162: The New GLP-1 Pills & What You Need to Know

Are GLP-1 pills just injectable drugs turned into tablets? Not exactly. Oral semaglutide is similar to the injectable version, but because your stomach naturally breaks down this type of drug, it needs a special ingredient to help it survive and get absorbed. That's why it has to be taken on an empty stomach with very little water. But another GLP-1 pill called orforglipron is different. It's a small molecule that can survive digestion on its own, So it can be taken more like a normal pill, with or without food. That could make GLP-1 drugs much easier to use. But the important part is this: whether it comes as a pill or an injection, it doesn't change the basic rules of metabolism. These drugs can help you eat less, but insulin still plays the major role in whether your body stores fat or releases it. The drug may be changing a lot, But the metabolic rules are not. This is Lecture 162 of The Metabolic Classroom. Welcome back to The Metabolic Classroom. I'm Ben Bikman, metabolic scientist and professor of cell biology. There are now 2 GLP-1 pills approved for weight loss, and I keep getting the same question about them. Are these just the injection in a tablet? The answer is that one of them, Kind of is, but the other one is not at all. One is the same peptide that has always been in the syringe. It's carried across the stomach in this case, but it has a chemical helper and it's been dosed in a very, very different way, as we'll get into in a moment. The other molecule is not a peptide at all. It is in fact what's called a small molecule, and it attaches to a different part of the same receptor. And does not have the exact same signaling, but it's close enough that it works. That difference is significant, and it changes how these drugs are taken and at what doses. What it does not change is anything about how the body actually stores and releases fat, and that's what we'll end with. Okay, before we get to the pills, let's just be clear about what GLP-1 is. Because it helps us make sense of these drugs. As you know by now, I'm sure, but I'm going to be a thorough professor and remind you of it anyway. GLP-1 is a hormone made by cells that line your intestine, and they are normally— this is released as food comes down the intestines. It does a couple things at the same time. In fact, it does a lot of different things, but with regards to weight loss and obesity, the most relevant one of all is that it slows the rate at which the stomach empties into the intestine. So in other words, the rate at which nutrients from your meal actually get into your blood is greatly diminished. So there's this significant downstream slowing down. The secondary effect— the secondary effect is that it can change appetite regulation. In the brain. That's a little more debated, actually, that there's some evidence to suggest that might not be so relevant of a mechanism. But until that's been really proven otherwise, I think we can still consider it a mechanism. All right, so let's get to the 2 molecules, the, the structural chemical point. GLP-1 is a peptide, which means that it's a short chain of amino acids. These are the same building blocks that make up every protein we eat or every protein hormone that our body makes that's a protein-based or a peptide-based. The drugs are built to imitate that peptide signal, and the drugs specifically designed as peptides to match the peptide— similarly match the peptide structure of GLP-1 itself— are the ones you've heard about: semaglutide, or, or the older one liraglutide, or the newer one tirzepatide, or the newer one still retatrutide. All of these are peptides. They, they're designed to last a little longer and be a little more stable than the natural version of the hormone, but it is still a chain of amino acids. That's a problem because the entire purpose of the stomach is to destroy These types of these types of molecules. It they the stomach is built to destroy peptides. The stomach acid is very it's very acidic. It's the pH is extremely low, which means it's very acidic, like roughly similar to the acidity of battery acid. And it is it works very well at opening proteins up. So when you eat a protein, the stomach acid helps denature or unfold the protein. That then helps it be in a position where enzymes can come and split up the protein. So the enzymes are ready to go, but they need the protein to be opened up. So you— if you swallow a peptide drug and it just gets straight to your stomach as it is, it's not going to get into your blood as the peptide that you took it in. It's just going to become this random bunch of amino acids that your body will do whatever it wants with. So if you just swallow a straight peptide, what will end up in your blood are the individual amino acids, and, you know, almost no chance that it would ever get rebuilt as the specific protein you just ate. So for most of the history of this class of drugs, for peptides, The answer has always been