178. Is Retatrutide the Most Powerful Weight-Loss Drug Yet? The Data So Far

Subscribe on Apple 

Subscribe on Spotify 

A weight-loss injection with results on par with bariatric surgery? With retatrutide, that is not an exaggeration.

Although it’s not FDA approved yet, retatrutide is one of the most talked-about medications coming down the line.

Unlike earlier medications that target one or two hormonal pathways, retatrutide is known as a “triple agonist” because it acts on GLP-1, GIP, and glucagon. These pathways may influence appetite, insulin sensitivity, energy expenditure, and fat metabolism.

In this blog, we’ll look at how it works, what the clinical trial results show, and what we know so far about tolerability and side effects.

How Retatrutide Works

To understand what makes retatrutide different, it helps to look at the pathways we already know. GLP-1 is the mechanism behind semaglutide. Tirzepatide (Zepbound) goes a step further, combining GLP-1 with GIP. Retatrutide adds a third piece: glucagon.

That glucagon component is the part worth paying attention to. Normally, glucagon and insulin work in opposite directions. Insulin tells the body to store sugar, while glucagon tells the liver to release it. In retatrutide, the glucagon receptor agonist brings two key metabolic benefits:

• Boosting calorie burning – it increases your basal metabolic rate, encouraging your body to burn more calories even at rest.
• Accelerating fat breakdown – this process, called lipolysis, triggers the body to break down stored fat to use as fuel.

This matters because so many people struggling with metabolic health carry excess fat stored in the liver. Having a tool that can help address that is genuinely significant, and the synergy of all three pathways working together is likely why we're seeing such striking results.

What the Trial Showed

Retatrutide isn't FDA approved yet, but Eli Lilly published Phase III results at the end of May. Here's the setup:

• Over 2,000 adults with obesity or overweight, plus at least one weight-related comorbidity (none had diabetes)
• A randomized, double-blinded, placebo-controlled design—the gold standard
• Three doses tested over an 80-week period: 4mg, 9mg, and 12mg
• Baseline mean weight of 248.5 pounds and a baseline BMI of 40

Now the part everyone's talking about. At the highest dose, participants lost an average of 28.3% of their body weight over 80 weeks. That is why retatrutide is being discussed alongside bariatric-surgery-level outcomes. 

A Closer Look at the Numbers

What’s remarkable is how strong even the lowest dose tested was: 

• 4mg: 19% mean weight loss
• 9mg: 25.9% mean weight loss
• 12mg: 28.3% mean weight loss

The 4mg dose alone led to an average weight loss of 19%, which is staggering when you compare it with what we usually expect from Wegovy. But the 12mg dose is where the numbers really jump out: 62.5% of people lost at least 25% of their body weight, 45% lost over 30%, and 27.2% lost over 35%. 

What About Side Effects?

This is where it's important to stay honest. Higher doses delivered more weight loss, but the tolerability trade-off is real. Discontinuation due to side effects rose with the dose: 4.1% at 4mg, 6.9% at 9mg, and 11.3% at 12mg.

The most common side effects:

• Nausea – roughly 27% at 4mg, climbing to 42% at 12mg
• Diarrhea – about 25% up to 32%
• Constipation – in the mid-20% range
• Vomiting – 10.6% at 4mg, rising to 25% at 12mg

For me, vomiting at that level is a major tolerability concern, and it's worth remembering that no medication works for everyone. Some people won't tolerate it, and some won't respond. It's also possible real-world discontinuation rates could be lower if people titrate more slowly than a trial protocol allows.

We're living in an incredible time. If past medications haven't delivered the results you hoped for, retatrutide is a reminder that more options, with different mechanisms hitting multiple pathways, are on the way. There's no firm availability date yet, but the science coming down the line offers real reason for hope.

As always, decisions about obesity medication should be made with a qualified clinician who can weigh benefits, risks, medical history, and alternatives.

For a deeper look at the trial data, how retatrutide works, and what the side effects may mean in real life, listen to the full episode of The Obesity Guide. 

TRANSCRIPT:

Disclaimer: The transcript below is provided for your convenience and may contain typos, errors, or grammatical inconsistencies, as it has not been professionally edited or proofread. Please enjoy it as-is and read at your own discretion.

Please note: The content shared in this podcast and blog post is for informational and educational purposes only and is not intended as medical advice. Always consult your healthcare provider for personalized medical guidance.  

