Triple Agonists: Revolutionizing Weight Loss or Too Much of a Good Thing?

James Hill:
Welcome to Weight Loss And, where we delve into the world of weight loss. I'm Jim Hill.

Holly Wyatt:
And I'm Holly Wyatt. We're both dedicated to helping you lose weight, keep it off, and live your best life while you're doing it.

James Hill:
Indeed, we now realize successful weight loss combines the science and art of medicine, knowing what to do and why you will do it.

Holly Wyatt:
Yes, the “And” allows us to talk about all the other stuff that makes your journey so much bigger, better, and exciting.

James Hill:
Ready for the “And” factor?

Holly Wyatt:
Let's dive in.

James Hill:
Here we go.

Holly Wyatt:
We're going to talk about something that I think is pretty remarkable and is happening in obesity treatment. All right. First, we had medications, and we've talked about these a lot, that target that GLP-1 receptor. And everybody knows about the GLP-1s. Then we had tirzepatide, and it came along and it targeted two receptors. It targeted GLP-1 and then a second receptor called GIP. And now we're talking about three receptors.

James Hill:
So we're talking about retatritude. Did I say that right?

Holly Wyatt:
No, let's say, I think it's retatrutide.

James Hill:
All right. We're talking about retatrutide, which targets GLP-1 and GIP, which was targeted by tirzepatide. But it also targets glucagon receptors. And the phase three results from the trials are extraordinary. We're seeing average weight loss is approaching 30%. Can you believe it?

Holly Wyatt:
Right. 30%, Jim. That's almost a third of your body weight.

James Hill:
Wow.

Holly Wyatt:
Yeah. And for most of our careers, I think if you've told us that we would have this treatment that could produce that kind of average weight loss, we would have been, we would have said, “Okay, yeah, it's metabolic surgery”, and it's successful metabolic surgery. And I love these results, but I saw these results and almost have two different reactions. The first one is, “Wow, look what we can do now. This is great.” And then the second one is, “Wait a minute. How much weight loss do we actually want?” Never thought I would say that.

James Hill:
Well, that's not a question we've had to ask very often. For decades, certainly our whole careers, we were just struggling to get enough weight loss to meaningfully improve health. Now we're entering an era where we have to ask, when is enough enough?

Holly Wyatt:
I know, I can't believe that. And that's what we're gonna unpack today. We're gonna give you the science around this new medications, not currently available, but probably will be coming out soon. We're going to talk about what is a triple agonist? Why are they adding glucagon? What do the new trials actually show? How is it different from the other medications we have? What are the potential benefits and trade-offs? And we're going to give you pie in the plate, though, not just the science, kind of what does it mean for you? Because this drug can produce 25 to 30 percent weight loss, it raises questions that go, I think, way beyond just the numbers on the scale.

James Hill:
Yeah, questions like, who needs that much weight loss? Does everyone need to go on the highest dose?

Holly Wyatt:
Yeah.

James Hill:
What happens to muscle and to your nutrition? And is completely turning off appetite really a goal we should be aiming for?

Holly Wyatt:
Yeah, I like that question a lot, Jim. And before we're done, we'll be looking at what's coming next, because there's another hormone that is on the horizon.

James Hill:
You mean this is not the end?

Holly Wyatt:
No, there's more. Oh, my gosh. Amylin's going to be coming into the story. Yeah, because retatrutide isn't the end of the story.

James Hill:
Well, Holly, we've got a lot to cover. Let's dive in.

Holly Wyatt:
All right. Great. So let's spend just one minute thinking a little bit about why this matters. I mean, Jim, this conversation has changed so quickly. Wasn't that long ago when we talked about 5% to 10% weight loss with medication and we were excited, that was meaningful.

James Hill:
Absolutely.

Holly Wyatt:
Then we moved to 15%. Then we started talking about 20% weight loss. And now we're looking or we're approaching 30%. What a moving target, right? From 5% to 30%.

James Hill:
Yeah, and the 30%, Holly, is historically associated only with metabolic surgery.

Holly Wyatt:
Right, right. And I think that comparison, when we compare it to metabolic surgery, matters for another reason, too. I think about surgery, and we treated that as a major medical intervention. And it is. Surgery is. But there was, you know, there's an evaluation beforehand. We had careful patient selection, not just anybody. Had metabolic surgery. We had education. We had structured follow-up. We understood that producing that much weight loss required medical management.

James Hill:
Yeah, Holly, and now we can do that with a once weekly injection.

