黑料网

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Falk – Hello and welcome to season two of the Chairs Corner from the Department of Medicine at the University of North Carolina, Chapel Hill. I am Doctor Ron Falk, chair of the department and the host of this podcast, where we’re dedicated to empowering patients like you with knowledge about your condition, enhancing your quality of life every step of the way, each and every day. Today we have an exciting guest with us, Doctor Andrea Coviello. She’s a professor of medicine here at the University of North Carolina and also the director of the 黑料网 Medical Weight program. She has been caring for patients with diabetes and obesity and other weight conditions for a long time. Over 20 years or so.听Welcome, Doctor Coviello.听

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听Coviello- Thank you. It鈥檚 a pleasure to be here听

听

00;00;58;21 – 00;01;25;24听

FALK – Oh, there’s so much talked about about weight loss, drugs. It’s an unbelievable hot topic. Let’s talk first about what the weight loss drugs are, what their names are, what brief mechanism there is. But let’s just start with the names, the participants in the drug world. 听

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COVIELLO –The place to start would be with the new medications. We’ve had literally just in the last couple of years, because those are the ones that really change the landscape of medical therapy for weight loss, because they’re so effective. Drug development for weight loss medications actually started a long time ago in the 50s. But that said, we only have eight drugs that are approved for weight loss for the general population. 听There are a few orphan drugs for specific rare conditions, but literally less than ten to combat what has become an epidemic across the United States in the world. I think there is a lot in the media now about these weight loss drugs, because the two that we have had approved in the last couple of years are the most effective ones, and that are those are the drugs Wegovy, which is a semaglutide and a drug called Zepbound, which is to trizepatide, which has literally only been out for about a year.听

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FALK – So Wegovy听has other names?听

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COVIELLO –It does. These drugs are have been developed in parallel to medications for diabetes, and they are generally approved for diabetes, type two diabetes first and then the pattern has been that they then get FDA approved for weight loss after that. So you know these drugs by the names Ozempic. That’s the same thing is Wegovy and Manjuro. 听That’s the same thing is trizepatide for diabetes. So they’ve been used actually for many, many years for diabetes, usually prior to them getting approved for weight loss. 听听

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FALK – So we’re really talking about two drugs that are both part of an interesting molecular approach. Tell us about the basis of that. Those drugs.听

00;03;02;15 – 00;04;13;05听

COVIELLO – So they’ve been in development for at least 20 years. Again, the initial ones that we actually had in 2005 for diabetes are in the same category a medication, and it was regarded as revolutionary because it was the first step away from insulin use. But the interesting thing about this class of medications is that they are basically synthetic versions of your natural gut hormones. So these are hormones that you naturally make after you eat a meal.听So the meal moves through your stomach into your intestines. And then this cascade of gut hormones gets released that helps you metabolize what you just eat, break it down. So the drugs that we have now are actually very similar on a molecular level to your natural gut hormones. They have been tinkered with a little bit to have them last longer. 听Your natural gut hormones disappear about ten minutes after they’re produced. And these newer drugs, the ones that we do once a week, actually last for seven days, on average. So the dosing is once a week. So the interesting thing about these drugs is that they’ve just amplified or magnified what are natural good signals for your metabolism. 听

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FALK – And they’re called what , their?

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COVIELLO – So the class is called incretins. In general, at present , we only have three actually approved for weight loss. There is one that was approved about a decade ago. That’s a once daily drug. The two that are weekly. That would be Wegovy or semaglutide or Zepbound or trizepatide. These are the once weekly medications that are associated with 15 or 20% weight loss on average.听

听00;04;40;20 – 00;04;43;05听

FALK –And the gut hormone is G L, 听

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COVIELLO – the GLP one. Most of the drugs in this class, with the exception of trizepatide, mimic a hormone called GLP one. But the newest one that’s more effective than Zepbound that’s actually a synthetic. It has the activity of two different hormones, GLP one and another hormone called GIP in combination, and the combination seems to be what has made it more effective both for blood sugar control if you’re using it for diabetes, but also for weight loss if you’re taking it for obesity.听

