Thank you, Dr. Petri. So we'll shift over to the grand rounds for today, and it's really an honor for us to have Dr. Jenn Kirby with us today from the division of endocrinology. Dr. Kirby earned her MD and PhD degrees here, and then stayed on for residency, chief residency, and fellowship in endocrinology here, before joining the faculty. 

And really, early in her training, her clinical acumen and ability to connect with patients was recognized, and she earned both the Ann Brody and [INAUDIBLE] awards as a graduating resident. And as she's continued on in her career, she's continued to be, really, an incredible advocate for her patients, as well as a great mentor and teacher that has earned her the appreciation of residents and fellows alike, and also a number of awards with her excellent bedside manner, as well as excellence in teaching. 

Additionally, she's become a leader at the institution as well, serving as the co-director of the cardiovascular diabetes consult service, and the quality liaison for the endocrinology division. Further through her research and clinical effort, she's become a national expert in a number of areas, and one of those areas is weight management, but primarily from the medical side. So in that context, we're very fortunate to have her here, and talk us through this kind of complex but important topic. So without further ado, please join me in welcoming Dr. Kirby. 

[APPLAUSE] 

Thank you. Happy new year, everybody. Probably a great talk to start off the new year as everybody's making their New Year's resolutions like I will lose weight this year. But you guys don't mind if I snack a little before we? No, OK. So I joke that the Fritos-- when I was a fellow in [INAUDIBLE] lab, we were using an obesity diet mouse model to study some stuff in adipocytes, and the high fat food that they used to feed these mice, it's this fluorescent greeny-blue, and it smells just like Fritos, and I can't eat it anymore. 

So this is a topic that I'm actually really passionate about. I'm actually just going to give a little shout out so Dr. Zach Henry in GI and myself are both diplomats on the American Board of Obesity Medicine, and we run a multidisciplinary weight loss clinic on Friday mornings over in Heart and Vascular Center. That's a long story. Some of my colleagues are here today. Thank you, guys. It makes it work. We have a good time over there. 

So for the residents and fellows in the room, if anybody's interested, we're happy to have you guys come and shadow, and see patients with us, and learn about obesity medicine. We have a lot of fun, and I think Dr. Henry and I both have a slightly different approach. He came at it from an interest in [INAUDIBLE], and I obviously came at it from an endocrinologic perspective, but I think you'll learn a lot from both of us. So without further ado, and I'm going to hopefully go forward. 

So the goal today is to really talk about some common myths around obesity and weight loss. This is obviously something that we see a lot of in the popular press, and patients are going to ask you about. So it's helpful to have a good understanding of this topic when you're addressing patients. So we're going to talk a lot about some of those common myths that are out there that are not only perpetuated by the popular press, but also by us as health care providers as well, and some of our biases that we have. 

We're going to talk briefly about some current strategies that are approved to treat obesity. I think the exciting piece is that we are nowhere near where we are in places like for diabetes therapies, and hypertension therapies and the like, that we're at the tip of the iceberg in understanding the physiology around obesity and weight management. So I think we're going to have a lot more tools coming down the pipe in my lifetime, and hopefully, in your younger lifetimes. But really, my goal is to kind of provoke some folks, and provoke thought and discussion. So if I'm being a little controversial, that's OK. I mean to be a little controversial at times. 

So I'm going to start with this slide, and this is just [INAUDIBLE] data over the last several decades. This came from a brief comment that was published in Lancet last year, and the authors basically said that when you look at rates of obesity or weight in the United States, what you can see is you can learn a lot, epidemiologically. You can learn stuff. So you can kind of start to figure out what things might be contributing to obesity, and I will tell you we don't know what that is. It's complex and it's complicated, but clearly, there was a shift in the late 70s that led to a rise in rates of increasing weight across the spectrum. 

So this does not single out any specific group. It actually is across the spectrum. So this hits everybody-- men, women, young, old, black, white. You name it, we got it. We're all getting bigger. And their comment, which I really, really liked, and it wasn't necessarily the best part-- it isn't the main point of their paper, but I really liked this piece which is we believe it is implausible that each age, sex, and ethnic group with massive differences in life experience and attitudes had a simultaneous decline in willpower related to healthy nutrition or exercise. We didn't all suddenly get lazy and start eating too much. 

We have to take this piece out of our interactions with our patients around this is weight bias when we interact with our patients. We cannot sit there and lay at the feet of the patient, well, this is all your fault, because it's not. Do behavioral lifestyle and behavioral patterns matter? Yes, absolutely, and they're an important part of the framework with which we have conversations with our patients in our clinics, but it's not the end all, be all. We do not tell patients with cancer, why don't you just go home and eat less and exercise more, and let's see how your cancer does, and we need to be thinking about obesity as the same type of process. It's a medical issue that needs to be treated in a medical way by experts that can do it. 

This is just one side, and it's not so that you can read all of this, but it's just an example of how complex this is. There's a lot of things that contribute to weight gain. These are just a small fraction of those things, and it's complicated, and there's a lot of stuff that's external to the patient, there are a lot of things that are internal to the patient, and I think Dr. Henry, as he's scanning this slide, will say yes, I've seen patients that can probably fit any of those number of things. 

And it's very complex, and it's fascinating to me because a lot of this is regulated centrally. So in an individual, there's a centrally regulated set point, and it makes a lot of sense. Our brain does everything for us, and controls a lot of our peripheral stuff. So it's going to have a control over our weight balance as well, and it's fascinating neurobiology, if you ever get a chance to look at some of that literature. I'm not going to talk about that today. 