Holly Wyatt:
And so, you know, that much weight loss, that's a different way of, you know, surgery, we had all these medical management going on, Jim. And with these injectables, how are we treating that? So it's incredible progress. But I don't think the biology cares whether that weight loss came from the operating room or from an injection. So that magnitude of weight loss, we need to take it, in my opinion, just as seriously as we did that metabolic surgery and care about what happens before it, during it, and after it.

James Hill:
And that brings me back to some questions that I think are really important to ask. One is muscle. You know, when you lose 30% of your weight, Holly, you're going to lose a lot of muscle.

Holly Wyatt:
You are. There's no doubt.

James Hill:
What's the long-term consequences? What about adequate nutrition? Because you're eating so much fewer energy. And are you having nutrient deficiencies? What's going on there? And how much weight do people actually need to lose? We may be at a point where people can lose more weight than they really need to lose. Never thought we would say that way before. And what happens when appetite becomes very, very low and may stay very low for a long period of time. And finally, let's rethink, what are we trying to do with health outcomes? What is it we're after here in terms of metabolic health, quality of life? So many important questions.

Holly Wyatt:
Yeah. And for the first time, it really does shift this conversation because we've never been to this point.

Holly Wyatt:
Now with this 30%, I think we need to ask these questions. So let's kick this off, let's just start out by what is retatrutide? What is a triple agonist? You know, I'll just say we call the, I don't know, this may be in the science world, but we call the GLP-GIPs. So there's a lot of different pharmaceutical companies now that are making the two receptors. So the GLP-1 and the GIP. And so we call them GLP-GIPs. Oh, here's another GLP-GIP coming. Now though, now we have three receptors. So what is this? Let's break this down a little bit more.

James Hill:
Yeah, the big one that started it all was GLP-1, which is glucagon-like peptide 1. And that one seems to be doing a lot of the heavy lifting, Holly.

Holly Wyatt:
Absolutely, yeah, for sure.

James Hill:
But GIP is another one that was added to GLP-1, and it stands for glucose-dependent insulinotropic polypeptide.

Holly Wyatt:
Aren't you glad we don't have to say that over and over again? We can just say GIP.

James Hill:
So GLP-1 and GIP, that combination is readily available right now. Tirzepatide is a great example. But the third one is glucagon. Now, glucagon is a pancreatic hormone that's involved in glucose and energy metabolism. Semaglutide activates one, the GLP-1 receptor. Tirzepatide actually activates two, GIP and GLP-1. And retatrutide is three, GLP-1, GIP, and glucagon in a single molecule. And that's why it's called a triple agonist.

Holly Wyatt:
So one injection, one medication hitting three, three receptors.

James Hill:
Not three medications, one medication that combines them all.

Holly Wyatt:
Oh, got it. Okay.

James Hill:
So Holly, what do each of these bring to the table?

Holly Wyatt:
Yeah. So, and we know a lot, but there's a lot we don't know. And it's interesting. So the GLP-1, I think we've studied that the most. It's been out the longest. When you think about GLP-1s, I think about its impact on appetite, satiety, and glucose regulation. Remember, these started as diabetes drugs. GLP-1s were monitoring or were helping, decrease and manage glucose. So GLP-1s are released from the gut in response to nutrients. Now, that's not how these medications work, but your natural GLP-1 is released from the gut. Now, in the medications, you're giving yourself an injection. GLP-1 increases glucose-dependent insulin secretion and helps the body regulate blood glucose. And I purposely said glucose-dependent insulin secretion. And what that means is only when the glucose is high does it cause insulin. And that's to be secreted, which is important because otherwise you would get low blood glucose or hypoglycemia. So that's an important thing that this molecule does. It slows gastric emptying. That's important, right?

Holly Wyatt:
So it keeps more food in your gut longer. We've talked about that on this show. And it acts on the brain and other tissues, lots of other tissues involved in appetite and satiation and helping reduce food intake and probably doing a lot of other things that we're just starting to learn about. So GLP-1 helps turn down that biological drive to eat while improving glucose regulation.

James Hill:
Wow. So what about GIP? How does that help?

Holly Wyatt:
All right. So GIP, like you said, stands for glucose-dependent insulinotropic polypeptide. What a mouthful. It's also released from the gut after you eat. It enhances glucose-dependent insulin secretion. And it's found in the pancreas. These receptors are found in the pancreas, the brain, the adipose tissue, and other tissues. And its role in body weight regulation is complex, and they're still trying to untangle it all. So we don't know everything. But we do know that when you add the GIP to the GLP-1, as we do in tirzepatide, it tends to produce more powerful effects on glucose control and body weight. It tends to enhance and modify its metabolic and weight effects. So it's kind of like put these two together and together they work well. Notice we don't have any GIP-1s alone.

