most gastro,
34:11most of the side effects with these
34:13newer medications are gastrointestinal,
34:15they are transient and primarily occurred
34:17during the dose escalation phase and are
34:20mostly mild to moderate in severity.
34:22Now overall for the medications,
34:24what are some important things to discuss?
34:27Well, first it's important to share
34:29with our patients that there aren't
34:31really medications for any disease
34:32that don't have side effects.
34:33So let's talk about the side effects
34:36before the patient starts the medication,
34:38so that they're aware and they know
34:40what to look out for and they tell you
34:42when they experience these side effects.
34:43So some common themes that we can do
34:46as providers to help our patients
34:48is to always start with the lowest
34:50starting dose of any medication to
34:52monitor our patients for side effects
34:54and invite them to share those side
34:56effects with us when they have them or
34:58if they have them and to up titrate
35:00the dose only is tolerated by the patient.
35:02So if a patient's having nausea,
35:04we wouldn't go up until that nausea
35:07dissipates because we don't want
35:08them to have vomiting.
35:09And to borrow a phrase that all of
35:11you I'm sure are very familiar with
35:14for for other treatments within
35:15the mental health space,
35:17our goal is to start low and go
35:19slow and that is the theme.
35:21And specifically with the newer medications
35:24and the gastrointestinal side effects,
35:26this slow dose escalation as I
35:28showed you in the previous slide
35:29that we learned from the trials,
35:31Our patients can also implement
35:33various mitigation strategies such as
35:36eating smaller amounts at mealtimes,
35:38stopping to eat when they're full
35:40and noting which foods may exacerbate
35:42their symptoms.
35:43And most commonly these are high fat foods.
35:46And again the goal is start low and go,
35:50go slow and don't go up.
35:51If your patient is having significant
35:53side effects,
35:54wait a few months and then go up on the dose.
35:57Now there's another challenge which
36:00is this perception that anti obesity
36:02medications are not effective and
36:04this is rapidly changing.
36:06So previously we would say well
36:08with one medication and you may
36:11lose somewhere between 5 and 10% if
36:13you are have a good response.
36:16Now if we obviously if we combine
36:18these medications as I showed you
36:20with the first patient this could
36:22be more but really Smeglitide was
36:24the first medication that changed
36:26this landscape and helped us to
36:28leap from the past to the future.
36:30And we are currently at this watershed
36:32that's brought on by the recent
36:34introduction of these medications.
36:36So here are the medications that
36:38that were that are
36:40currently FDA approved and here are
36:42some of the medications that are in
36:44development and leading the charge
36:46are nutrient stimulated hormone
36:47based therapies and I'll share a
36:49few of the new ones with you today.
36:51There's others that I don't
36:52have time to get to.
36:54So active and receptor inhibitors
36:56that actually can help maintain muscle
36:58mass while decreasing fat mass.
37:01There's also an MC4 agonist for
37:03monogenic obesity and there are many
37:05other mechanisms being explored.
37:07So let's focus in on nutrient
37:09stimulated hormones. What are these?
37:11Well, GLP One is the nutrient stimulated
37:14hormone that we're most familiar with,
37:16used for the treatment of type 2
37:18diabetes as a receptor agonist.
37:20But what are these in general?
37:22Well, these hormones are any hormone
37:24that is stimulated when we eat
37:26food and they signal to our brain
37:28and to various tissues in our body
37:30about energy homeostasis and that
37:32includes food intake as well as
37:35potentially energy expenditure.
37:37So starting with GLP one,
37:39we saw that there was weight reduction
37:40in our patients with type 2 diabetes.
37:42But now we know that pairing GLP
37:45one with other nutrients stimulated
37:47hormones such as Glucagon,
37:49Amylin or *** and dual agonist or
37:51triple agonist can actually increase
37:53the amount of weight reduction that can
37:56be attained as well as other health benefits.
38:00And so this slide I update almost daily.
