150: Why Tirzepatide Works Better Than GLP-1 Alone

Everyone says drugs like tirzepatide work by increasing insulin, but the research tells a different story. In study after study, people taking tirzepatide actually needed less insulin, not more. Why? Because the drug reduces appetite, helps people eat less, especially carbs. It slows stomach emptying and it improves insulin sensitivity. All of this means that the body is becoming better at responding to insulin instead of constantly needing more of it. In fact, fasting insulin levels often go down during treatment. That's a big deal because chronically high insulin is one of the biggest drivers of metabolic dysfunction. So while these medications can absolutely help with weight loss and blood sugar, they're not magically fixing metabolism. They are simply helping reduce the constant carbohydrate overload that drives the insulin resistance in the first place. And that's an important distinction. This is Lecture 150 of The Metabolic Classroom. Welcome back to The Metabolic Classroom. I'm Ben Bikman, metabolic scientist and professor of cell biology. Today we are taking a close look at tirzepatide. That is the newest addition to the GLP-1 weight loss drug family, but as you'll see, it's GLP-1 with a twist or a twin or a sibling. You'll see what I mean. Let's talk about what GLP-1, what tirzepatide is. To make sense of it, you, you have to understand the two hormones that it is mimicking. And this is where I joke that it's a bit of a sibling here, that there's— it's two for one. Both of these hormones belong to a family called incretins. And the incretin idea, it's something I've spoken about before, but it comes from a clinical observation that goes back about 50 or 60 years. When you give someone a fixed amount of glucose by mouth, the insulin response is much larger than when you give that same amount of glucose directly into a vein. So if you infuse it directly, that gap, the difference between the oral and the intravenous load or delivery, is— but while— but the glucose amount is, is kept constant. That's what we call the incretin effect. It exists because the gut when it senses food will release its own hormones that in turn talk to the pancreas, and those hormones can amplify the insulin response in a way that intravenous glucose, uh, does not. It bypasses that effect. Two hormones do most of that work. The first is the most famous one, glucagon-like peptide 1, or GLP-1. The second is glucose-dependent insulinotropic polypeptide, or GIP. I'll just call it GIP. So we have GLP-1 and GIP. Both of these hormones are released from cells that line the inside of the intestine when there are nutrients coming from the stomach. So that's again, coming back to the delivery method, whether in this case the glucose was coming through the mouth or directly into the blood. These two hormones share a job, uh, but they still have their differences, and we'll get into some of that. In a healthy person, GIP is actually the dominant insulin-stimulating incretin. So of those gut-derived hormones that are pushing up insulin a bit, GIP is the main one. It does account for the largest share of the meal-related insulin response with those incretin hormones in mind. GIP receptors also exist on fat cells and on bone cells, and likely many others that are going to continue to be discovered. The classical view is that GIP on fat cells promotes lipid storage, and that's part of how GIP earned its reputation as the obesity hormone. But as you'll see when we come to the GIP paradox later on, that picture does get more complicated than the textbook description suggests, and it makes us actually come back to the humble hormone insulin. But I'm getting a little ahead of myself. GLP-1 has a, a broader portfolio. It helps the pancreas release insulin in response to a rising glucose level. It suppresses glucagon, and then it has the more famous effect of delaying gastric emptying, so the rate at which the food is going into the small intestine from the stomach. And it acts on the appetite centers in the brain to reduce hunger and the, and the food reward, that, that those craving signals. That last effect, the action on appetite, turns out to be far more clinically consequential than anything happening at the pancreas. But again, I'm getting ahead of myself now. In obesity and type 2 diabetes, this entire system gets a little messed up. The insulin-stimulating effect of GIP does become blunted. Patients with established type 2 diabetes show dramatically reduced insulin secretion when given GIP, so when it's infused or administered, while the response to GLP-1 is a little more preserved. For about 2 decades, this is why practical drug development was built almost entirely around GLP-1. GIP was considered a less attractive target. Now, the fact that tirzepatide engages both receptors and outperforms pure GLP-1 drugs like semaglutide is— with this thought in mind, it's a little surprising, but we're going to reconcile all of it, all of this. Now let's focus on what tirzepatide is. I've mentioned these two hormones, and that may That might make you think that tirzepatide is a cocktail of two hormones, but it's not. Tirzepatide is a single synthetic peptide, so it's the small little protein, this, this chain of amino acids, and it mimics both of the incretins. It binds to and activates both the GIP receptor and the GLP-1 receptor, but all in one molecule, which is of course a little unusual. Most drugs typically have just a single target. The molecule has been chemically modified so that it sticks to a protein called albumin. Albumin. Albumin is the main protein that