James Hill:
Right, right. Now, so the third one, what's added that isn't out there currently?

Holly Wyatt:
So glucagon is the new piece. And I have to admit, when I first heard that they were adding glucagon, I was like, why? Because as an endocrinologist, we use glucagon to increase glucose. So someone is having low blood sugar and we need to quickly get their blood sugar up. We would give them glucagon. That's what we would do because it causes release of glucose from the liver kind of as an emergency treatment. So I was like, why is this going to be a good thing? So like I said, it's best known for telling the liver to release blood glucose, blood sugar, which makes its inclusion in obesity seem counterintuitive. But glucagon also affects lipid metabolism, nutrient handling, and potentially energy expenditure, Jim. And this is where it's kind of coming in from a different way. It's an effect on energy expenditure. So not just on intake, but on expenditure. And the idea is to capture those same metabolic effects while GLP-1 and GIP help counterbalance glucagon's glucose-raising effects. So you put it in with these other two. And so this glucose going up is not as much of a factor. And you may be getting some other impact. It may be doing more than just reducing how much energy comes in. The glucagon component may also be influencing what the body does with that energy along the energy expenditure side of things.

James Hill:
So retatrutide may not be just adding a little bit more to the two agonists. It might be doing something fundamentally different. Is that what you think?

Holly Wyatt:
That's what I think. I think the first two, they're kind of modifying each other, right? And, you know, you use them together. And now you're introducing the glucagon and the other two help keep that glucose effect in play. But it's adding something different. It's adding something more.

James Hill:
So, what results do we have from clinical trials to show how effective retatrutide is?

Holly Wyatt:
So, Jim, let's start with the first trial that came out that's already been published. One of the trials is a phase two obesity trial. And this was really the first big retatrutide study. It came out, I think, in 2023. It was published in the New England Journal. So, you know, a really big publication. And it was a randomized, double-blind, placebo-controlled trial. Had, I think, over 300 adults in it. And they were tested for 48 weeks. And this was phase two. So you do phase two trials first, Jim, to see if you want to go into a bigger phase three trial. But what they found was at 48 weeks, average weight loss reached around 24% on the 12 milligram dose.

James Hill:
That's pretty good.

Holly Wyatt:
Yeah. And I think it was 26% of participants lost at least 30% of their starting weight.

James Hill:
So a quarter of the people lost 30%. That's pretty amazing.

Holly Wyatt:
Yeah. So these were results that said, yeah, it seems to be worth maybe studying this in a larger trial. The side effect profile seemed to be tolerable, you know, seemed to be okay. So, I can remember when this came out, Jim, what did you think when you first saw these phase two results?

James Hill:
I was amazed at medications producing that much weight loss. I mean, we struggle behaviorally to do 10%, 12%, and here you saw a quarter of these people achieving 30%. And the other thing, Holly, is the weight didn't plateau very quickly. Even at 48 weeks, it hadn't plateaued. We always talk about behaviorally, we see most of the weight loss occurring in the first three to six months. But with these medications, weight loss seems to continue longer.

Holly Wyatt:
Yeah, and so that was this phase two trial showed this signal. And then I think that made them think, okay, we need to, when we do a phase three trial, we need to even go out further than 48 weeks to see, you know, what's the max, or I think they're thinking at least, what's the max weight loss we could get, how many people could get up to 30% weight loss. So that's really the difference in a phase two and phase three. Now we're going to do it or prove it in a much larger group of people.

James Hill:
Well, and they did a phase three, Holly, which is doing it in a larger group of people. Now, this one hadn't been published yet, but it was presented at this year's meeting of the American Diabetes Association in June of 2026. This was the TRIUMPH study. Who comes up with all these names?

Holly Wyatt:
I don't know. But I think it's TRIUMPH1, so I think we have more coming.

James Hill:
So they're going to be a whole bunch of triumphs. So here at 80 weeks, 80 weeks.

Holly Wyatt:
Okay, so they went out further. They were 48 before. Yeah.

James Hill:
12 milligrams of redditrutide lost an average, an average, Holly, of 28.3% of their starting body weight.

Holly Wyatt:
Wow.

James Hill:
Participants receiving a lower dose, 4 milligrams, lost about 19%, which is still pretty good, right?

Holly Wyatt:
Okay, so, I mean, think about that. A low dose, 19%.

James Hill:
A low dose, 19%.

Holly Wyatt:
And where we've come from, right? Like 19%, we would have been doing backflips for 19%.