 Welcome back to another episode of the podcast. How are you all doing today? The summer has been flying by, as I'm sure is happening for the rest of you as well. Our summer, with my kids at least, it's really June and July because they go back to school literally right at the beginning of August. So I always feel this intense sense of pressure to get a lot of things in in the summer, and I have found personally the best way to make this happen is to get rather intentional. Honestly, at the end of May, I typically s- we sit down as a family and we decide what are the type of things that we wanna do, and then I document the summer. I have one list on the fridge, and we put all the things. If we do something new, we put it on the list, or if we're gonna do it, we have it on the list. And you have to see, look how many things we're doing because otherwise time goes by and you don't realize how many incredible things you're doing all the time. So I have a little list here, things that we've recently been doing. We went to the Indiana State Museum. That was so super fun. It's interesting, in my mind I'm always like, "Ugh, I don't wanna go to a museum," and then when I'm there, gosh, do I nerd out about facts about churning butter and what old TV cameras used to look like, it's just so fun. They have a lot of good exhibits where they have progression of time, which obviously is what museums do, but I find it to be really interesting. And also I went all the way with ages, so my son is now seven, and then all the way up to my, oldest stepchild is 18, and all of us had fun. So that's a tall order, right? Also, I don't know if you guys know this about me, the gift shops at museums could quite possibly one... be one of my favorite places. That, independent bookstores, of course, I end up leaving with a bunch of things from the gift shop. That was so fun. I did something in May called, the Secret Burrito Society. Well, that's what it's affectionately known online, there's a traveling pop-up burrito thing. It's Cali Boys Burritos. I'll link all this. Again, it's all always linked in the show notes. You have to pre-order on a Tuesday on their Instagram stories. You say how many you want, you pay, and then on Sunday they tell you where it is. You pick a pickup window, and they bring these burritos out to your car. It's a really good time. It's one of the best breakfast burritos that I've ever had. Now listen, these are expensive burritos. I think it's like $18. However, it lasts a few meals, so if you are a little bit more volume restricted or just in general you're eating healthy, 'cause there, there are a lot of great ingredients in there, but then, for example, there are some tater tots and other things in there. It's what I call like a high-low burrito, there's some great stuff and some stuff that's maybe just, more on the fun food category. But it was such a nice addition to be able to try that out. We did... What else did we do here? Ooh, I tried a new cafe. This is in the Indianapolis area. It's called Rabble, R-A-B-B-L-E. I hope I'm saying that right. Best latte I've had in years. I've been doing a lot more of a push, I forget how much I've talked on the podcast about it, to go to more independent coffee shops, independent bookstores. So I'm really about small business, people doing things outside of these massive corporate structures, it is so nice to go somewhere where not only do the drinks taste amazing, but there's also a real striving for building community, and it just has the most amazing energy in this as well. We had multiple graduations. My son had a birthday party. I mean, there's just been a lot, and it's all in the best way. Oh, we're getting to a lot more walking trails, this kind of fights who I am as a person, because growing up, I always just wanna be on the couch doing nothing in hermit mode. Now, I've gotten better about that. I've transitioned that more to crafting time, but I really challenge myself nowadays to get out of the house, go do a walk, go do these things. I will say separate than the morning walk that I do, because that I'm pretty good at. All right, I wanted to share one thing. I love that sometimes you guys share with me different links to maybe you see, a New York Times article that you think is really interesting. Someone just sent me one on longevity and some different science, and I love when you guys think of me and, you send that to me. Another person sent me here a Harvard study, and I thought this was really interesting. I just wanted to bring up a little fact about this. So it-- and we'll link to the press release that they had for this. But the title of this press release was, "Micro-walks can have bigger health benefits, experts say." So when you read down here, this is-- I'm just gonna read a little paragraph that just says a little interesting fact here. Research has shown that the body works hardest when it first starts moving, expending slightly more energy within the first 30 seconds of walking than in subsequent minutes. Quote, "A person who walks for 30 seconds would get this extra boost, but so would a person who walks for four minutes. They both get the same boost for the first 30 seconds before it levels off," Lee said. That's the person who ran the study. Okay, I just think that's really cool because it really highlights I'm really about I don't care how you get your movement in. I don't care if it's a minute here or there, if it's an hour all at once. The reality is I want you to move, and I want you to figure out how it can fit into your world. Something that I really work on with patients is we have to get away from perfection. A lot of people don't have the time for this really big dedicated exercise window. You might have a lot