circulates in your blood, but by being carried on albumin, it helps slow down its breakdown. That— the, the practical consequence of this is that tirzepatide has a half-life of about 5 days or so in the body, which is why it can be given just with a single weekly injection. The dosing in the major trials ranges definitely on a much higher end than you see with semaglutide. It's 5 up to about 15 milligrams weekly. And the higher doses, of course, produce the largest effects on both controlling blood sugar and on reducing body weight. And it does seem to work well in direct head-to-head comparisons. Tirzepatide consistently produces greater weight loss and better glucose control than the closely related but single-target GLP-1 version, just like semaglutide. And we'll come back to why that matters when we discuss the GIP component in just a few minutes. Now, anytime I talk about these GLP-1 family of weight loss drugs, I find that I have to spend at least a few minutes talking about insulin, which of course is something I enjoy doing anyway. But it's in part because there's so much misunderstanding. The conventional summary that you'll find in any patient or clinical education material, certainly in the news and main headlines, is that tirzepatide acts as an incretin agonist, and so it raises insulin levels, and the higher insulin produces better blood sugar control, and then somehow it drives weight loss in the midst of that elevated insulin, which in fact is a bit of a metabolic impossibility. Each of those comments that I just made, those, those clauses, sounds reasonable in isolation, and there's evidence to support each one. But the problem is that the human evidence does not support the chain of of causality as I just outlined it. Now, let me start with the most direct evidence. In a careful mechanistic trial in adults with type 2 diabetes, 28 weeks of tirzepatide treatment produced a very interesting pattern. They found that fasting insulin concentrations went down, not up. Insulin sensitivity roughly doubled. So it got that much better. And while the pancreas's overall ability to match its insulin output to any given amount of glucose, it— that improved, but that improvement came almost entirely from the body becoming more insulin sensitive, not from the pancreas pushing out more insulin. That's an important distinction. So think about what that means. Uh, in this study, after almost like about half a year on tirzepatide, the pancreas was not being driven to secrete more insulin. The body needed less. and as a result, fasting hyperinsulinemia, that telltale signature of insulin resistance, it regresses. The tissues have become more insulin sensitive and glucose control improves, not because insulin production is necessarily going up, but because the same amount of insulin now does more work. It's more effective than it used to be. Now, you might object that the insulin stimulating capacity of these molecules is well documented under certain conditions, and that is absolutely true. There's certainly evidence to, to support that. Under conditions where glucose is artificially clamped high in the bloodstream, tirzepatide will increase insulin secretion. But this is where one of the most important features of incretin biology becomes critical. The insulin-stimulating effect is glucose-dependent. That's the G in the, in the GIP that I mentioned earlier. It literally stands for glucose-dependent insulinotropic. Now, and it notes that for a reason. These hormones only push the pancreas to release insulin when blood glucose is elevated, and I dare I say artificially elevated in these clamp studies. When glucose is in its normal levels with even normal meal consumption, the effect on insulin secretion totally disappears. So in real meals, in real humans whose glucose excursions been blunted with the appetite suppression effects and the slower gastric emptying, the meal-related insulin response is not amplified. In fact, it is reduced, in large part because the glucose itself is reduced. Now let me just mention a study that really supports this. It's the SURPASS-5 trial. In this study, tirzepatide was added on top of an existing basal insulin therapy, where these are type 2 diabetics. So they're taking, in this study, once daily insulin glargine. That's just one of the forms of insulin, an exogenous insulin that a diabetic can take. So this is adult type 2 diabetics, and they were not reaching their glucose targets with just the insulin therapy alone. The placebo group continued to titrate, or increase, their insulin upward as glucose targets demanded. So they were finding that they needed more and more insulin in order to keep their glucose in check. No surprise, of course, because you all know that more insulin drives insulin resistance. The tersept— the tirzepatide groups achieved dramatically better glucose control, with up to 90% of participants reaching the glucose target, compared with about only a third on placebo. And they did so with substantially less injected insulin than the placebo groups needed. The investigators, in fact, used the phrase insulin sparing to describe this effect in their discussion. So if tirzepatide worked primarily by squeezing more insulin out of the pancreas, the body's need for injected insulin in this scenario should have remained roughly stable or increased. Instead, the total insulin burden went down. The drug is insulin sparing. The body needs less insulin to handle the same food, not more. This pattern is not unique to tirzepatide. Across the broader family of the GLP-1 drugs, when the drugs are added to existing insulin therapies, the clinical