James Hill:
And again, remember in the previous study, about a quarter of people lost 30%. In this one, at the 12 milligram dose, 45.3% lost at least 30% of their body weight. You're getting to the point where almost half the people are losing 30%. And in an extension among participants that had a BMI of at least 35, the average weight loss was 30% at 104 weeks. Now, this is just mind-blowing.

Holly Wyatt:
And average, meaning some people are doing, half the people, right, are doing, or a large chunk of the people are doing more than 30%.

James Hill:
Holly, I remember papers talking about how great 5% weight loss was. When we got 10%, we were patting ourselves on the back. 15%, boy, we're rolling. 20%. Now we're talking about average weight loss is approaching 30%.

Holly Wyatt:
Yeah. And I think, you know, the question that starts to jump out is if, like you just said, four milligram, a low dose produced 19% weight loss, does everyone need 12 milligrams?

James Hill:
Well, there are a whole bunch of people that don't need to lose 20% of their weight. What about the people that need to lose 10% or 15% of their weight? What happens if they go on the higher dose?

Holly Wyatt:
We're always thinking about maximum weight loss. That's what's been in my head. Like, how do I get as much weight off of people as possible? That's always been kind of my goal for people who needed to lose weight, obviously. And now I'm having to kind of sit back and go, wait a minute. This is changing things. Maximum dose may not always be the goal. Maximum weight loss may not be the goal for everyone.

James Hill:
One of the things I want to jump in here and make sure people know is this medication is not approved yet. It's not available to get yet, but it's probably coming down the road. So it's probably doing more than just changing weight. What do we know about that?

Holly Wyatt:
Yeah. They have studied this drug, retitrutide. It's doing more than changing weight. It's also been studied in diabetes trials. So there's a trial that has been published. Jim, the weight loss you just talked about, you talked about was in the ADA meeting, but it hadn't been published yet. I'm always like, until we see it in a publication, I always want to be a little bit careful.

James Hill:
Yeah, but these trials are pretty well done. I'd be shocked if it didn't come out the same, but you're exactly right. We want to see it peer-reviewed.

Holly Wyatt:
Yes, but this trial, the TRANSCEND, so that was the triumph, but the TRANSCEND type 2 diabetes trial has been published. So we do know this. That one's been peer-reviewed. Yeah, and this just came out in The Lancet in 2026. So what did this study show? It was around 537 adults with type 2 diabetes whose glucose was in adequately controlled with diet and exercise alone. The average age was about 49. The average BMI was about 36. And the average hemoglobin A1C was around 8%. And these participants had relatively early type 2 diabetes and they were not taking any glucose-lowering medication. That's important. So they weren't on another medication. And so this really allowed the researchers to examine retatrutide as a single therapy. We call it monotherapy, just as the only therapy they're on. And so this treatment lasted around 40 weeks. And they found that the hemoglobin A1c dropped substantially at every dose they gave. So they had, I think, placebo plus three doses. And so there was a dose response curve. At the four milligram, the lowest dose, it reduced, the hemoglobin A1c went down around 1.69 percentage points, and at the 9 milligram, 1.86, and at 12 milligrams, almost 2.

Holly Wyatt:
And if you compare that with placebo, that was at 0.81.

Holly Wyatt:
So, what we're trying to show here is not only was it impacting weight, it did impact blood glucose control, and it did it very well. So, this is not just, you know, statistically significant. This is clinically meaningful glucose lowering.

James Hill:
What we're seeing here on all these medications is there's one version for diabetes and another version for weight loss, right?

Holly Wyatt:
Usually.

James Hill:
Is that going to be the same with retatrutide?

Holly Wyatt:
Yeah, I don't know. We'll see how they decide to do it.

James Hill:
But even if it impacts diabetes, it also produces weight loss. So you get both benefits, but it'll be interesting to see how it's marketed.

Holly Wyatt:
Exactly. And I guess they did look at the weight loss in this trial that's been published, and it was at that lower dose, that four milligram dose, it was around 11.5%. And then at the highest dose, the 12 milligram dose is around 15% compared to only around 2.6% with the placebo.

James Hill:
So losing 12, 15% and improving your glucose control, that's huge.

Holly Wyatt:
Yeah. So it did both as one single. Yeah. And you may say, well, I mean, the first thing I said, wait, it didn't produce as much weight loss as what we heard about in the triumph. But that's not uncommon, Jim. We see that.

James Hill:
It's true.

Holly Wyatt:
Yeah. Diabetes trials usually do not produce as much weight loss for whatever reason.

James Hill:
That's right. So, Holly, we've got another really powerful tool coming down the pike. And I think it's very likely this will be approved at some point in the not too distant future. But once again, I think we have to think about how is this tool going to be used? We don't want everybody out there on the higher dose because some people don't need to lose 30%. So there are a lot of questions about how we're going to add this to our arsenal of obesity treatment strategies.