听

00;06;33;23 – 00;06;42;59听

FALK听

So when you’re then, prescribing these drugs, how much weight do you really want somebody to lose weight on a percentage basis? 听

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COVIELLO –Yeah, I think that really depends again, on what their initial profile looks like. We know that 5 or 10% weight loss, total total weight loss, not necessarily just fat mass, but total weight loss improves many chronic conditions.听

That’s enough to improve blood pressure. That’s enough to improve your sugar control. Maybe not completely regress, to normal, but to definitely improve things. So we sometimes start there. We start with what’s reasonable and practical. I think many people come in to their first visit and have a really large amount of weight. You know, they’re focused on a number that they want to lose.听

But it may be impractical. It’s certainly likely impractical in the short term and probably not advisable for most people to lose dramatic amounts of weight very quickly. So we really kind of try and reframe that.听

00;07;28;00 – 00;07;33;07听

FALK –Why why, I mean, why is it bad to lose a lot of weight real fast? One generally because the mechanisms that people use to do that are not sustainable, right?听

听00;07;33;49 – 00;08;44;00听

COVIELLO – One generally because the mechanisms that people use to do that are not sustainable, right? 听So they go in severely restricted caloric diets, or severely restrict time restricted eating. So they’re they’ll eat like in a four hour window, which means one meal a day, short term diet programs or, diet and exercise programs that are six months or a year and you lose a tremendous amount of weight, but that you can’t sustain to will lead to weight regain and sometimes back to higher than their prior baseline.听

When you lose weight successfully 5 or 10%, your body actually, changes in ways that promotes regain. We have evolved in a way that the body likes to protect its fuel sources. Right? You’re always preparing for the coming famine in your body, sort of old school evolutionary viewpoint. And now that famine never really comes. But when you lose just even 8% of weight, the hormones that drive your hunger and your feeling of satiety, they shift in a way that you’re more hungry all the time and less satiated even when you eat a meal. And this has been shown in in research studies. So we actually know that your hormones shift in a way that make it harder to continue to lose weight.听

听00;08;44;02 – 00;08;45;09听

FALK –Even on these drugs?听

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COVIELLO –No. So these drugs actually came along and now these drugs mimic these satiety hormones. So I think the big difference has been when people go on these and they are implementing their lifestyle changes, they have long term success.听

They feel that drive to eat more of that hunger that happens when you have successful weight loss is blunted by these drugs, because these are the synthetic versions of the hormones that promote satiety make you feel full.听

听

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FALK – Does that also mean, though, that you can’t come off of the drug? 听

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COVIELLO –You know, these since these drugs are synthetic versions of your natural hormones, they last longer than your natural hormones, but they’re still gone. 听

You know, they degrade in your body and they’re gone. So once these protein hormones are gone, they’re not exerting their effects. So if you stop the medication entirely, with for most people, the data has shown that they will regain weight. And people people say that even if they have a problem getting their medication from the pharmacy and they miss 2 or 3 doses, some people report it right away that they can feel their hunger coming back, even in that short a time frame. So for a lot of people, being on these drugs is a is a great way to lose weight. And then potentially they need to be on some dose to maintain that healthier weight. If they go off, most people will regain some of the weight. And it looks to be about 50% and about a year to two years time.听

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FALK –That means everybody who starts these things, or most people who start these drugs are more than likely going to stay on them for for life?听

听00;10;11:00 – 00;11;13;10听

Coviello – Possibly some people. I have certainly had people who potentially go off these medications who have made very significant changes to their lifestyle, have, you know, are eating, you know, some patients go, they’re eating vegan now and they’re exercising five days a week, and they maybe don’t need that medication to maintain that weight.听

But most people will likely need something. I think a lot of the development in the pharmaceutical world now is actually going towards how to sustainably change your own metabolism or your production of these hormones in a way, maybe potentially amplifying these. There are some animal studies going on with gene therapy to just augment how much natural GLP one you make.听