All right, so I'm going to start with the big myth, and this is the kind of the big whopper that gets told, which is if you just eat less and exercise more. So this is the patient that comes to see me. They are a 65-year-old woman. They have gone to see the orthopedic surgeon because they need a knee replacement, and the orthopedic surgeon has said just go lose 85 pounds, and then we'll do your surgery. And they're like, OK, how do I do that? Well, you just eat less and exercise more. 

And the fact is that, although physically true-- because we're not talking about violating the laws of physics with the creation or destruction of matter here, but it's much more complex, and very difficult to do that. And so we have told this to patients for a long time, and the fact is if it was easy to do, we probably wouldn't be in the predicament that we are in terms of increasing rates of obesity across our country. So yes, we do try to get our patients to eat less and exercise more, but we have some other thoughts on that. So it's more simple than that. 

Anybody use this in clinic? I do. I did. So all you have to do is eat 500 less calories a day, and you'll lose a pound a week. So the equivalent of a pound is 3,500 calories, and so this is very simple math. If you cut 3,500 calories from your diet in a week, you're going to lose a pound. So the problem with that math is that-- and this is why I'm an endocrinologist because we love feedback pathways, is our bodies feedback against us, and prevent this from happening. So if you are able to cut 500 calories a day from your diet, every day, 100 kilogram person would disappear in four years. That doesn't happen. 

So this is a really interesting paper. Kevin Hall, who's up at the NIH, he's classically trained as an exercise physiologist, but he does a lot of this really preeminent work. But they did this really interesting study based on several studies, and then they did some mathematical modeling. But basically, what this shows-- and I'm going to have you pay attention to the top graph first. 

This is a classics curve for a weight loss intervention, and it doesn't matter what that weight loss intervention is, it can be a behavioral intervention, a dietary intervention, it can be a medication, and it can be bariatric surgery. The degree of weight loss at the beginning is dependent upon the intervention, but you basically always get this curve, where you get a rapid decline in weight that nadirs, and then eventually, you start to see weight recrudescence, and this is pretty classic for weight loss interventions. 

And what happens and what they've modeled is that [INAUDIBLE] the decrease in energy intake with a lot of these interventions happens pretty quickly upfront. So this is now in the bottom half of your screen, where a decrease in energy intake actually decreases pretty rapidly, but it starts to creep back up. And honestly, and it's not like patients are lying to us, but they may not actually perceive that they are increasing their caloric intake again because there's these powerful cues that are coming from their bodies, and I'm going to talk about those. 

And so actually, by the time they reach their weight meter, their energy intake is almost getting back up to where they were prior to the intervention. But what the perception is-- I am working really, really, really hard at this, and that's because their appetite is surging because our body is constantly feeding back saying, nope, you are not going to lose weight. And so even when I have a 400-pound patient who's sitting in clinic with me, and we're talking about this process, his or her body is actively defending against weight loss, even though 400 pounds is clearly an unhealthy weight. It's actively fighting against that weight loss. 

So I think that that's just a helpful way to think about this. So I'm going to talk a little bit about what some of those hormonal cues are, and this is a really nice study from 2011 in the New England Journal. This is sort of a classic weight loss intervention through dietary and behavioral interventions. They actually got pretty good weight loss-- a little over 10 kilograms, which is pretty good. It was a 10-week intervention. I believe it was around the 800 calorie diet, which is pretty restrictive, which is probably why they got this good of weight loss. But these patients were monitored for a year following that, and they actually were able to-- they were involved in this program, and they were able to maintain even some weight loss. But again, you see this classic pattern. Significant weight loss upfront, and then weight recrudescence come the end. 

But what they did was, both at the 10-week period-- so at the nadir of their weight loss, and then at week 62, which is the year after that period, they looked at some of these peripheral gut hormones that are involved in appetite stimulation and appetite suppression. And what they found was that not only at 10 weeks their appetite stimulating ghrelin was higher, their appetite suppressing hormones were lower, but it was persistent all the way through to one year after the study. 

So this is, in part, one of the difficult tasks for us as providers and patients, that there is this persistent drive for people to really want to eat more, constantly, as they're trying to lose weight. Anybody who has tried to diet or starves themselves to diet, it just doesn't work. You finally sort of break down. So this is important. All right, this one's really subtle, but it comes across in all of our like social stuff. And it was funny, if you ever watch TV on a Sunday morning, which I don't do, but my favorite is the Total Gym, the Chuck Norris Gym. Six to eight minutes a day. Helps with weight loss. Total crap. 

It's great, but six to eight minutes a day? Really? Come on. That's not even good for cardiovascular strength training. But this is really pervasive, and it's kind of insidious. We're kind of bombarded by this idea. So if you make your New Year's resolution, I am losing weight this year. It's 2019. I am going to drop that 10 pounds, that 20 pounds, that whatever. I'm joining the gym. I was googling images for this talk, and one of the things that comes up is the series of images of the thin person or the obese person to the thin person, and the obese person sitting there, and the thin person's running. So it's really insidious. 

And the fact is that exercise plays a very modest role in weight loss-- very modest. So let's talk a little bit about energy expenditure, and this will help explain why that's the case, and I think it's really important for your patients to understand this because they come to you, and they're like, I don't get it. I'm running five miles a day, six days a week, and I am not losing any weight. It's because weight loss is not driven by exercise. So Costi, you can quit running up those mountains. 