Holly Wyatt:
Yeah. To me, it just opens up so many different questions about what are we treating and how do we do it and what's important, not only from a medical standpoint, but what's important for the individual to be able to treat. What are we really treating?

James Hill:
Right. And is the goal just weight loss? When we couldn't produce very much weight loss for just about everybody, the goal was weight loss. Now that we can reach weight loss goals, Holly, I wonder if we don't broaden this because we've been saying for years, it's not just the number on the scale.

James Hill:
It's metabolic health. It's feeling good. It's quality of life. Are we finally going to get people to stop looking at just the number on the scale and look at other potential positive outcomes?

Holly Wyatt:
And to make it even a little bit more complex, Jim, is do you consider those independent of weight?

James Hill:
Yes, exactly.

Holly Wyatt:
So meaning, you know, so if things like reduction in cardiovascular risk or improvement in sleep apnea, things like better mobility, because when you start to lose a third of your body weight, we know your knees feel better. We know there's a lot of physical function that improves. And with that, quality of life improves. So does that become the end points? And we're not even looking at weight, or at least weight may not even be that important. Maybe these other things are more important. I mean, I don't know.

James Hill:
One of the really interesting questions that I have is, are we going to see these medications used in people that don't necessarily need to lose weight or very much weight at very low doses?

Holly Wyatt:
Yes.

James Hill:
So four milligrams per, what about one and two milligrams? Are we going to see smaller doses used in a larger population? And is that going to help metabolic health?

Holly Wyatt:
Yeah, because if you see the slippery slope, in a sense, we're now not just looking at weight loss, getting as much weight off. We're now moving to other endpoints that are important. Well, then... Maybe it just is about those other endpoints. And then you're right. Do we use smaller doses and weight doesn't become the indication?

James Hill:
It's incredible how powerful these molecules are at tiny, tiny amounts. Wow. So the future is going to be exciting.

James Hill:
But is there a trade-off? What's the cost of greater efficacy and weight loss? Is there a potential downside?

Holly Wyatt:
And there is. I always say this. The more powerful the medication, usually in medicine, the more potential for side effects, right? If you have something that's changing physiology at that magnitude to produce 30% weight loss, chances are it's changing physiology in a way that can produce some side effects or some risk. And so you always want to look at that. And just like the GLP-1 medications, this drug has a lot of adverse events that are associated with the GI system, with your gut. These include the nausea, the diarrhea, vomiting, constipation, and then decreased appetite, which is really what the outcome that most people are wanting. Most of them were mild to moderate, but I do think in this study, a lot of people did have some GI side effects. So there was something that they did notice, and it tended to become more common at higher doses. And that's one reason why you don't want to just start on a higher dose. It's a big reason why you want to slowly increase and why you want to be under the care of a healthcare professional that can adjust it and not just, here's the dose you need, right? Other side effects that might be different that they saw in the retatrutide.

Holly Wyatt:
There was a, let's see, tended to be a little bit of an increase in heart rate, which I think was interesting. It tended to peak and then to go back down, but that's something to watch. We'll need to pay attention to that. There's something called, and I'm maybe going to say this wrong, I know what it is, but dysesthesias. How do you say that, Jim?

James Hill:
I think it's dysesthesia. Yeah, that's a tough one.

Holly Wyatt:
Yeah, and we had some of this, we've had patients to experience this in some of the clinical trials. And this is where people describe a tingling, a burning, a sensitivity, an uncomfortable sensation when the skin is touched. It does tend to be dose-related and it happened more in these retatrutide studies than some of the other studies out there.

James Hill:
So the bottom line is this new medication produces amazing weight loss.

James Hill:
From 4 milligrams to 12 milligrams, you get anywhere from 20 to 30 percent weight loss. Okay, Holly, the big question I want to ask you, what about keeping it off? Does this solve the problems of long-term weight loss maintenance?

Holly Wyatt:
Well, no, it's just like the other drugs. If you stop this medication, just like if you stop the other new generation obesity medications, the effects that we've just talked about, the three receptors, the triple agonist effects go away. Returns, your appetite returns, everything, you know, the energy expenditure, if there's an impact from the glucagon on that, it's going to come back and you are going to regain the weight. You have to stay on the medicine to continue to have the impact that the medication had.

James Hill:
So you and I always talk about there's the losing weight process and the keeping it off. We have knocked it out of the park on the losing the weight thing, right? But to show that we've made a long-term impact of the population, we have to show how these medications are used potentially with a combination of other tools to help people maintain weight loss long-term.