38:03It is just a snapshot of some
38:04of the nutrient stimulated
38:06hormones that are in development.
38:07These are just the ones in phase two
38:10and three double this and that's how
38:12many are in development in phase one.
38:14And the ones that are outlined and
38:17that I just highlighted here are the
38:19ones in phase three and I'll share
38:22with you very briefly about these.
38:24So some maglitide was the first one
38:26that is a long acting GLP and receptor
38:28agonist that was FDA approved.
38:30It is once weekly and injectable
38:32and it demonstrated an average
38:34weight reduction of 16.9% at 68
38:37weeks and that's an average weight
38:39reduction of £34 in this trial.
38:41It was also demonstrated that there
38:43were improvements in cardio metabolic
38:45measures and one of the questions was
38:47well do does improvement in these lab
38:49values and these these risk factors,
38:52does it actually improve outcome And
38:54now we're at the cusp of knowing
38:56the answer to that the select
38:58trial which we were a site for here
39:00as well with the help of YCCI.
39:03This trial resulted in a 20% reduction
39:08in major cardiovascular events.
39:10So receiving some agletite as compared
39:12to placebo did improve and and
39:15decrease the the cardiovascular events
39:17that our patients are experiencing.
39:20Now these are just top line results
39:22and will be the results will be the
39:25full results will be presented at the
39:27American Heart Association next week.
39:28So stay tuned for that.
39:31Now Tirzepatide is the next molecule
39:34that that is farthest along in terms
39:37of phase three and coming next it
39:39is a GIPGL P1 receptor agonist.
39:41It is one molecule targeting both
39:43receptors and it is also a once weekly
39:46injectable and we were fortunate to conduct
39:48this trial and I was the lead author
39:50on this study that Regita mentioned.
39:52This treatment with tirzepatide with
39:55the highest dose resulted in an average
39:58weight reduction of 22.5% at 72 weeks and
40:01this translated to an average absolute
40:03weight reduction of £52 at that time point.
40:07Additionally, on this dose,
40:08nearly 40% of participants lost at
40:10least 1/4 of their body weight.
40:12So that's somebody starting the trial at
40:15a weight of 200 losing down to 150 pounds.
40:18Tirzepatide also resulted in improvements
40:20in cardio metabolic measures as
40:22we had seen with some agglutide.
40:24Now where is tirzepatide?
40:26Well the phase three trials are
40:28are moving forward and completing.
40:31There is an extension of the surmount
40:33one trial.
40:33Surmount 2,
40:34which was participants with diabetes also
40:37resulted in significant weight reduction
40:39as well as a hemoglobin A1C reduction.
40:42Tirzepatide after intensive lifestyle
40:45intervention also resulted in
40:47significant weight reduction as did
40:49longer duration of tirzepatide use,
40:51which resulted in 26% total body
40:54weight reduction at 88 weeks.
40:56There's also a cardiovascular
40:58outcomes trial looking at both
41:01heart and renal outcomes ongoing.
41:03And tirzepatide is currently under
41:04FDA review for chronic weight
41:06management and obesity treatment.
41:08It's already FDA approved for
41:10type 2 and the obesity indication
41:11we should know very soon,
41:13so stay tuned for that as well.
41:16Now the next one that is in
41:19the works is CAGRI SEMA.
41:21It is a combination.
41:22It's an Amylin analog with a GLP
41:25one receptor agonist.
41:26So this is 2 molecules both once
41:29weekly that are used in combination
41:31to see if there's synergistic
41:33effect on weight reduction.
41:34And what you can see in this
41:36trial is when you compare some
41:37maglitide to the combination of
41:39cagrillantide with some maglitide,
41:40you achieve greater weight reduction
41:42with the combination at 20 weeks.
41:45What you can see is a 17.1% reduction
41:48with this combination and you can
41:50see as depicted by the red arrow that
41:53participants were still losing weight.