So the vast majority of our energy output is really around our resting metabolic rate. So somewhere between 60% and 80% of our energy is spent just in our normal cellular processes, ATP generation and use. This is really where we spend most of our energy. This is where when you go into-- or when we put our mice in the metabolic cages, or we go and we do our metabolic cages, or those fancy hoods to test, this is really what they're trying to measure, is how much energy do you need just to live. 

The other big part of what we do is this activity, really. This is the exercise. This is anywhere from 10% to 30% of our daily output, depending on the person that you are. The rest of it, about 10%, comes from diet induced thermogenesis. So this is the energy that you expend to break down the food that you take in. This is why I tell people don't drink the smoothies. Chew the food. You got teeth. You got enzymes and saliva that have ATP. That requires energy to ea your food, and eat food that's hard to digest. If you're blending it all up, you're bypassing that beautiful natures way of expending some energy. 

So this is just one example. I think it's a really nice example of why exercise just doesn't help with weight loss. I show this example for two reasons. One is because it shows that exercise interventions often don't result in a whole lot of weight loss, but the other thing is this was actually an intervention on older patients. So 65 years and older. There's about 160 in this study. When I was in med school-- and I'm no going o tell you how long ago. It was a long time ago. When I was in med school, it was kind of anathema. Older patients were not told to lose weight. It was this all idea of oh my gosh, you're going to make them frail if they lose weight. And the fact is I'm going to tell you why that's why that's bunk, and we can help patients who are older lose weight safely. 

So these are older patients who've been involved in a controlled study, an exercise arm, a diet arm, and then a diet and exercise. And you can see that the control and the exercise, basically, are overlaid. You may have a little bit of significant weight loss in the exercise group at the end of 12 months, but really, you could overlay the diet and the diet and the exercise. So what's driving the weight loss is really the reduced calorie diet. 

But when you look more detailed into this, and this is why when I'm talking to patients about exercise, this is why the very first visit when we're talking about what are we going to do and how are we going to help you with weight loss, we're also talking about how are we going to get you to move more because this is the piece that's really important. Because when you lose weight, you lose not only fat mass, but you lose muscle mass. It's indiscriminate, and what we don't want are 65-year-olds or our 35-year-olds to lose muscle mass. We all lose muscle mass as we're getting older, so we have to exercise to preserve that muscle mass. 

So independent of the scale, this becomes really, really important. So what you can see here in the slide is you look at the diet alone, and so what you're seeing is a loss in kilograms, I believe, a change from baseline. There's a pretty substantial amount of loss. About three or so kilograms of lean mass in just the died alone, but there's a lot of fat mass loss there. But when you add exercise-- so when you go over to the far right, if you add exercise to the diet, you really reduce by about half, that loss of lean muscle mass, and that's the key piece. So when you're talking to patients about losing weight, you've got to be talking about exercise. In part, because of this. 

The other part is the other half of that equation, which is losing weight is really, really hard. Our body fights against it. But I think the other piece of this that we don't talk enough about is maintenance of weight loss. That's also really hard. So if you've known anybody or you have been that person who has lost weight, people are like oh my gosh, you look great. Wow, what are you doing? You look fantastic. Hey, you look really good. A year later, if you're at that same weight, people are not coming up to you-- wow, you look really good. How are you keeping that weight off? Nobody does that, right? 

But that second piece of keeping weight off is also incredibly difficult, and this is where the physical activity comes in as well-- this exercise piece. So I'm taking this splashy paper. That was two of them that were published in 2016 and '17 in obesity, looking at some participants in The Biggest Loser. You guys know The Biggest Loser? By the way, don't do this in your offices and in your clinics. The Biggest Loser was not the way to do this. Just don't do those competitions. But basically, these were people that were put on a TV show, and they were tortured with scads and scads of exercise because exercise helps with weight loss, but they were also taught to eat well, and they were taught to cook, and they were taught how to be better from a nutrition standpoint. 

The bottom line is you can see in this far left part, at 30 weeks, most of the patients have lost a pretty significant amount of weight. So that was the whole thing, was to be the one that lost the most weight. So these were people who had lots of weight to lose, and were losing in excess of 100 pounds. This is extreme weight loss. At six years, not surprisingly, most of these patients had gained that weight back. This is typical. So the patient that comes to you in clinic. I can lose 15 pounds, I can lose 50 pounds, but I regain it. These are the people who are doing this. They have gained and lost multiple people over their lifetime because weight loss maintenance is also incredibly difficult. 

But what they did was they looked at, through a variety of methods, including doubly labeled water, and calorie mixed-- I can't say it. Doubly labeled water experiments, looking at energy expenditure and food intake, and it turns out that their food intake was not really substantially different across these two groups. The ones who had kept more than 13% of their weight loss, and those who had gained back most of their weight, if not more. It turns out that the difference between these two groups is the physical activity, and this is just consistent with other data that's in the literature over the last several years, which is the key to weight loss maintenance is really, that physical activity. 

So again, if I'm sitting with my patients, and we're talking about weight loss, I'm talking about how are we going to get you moving because that's going to be the key. So if you lose 20 pounds, or 50 pounds, or whatever it is that we're working towards, this is how you're going to keep it off in the long run. Is that physical activity. This is challenging. How do you help a 400-pound woman with heart failure to move? I don't have a degree in exercise physiology. I would love to have an exercise physiologist in our group, hint-hint, but this is really, really, really key in terms of this. And so this is true for all types of weight loss. If you look at the bariatric surgery data, patients who are more successful keeping it off long-term, more highly active. 