Holly Wyatt:
Right. Yeah. So that has to be a plan. You have to know that going in. And we've talked about that before, really understand that.

James Hill:
All right. Whew. So the whole idea of how much weight loss you need is a question I don't think you and I've ever talked about this before. But with these new medications, I think it's a question that's going to come up more and more and more.

Holly Wyatt:
Yeah. One group that I do think this new medication could be good for is something that we call refractory obesity. And what do we mean by refractory obesity. Not everyone responds to obesity treatment the same way. We talk about that a lot. And some people are achieving weight loss with the currently available medications, while others have been the non-responders that we've talked about. And they have a much smaller response despite the treatment. So like we've talked about before, more options gives you more possibility. And some of the people who have had this refractory obesity, this may be a drug that they will be able to respond to.

James Hill:
So we may very shortly have a medication. Some medication is going to work for just about everybody.

Holly Wyatt:
I mean, I think that's where we're headed. More like antihypertensives. We have so many different pills for blood pressure.

James Hill:
So I want to turn to another question that we mentioned earlier, Holly. Do we really want to turn appetite off? Is that always a good thing.

Holly Wyatt:
Yeah, that's one of my biggest thoughts. One of the things I think about, it kind of keeps me up at night. I'm worried, I think I've said this on the show before, that we're going to swing too far. And we're going to see like appetite as being the enemy. And cut off appetite is what we want to do to completely get rid of appetite. And I worry about that. The appetite's there for a reason. And while I know people think about I've had to work so hard to push against it and think about it. And that's that food noise that comes in, you know, having it completely gone, I think may produce its own set of problems.

James Hill:
Wow. It's a whole new frontier here, isn't it?

Holly Wyatt:
Yeah. I never thought I would be sitting here saying this.

James Hill:
Wow.

Holly Wyatt:
And I get it because people like I've struggled with my appetite for so long. Oh, my gosh. It's like taking a deep breath to not have to fight it. And I understand that, but, ooh, it serves a purpose to say I need to eat something to remind you to eat or to have you seek out certain foods.

Holly Wyatt:
There's probably some physiology behind that that's pretty important.

James Hill:
So, Holly, big question for you. What's the goal of obesity treatment in this day and age?

Holly Wyatt:
Well, Jim, that's really what we're talking about. I would have said it's to lower body weight and to get people into that happy body weight range that we've talked so much about. But I don't know if that's going to be the question anymore.

James Hill:
Wow. You want enough weight to meaningfully improve health? You want to preserve lean mass? You want the person to have enough of an appetite to get adequate nutrition? You want acceptable side effects? And I think this is going to cause people to re-examine what their real goals are with even entering into weight management.

Holly Wyatt:
Well, I mean, it brings us to this point we have obesity medications have become so effective that our clinical thinking now has to catch up with the pharmacotherapy. Before, we were always trying to pull the pharmacotherapy with our thinking, with our knowledge. And now it's like the other way around. In my book, it's like the pharmacotherapy is having to pull us in terms of our clinical thinking.

James Hill:
Wow. So is retatrutide, is that the end? Is that all we need? Should we kind of stop drug development now that we've got it solved?

Holly Wyatt:
No, I think now there's so much going on. And we talked a little bit about the beginning. Amylin's going to be coming. So we're going to have even more. And we're going to be using combinations. Amylin's a hormone that is normally released from the pancreatic beta cells.

James Hill:
Why is it going to be any better than what's out there?

Holly Wyatt:
Well, I think it's different, right? Different pathways, you can combine it. Certain people will respond to it that might not respond to other things. And I think we're looking now, the future may not simply be stronger and stronger GLP-1 receptor agonism. We may be entering into a time where there's different biological pathways and we get to choose and combine what fits best for the individual. And I like that. I like that idea.

James Hill:
Wow. So the clinician's job then is matching the treatment to the patient. Do we really know? Can we predict who's going to respond best to which medication?

Holly Wyatt:
Not yet.

Jim Hill:
But it's coming?

Holly Wyatt:
I hope. Well, you know, this is a question I'll have for you, Jim, because I'm always thinking about this last night. So these pharmaceutical companies have these big data sets we've just been talking about. We talked about Triumph, but there's all these, should they be able to put their data sets together? So not just sit as one pharmaceutical company, but all the pharmaceutical companies put their data together.

James Hill:
Thousands of patients.

Holly Wyatt:
And then use, you know, AI or use some of the machine learn, learn some of the new ways to look at it and come up with predictions, come up with stuff like that.