of obligations in the morning. Then you're doing work. Things are busy. Some days might be shifting often as far as what you need to do during the day. And the reality is I know that you have a minute here or there. We've all got it. You're scrolling online. You're sitting there letting your brain relax for a second. No one is working twenty-four/seven. You're like, "No, Mathea, I do." Listen, I'm someone who works a lot, and I'm telling you, you do not focus well when you don't ever move your body. Fact. If you can move your body, if you are able, I know that some people might have disabilities or certain limitations. That's okay. We all work within our bounds of reality. But if you can, just get to moving a little bit when you can. The easiest place to start putting this in is when you have to go to the bathroom. Hopefully, you're going to the bathroom a few times a day. The average person, if you're hydrating okay, you're likely going to the bathroom about seven times, if not more. If you each time you did that, even if you're at home, you walk back and forth a few times, you will get more movement in that day. Start small. Start however you need to have that happen. But I think that this is just interesting that right in the beginning you're getting a little bit more benefit. And so maybe this could be motivational to some of you if you can only get these little movement breaks in during the day that maybe that could still be amazing at the end of the day. Hopefully that motivates you a little bit. Today we're gonna talk about Retatrutide. I've mentioned it when I've talked about the medications coming out in the next few years, but let's talk about this. Real quick before we get into the data, let's just talk about first what is retatrutide? So retatrutide is what we're calling a triple agonist. A triple G is how some people are referring to it. Up to this point, you will already know GLP-1 and GIP because GLP-1 was semaglutide. When you think about tirzepatide, it's a GLP-1 plus GIP. Tirzepatide is Zepbound. So now with retatrutide, it's GLP-1, GIP plus glucagon. So let's talk about what does glucagon do. The glucagon component in retatrutide, it acts to increase energy expenditure, meaning you're burning more calories at rest and accelerate fat metabolism in the liver. So let's go through what are the effects here. So in the body, glucagon raises blood sugar by promoting the liver to release stored glucose. You have insulin that says store the sugar, and then glucagon says release. Those two are opposite of each other in Retatrutide, this glucagon receptor agonist, it's giving metabolic benefits with number one, boosting calorie burning. It's increasing your basal metabolic rate. It's encouraging your body to burn more calories even when resting. And then the second thing is this accelerating fat breakdown. This is called lipolysis. It's gonna trigger the body to break down stored fat that can be used for fuel. And this is really significant because a lot of people that struggle with their metabolic health, they will have excess fat stored in the liver. This is really significant that we're having a tool here that can help treat that. This synergy of these three acting together is likely why we're seeing such incredible results. So let's talk about that now, what that looked like. Retatrutide is not FDA approved yet, but it has had a phase III clinical trial that was released at the end of May that Lilly, published the results it's interesting what it's showing. We've heard this buzz for the past few years here, how this is really going to be a game changer medication. Just to give you a little bit of a ballpark here, the mean weight loss-- let's just have a moment here. It's not average weight loss, it's if you take everyone that's in the study, we'll talk about how many were in it and how they did it, and you line 'em up, who had the smallest weight loss, who had the biggest weight loss, you put 'em in a line. Right in the middle, that person lost twenty-eight point three percent of their body weight within 80 weeks. So more than a year, this person lost twenty-eight point three percent of their body weight. Guys, this is on par with bariatric surgery. So this is very exciting. Bariatric surgery, we typically think about thirty, thirty-five, maybe up to forty-five percent, depending on how extensive the bariatric surgery are. There's different levels to it people typically think of sleeve, which is just where you cut out part of the stomach, but then there's your own Y, and it goes all the way to other procedures as well. But right at the beginning when we think about sleeve, this would be a very acceptable result if you had a surgery to get to this. So that's absolutely incredible. Let's talk about how they did this. They took adults who had either obesity or overweight and more than one weight-related comorbidity. These people did not have diabetes. This was a randomized, double-blinded, placebo-controlled trial, and guys, this is really the top-of-the-line study design because the patient doesn't know what they're getting, the person administering the medication, like the physician who's following that person over this time doesn't know. No one knows. Now, it becomes very obvious at some point. You're seeing some people lose nothing and other people lose a bunch. But the point is that this is the best study design. They had over two thousand people in this study, they did several different doses. So there was a four milligram starting dose, nine milligram, and then 12 milligram. It was an eighty-week period. Baseline mean weight when people were starting was, two hundred forty-eight point five pounds, baseline BMI 40. The mean weight loss at week eighty was twenty-eight point