So our bodies fight against us. Weight loss is hard. Weight loss maintenance is hard. So as we are trying to lose weight, our bodies are sending out hormone cues that say nope, you're going to eat more-- subtly. We may not even realize it. We have more hunger. It wants to drive our energy intake, and the other part of it-- and I didn't mention this too much, but the other part is that there's also a decrease in resting metabolic rate that happens. So as you lose weight, you develop what's called a metabolic gap. You don't need to expend as much energy to maintain that resting metabolic rate. 

So if you take two patients-- two women, same age, same everything else, both 150 pounds. One has always been 150 pounds, but one has been 180, and now is down to 150 pounds, the person who was at 180 and now at 150 will require far less energy to maintain that 150 pounds. That's that slowed metabolic rate. So I've got lots of patients coming in, they're like I know I've got-- I just have a slow metabolism. I'm like yeah, you might. 

So there's a bell curve, and everybody needs their own variety or their own number that they need to maintain that weight loss. And for most patients, it's probably around 200 to 250 minutes a week. That's a lot, and that's far more than what is recommended by all of the groups that say 150 minutes. That's what the ADA recommends for our patients with diabetes-- 150 minutes of moderate intense cardiovascular exercise per week, which is 30 minutes most days. Or five days, excuse me. There are patients that need 300 to 350 minutes. So I think preparing patients for that is important. Setting expectations. 

I say this all the time. You can't out run your fork. So this is a picture of my husband after his first 100-mile race. So you would say oh, 100 miles. So you can outrun your fork when you're doing 100 miles, but you can't. So the interesting thing is my husband took up running when he was 47, and he went from literally couch potato to 100 miler in less than three years, which is really, really impressive. And the funny thing is he lost 40 pounds, but he didn't lose 40 pounds because he was running like a maniac. He lost 40 pounds because he wasn't eating the chips at night because he was running instead. 

It's actually been really difficult, and he can attest to this. I hope he doesn't mind me sharing his story. I told him. He knows that I was going to do it. But it's been really difficult. So he runs a lot. He's completed several hundred mile races since the time he runs way more than I do. He doesn't let me forget it, but he also still has to really watch his caloric intake because when his mileage starts to go down, as he's having a little break from training, the pounds start to creep up, and so he has to be really careful, and so he's really-- it's a struggle. 

Whereas you can't outrun your fork, I always advocate for exercise. We all need to be moving more. I'm a huge fan. It's really important for weight maintenance. It's really important for preservation of our lean muscle mass, especially as we get older, and it's got scads and scads of other health benefits, which is why we have to be talking about physical activity to our patients every single time. It's hard to do in a 10-minute visit, I get it. 

My favorite. My favorite myth. Fill in the blank. This diet is the best diet for weight loss. Let's talk about the diet of the year-- keto or Mediterranean. A little shout out to Dr. [INAUDIBLE] back there. It turns out-- and I love the Mediterranean diet, don't get me wrong. It turns out that there is actually-- if you're just talking about weight loss, and I am not talking about prevention of heart disease, I'm not talking about the best diet for treatment of diabetes, what I'm talking about is strictly for weight loss. There is actually not one specific diet that works better than others. Albeit it, I will say as we are tribal in our politics, oh my gosh, talk about tribalism around specific diets. Holy cow, man. 

But there is a list, and this is a nice article if you want to take a look at. It's a little outdated, but it's not a bad article to reference. It talks about 15 different diets that are shown that have data, and they basically all drive to one conclusion, which is reduced caloric intake. So I have patients that come to me, and they say what diet should I be on? Just tell me. What do I do? And I hate to disappoint them. I'm not very prescriptive. I say is whatever it is that you can stick with because if they don't like the keto diet, they're not going to do it, contrary to what some of the people who are very pro keto will tell you. And those people who are pro keto are probably the ones that do great on it. 

So actually, Dr. [INAUDIBLE] had this conversation right before clinic. He had a couple that he saw. They both went ketogenic. The man lost 20 pounds, the woman gained 20 pounds, and that is the truth. Not to mention the fact that men often have an easier time with weight loss than women, and postmenopausal women, we're all hosed. It's tragic. But I do want to talk quickly about this trial. The Dietfits trial because it's a great trial. It was well done. I think it's a great example of some of the literature that's out there. This was one of these really outstandingly done trials. 

What the authors did was they wanted to see-- they randomized patients to either a low carb or a low fat diet. They also said we want to understand if there's an interaction with diet with genetics, and so they looked at three SNPs that are involved in carbohydrate and lipid metabolism that in a prior study, had suggested that it would predict whether somebody would respond to a low fat or a low carb diet. They also wanted to look at-- and this as sort of this insulin model of obesity. They wanted to look at the diet interaction with insulin, and so they looked at after glucose load, what your insulin levels at 30 minutes were. And the endocrinologists in the room can debate how appropriate that is, but they wanted to look at that interaction. 

