Anti-Obesity Pharmacotherapy: Sparks from the Pipeline

Transcript

• 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.