James Hill:
You would think so. But the bottom line is, we have more effective medications than we've ever had. New ones are coming down the pike. Lots of companies are developing new ones. We are going to have a ton of medications that can be used in treating obesity.

Holly Wyatt:
Yeah. And this retatrutide, I think, is going to be one of the next. It's probably going to be coming out in, it has to jump through some FDA hoops, 2027, 2028, I think.

James Hill:
So stay tuned. All right. You want to take some listener questions?

Holly Wyatt:
Yes, we do, because we definitely got some questions around this. This is why we did this episode. So first one, if retatrutide causes more weight loss than today's medications, why wouldn't everyone just take it? We're going to get rid of the other ones, Jim.

James Hill:
Great question, and it's the heart of what we talked about. More weight loss isn't necessarily the goal for everybody. There are a ton of people that love to lose 10 or 15 percent of weight loss, and this might produce more weight loss than they need to do. So we need to understand medication levels and how that affects it. We need to understand why some people respond better than others. We need to think about side effects and tolerability, what's your starting weight, what's your health conditions. So ultimately, on one hand, you say, “Well, everybody should take the most effective.” Not necessarily. And I think from a clinical perspective, it's not just giving people a medication. It's understanding the patient and then trying to choose a medication that works. And the good news is we have several to choose from.

Holly Wyatt:
Right. And the other thing I always tell patients is just because this is the most, it shows the most weight loss overall in a trial doesn't mean it produces the most weight loss for an individual. So you got to be careful there and kind of trying to understand that. So I wouldn't say that everyone just needs to jump on the bandwagon, and take it or that it would be the best medication for everyone. And this having multiple options really is key to getting everybody on the best medication for them.

James Hill:
So here's a good one. If I'm doing well on tirzepatide, should I plan to switch to retatrutide when it becomes available?

Holly Wyatt:
Yeah, and I would say not necessarily. If you're doing well, if you've lost the amount of weight you want to lose, if it's producing medical health improvements, if your side effects are acceptable, then I don't know that there's any reason to switch. So we don't have any data that says that this medication that would be coming out would be better for some reason.

James Hill:
If it's working on the one you're going with, go with it.

Holly Wyatt:
Yeah, new doesn't automatically mean better for you.

James Hill:
Right.

Holly Wyatt:
All right, here's another one. Should I be worried if I have almost no appetite on my medication?

James Hill:
Yeah, I think you should be because you can eat too little because, you know, what you eat meets some real key nutrient requirements in your body. So trying to eat as little as possible is not necessarily the right therapeutic goal. We have to look at our, in the food you're eating, you're going to eat less on these medications. Is the food you're eating, giving you adequate nutrition, adequate hydration? Because Holly, we're seeing people with nutrient deficiencies because they're eating 30, 40% less than they used to. So they're not getting enough vitamins and minerals and fluids. So, yes, I worry that appetite can be too low.

Holly Wyatt:
Appetite can be too low. Therefore, nutrients can be too low. And yes, you can lose too much weight. I never thought I would say this. You could lose too much weight on these medications.

James Hill:
That's a new one, isn't it?

Holly Wyatt:
Yes. We need to watch for that now. We really need to start thinking of this like metabolic surgery, where we're producing that amount of weight loss. And the medical oversight that was involved in metabolic surgery. We need that degree of medical oversight with these medications.

James Hill:
So one of the things that I think it's important to understand is prescribing a medication is not prescribing a comprehensive weight management plan, right?

Holly Wyatt:
Right.

James Hill:
And that's why we did an episode on how easy it is to get these medications without any plan. And I don't think that's a good idea. The medications are effective, but you need a comprehensive plan along with the medications.

Holly Wyatt:
And this new medication, when it becomes available, even makes that more important because now we're at 30% on average for people.

James Hill:
Are we going to see people with nutrient deficiencies out there that are getting this off the internet, losing 30, 40% of their weight, losing a lot of muscle and having nutrient deficiencies?

Holly Wyatt:
Yes, we will. We absolutely will. And that's what worries me. And I never thought I would be here like, oh my gosh, we've got too much, you know, too much appetite.

James Hill:
But don't get us wrong. We're excited about these medications, but we have to figure out how to use them. And the medications alone aren't solving the problem. They're a wonderful tool, but we've got to figure out how to use that tool with the other tools we have.

Holly Wyatt:
I think what's coming out in me is this do no harm. I'm, you know, I was always like, oh my gosh, don't do harm, Holly. And for the first time, I'm like, oh my gosh, weight loss is good. My whole career has been about helping people lose weight. And now suddenly I'm like, oh my gosh, I could do harm. And I just want to make sure we recognize that. And I think with the right plan and medical oversight, we can minimize that, right? We can mitigate it. But without it, I think people really are at risk.