They said to each group they had dietitians that worked with each group equally over multiple visits. They basically said you're going to reduce your intake of either fat or carbs to 20 grams during the first eight weeks, and then you can add back five to 15 grams per day, per week, until you can get to the lowest tolerable levels. So if you're 15 grams of carbs, you may feel lousy, but at 25, you may be doing OK, and that was acceptable. They told the low fat group you want to avoid oils, fatty meats, low fat dairy, and nuts. For the low carbs, cereals, grains, rice, starchy vegetables, and legumes. Some of the stuff that we actually talk about as being healthy for people. 

I love this piece of advice. Memorize this, guys, because this is really where it's at. Maximize your vegetable intake, and minimize your added sugars, refined flours, and trans fat. Simple. That's probably where we need to be. Focus on whole foods minimally processed that are nutrient dense and prepared at home when possible. So this was what they told both groups. This is great advice. At the end of the trial at 12 months, you can see there was good separation. The folks that were in the low fat group, about 29% fat. In the low carb, they're about 30%. So they had a pretty decent separation in the groups. 

But this is the beautiful thing about this trial, and I love these waterfall plots, and they don't publish them in the main article, but they published it in the supplement, and this is looking at every single participant in this trial and what happened with their weight, and this is classic for every weight loss intervention-- diet, meds, even bariatric surgery to varying degrees. And so you can see on the left that there are people who do really, really well. They did great. Oh my gosh, 30 kilos? That's awesome. That's a success. But you also have the patients who come on the other end-- 10 kilos. 

This is what Dr. [INAUDIBLE] was referring to, the husband and the wife. They are clearly on different spectrums, here. And this is what happens, and so this is where-- and the fact is that the average weight loss was about 10 pounds across both groups. No statistical difference between the two groups, and there was absolutely no interaction with the genetics or the insulin. 

So basically, kind of null. But it told us really important data, which is you got to find what works for you, and we are not smart enough yet to predict. So I really like this study for those reasons. So yes, diet's important. Exercise is an important. Diet is really going to sort of drive the weight loss. Reduced calories is going to drive the weight loss. The exercise and physical activity is going to be important for the weight maintenance piece. 

It's also important for preservation of lean muscle mass, but we know that behavioral therapies don't necessarily work all the time. It does work for some patients, and there are some patients who have 100-pound weight losses that are sustainable over years, but that's hard, and that's the minority. And we get told these stories-- the Runner's World article on the man who lost 100 pounds when he was training for a marathon. So all of those poor people who didn't lose 100 pounds while they were training for the marathon feel like failures, and they shouldn't because they're out there training for a marathon, which is really awesome. 

We do not treat obesity in this country or in the world. We treat our patients with type two diabetes, but there's-- where does type two diabetes come from, arguably? There's a lot of perceived barriers. So some of the myths that exist are around medications, and I will say there is no magic pill, and we'll look at the data, but we're talking about 5% to 10% of weight loss, but that has clinical significance. There's a lot of providers who really feel like this is really just behavior, and we need to be focusing on only behavioral, and why would we give people the easy way out with a pill? 

Safety concerns and side effect concerns. I think the safety profile for our most recent generation of medications are actually quite good. The most recent data that just came out for lorcaserin was encouraging. Didn't show any increased risk of cardiovascular disease or events, excuse me. Lack of efficacy? Sure. When you look at the data, there's a lot of dropout, and there's a lot of patients who don't respond. But if you look at the waterfall plots, there are patients who do respond. So you have to find the right agent for the right patient. It's just like finding the right diet, but that doesn't mean we don't try. 

Lack of knowledge. I'm an obesity medicine expert specialist. That's my training, and so it's hard to do as a primary care provider in a clinic visit for 10 or 15 minutes. How do you have this complicated discussion? And cost is a huge issue, and I openly admit that. Cost around being healthy is always an issue. Costs are on medications-- there's very few company insurance companies that are paying for weight loss medications. 

And poor patient compliance. So this is sort of the lump sum data looking at the phase three trials for the agents that are currently approved for weight loss. May vary in their efficacy in terms of all-comers from lorcaserin, which is about three to five-- it's interesting because to get approved by FDA, you have to be at 5%, but if you look at that data, it's around 3%. Having said that, I have a patient on combination metformin and lorcaserin who's lost 80 pounds, and has done great over three years. So go figure. 

Phentermine topiramate combination tends to be the most efficacious when you look at this, but 3% to 10% weight loss has an impact. 10% weight loss has an impact on risk for diabetes and blood sugars, if you have diabetes, hypertension, hypercholesterolemia, as well as the beginnings of fatty liver, although you usually need about 15% or more for fatty liver. 3% makes a difference in blood sugar. So as anybody who's done diabetes management, people lose a few pounds, and you're like oh, look at the blood sugars. We're going to have to reduce your insulin. This is good. 

There's some really exciting stuff coming down the pipe. This is just one. So you notice on the prior slide-- let me see if I can go back. The prior slide, one of these medications, liraglutide at three milligrams. Tell me you guys will recognize that name. It's a GLP-1 receptor agonist, commonly known as Victoza for type two diabetes. It's marketed at a higher dose for weight loss called Saxenda. Same drug. Victoza is usually covered, Saxenda not. You get pretty decent weight loss with liraglutides. So anybody who's used that in patients with type two diabetes may have found, oh wow, my patients are losing weight. Their blood sugars are getting better. This is great. 

A relative to this that just actually got approved early last year for type two diabetes, semaglutide. This is interesting because it's kind of like the eighth drug or ninth drug into this class, and that would, in general, be a me too drug. What's really interesting about semaglutide is as opposed to liraglutide, it's once a week instead of once a day, and they're also coming up with an oral formulation. So all of these drugs are currently injectables, but semaglutide, they're working on oral formulation. So early phase trials have been really successful. So it's kind of interesting. 