And so that’s a treatment that’s thought to be a one time treatment. There’s a lot to be worked out in that space. But at the moment, what we know is if we can increase your own, your gut hormone signals, that works for most people. But I think there’s still a lot to learn about what has caused the obesity epidemic. Certainly a lot of it is environmental.听

听

00;11;14;40 – 00;11;32;01听

FALK – So the problem with all of this is these drugs are ridiculously expensive and their health plans that won’t pay for them, and the population that may be at most at risk, with no insurance or insurance that won’t pay. What are your suggestions for them? 听

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COVIELLO –I’m very hopeful that this is a phenomena that we see because these two drugs just came out in the last couple of years. Wegovy in 2021 and Zepbound in late 2023? So now there are two companies that are in this space producing these medications. They’re going to be more companies coming in with with versions of incretins. And I think that will help just from a general market perspective start driving the price down. I think the price will come down. We have seen this with other classes of medications, and I think that will be helpful in terms of access. I think there is still stigma about treating obesity as a disease. There is legislation, before Congress right now to recognize obesity as a disease so that Medicare and Medicaid will actually add these medications to their formularies. And frequently when that happens, more commercial insurers are employer based insurers will follow, follow suit. The good news is that their proteins are actually not that hard to make. And so I’m hopeful that we when we move into the generic space that many of these will be produced at much, much lower cost. Okay. So they these medicines work. You do lose weight.

听

00;12;42;00 – 00;12;52;01听

FALK –Okay. So they these medicines work. You do lose weight. What are the side effects? Because there are lots of people who really can’t tolerate these medications.听

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COVIELLO –Yeah, these side effects are actually somewhat predictable. Knowing the mechanism of action of these drugs. GLP one in particular, one of the effects by which it exerts some of the benefits is to slow your gut, but that also can be responsible for some of the side effects that people experience. So when you slow gut motility, you get sort of a buildup, stomach contents.And that can make some people feel bloated, a little bit nauseated. Some people just call it the feeling in their stomach. In the extreme, less than 10% of people ten sometimes get actual vomiting. Some belly pain, some people get diarrhea. So this is a reason why actually we start at low doses for these medications, all of them.听

And we go up very slowly with dose increases at the fastest once a month. And that is to let people get used to these potential, you know, side effects. And the most common thing is mild nausea when you start the medication. And that’s usually in the day of injection, maybe the day afterwards. And then that slowly gets better over time. But the one thing about adding GIP, that’s the two GLP one. So that’s the newest drug trizepatide or Zepbound that seems to ultimately decrease the gut motility less so you have less gut slowing and therefore less GI side effects that some people definitely get severe GI symptoms. And this is not a medication for them.听

听

00;14;10;18 – 00;14;13;17听

FALK –What’s the word food noise mean? 听

00;14;13;51 – 00;15;02;17听

COVIELLO –Patients refer to food noise as it’s basically, cravings and hunger. So they a lot of patients, say that most of their day or a significant portion of their day is bothered by the, their the little voice in their head that says, go to the snack machine. We want some chips. We want, you know, is it lunchtime? You know, it’s at lunchtime now. No, an hour at five minutes later is at lunchtime. So they just spend a lot of time thinking about food or craving certain types of foods. And the satiating part of these medications seems to take that away. So patients will, they call that food noise, and they’re like, it’s just gone.听

It’s such a relief, meaning that they’re not craving things. They’re not thinking about food during the day in the same way that they used to. And they find that sort of a relief. I think that’s partly why some of the anxiety goes down when people are on these medications.听

听

00;15;03;18 – 00;15;34;00听

FALK –听Let’s also talk about the whole use of either Wegovy or Zepbound in terms of preventing obesity.So you have a person now who has a BMI of 30 or it has a BMI of 30 and hasn’t yet developed any of the cardiovascular problems. Is there a use for these drugs at that point as prevention of downstream cardiac blood pressure or joint disease? 听

