151: Why Retatrutide May Outperform GLP-1 Drugs

There's a new class of metabolic drugs emerging, and they may change obesity treatment completely. It's called retatrutide, and unlike Ozempic, it activates 3 metabolic pathways at once. Not just GLP-1, not just GIP, but glucagon as well. And that third pathway is what makes it very different, because while GLP-1 helps you eat less, glucagon helps your body burn more. It increases fat burning. It raises energy expenditure and may help clear fat from the liver faster than anything we've seen before. In clinical trials, people lost nearly 29% of their body weight, but these drugs work best as a bridge, helping people learn how to eat differently and restore metabolic health long-term. This is Lecture 151 of The Metabolic Classroom. Welcome back to The Metabolic Classroom. I'm Ben Bikman, metabolic scientist and professor of cell biology. Today, I want to teach you about a molecule that has every reason to dominate metabolic medicine over the next several years, and that is retatrutide. This is the first drug in clinical development to engage three of the most important hormonal levers of metabolism and satiety at one time. And the weight loss that we see in the human trials is quite remarkable. It's certainly noteworthy. But the more important story and the one that I want to spend our time on today in this mini lecture isn't the weight loss numbers, but we'll, we'll cover that, but rather the third and new aspect to this, the new receptor that it's targeting, and that is glucagon. So to get started in the mini lecture and to help you appreciate just what this new drug retatrutide is doing, let's briefly review some of the evolution of this class of drugs. You're by now, of course, very familiar with semaglutide. Semaglutide is the single receptor agonist that activates the GLP-1 receptor. And then of course, just recently I gave a mini lecture on this, but regardless, you might have heard about tirzepatide. That's a dual agonist which engages not only GLP-1 receptors but also the GIP or jip receptors. Now retatrutide takes the next step, adding that third arm, that third receptor agonism or activation. That's the glucagon receptor. And in so doing, it produces— we, or we're left with this single peptide, the single molecule that activates all three of these receptors at once: GLP-1, GIP, and glucagon. What makes retatrutide interesting from, from a pharmacology standpoint is the relative potency at each of those three receptors. Compared to the native or endogenous hormones. In other words, the hormones that we make ourselves— GLP-1, GIP, and glucagon— retatrutide is about 9 times more potent at the GIP receptor, the GIP receptor, and it's slightly less potent at the glucagon and GLP-1 receptors, again, compared to the native hormones. That is, that's somewhat of an intentional— it's not somewhat, it is an intentional imbalance. And in other words, activating, having a stronger effect on one, less of a weaker effect on others, because it helps give especially glucagon a little bit of nuance. Glucagon, after all, is a powerful metabolic hormone, and pushing it too hard would drive the liver or hepatic glucose production too much. Now, of course, that's glucagon's most famous, um, effect. That's why it's called glucagon, from glucose. And but that, of course, would work against someone's glycemic goals. Someone who's trying to lower their blood glucose, if they're stimulating their glucagon receptors in their liver too much, that's just going to make the glucose worse. So the challenge was to engineer enough glucagon receptor signaling to harvest the metabolic benefits like the fat oxidation and the energy expenditure stuff we'll get into in a moment, without tipping the body into hyperglycemia. And as you'll see with the clinical data, it certainly seems like that's been accomplished. Now, this will be a little bit of a primer, but I want to make sure we spend a little bit of time reviewing what these receptors are. Now, it's a primer in the sense that I just recently recorded a metabolic classroom mini lecture about Trezepatide. So focusing more on GLP-1 and GIP, but let's just review that again. Now, the GLP-1 arm of this is the foundation. This is the part of the molecule that does what Semaglutide does. It slows gastric emptying. It acts centrally. So in the, in the brain to suppress appetite and control cravings, and it lowers postprandial glucose levels. With what we can call an insulin-sparing effect. Most of the appetite suppression and a large portion of the early weight loss seen with retatrutide is very likely attributed to this GLP-1 activation. It's the very well-understood backbone of every drug in this class. Now, the GIP arm, or the GIP arm, contributes an amplifying effect that we now recognize is part of the benefit of tirzepatide. GIP receptor activation enhances the appetite-suppressing effects of GLP-1, and it improves the GI tolerability. In other words, the— you're able to stimulate GLP-1 more without the nausea that comes from too much GLP-1 activation. And as I noted previously, the GIP receptors are also expressed on adipocytes, or fat cells, which can influence how those fat cells store fat. So it's not that it's having a direct fat-burning effect, but it's actually helping the body have better fat storage, where you have fat cells that are releasing more adiponectin, for example. And adiponectin is a very beneficial insulin-sensitizing hormone in its own right. And now then we get to the glucagon arm of this three-armed oddity. This is the receptor that changes what kind of drug retatrutide is. GLP-1 and GIP work on the, on the input side of energy balance, if you will, by helping reduce how much the person's eating and controlling their cravings. You know, this is where you have the