This is a phase two weight loss trial. So this is not diabetes. This is just solely for obesity treatment. This is semaglutide, and what you can see is they actually compared it-- and the reason they did a direct comparison is because it's made by the same company, but they did a direct comparison between liraglutide and semaglutide, and you can see it's basically two-fold more weight loss. We're talking about-- we're starting to get into laparoscopic band weight loss with semaglutide. So this is very encouraging and exciting information, I think. There is some dual and triple agonist medications that are going to-- these peptides that are going to target not just GLP-1, but also GIP and plus minus glucagon, and those are also being looked at for weight loss as well as diabetes. 

And I think that class-- that grouping-- is going to be really an interesting group to come around. The interesting thing is semaglutide had some interesting cardiovascular outcomes. liraglutide has an indication for patients with type two diabetes and cardiovascular disease. They've got an FDA labeling indication that says if your patient has type two diabetes and cardiovascular disease, you can use this medication. So it starts to bode well for risk in these patients who may be higher risk for heart disease. 

Quickly, I'm going to talk really quick about surgical procedures. We under utilize them, and it's our most durable and most effective weight loss therapy. It is not a cure. Repeat, it is not a cure. This is chronic disease management. The sleeve gastrectomy me is quickly outpacing the gold standard Roux-en-Y gastric bypass, and that's the same at our institution as well. You'll see mostly sleeved. We don't do a whole lot of the other things, and the balloons are not here yet. They're not covered by insurance. They're being done at other institutions where people are paying out of pocket. So I won't talk. 

These are sort of the common views that I hear from patients and actually other physicians around bariatric surgery. It's the easy way out. Well, we've already talked about how most patients, by the time they come to see me, they've spent their entire life battling obesity unsuccessfully. This is not the easy way out. Too dangerous. So the mortality rate is better than our equivalent to laparoscopic, cholecystectomy, elective cholecystectomy. It's less than 1%. This is not your grandfather's bariatric surgery. You'll hear this-- well, I know the person who did the gastric bypass, and then they regained all their weight back. I've heard another clinician friend of mine who said oh, she'll just eat her way through the bariatric surgery, and I politely said well, I beg to differ, and he said whatever. 

And that gets to this last point, which is the restriction malabsorption piece. So if you'd asked Dr. Schirmer 30 years ago when he first started doing these surgeries how they worked, this was the mechanism. You create a small stomach, you bypass so you're not absorbing nutrients, and that's how you lose weight, and it turns out that's far more complex, and probably doesn't have very much to do with this. It probably has a lot to do with gut bacteria and hormonal feedback to those areas in the brain that are involved in weight set point. So really exciting information. I joke with my bariatric colleagues that we're going to put them out of business once we understand that physiology and develop targets. Maybe, we'll see. 

This is just data from the Stampede trial. It's a good indication of what ends up happening. You will notice the curve is the same. You lose a lot of weight up front, and then you often have weight recrudescence. But by and large, most patients end up at a weight, five years after a surgery, lower than their starting weight, and you can look at the same curve in the Swedish obesity study. This is the US randomized control trial. This is actually patients with type two diabetes assigned a medical therapy versus sleeve and gastric bypass. We think sleeve is probably a little less efficacious, but still a really good surgery. You have a little less of the complications in terms of nutritional deficiencies. 

This is data from our cohort in our institutions. So this idea that if you regain your weight-- you regain your weight, and so why go through the surgery. So we looked back. So Dr. Shirmer, in his infinite wisdom, started a collection of his patients right from the get go, and we went back and looked through his 30 years of-- our 30 years of patients here, and even when you take patients who have regained all of their weight at 10 years, that they had about 67% of their comorbidities were resolved, even at 10 years with complete weight gain. 

Listing of things like apnea, degenerative joint disease, diabetes, GERD, hypertension. So this is actually, even if you weigh the same at 10 years than you did before, if you lost that weight and regained it, you still had clinically relevant resolution of your preexisting comorbidities, and about the same amount percentage of patients with even those who had weight loss success. This isn't a cure, but it can be a very helpful tool. 

I hopefully-- and I'm going to get you out of here on time. Hopefully, have convinced you guys. Obesity is a complex, chronic disease. This is how we should be thinking about it-- this chronic model. It's difficult to lose weight. It's difficult to maintain that weight loss. So maybe, Costi, you should go up and down those mountains some more. Keep doing it. Modest weight loss has health benefits, and there are some effective treatments available. I've talked about how we don't have a cure. We don't, but we need to start thinking about how we're going to manage this in the long run. 

I'm going to finish with a little bit on weight bias. I'd highly encourage all you guys, especially the trainees, there's a great implicit bias testing site on the Harvard website, and I put it here. I don't know if any of you guys have done any of these. There's one on weight, and I've done it. I have moderate bias against weight. I'm an obesity medicine practitioner, and I have these implicit biases. We all do for lots of different things. 

I would encourage you, and I think the take home is that we tend to think about obesity like this figure. Is that the people who weigh more are eating crappy and are not doing as much as they should, and I will tell you, I work out with people who weigh four times that I do-- are just beasts. They are awesome in the gym, and they also eat a lot better than I do, try as hard as I might. So I think we have to get away from that viewpoint. We need to be mindful of our language and how we're talking about it. I had a conversation this morning with one of my patients who was a new patient. 