00;15;34;12 – 00;15;13;23听

COVIELLO –Yeah, I, I come from a public health background and I think the, the one thing, even as a, as a health care provider that I’m always thinking about is how to prevent these diseases from ever happening, right. The, the guidelines unfortunately, kind of do the reverse. I think it’s a risk versus benefit, analysis that has caused people to get things approved for the sickest patients. Right? So the people with a BMI greater than 40 who have other health problems. But when you think about it, you don’t ever want the patient to get to that point. And so when I’m when I’m talking to providers or people in the community in general, I’m always saying, you know, you really want to start treating weight once the , if you’re using BMI, weight adjusted for height, which is super convenient and available in most health care clinics, you know, since you’re hitting 27, that middle of the overweight range, you want to be even, you know, just as people are getting above 25, you want to start talking to them about weight and health and what their strategies are, to have to not gain weight over time with there is a natural tendency as people age to gain weight. And so I think one other area that needs attention is to develop age specific healthy, weight ranges, which we don’t really have at the moment. So but, but my point is just that, you know, prevent people from getting to obesity or as soon as they cross that, that line of 30 in the BMI, you know, start working with them to try and reduce that weight so they never get to the point where they have a BMI of 40 and diabetes and have had a heart attack right then.The medicines will certainly help those people. But the main point is to never have them get to that point听

听

00;17;11;18 – 00;17;25;00听

FALK – and there are new drugs being thought about on the horizon, that actually may help with, avoiding muscle loss. And can you tell us what the future holds? Get out your crystal ball. 听听

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COVIELLO –Because of all the, I think we’re just getting much more elegant about, targeting different tissues in the body. 听I think it was such a breakthrough in 2005 when we discovered, that we could pharmacologically mimic GLP one. But that was 20 years ago. And it seemed genius. But we’re really just mimicking. It’s discovered in lizards there, but really, we’re just mimicking natural signals. And so I think the work that’s going on now that we see in the research space has really elegant approaches to stimulating, the weight regulation pathways in the brain. So that’s the hunger balanced by your satiety centers or fullness. But also by targeting, muscle. So energy expenditure in the muscle, more specifically, in generating increases in muscle, because that’s certainly a way to increase your energy expenditure, which is half of the weight equation. Right. It’s it’s calories are fuel in and then calories in, fuel out.There’s a lot going on in the middle of that equation. It’s not simple, but definitely focusing on muscle and energy expenditure is coming. We just don’t have any compounds yet in that space. Everything is really directed towards helping people to feel fuller. And that reflexively downstream does affect your, your energy output, but in a very subtle way.听

听

00;18;44;02 – 00;19;02;09听

FALK- So there’s stigma associated with weight gain, this stigma associated with eating too much food, and there’s stigma associated with dramatic weight loss. If you’re on one of these drugs, think Oprah Winfrey, can you talk to us about all these?听

00;19;02;34 – 00;20;15;05听

COVIELLO – I听think this is a really important aspect of, health care, because I think people come in with a lot of anxiety about the reactions that they get from family and friends, or just being out in public. There has always been stigma, stigma about being overweight or obese, but there’s also stigma about being too skinny. And actually, thinness is more heritable than being overweight. And I just always think about the patients that I have in my practice who may have celiac disease or food allergies or irritable bowel syndrome, and really have a lot of restrictions on what they can eat, related to a lot of different health conditions. So I think in general, we should be a lot kinder to the people around us and not make assumptions, about what they’re struggling with, in their, in their own, diet, and, and health. So I think one thing we should do is not assume and not comment to other people, as much like you should really have a second helping or you didn’t eat very much of that, or, gosh, you never eat fruits and vegetables. Well, some people with IBS really can’t and still struggle with their weight. So I just think we should be kinder and, not make so many assumptions about what people are dealing with on the home front, particularly around the holidays. 听

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FALK – Thanks so much for teaching us all about these drugs and good approaches to staying healthy. 听

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COVIELLO –It was a delight to join you this afternoon, and I hope everybody, moves on to greater health in 2025.听

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FALK-听Remember, you are not alone on your health journey. Stay informed, stay proactive and together as a community, we can make a positive difference in managing your health and well-being. Thanks so much for joining us. Until next time, take care.听