James Hill:
I never thought we'd be having this discussion, Holly.

Holly Wyatt:
Didn't I either.

James Hill:
All right, you want to do some rapid fire?

Holly Wyatt:
Let's go for it. Okay. All right, I'll start. GLP-1, dual agonist or triple agonist? So you get to pick between the three. Which is the best? GLP-1, dual agonist or triple agonist?

James Hill:
If you've listened to the first part of this podcast, you realize the answer is it depends on the patient. You have all three can be very effective. And this is where you have to work with your health care provider to find the right medication And the right dose is for you. So it depends on the patient. There's no one that's automatically best.

Holly Wyatt:
Okay.

James Hill:
All right, here's one for you. 20% weight loss and feeling great or 30% and struggling with side effects?

Holly Wyatt:
Ooh, 20 and feeling great.

James Hill:
See, I agree because it's the feeling great. It's not the number on the scale. It doesn't matter what your weight is if you don't feel good.

Holly Wyatt:
Right, they're related. I think the weight and how you feel can be related together. But I think ultimately it is feeling good that you're wanting. So I'll take 20% weight loss any day and feeling great over 30% and not feeling great.

James Hill:
Love it.

Holly Wyatt:
All right. Here's one for you, Jim. Maximum dose or optimal dose?

James Hill:
Easy. Optimal dose.

Holly Wyatt:
Yeah.

James Hill:
Maximum dose is not right for everybody.

Holly Wyatt:
And I want the listeners to start putting that in their head because I think they think max dose, max dose, because we haven't been able to get enough weight loss. Now I really want them to think optimal dose for me.

James Hill:
Okay, last one for you. One word that describes where obesity pharmacotherapy is headed.

Holly Wyatt:
Hmm. Personalization.

James Hill:
Cool.

Holly Wyatt:
All right. Do we have time for a couple of vulnerability questions?

James Hill:
Let's do two vulnerabilities.

Holly Wyatt:
Okay. All right. So, Jim, after spending your career studying weight loss, is it strange to imagine that we may now have medications capable of producing more weight loss than some people actually need?

James Hill:
It's astonishing. I never thought we would be here. And this has changed just in a few years. Five years ago, we were still struggling out there to help people lose weight. There were no conversations about, are we producing too much weight loss? So I am totally astonished by how things have changed so quickly.

James Hill:
Here's one for you. How you talk a lot about appetite as part of the biology of weight. Does it concern you when people celebrate having absolutely no appetite on these medications?

Holly Wyatt:
Yeah, I already said this. This is what concerns me the most. And I get it. And part of me is happy because people have struggled with this appetite for so long. And I understand that, oh, for the first time, I'm not struggling. But I do worry, just like anything, that appetite serves an important purpose. And so to completely try to get rid of it, to see it as the enemy, I think will come back to hurt us if we do that.

James Hill:
Wow. Well, sort of to sum this up, retatrutide shows us something extraordinary. We will soon have medications capable of producing amounts of weight loss that we once thought could only be done through surgery. And we are excited about that. But for the first time, we are worried about the medications being too effective, people losing too much weight, people eating so little that they hurt their health through nutrient deficiencies. More weight loss is not always the goal. So at the time we welcome these new tools, I can't wait for this to be out there, but we still have to figure out how to use it in the right way. And Holly, I'll come back to, we're pretty close to solving this weight loss part of the equation, but we still have the weight loss maintenance that is still a challenge.

Holly Wyatt:
We didn't really, we hit a little bit, but yeah, that's the second half that is a whole separate problem. So I agree. Never thought I'd be sitting here doing this episode, but here we are.

James Hill:
Stay tuned. And I think you're going to see this medication out pretty soon. But for right now, it's finding the right treatment, the right dose, and the right amount of weight loss for you. So thanks for listening to Weight Loss And, and we'll see you next time.

Holly Wyatt:
Bye, everybody.

James Hill:
And that's a wrap for today's episode of Weight Loss And. We hope you enjoy diving into the world of weight loss with us.

Holly Wyatt:
If you want to stay connected and continue exploring the “Ands” of weight loss, be sure to follow our podcast on your favorite platform.

James Hill:
We'd also love to hear from you. Share your thoughts, questions, or topic suggestions by reaching out at weightlossand.com. Your feedback helps us tailor future episodes to your needs.

Holly Wyatt:
And remember, the journey doesn't end here. Keep applying the knowledge and strategies you've learned and embrace the power of the “And” in your own weight loss journey.