three percent. But this is what is just mind-blowing, okay? The beginning, that four milligram dose, the mean weight loss was nineteen percent. At nine milligrams, the mean weight loss was twenty-five point nine percent, and at 12 milligrams, twenty-eight point three percent. That's unheard of for a first dose to lead to that amount of weight loss. Think about the starting dose of this medication it surpasses by multiple percentage points what you on average would achieve with Wegovy, which is semaglutide, and you're lucky if you get there. Not everybody even gets there with Zepbound. The fact that Retatrutide that you're already there on the first dose, just incredible. Also, when you look at this, how many patients reached a significant amount of weight loss, again, this is staggering. So if you look at the four milligram starting dose, over twenty-five percent loss, close to thirty percent of people lost that. Over thirty percent of total body weight loss on the four milligram dose, keep this in mind. Over fifteen percent and over thirty-five percent total body weight loss, close to six percent. That is tremendous. Then let's go all the way up to the twelve milligram dose. Sixty-two point five percent are losing twenty-five percent or more. That six out of ten people are going to lose twenty-five percent or more. We don't have that high of a number that can achieve it on previous medication. And I bring this up because there's this misconception when we talk about Zepbound, for example, which is tirzepatide, where people think, "Oh, everyone's losing over twenty percent." That's not true. On average, some people might get to twenty-one, twenty-two percent. Some might get much higher. But there's a lot of patients that I might have where they're at twelve percent, fifteen, nineteen percent. But we're not getting a six out of ten people that are getting to over twenty-five percent weight loss with Zepbound. With that top 12 milligram dose, over 30% of body weight loss, 45% of people. Again, that's almost 50%. Can you imagine almost 50% of people losing over 30%? And then over 35% weight loss, 27.2%. Again, we're living in an incredible time where this is the case. The one thing I wanted to go over, which I think majority of you are probably interested in, what about the side effects, tolerability, things like that? So one thing, let's just talk about who had to discontinue due to side effects that they couldn't tolerate it. So on the four milligram dose was 4.1% quit, not super high, but there are some people that won't tolerate it. I bring this up because there's this misconception that everyone is gonna tolerate these meds and they're gonna work for everyone. And we do know with the previous medications, some patients will not respond to them. They don't lose 5% or more. They hardly feel a difference on them. And to the patients where it works they say, "I can't believe that that person had no response." Well, there are reasons for that. So some people will not be able to tolerate it. On the nine milligram, 6.9% discontinuation rate, and then by the 12 milligram, 11.3%. It's clear here that while the weight loss is higher with the higher dose, the tolerability trade-off really comes into play. A lot of these studies, they have set parameters as far as when they're going up and what they're doing. They're not typically seeing, okay, can we stay on that same dose longer, right? They have-- everyone needs to follow the same protocol. When you have these protocols approved, the only way that these studies are valid at the end of it, is if everyone's following the same rules, right? So it's quite possible that these discontinuation rates might be lower in the real world if people can do it slower and have more adjustments in between, who knows? Top side effect was nausea. I'm just gonna round these numbers, okay? So it was about twenty-seven percent on the four milligram dose, and it went all the way up to the twelve milligram dose to forty-two percent nausea. That's high. Okay. That's high. Diarrhea, again, on the four milligram dose, twenty-five percent went all the way up to thirty-two percent on the twelve milligram dose. Constipation, anywhere, mid twenty percents. Vomiting, this I'm not excited to see. On the four milligram dose, ten point six percent vomiting all the way up to the twelve milligram dose, it was twenty-five percent vomiting. That's not a fun number to see. In my mind, I really feel like I think vomiting is an unacceptable trade-off for these medications. But again, when you look at this, I didn't go all the way into it. Is it just that they once vomited, that they ever reported vomiting? There can be a lot that goes into this, but again, just something to look out for the other thing, I think people always think about mood, sort of not caring about things. We use this term dysthymia, that at the beginning dose was 5.1% and went all the way up to 12.5. Then the last one on here is gonna be for UTIs. Okay, I hope that this was fun today to go through this trial, to hear the numbers, to give hope to some of you that maybe previous medication you either didn't have results or had results, but they weren't as great as all these examples that you hear out there that get glorified all day long, and that you have some hope that there are other medications coming down the line that can be helpful, that have different mechanisms of action, that are hitting multiple different pathways, and that potentially that can be really helpful for you. Again, we don't have an exact date on that. If I ever get any changes on that, I'll always update you, but now you at least have an idea of what is coming down the line. I hope that you have a great rest of the week, and we'll talk soon