effect of, I would say, people less interested in these addictive foods, these refined starches and sugars. But that's where you also see people experiencing a benefit in other addictive behaviors, like with alcohol, or even just a paper published today looking at their use in helping people get off cocaine. All right, so that's all on the input side, so controlling— helping control what the person's putting into the body. But glucagon works more on the output side. It raises metabolic rate, it increases fat burning, and it also helps the liver remove its fat, um, very, very quickly, as you'll see when we get to the human evidence. This is why I, I do want to spend the bulk of our time in the mini lecture focusing on glucagon, because that's the novel addition. That's the unique advantage of retatrutide over the previous iterations or the other versions like semaglutide or tirzepatide. All right. So let's focus on glucagon. Before we get into how glucagon contributes to fat loss, we need to be clear about where its receptor is expressed, because the tissue-specific expression of glucagon receptor— of glucagon responsiveness is really the key to understanding which effects are direct and which are going to be indirect. The glucagon receptor is most abundantly expressed in the liver by a wide margin. The liver is the primary site of action with regards to glucagon responsiveness, and the, the liver cells, the hepatocyte, is where most of the metabolic benefits of the pharmacological glucagon agonism originate. In the liver, glucagon signaling stimulates fatty acid oxidation, it inhibits de novo lipogenesis, and it promotes the clearance of fats from the liver. Now, those are all complementary. So it's increasing fat burning, it's reducing fat production, and it's helping, um, just thus clear fat from the liver. And you'll see the results on fatty liver numbers are quite remarkable. Now, it also drives what's known as hepatic futile cycling. Futile— I'm being deliberate in my pronunciation there. I don't want you to make— I don't want to say futile where you're thinking it's some archaic mechanism of economy, but this futile cycle is a pair of opposing reactions. One direction of a biochemical reaction that's building up products, and the other pathways are breaking it down. So this, this cycle of anabolic building and catabolic breaking down But of course, each round, each cycle that this is happening, when you're building something up just to break it down, means you're wasting a lot of energy. You're burning a lot of ATP without really getting anything productive out of it. Now, the productivity here, we could say, well, it's, it's burning energy and there's too much energy. Absolutely. That's right. But it is futile in that you're not left with anything productive. You're just spinning your wheels metabolically. But again, that's a good way to burn up fuel, and that's just what's happening. So the cell ends up using fuel just to keep this loop, this futile cycle going, and that fuel will show up as it's getting burned rather than a productive molecule at the end. It's just showing up as heat and an increased energy expenditure. Now, I should clarify here, there's no evidence that you're actually— that your body temperature is higher, but it would be this, if you will, I, I, I wanna use the word microscopic heat, but it's not something you can measure under a microscope. But I think you get the idea. There's a very, very modest increase in what would be heat production as you're just having the— it is kind of like you're revving the engine, but you're not going anywhere. You can still make the engine warmer from doing that. Several of these cycles will run faster. So there's a few to point out. There is cycling between gluconeogenesis and glycolysis with each turn consuming ATP. There is a also lipid cycling. And I've mentioned the lipids here as hepatic triglyceride is broken down and reformed. And glucagon accelerates hepatic amino acid catabolism and the, the urea cycle, which is the pathway of disposing, if you will, spent amino acids and, and the nitrogen that comes from breaking those, those amino acids down. The amino acid pathway is maybe the, the, the strongest here that is the futile cycle worth mentioning. Glucagon will pull circulating amino acids into the hepatocyte through upregulated expression of these amino acid transporters. Then once inside the cell, the amino acids are stripped of their nitrogen. Then the nitrogen is processed into urea. Um, and then that costs a lot of ATP. Every urea molecule you're generating, you are spending several ATP molecules. And then the carbon skeletons of that that kind of wasted amino acid could be used to make glucose, which costs more ATP. So the whole sequence is energetically expensive, and that expense is paid in calories burned. Now, beyond this futile cycle, the liver will also secrete something called fibroblast growth factor 21, FGF21, in response to sustained glucagon signaling. FGF21 has its own systemic effects that support fat oxidation and increase energy expenditure. I've talked about that previously, but suffice to say, increased FGF21 is going to increase fat burning and metabolic rate. Well, glucagon does that. A meta-analysis of human studies has confirmed that acute glucagon administration increases energy expenditure, and preclinical work— so animal models— demonstrates that this energy expenditure response runs through the glucagon receptor signaling rather than another cell type like, say, fat tissue or adipocytes. When you look at the reductions in liver fat seen with retatrutide— and I'll get into those numbers in a moment— the glucagon arm of retatrutide is really doing most of that fat-clearing work from the liver. Now, beyond the liver, The glucagon receptor is also expressed, albeit