41:55Now what happens when you
41:56stop the medication?
41:57Well, as any chronic disease,
41:59when you stop the medication,
42:00the weight is regained and that's
42:02because the defended fat mass set point
42:05goes back up and we're going to come
42:08back to that with our patient at the end.
42:10Now the next one or the next few that
42:13are in development are Glucagon GLP,
42:16one receptor agonist,
42:17cervutatide is the farthest along here in
42:21a phase two trial that was just presented.
42:23This resulted in an average weight
42:26reduction of 18.7% at 46 weeks.
42:28The next one after that is a triple
42:32hormone receptor agonist retatrutide
42:34and this is a combination of GIPGL
42:37P1 and Glucagon receptor agonism.
42:39And we also just published on this and
42:43I was the lead on this trial as well.
42:45And at 48 weeks,
42:47what we found in this phase two
42:49trial was placebo lost 2.1% of
42:51their total body weight,
42:52whereas with the highest dose
42:54of retatruitide on average the
42:56weight reduction was 24.2%.
42:58So nearly 1/4 of the body weight was
43:00lost at just eleven months and you
43:02can see that participants were still
43:04actively losing weight at the time
43:06that the study drug was discontinued.
43:08This translated to an absolute
43:11weight reduction of £58 during
43:13the course of this trial.
43:16Now additionally,
43:16when we think about weight reduction,
43:18we look at weight reduction targets 5%
43:20has traditionally been focused in on.
43:23This is something that can certainly
43:25be attained with lifestyle intervention
43:27as well as with the older generation
43:30of medications and the FDA uses it now
43:33with the two highest doses of retatrutide,
43:35we found that 100% of participants
43:37lost at least 5% of their body weight.
43:40I don't know if I'll ever be able to
43:42say this in a scientific presentation.
43:43Again, this was a phase two trial.
43:45So we'll have to wait the results
43:47of the phase three trial that we
43:49are now moving forward with.
43:51Now looking at higher body weight
43:53reduction targets, I'll just follow.
43:54I'll just focus in on the highest dose,
43:57the 12 milligram dose.
43:58We found that 9 out of 10 participants
44:00lost at least 10% of their body weight,
44:03nearly 2/3 lost more than 20% of their
44:05body weight and a quarter of participants
44:07lost at least 30% of their body weight.
44:10So really significant weight reductions.
44:12And again,
44:13this is just at 11 months now.
44:15I just want to highlight that
44:17with any obesity treatment,
44:19there is a variability in response.
44:22So these are different doses of
44:23retatrutite and what you can see
44:25is individual participants and how
44:27much weight they lost in the trial.
44:29And what you can see is that most
44:31participants lost a lot of weight,
44:32but there are differences in terms
44:34of how much weight they lost.
44:35And we don't have great predictors
44:37to know how people will respond.
44:39So there is great variability in
44:42terms of response and this is true
44:45with any treatment for obesity.
44:47Now all the medications I've talked about
44:49till now are once weekly injectable.
44:51What about oral GLP one receptor
44:53agonist or oral nutrient stimulated
44:55hormone based therapies.
44:56So there is an oral formulation of
44:59some maglitide and at higher doses
45:01that are not yet FDA approved.
45:03The trial demonstrated that the average
45:05weight reduction was 17.4% at 68 weeks,
45:08so on par with the weekly injectable.
45:11There's also small molecules that
45:13are under investigation that are GLP
45:151 receptor agonist and the farthest
45:17one along here is orphorglipron and
45:19it resulted in an average weight
45:21reduction of 14 percent,
45:2314.7% at just 36 weeks.
45:25So we'll have to wait for the phase
45:27three trials of these agents as well.
45:29Now there's also a monthly formulation
45:32of a *** receptor antagonist and
45:34a GLP 1 receptor agonist.
45:36So if if taking something once
45:38a week is too much,
45:40there may potentially also be a
45:43once monthly formulation at some
45:45point in the future.