outcomes the same. They have better glucose control, all while reducing any amount of insulin and improving insulin sensitivity and improving baseline or fasting insulin levels. These drugs are decreasing the body's demand for insulin rather than supplying more of it. So the conventional narrative that the drugs work by squeezing more insulin out of the pancreas, it has the arrow of causality, I think, pointed in the wrong direction. The pancreas is doing less work, not more. So we just need to keep that in mind to counter the prevailing narrative that these drugs all just work by increasing insulin. All right, now let's move on to tirzepatide again and really outline where its benefits in weight loss are coming from. Compared to semaglutide alone. The dominant mechanism by which tirzepatide is producing weight loss is, of course, not the pancreas. It's really driven, uh, largely by the suppression of food intake. But there are two cooperating effects here. One is the central appetite control in the brain, and next, it is the slower or delayed gastric emptying, so the rate at which food is moving from the stomach into the small intestine. In a controlled study in adults with type 2 diabetes that measured these things directly, tirzepatide reduced subjective hunger ratings, reduced the urge to eat at any given moment, and increased a sense of fullness between meals. And it reduced cravings for these savory, sugary foods that can tend to drive overconsumption in obesity. When participants were offered a controlled meal under laboratory conditions, they ate noticeably less than when they were on the placebo. Similar work has been done with semaglutide, of course, which is the closely related single-target GLP-1 drug. Under controlled buffet conditions, treated adults with obesity consumed about 35% fewer calories compared to when given free access to the food. Compared to when they did, compared to what they ate when they were on the placebo. They had, as I noted earlier, less hunger, more satisfaction, and they had reduced cravings for these carb-y and with fatty— carb plus fat, but not fat alone, because no one craves that— these, those, those types of foods. The food on the offer, the food that they were offered, was identical. So there was no change in what they were, what was available to them. Now, where's all this happening? Well, A main effect of this is in the brain. GLP-1 receptors are densely expressed in the appetite-regulating centers of the brain, and brain imaging studies in humans treated with GLP-1 drugs show reduced activation in the brain's reward circuits when participants are shown pictures of food. The pull of a calorie, carb-dense meal, it weakens and the portion size that would have felt, uh, unsatisfying prior to treatment begins to feel somewhat excessive with therapy. And, uh, when we add to this the peripheral effect on the stomach, it gets even more relevant. Tirzepatide, like the GLP-1 alone drugs, slows the rate at which the stomach empties its contents into the small intestine. This is most pronounced After the first few doses in carefully controlled studies, the effect partially fades over the first few weeks as the body becomes somewhat accustomed to it. But during active treatment, which I think is an important opportunity for people to learn new habits— I'll come back to that later— the fullness signals from a distended stomach are sustained and the desire to eat again is delayed. Now, when we put these two mechanisms together, the appetite suppression and the delayed gastric emptying, we start to see a substantial reduction in how much someone's eating day after day and week after week, hopefully month after month, as it's sustained. The, the cumulative reduction in carbs and calories is what accounts, I think, for the weight loss. There's no mysterious metabolic magic here. That is so important because people need to know that the drugs are working because it's changing how and what and how much you're eating. If you are taking the drug because you think it's a magic weight loss effect in a syringe, you might not be mindful of how you're changing your habits. And then the drug starts to lose its efficacy, and you go right back to the old habits without ever realizing you changed them. All right, now let's focus more on GIP, GIP, because you're wondering, well, what happened to GIP in the story? After all, I just got done spending a few minutes talking about GLP-1, which is something I've already done previously, and I'm just revisiting it briefly. When we add GIP to the story, it gets a little more interesting, but it also gets a little paradoxical. The, the puzzle or the paradox begins with the fact that blocking the GIP receptor, so doing the opposite of what tirzepatide does, also produces weight loss in animal models. Remove the GIP receptor from a mouse genetically, and that mouse resists weight gain on a high-fat diet. Give an antibody that blocks the GIP receptor and the obese animals will lose weight. For nearly two decades, this actually fueled a major pharmaceutical effort aimed at blocking GIP signaling as an anti-obesity strategy. And yet tirzepatide does the opposite. It activates the GIP receptor, and the result is greater weight loss than activating GLP-1 alone. How can both blocking and activating the same receptor lead to weight loss? The resolution starts with a principle I've defended on this podcast many times. Insulin is the primary hormonal signal that drives fat storage. Insulin activates lipoprotein lipase. It drives glucose and fatty acids into adipocytes. It is, is very effective at suppressing fat breakdown, and it promotes