Status post-sleeve gastrectomy. She's regained weight back. She's devastated. She feels like a failure, and she says I don't know. I don't eat. She was out to breakfast with some friends, and she literally told me what she ate, and there was another friend of hers who ate three times as much who's also had bariatric surgery, but has managed to keep his weight off, but was eating three times as much as her, and she says I don't get it. I'm a failure, and I said no. I said we need to change how we think about our language. You had a great success. She lost 80 pounds with her sleeve gastrectomy. She's had about 35 to 40-pound weight regain. She's still less than what she was pre-surgery. 

She's had recurrence. She had a recurrence of her disease. People go into remission-- we talk about remission of diabetes after gastric bypass. It's not a cure, and we definitely have non-responders. So I have plenty of patients that I've seen in clinic after gastric bypass who didn't respond, or they lost 20 pounds. These are non-responders. They didn't fail. They just don't-- there's biology behind that. I'm going to end there. If there's anybody who has any interest, the American Board of Obesity Medicine, if anybody's interested in becoming certified. 

The Endocrine Society, Obesity Society, and the Obesity Medicine Association all have great websites and resources on obesity for both you and your practice, and for your patients. There's some great little videos on the ASMBS website explaining bariatric surgery risks, benefits, et cetera. I use this frequently when patients are-- we're talking about, and I'm introducing the topic of bariatric surgery. And if you're interested in more of an arm where you're being more active in terms of going up to Capitol Hill and lobbying, the Obesity Action Coalition is a great patient-led group that is involved in that, and in fighting weight bias. 1:15, I will end there. And if you guys, you want to come up, and I'll take questions. Thank you. 

[APPLAUSE] 

Andy. 

So I know [INAUDIBLE] 

So there is actually really great animal data for this, and so Randy Seeley out in Colorado has done a lot of some of this work. There's also looking at things like bile acids, and how bile acids, both pre and post surgery, may have an impact on the microbiome. So it's interesting. Bile acids are hormones that are probably signaling, and so there's a lot of really interesting work. That's a whole-- that could be a whole course in and of itself on the microbiome. That's where the money is. I think that's what we're learning, which is the microbiome, this 10 pounds of bacteria that we live with, have a huge impact on our overall health. Our risk for depression, for obesity, for diabetes, you name it. 

And so that's going to be-- what we don't have yet is here's your capsule of the four organisms that are going to cure your obesity. We know that stool transplant's great for C. diff, and there's actually some-- I believe in Europe, they've done some proof of principle human studies where they've looked at stool transfers of lean stool into obese subjects, and looked at metabolic markers. Obviously, not weight loss because that's too long a time frame, but they've looked at some of the metabolic markers, insulin resistance, et cetera, and shown some proof of concept stuff. So it's fascinating. I think that's the really cool piece of where we're headed. Yeah. 

[INAUDIBLE] 

I'm going to premise this and say that what I'm talking about is non-FDA approved and off label so that I don't get into trouble. So the FDA on the weight loss medications are not approved for duplication. Not to be used with other weight loss medications. But I will say that there is a lot of us in practice who do this. I have used combinations, and the way I think about it this. When we talk about treating hypertension, we start with a medication, and before we max that medication out, we're going to hit a separate pathway. If we haven't gotten control, we had a second drug to hit a different pathway, and we know that's more effective. 

This is the way to think about obesity. Obesity is a complex disease. It has multiple pathways. So yes, we are going to move in that direction. So I think about it as the post gastric bypass patients who come and who are having weight recrudescence. We start thinking about medication tools as a way to help them. They've had an adjustment in one or more of those pathways. I don't think we fully understand. But yeah, I do, but that is off label, and non-FDA approved. 

You talked about the two situations in which exercise is beneficial. 

Well, there's more than that. 

There's prevention of regaining weight, and the second is preservation of muscle mass. Can you distinguish aerobic and anaerobic exercise [INAUDIBLE] 

I think there's a lot of debate around what's the best exercise, and I'll be honest, I don't proclaim to be an expert on that data. There have been studies that have looked at both aerobic and then shorter bouts of higher intensity exercise, both of which are effective. I think there's a lot of debate about what-- again, I didn't get too much into this, but there's a lot of debate like what's the best diet. Also, there's a lot of debate about what's the best exercise. I think, by and large, for most of the patients that I'm seeing in my clinic, it's literally getting them from going from nothing to something, or really sort of increasing the amount that they're doing to a reasonable. 

I start with we're going to try to get you to 150 minutes a week, knowing that we may need to go beyond that of moderate intense cardiovascular exercise, but there's a lot of complicated literature out here, but I think it's a great question. My personal take on health, and I'll just throw this out there, is I think there's multiple things that people should be doing. I think there's cardiovascular fitness, I think there's muscle strength as well that is important, and I also think flexibility is another piece, and so I look at that as sort of the tri part piece of being fit, if that makes sense. Yeah. 

I have a question. [INAUDIBLE] 

They also drank whole milk. 

Throughout college, I was never doing less than three hours a day. [INAUDIBLE] and I had a pulse rate [INAUDIBLE]. So I completely underestimated how much exercise I actually needed. The other thing is that I am surprised that televisions don't-- there's a picture of the [INAUDIBLE] it's really interesting. None of them were obese. [INAUDIBLE] physical activity is the thing that [INAUDIBLE]. 