45:47So I hope I've shown you
45:49with these medications that
45:50substantial weight reduction
45:51is possible and we are filling
45:53the treatment gap and beyond.
45:55So we have current pharmacotherapy and
45:58intensive lifestyle that could achieve
46:00this weight reduction of five to 10%.
46:02We have bariatric surgery that
46:04could achieve a lot more,
46:06but now we're filling the treatment gap.
46:08And I only had time to highlight
46:09a few of the agents,
46:10but there are so many more in development
46:12and so many different mechanisms.
46:14And all of these can be paired with
46:17other therapies using combination
46:19therapy to really help our our patients
46:21achieve the goals that they need.
46:23So I'm going to just highlight that
46:26all of this work we're going to try and
46:29continue at the Yale Obesity Research Center,
46:31which is a new center that I've
46:33been asked to create and direct.
46:36And the focus of the center is
46:38on the investigation of novel
46:39anti obesity medications.
46:41The focus is also on clinical obesity
46:43research where we're going to be looking
46:46at the clinical Physiology of obesity,
46:49conducting these clinical trials,
46:50many of which I've shown you and there we
46:53have many that are ongoing and starting up
46:55as well as looking at patient outcomes.
46:57And this will of course take collaboration.
46:59We want to mentor the next
47:01generation of physicians,
47:02scientists and investigators and we
47:04want to educate academic leaders and
47:07integrate all of this into clinical practice.
47:09Now I'm going to come back to our
47:12patient to kind of sum everything up
47:14and and and really highlight some of
47:16the points that we've talked about
47:18about treating obesity as a disease.
47:20And again,
47:21the highlight here is we treat these
47:23other diseases with medications.
47:24And let's ask ourselves three
47:26questions and then ask ourselves
47:28the same questions for obesity.
47:30So when we care for this patient
47:32with obesity,
47:32do we find it unusual that he requires
47:35several medications for his diabetes?
47:37Do we think that the anti hyperglycemic
47:39medications are not effective if
47:41his A1C is not less than seven?
47:43And now that his blood pressure is at goal,
47:45would we stop his anti hypertensive
47:48medications?
47:49And of course the answer to all of these
47:51questions is very easy for all of us.
47:54We would answer no to each one
47:56of these questions.
47:56And now let's ask ourselves these
47:58questions for obesity in the
48:00context of overcoming the barriers
48:02to treating obesity as a disease,
48:04as a disease that is heterogeneous,
48:06that is chronic and that is complex.
48:09So first heterogeneous.
48:10The question here is do we think
48:12that his anti hypoglycemic medication
48:14is not effective if his A1C is not
48:16less than seven?
48:17And the parallel question is,
48:19do we think that his anti obesity
48:21medication is not effective if
48:22his BMI is not less than 25?
48:24And of course BMI is not a great measure.
48:26We're just using it as a surrogate here
48:28and of course the answer would be no.
48:30But let's look at this.
48:32So the average efficacy of
48:34medications to treat diabetes also
48:36has variability just like
48:38medications for obesity treatment.
48:40And so because there's great variability
48:42in response to any medication,
48:45we may need to use different
48:47medications and try and determine
48:49what a patient will respond to.
48:51So if we start a patient on any medication,
48:54they may lose a little bit of weight
48:55or they may lose a lot of weight,
48:57but we can use this and incorporate
48:59this into our treatment plans.
49:01So as with the first patient,
49:03you saw that I used several medications.
49:05And if a patient loses 5% with one medicine,
49:0810 with another,
49:09five with another,
49:10they may potentially have an added
49:12benefit or total body weight reduction
49:14of 20% or there may be synergy
49:17with some of the medications and
49:18they may lose more than 20% or the
49:21medications may not be synergistic
49:22and they may lose less than 20%.
49:24But we don't know until we try.
49:27The take home here is there's wide
49:28variability in terms of responses
49:30to these medications because
49:31there's not one type of obesity,
49:33there's many different types of obesity.