at lower levels, in the adipocyte, the fat cell. This is a point of debate in the literature, and I want to address it because I think it's relevant to helping you understand through this mini lecture how retatrutide may be amplifying some of the fat-burning effects directly. For years, the, the textbook paradigm was that the adipocyte was a glucagon-responsive cell capable of lipolysis when glucagon engages its receptor. Now, more recent work in, in animal models kind of complicated this a little bit. When researchers deleted the glucagon receptor specifically from fat tissue, fasted— fasting-induced lipolysis was unchanged. And exogenous glucagon. So treating the animals with glucagon at physiological levels had very little effect on the fat pad or on the fat mass. The interpretation from that work was that at normal circulating levels, glucagon does not regulate fat cell function on its own. But here's the distinction that matters when it comes to a drug like retatrutide. The glucagon receptor is expressed on human fat cells, and when human adipocytes are exposed to elevated glucagon concentrations, like the kind that a pharmacological agonist sustains, then lipolysis was shown in humans to increase by 4 times. So a fourfold increase in fat breakdown. And the effect compounds when the cell is also receiving a normal epinephrine or adrenaline-like signal that drives— that further drives fat breakdown. Now let me Let me rephrase all that. So they did find that increased glucagon was sufficient to increase lipolysis by 4 times. And then when they further looked at the addition of epinephrine, which is just one of the hormones in the body, it amplified that even more. So to me, there— this might be, and I'm speculating now, it might suggest that when you combine a glucagon agonist like retatrutide with something that's also increasing epinephrine, whether it's exercise or cold plunge, it, it, it appears that it would amplify that fat-burning effect as well. So to me, there is a resolution here with this slight contradiction. But again, the contradiction is almost moot because the contradiction is coming from an animal model, um, but the human model supports it. But at But suffice to say, if I were attempting to reconcile this modest, um, contradiction at strict physiological glucagon levels, the direct adipocyte effect may be modest, but higher glucagon activation does activate adipocyte lipolysis through that glucagon receptor. Retatrutide, of course, delivers a sustained glucagon receptor signaling that produces a direct lipolytic effect at the fat cell, and then you layer that on top of the indirect effects through hepatic signaling and through enhanced sympathetic or, or the epinephrine signal, and then it gets a little more dramatic. Now, there's an important point to make here. The glucagon receptor is not expressed on human skeletal muscle. Skeletal muscle has no functional glucagon receptor, which means that when retatrutide activates the glucagon arm of this, of its mechanism, none of that signaling lands on the muscle. This is important, I think, to just appreciate this drug. The, the catabolic effects of glucagon that you see in the liver, especially the increased proteolysis or the, the protein breakdown and the accelerated amino acid clearance or catabolism, they do not occur in the muscle because the muscle cannot hear the glucagon signal. This is significant. One of the legitimate concerns with any aggressive weight loss agent is the proportion of lean mass lost alongside fat mass. With retatrutide, you have a molecule that drives fat oxidation through hepatic glucagon receptor signaling that stimulates lipolysis at the adipocyte under the— under a level of pharmacological signaling, and it boosts overall energy expenditure not only through hepatic futile cycling but also FGF-1, FGF-21 2021 release. And it does all of this with any direct glucagon-mediated catabolic signal at the muscle. In other words, the fat will respond, the liver will respond, but the muscle will ignore it. Now, I've already articulated somewhat previously, and certainly in my research reviews, the, the other, uh, the other kind of insider-only material that I generate, that the— there's, there's evidence nowadays that questions the degree to which a person's actually losing muscle. And there's human evidence to suggest that on these drugs— and I was wrong about this, um, and I want people to know, I was— one of my very initial, um, strong sources of opposition for these drugs was the loss of lean mass. But it appears that it's mostly from a reduced liver mass. One of the quirks of DEXA scans is that it can't distinguish just general liver mass from whether the liver is heavier because of it being loaded with fat or not. So just to be clear about that, liver fat is included in a fat-free mass measurement when it comes to a DEXA scan. The DEXA cannot distinguish that. And so what they found was that most of the, the apparent loss of, of lean mass was actually coming from the liver having less fat. So a bit of an artifact or an error in how we interpreted those earlier data. All right, now let's move on in the mini lecture and get to the clinical evidence and even touch on some of the dosing that is used here. The clinical data on retatrutide are, of course, still emerging. This is not a drug that is released yet, but the early clinical trials are worth sharing. The Phase 2 obesity trial with retatrutide enrolled adults with obesity or overweight people without type 2 diabetes, and they randomized them across several doses of retatrutide or placebo and followed them for almost a year, 48 weeks. At the highest dose tested, which was 12 milligrams injected once daily, mean body weight was reduced by over 24%. To put that in context, semaglutide shows roughly 15%, and then