triglyceride synthesis. Without elevated insulin, fat cells simply don't have the molecular instructions to fill up. Let me just put a fine point on that. In the absence of insulin, it is totally and completely impossible for a fat cell to get big, indeed even to keep its current size. GIP in this picture is not the primary fat storage signal. It's at best an amplifier of insulin's signal. Carefully designed human studies have demonstrated this directly. In lean adults studied under conditions where insulin and glucose were experimentally held high, infused GIP did increase, even microscopically, adipose tissue blood flow. It activated lipoprotein lipase activity a little more than just insulin alone. So there was this, you know, slight but statistically significant net gain in fat storage with a little more GIP. But the experimental condition is the key detail. The whole sequence occurred only when insulin was elevated. GIP infused without insulin co-stimulation did not drive the same lipid storage. The amplifier needs a signal to amplify, or to put— say that more directly, GIP needs elevated insulin if it's going to help promote a little greater fat storage. That matters enormously for understanding tirzepatide because the drug itself kind of dismantles the condition under which GIP would historically drive fat storage. As we established earlier, to— terzepatide lowers fasting insulin, it improves insulin sensitivity, it reduces the insulin, um, bump, the insulin curve after a meal. And importantly, it doesn't just reduce overall food intake, it specifically reduces cravings for the foods that would otherwise drive the insulin up upward. In a recent analysis of a Phase 1 trial in adults with obesity, tirzepatide produced significant reductions in self-reported cravings for sweets, for carbohydrates and starches, and yes, for versions of those with fats. But the cravings for things like protein or just less starchy, sugary fruits and vegetables were not as much changed. The drug appears to selectively suppress appetite for the sugary starch-heavy, yes, even fatty versions that would otherwise drive the largest postprandial insulin excursions. So you have a single molecule that lowers fasting insulin, reduces meal-related insulin demand, and pulls down the food behaviors that would normally push the insulin upward all at once. The metabolic environment in which GIP's classical fat-storing partnership with insulin operates is totally dismantled. By the same therapy that activates the GIP receptor. So the question that actually matters really then becomes, what is GIP doing in this low insulin state, and how does it contribute to weight loss rather than weight gain? Well, there are two parts here, and they're going to sound a little familiar. The first is in the brain. GIP receptors are expressed in the appetite-regulating centers. Yes, just like GLP-1, and their activation reduces food intake and attenuates nausea. That's something we're going to come back to in a moment that would otherwise limit how high of a dose the GLP-1 levels can get. This is really a direct anorectic effect. The, the central action of JYP reduces the eating, and it's also what allows clinicians to push the GLP-1 arm of the drug into higher doses than you could on their own, because too much GLP-1 alone is really going to drive some nausea. Both arms of the molecule are working in the same direction at the level of the brain, and both are reducing the drive to eat. And then second is at the fat tissue, where the contemporary view is more favorable than the older textbook version. In the absence of the insulin co-signal, GIP receptor activation at adipose appears to support healthier lipid handling or healthier fat storage. Especially better blood flow to fat tissue, and it drives the adipocyte to release more adiponectin. That better blood flow is very important. It prevents the hypoxia from developing. You'll recall that in— I've previously described that one of the reasons that the fat cell becomes harmful or promotes insulin resistance throughout the body is that it becomes hypoxic. It can't get enough oxygen, and then it starts releasing a bunch of pro-inflammatory cytokines. GIP helps maintain healthy blood flow. And so thus you are preventing the hypoxia, which prevents the adipose-induced inflammation. And remember, um, another effect here, especially with adiponectin, which can stimulate fat burning in the liver, is that what we start to see is that if you can have the fat cells store fat in its healthy way. And I don't mean by getting bigger, but by releasing more adiponectin, you're reducing liver fat. That is important because one of the newest papers published in this field of, of incretin research found that a lot of the apparent loss of fat-free mass or lean mass isn't in fact coming from the muscle. It's coming from the liver. Getting rid of its fat. It's true, one of the limitations of, of DEXA scans, which is considered a gold standard here in measuring body fatness versus fat-free mass, is that any mass in the liver is considered fat-free mass, even if it's liver fat. And so what they found is that the liver, which has become so fat in the overweight, especially diabetic, starts to lose a lot of its fat, so the liver shrinks. and that is starting to confound some of the results, leading the researchers in some studies to conclude that there's a loss of muscle. It appears that it is not a loss of muscle. Most of the so-called fat-free mass loss is again coming from the liver getting smaller. When you put the pieces all together, the dual action of tirzepatide starts to become a little