49:35We just haven't had a way to
49:37figure out what those are yet.
49:39The next concept is that obesity is complex.
49:42And the question here is do we find
49:44it unusual that this the patient may
49:47require several medications for his
49:48obesity as he does for his diabetes.
49:50And so if we look at a patient with diabetes,
49:53we then they come in with
49:55an elevated hemoglobin A1C.
49:56We may start them on one medication,
49:59then there are hemoglobin A1C decreases,
50:02but it's not yet at goal.
50:03So we started different medication and
50:05perhaps the patient doesn't respond
50:07or maybe they have side effects.
50:09So we stop that medicine and
50:10we start a third medication.
50:12And now the patient's A1C
50:13decreased and is at goal.
50:15But what we've done here is we've tried 3
50:18medications and continued to just in the
50:20same way in a patient who has obesity,
50:22we may try one medicine,
50:23then a second medication.
50:24If the patient has side
50:26effects or doesn't respond,
50:27we try 1/3 and we keep on going and
50:29adding these medications sequentially
50:31to see how the patient may respond
50:34until they reach their goal.
50:36So obesity is complex as so many
50:38other complex chronic diseases.
50:40So combination therapy is often needed.
50:43Now what about chronicity of disease?
50:46So the question here is,
50:47when this patient's BMI or weight is at goal,
50:49would we stop his anti obesity medication?
50:52In the same way would we stop a medication
50:54for a patient who has high blood pressure?
50:57So here's our patient with hypertension.
50:59We start a medication and what happens?
51:01The blood pressure decreases.
51:03But what happens when
51:04we stop that medication?
51:06Well,
51:06when the medication is stopped,
51:07the blood pressure increases and
51:09we're not surprised we stop the
51:11treatment for chronic disease.
51:13And so when we have a patient with obesity,
51:15when we started treatment and
51:18the medication decreases that
51:20patients defended fat mass.
51:22What happens when we stop that medication?
51:24Well, the defended fat mass goes back
51:26up and the weight is regained and this
51:29has now been shown in clinical trials.
51:31So in the step one extension with some
51:34Maglatide, what was done was after a
51:36year of some maglatide and you can see
51:39here depicted in the blue squares,
51:40participants lost weight when
51:42the medication was stopped.
51:43After a year, what happened is that patients
51:46began to regain the weight and again,
51:48we shouldn't be surprised because
51:50that defended fat mass set
51:52point continued to go back up.
51:53Now there is a difference here of
51:55about 5% and there's a question of,
51:56well, what if we had continued
51:58to follow these patients,
51:59would they have regained the weight or
52:02potentially would they have been able to
52:04maintain some of that weight reduction?
52:06There's also a question of did
52:08patients regain mostly fat rather
52:10than lean muscle mass?
52:11And we don't have the answers
52:13to those questions yet.
52:14What we do know is there's no cure
52:16for obesity yet, and so chronic,
52:19lifelong treatment is needed.
52:21OK, So what happened with our patient?
52:23So just to remind you again,
52:25he had tried all these different
52:27things over the course of his lifetime.
52:28And when we came to see me,
52:30his BMI was 47 and his A1C was 8.5.
52:33So what did we do?
52:34Well,
52:35we we started the lifestyle interventions
52:37that had worked for him so well in the past.
52:40We then added several medications.
52:42We added Laraglatide for his
52:43weight and his diabetes,
52:45an SGLT 2 inhibitor for his diabetes,
52:47which helped his weight plateau.
52:49Then we added a higher dose of Laraglatide.
52:52We then added naltrexone bupropion.
52:54Unfortunately,
52:54he did develop side effects.
52:56He developed Constipation.
52:57One of his providers recommended prune juice,
53:00which unfortunately did not resolve his
53:02Constipation and instead increased his A1C.