tirzepatide is around 20, low 20s. So retatrutide is the winner here. Phase 2 trial in type 2 diabetes showed similar effects, about a 17% weight loss at 36 weeks at the highest dose. Again, that's at 12 milligrams, and the HbA1c see reductions of over 2 percentage points, which are really remarkable, um, for any of these drugs, any of these anti-diabetes drugs. And then let's get to the liver fat, because those data are perhaps the most impressive. In a follow-up Phase 2, a sub-study of the Phase 2 participants, in people specifically with fatty liver disease, retatrutide reduced, um, the relative hepatic fat content by over 80%. With almost 90% of the treated participants achieving what was considered a normal hepatic fat level. So that's just— that is fantastic. I mean, it really is quite remarkable. Then at the end of 2025, so just a few months ago at the time of this recording, the first of the upcoming Phase 3 results came out. The TRIUMPH-4 trial, which enrolled adults with obesity or overweight together with knee osteoarthritis, and then it randomized them to retatrutide at 9 milligrams or 12 milligrams or placebo. And they reported a mean body weight reduction of about 29% at, at 68 weeks on that higher 12-milligram dose. That's an average, um, loss of about 32 kilograms or roughly 71 pounds. Cardiovascular risk markers also improved, like triglycerides dropped C-reactive protein dropped, systolic blood pressure dropped. In fact, the systolic blood pressure fell by about 14 points, um, on that higher dose. But also I mentioned osteoarthritis. It's been interesting for me to hear anecdotal reports of people who aren't necessarily losing a lot of weight, but they're experiencing a lot of relief when it comes to joint pain. And that was a, um, a secondary indication for this trial, the osteoarthritis. But they found that it improved by roughly 75% with, uh, as measured with what's called a WOMAC, a W-O-M-A-C pain scale. So that's just a measurement, an indication of someone's joint pain. And then they found that more than 1 in 8 participants were totally pain-free at the end of the study. Said there are many other, others, there's, there's 7 additional reported phase 3 readouts that are coming that are going to be touching on more of the outcomes related to type 2 diabetes, to sleep apnea, more liver fat markers. And more. Now, when it comes to dosing, I've mentioned this a little bit. Retatrutide is administered as a once-weekly subcutaneous injection. The trial program, it titrates, or, or, you know, steps, um, change— it has these stepwise changes from a starting dose of 2 milligrams upward over roughly 12 to 16 weeks, escalating to the therapeutic dose of 8, 9, or 12 milligrams depending on the indication. So what the outcome is intended to be and what the trial has been. A 4mg maintenance dose is now being evaluated on the rationale that once a patient has reached the target weight loss, a lower dose may be sufficient to hold the result with less of the gastrointestinal side effects. Now, that's a good opportunity for me to state it again, which I've hopefully stated abundantly. I firmly believe that the best use case for this and any similar drugs is to learn to eat differently. Think of the drug as a crutch. It's a crutch that will help a person who can't yet walk on their own, if I just continue with that metaphor. And it works best when it's treated— viewed as temporary. Retatrutide will certainly help control the cravings. It can help kind of calm the appetite. It certainly will clear the liver, and it will give the patient some breathing room. But the breathing room, I think, is the opportunity, the time to learn what meal looks like when it isn't built around processed carbohydrates. So it's— it helps the person learn to recognize the— what are the foods they struggle with, although they probably already know. But what does it feel like when the addiction to those foods has been calmed? Um, and we're seeing this again with very addictive substances. We're seeing it with food. The refined sugars and refined starches are the foods that people can't stop eating, and they're the foods that drive the disease these drugs treat. So to me, the goal is to lean on crutch less and less over time. The best outcome is to not need the crutch, that you can put it down. So the next best thing would then be to just rely on the crutch very lightly. So to me, the moment a person gets on these drugs, they should be thinking of them as drugs that are helping them learn to change their habits, not just drugs to help drive weight loss, because that paradigm won't enable new habit development. So to me, the best outcome is weaning yourself either off the drug completely or going to a very low dose that just helps you keep it going if needed. All right. So to wrap this up, if you step back and look at retatrutide, what I think you see is the next step in this progression. Now, having said that, there are multiple steps being taken in different directions. Future metabolic classrooms, for example, are going to focus on the addition of amylin, because that's being viewed as a new treatment therapy here. But the evolution has been the single receptor agonism of GLP-1 to the dual receptor with the addition of GIP. And now we have the triple agonist with the addition of glucagon receptor activation and its contributions on the energy expenditure side, on the output side. The glucagon arm is what drives the molecule and gives it this unique character, the direct fat oxidation, the futile cycling, the direct lipolysis. In the fat cell under the pharmacological levels of the signaling here. All of those, um, help contribute to, uh, what's pretty significant weight loss and fat loss specifically. That's it. Class dismissed. Until next time, more knowledge, better health.