more, uh, coherent. The, the paradox starts to resolve itself a little bit. GLP-1 activation can suppress appetite. It delays gastric emptying. It helps lower the meal-related insulin requirement. GIP receptor activation suppresses appetite as well, but it also attenuates the nausea that would otherwise limit the GLP-1 dosing. And it operates at the fat tissue to help maintain adequate blood flow and prevent adipose hypoxia. Both receptors are pushing toward reduced, um, food consumption. And I would say carb cravings, both are operating. In a metabolic environment of reduced insulin that isn't allowing the fat storage to happen at all. Now, I want to revisit this nausea effect because that's a very important piece of this mini lecture that I've just alluded to, but it helps us understand why the dual-action drug can be more effective than the single-action GLP-1 drug alone. Now, to understand this, we have to recognize that part of what limits GLP-1 drugs in clinical practice is the nausea that with pure GLP-1 receptor agonism or activation, um, the nausea can get so bad that it can lead to vomiting. It's really one of the most prominent dose-limiting side effects. Now, I am loath to see anyone go to a higher dose than they need to with these. I have long maintained that you want to be on the lowest effective dose. But this is part of how it works. Patients can tolerate these higher doses of GLP-1 with the dose escalations because the main symptoms of nausea are attenuated because of the GIP. And here's what's interesting. A 2021 paper looked at the central nervous system effects of GIP in some animal models, and they found that GIP receptor activation directly blocks the nausea and vomiting that GLP-1 receptor activation otherwise produces, but all while preserving GLP-1's effects on food intake, um, with, with appetite suppression, gastric emptying, and weight loss. The mechanism is in a specific region of the hindbrain that processes signals for vomiting and food aversion. GIP receptors in that region sit predominantly on these inhibitory neurons. The clinical translation of this mechanism is not totally complete, though, because in humans, in the head-to-head trials between tirzepatide and semaglutide, the rates of nausea are generally similar between the two drugs. What the data do show is that tirzepatide achieves substantially more weight loss at those similar nausea rates. In other words, the weight loss to nausea ratio is much more favorable. You get more weight loss signal for the same tolerability cost, if you will. Now let us wrap up with some concluding thoughts. First, the data force us to further cement the idea that insulin matters here, but not like most people think. Saying tirzepatide works by raising insulin is simply not accurate. The drug reduces the body's demand for insulin by producing a reduced glycemic excursion. So you're reducing food intake and improving the body's sensitivity to insulin. Fasting insulin levels get better on the drug. Second, the weight loss is robust and it is explained by mechanisms we can describe in some detail, like the appetite suppression, the delayed gastric emptying, the reward circuit modulation of the brain, and the dismantling of the insulin context that would otherwise allow fat storage. The drug works by reducing intake, which is the same fundamental driver of the weight change that has always existed. Third, the GIP component, um, once kind of worrying or even confusing with its— the classical association with fat storage, it turns out it makes some sense once you account for the insulin context the drug creates. GIP requires elevated insulin to drive fat storage, and tirzepatide lowers insulin while also reducing cravings for the foods that raise it. The same receptor activation that historically caused some concern in this context does not contribute to any problem. And finally, these drugs are not a substitute for the underlying metabolic conversation. If I were thinking about these drugs and how they fit best in a real clinical conversation, it isn't as a permanent appetite override that someone is taking indefinitely. I feel very strongly that this drug and all of its related sibling drugs is at its best when used as a tool to help a person who has lost control of carbohydrate cravings to regain that control. The published evidence shows the drug pulls down these cravings very heavily. The cravings for sweets and for starches, yes, including fatty versions, that always gets thrown in in the research, but also just for the simple starches and sugars themselves, all of which are the primary culprits that are driving the largest insulin excursions. And the period of months or a year or two that someone is on the drug, I think, is an opportunity. It's an opportunity to eat differently, to experience what satiety feels like at a lower carbohydrate intake, to, to lower fasting insulin, and to begin reshaping the eating habits that drove the metabolic dysfunction in the first place. Remember, the food you eat is either the culprit or the cure. The drug, I think, if it's used with this frame in mind, is less a pharmacologic shortcut and it's more of a crutch to help a person learn to move forward on their own. In other words, kind of rewire their association and their habits with food. What does it feel like to be able to walk past something that used to be an irresistible temptation, or to have, in fact, the ability to moderate your consumption, moving from addiction to moderation. That, to me, is the best use case for these drugs. That's the deep dive on tirzepatide. Class dismissed. Until next time, more knowledge, better health.