53:05He appropriately discontinued the naltrexone
53:07bupropion and instead at that point we
53:10had some agglutide available on the
53:12market and we were able to start that.
53:14And what you can see is during the
53:16course of these several years,
53:17he lost over 85 pounds with a total
53:19body weight reduction of 27% and
53:22he normalized his A1C.
53:24We continued three of his previous
53:27medications and discontinued three others.
53:29And overall he's feeling much
53:31healthier and much better.
53:32Now overall though,
53:33what we have to keep in mind is
53:35that the focus of obesity treatment
53:37is not just weight reduction,
53:38it is optimizing health where
53:40we're treating obesity and we're
53:43treating the patient at the focus.
53:45And I'm going to breeze through
53:46the next slide,
53:47but I actually think it's really,
53:48really important and this is that we
53:50need to support our patients through
53:53their weight and health journey.
53:54So we have our patient at the center
53:56here and there are many things to consider.
53:58One,
53:58we need to target the neuro metabolic
54:01Physiology of obesity that we talked
54:03about at the beginning of the talk today.
54:05We need to consider the heterogeneity
54:07of obesity and that not everybody
54:09will respond to the same thing.
54:11We need to consider factors
54:12in treatment selection,
54:13so whether that's the severity of obesity,
54:16other obesity condition related
54:17conditions a patient may have,
54:19their overall health including mental
54:22and metabolic health and various
54:24treatment targets we can consider.
54:26We need to individualize combination therapy,
54:29what's right for that patient who's sitting
54:31there in front of you in the office.
54:33We also need to optimize health.
54:35There's no medicine that helps us to make
54:37healthier food choices or to exercise more.
54:39When one of you develops that,
54:41please let me know.
54:43Until then, we really need to focus on how
54:45can we help our patients optimize health.
54:47Maximize nutritious food intake,
54:50prioritize protein intake,
54:51especially during the weight reduction
54:53phase when they're eating less,
54:55maximize physical activity, reduce stress,
54:58improve sleep quality and duration.
55:00We need to consider the rate
55:02of weight reduction,
55:03Make sure our patients aren't
55:05losing too quickly.
55:06Consider the quality of
55:07that weight reduction,
55:08so losing more fat than muscle.
55:10We also need to consider potential downsides,
55:13bone loss, vitamin deficiencies,
55:15muscle loss function,
55:16etcetera.
55:16We can achieve these degrees
55:18of weight loss now,
55:20but but all of these other
55:21things have to be considered.
55:23We also have to consider the bias and stigma,
55:26the psychosocial and the psychological
55:28implications of obesity.
55:29Treatment and access and
55:31affordability is key.
55:33Half of Americans are impacted by obesity,
55:361/4 of the world population by the year 2035.
55:39So this is really important
55:41to consider as well.
55:42And I'll end with this patient quote.
55:46And I really believe that our patients
55:48and our participants teach us everything.
55:51They give us clues to everything.
55:53And this patient was one who was
55:55in the surmount 1 tirzepatide
55:57trial and she lost nearly £100.
55:59She lost over 90 pounds in the trial
56:02and she taught me about Physiology.
56:04And this is what she said to me
56:06during the course of the trial.
56:07And let me just set the stage
56:09before the trial.
56:10She ate healthy food,
56:12she exercised,
56:13she went to PTA meetings after the trial
56:17and during the trial she ate healthy food,
56:19she exercised,
56:20she went to PTA meetings,
56:22She did everything the same.
56:24The one thing that changed was that
56:26she received something during the
56:28trial and we think it was tirzepatide.
56:30And what she said to me is it's
56:33just as easy to lose weight as
56:35it ever was to gain weight.
56:36So all the things she had been
56:38trying for all those years now
56:41in the setting of tirzepatide,
56:43she was able to lose that weight.
56:45So thank you so much for your
56:47attention and the invitation to speak.
56:49And I'm,
56:49I would be very happy to take your questions.
56:51Thank you so much.