So it's interesting because when you read on this, again, it's debatable. I don't think there's been a single piece of-- the missing piece the link that says, hey, this is what caused it. Yes, we probably are not as active, but there's actually some really interesting studies where they've tried to address that question about the activity piece, and it turns out that when you retrospectively look at activity levels then and now, your energy expenditure is probably not much different. So even though we may not move as much, our resting metabolic rates may be lower. Again, sort of akin to what happens, but our total caloric needs for the day may not be much different than they were in the 1960s. 

So what people have argued is that physical activity, because it's really only about 10% to 30% of energy expenditure, yes, we all need to be moving more, and we need to be outside running around crazy and off our screens, but the obesity piece or the weight gain piece has really been thought to fall on the food consumption side. But it's really interesting because I think we've done a disservice to our patients. For a long time, we were like oh my gosh, fat is bad. No fat, no fat, and well, it turns out kids who drink whole milk compared to kids who drink skim milk, the whole milk drinkers are leaner. 

So we've gone down some really bad rabbit holes, and I just don't think we understand it yet. We aren't smart enough. We haven't done the right studies. We have a long way to go, I think. Your point is well taken. We don't know what that shift was, but clearly there was something because it's a very dramatic shift. Yeah, Dr. Henry. 

I have a comment about that. Personally, I think there is a remarkable change that happened in the [INAUDIBLE] pyramid was the biggest enemy? 

Carbs. 

Carbs. [INAUDIBLE] and that's when you really started to see this uprise in processed [INAUDIBLE] foods and all [INAUDIBLE] added sugars. In the 80s, you saw trans fat, and [INAUDIBLE] and now we'll back off on that, but essentially [INAUDIBLE] and actually, if you look at obesity [INAUDIBLE] 

Just to give my pediatrician and health policy people some props, they're working on it. But there's a lot of weight bias, and a lot of uphill battle around that. Yeah. 

[INAUDIBLE] 

I absolutely agree. So I will go back quickly to what they recommended in the Diet Fit study for all of the participants, which was eat mostly vegetables, get rid of your refined sugars and the trans fat, and that's probably not a bad place to start. And cook at home. Know what you're eating. Stop eating out. The highly caloric dense palatable foods. Yeah. 

[INAUDIBLE] Can you comment on the role of sleep and or of this new discussion about a full-blown depressed [INAUDIBLE] 

Yeah, it's great. I put diet and exercise up there, but the third pillar is sleep. And so we know-- and I recall this from my residency days. At 3:00 in the morning, it is far easier to go downstairs and get French fries than a salad. My hypothalamus is like French fries, French fries. So we know that sleep deprivation and sleep disruption often is associated with poor food choices, higher caloricaly dense carby sweet stuff. We also know that shift workers and patients who have sleep disruption are not getting enough sleep, it's associated with obesity. 

So obstructive sleep apnea, the fascinating thing-- and the studies are not great, but when you treat obstructive sleep apnea, most of the studies, and these are short-term, show a modest increase-- a couple of pounds of weight gain after you treat their sleep apnea. Now, these are short-term. Six months, maybe 12 months at the most. So sleep is incredibly important, but I used to think that hey, if I send everybody for their sleep study and fix their sleep apnea, they'd drop 20 pounds. Well, that's not going to happen, but it is an important key. And actually, in our assessment in our H&P, I have weight history, diet history, physical activity, and sleep, and I ask patients about that, for sure. 

The intermittent fasting or the time limited eating is a fascinating thing. We need more human data. There's some interesting stuff. So there was a great paper that was published, I don't know, maybe six or seven years ago on mice. That they were fed ad libitum high fat diet versus chow, but then they did a time restricted feeding. So they were only allowed to eat in the eight hour window when they were awake at night, and they got chow and high fat diet. And it turns out that the mice who had a high fat diet for that time restricted window didn't gain that much weight compared to the chow mice who maintained their weight. 

So there is, in animal models, some interesting data. There is some human data as well about this idea of having this intermittent fasting. I certainly have tried some of that myself. My weak time is in the evenings, so I try not to eat after 6:00 PM. I'm not always successful, but these are little strategies that if they work for the patient, great. They're not going to hurt. The place where I would be a little more cautious is the patient who-- particularly for patients that I see with diabetes who on sulfonylureas or insulin, and they're doing extended fast-- 48 hours, 24 hours. 

You need to prepare them so that you're cutting back on their insulin, or they're not getting hypoglycemic because they're not eating for a period of a day, and they've been having to eat to keep up with their insulin or their sulfonylureas. There's some fascinating stuff literature around that too that I think is-- this idea of resetting our insulin sensitivity and diurnal variation. There's some really interesting literature around patients with type two diabetes who eat like a king. So more like a triangle, where they consume most of their calories in the morning, 30 grams of protein with breakfast, have better postprandial glycemic control later in the day, as opposed to what we do, which is the upside down triangle. 

We eat not a lot of breakfast stuff at all, we eat some lunch, and then we come home, and we way over eat at dinnertime. So time of day may make a difference as well. When we consume, how we consume things. So I throw these strategies out to patients, knowing that they can take or leave and try, but I'm not expecting there to be the one size fits all, or that they're going to be a cure all for each patient. There's some really interesting literature about that, though. I think it's going to be interesting to see what happens. Great. Thank you, guys. 

[APPLAUSE]