a needle, because if you inject it into the body, it can bypass that digestive complication entirely. Okay, now what about the the drug then? How does the drug get around this? Oral semaglutide is the exception. It's still a peptide, and it's interesting and helpful, I think, to understand how the workaround is is worked out. Because the compromises show up. Um, this is what you actually see in some of the, the instructions on the bottle. So the tablet will contain semaglutide, and it contains a much larger quantity of a second compound, and it's, it's what's called an absorption enhancer, abbreviated as SNAC, or we'll just call it snack. That second compound does 3 things in the stomach, this absorption enhancer. First, it buffers the acidity immediately around the tablet. So it makes it so that right around the tablet, the stomach acid isn't quite as acidic. So it helps the protein— the denaturing or the unfolding of the protein not work as well. Second, this absorption enhancer also keeps the semaglutide molecules from clumping together, because the clumps can't be absorbed If the if the if they are you know if it's all clumped up, but the individual molecules can, so it separates them out. And then third final part of this absorption enhancer is that it can temporarily slightly loosen the membrane of the stomach lining so that the molecule has a better chance of getting through the stomach. That last detail is a unique one. Almost every drug you swallow is absorbed further down. the, the digestive tract in the small intestine. That's where the lining is a little thinner. You don't have that big thick mucosal lining, and there's much more surface area as the molecules moving through the small intestine. But this one is absorbed in the stomach. The stomach does not have a lot of absorptive capacity or surface compared to the intestine. And so even with all of that engineering that I just mentioned, but even with all that absorption enhancing, Only about 1% of the dose you take in actually reaches the bloodstream, and depending on conditions, it might even be lower than that. It can be closer to a half a percent. Almost the entire dose is destroyed or just passes right through. This is what you see on the label of the drug: the tablet needs to be taken in the morning on an empty stomach with just a little bit of water, just a few ounces of water, and you're not eating anything else for a period of time. You're not drinking anything else for a period. Period of time. It's about, you know, 30 or so minutes. If you have anything else in the stomach at the time, it disrupts everything that the absorption enhancer snack is trying to create. All right, so that is when the injectable drug semaglutide is used in an oral version. Now let's talk about a different one, orforglipron. This is, um, sold as a drug called Foundeo by Lilly. Orforglipron takes a different approach because it abandons the peptide problem altogether. It avoids it. So it circumvents the peptide problem by just abandoning being a peptide. This is what chemists call a small molecule. It's closer in kind to something like antihistamine than it is to generally like a hormone. It doesn't have an amino acid chain that the stomach can cut. So the acid and the enzymes have nothing to work on. It simply remains intact. as you take it in. Now, I know what you're thinking. If this molecule looks nothing like GLP-1, the peptide, how does it actually activate the receptor? Well, the answer is that it does not bind where GLP-1 binds. It still activates the GLP-1 receptor, but it does so at a distinct attachment point. So it's going to active and give the same effect, but it does so by, if you will, knocking on a different door. Of the cell, or knocks on the same door, but it's not knocking on the door, it's ringing the doorbell. But all of this to say, I'm trying to think of a metaphor where it is still the same receptor, but it's being activated in a slightly different way. So we would say in one case it's knocking on the door, in the other case it's just ringing the doorbell. The door is still going to open. All right. In a study that measured this most directly. They used what's called a tracer method, and they, they labeled this small molecule. So orforglipron was labeled or tagged in a way as a molecule that they could see where it goes in the body. And they compared that oral ingested way with, with an intravenous or an injection, and they found that about almost 80% of the oral dose That was taken got into the bloodstream. Now again, compare that to the 1% for the oral semaglutide. I mean, that's a pretty enormous difference. So the, the, the drug stays in the body long enough also that you can just have a once-daily dose. The fact that you can take it, um, with food is helpful. There's some evidence to show that if you do take it with food, it can lower that by a little bit. It can go to about 80% of its 100% absorption. So it can be diminished a bit, but it still falls within a range of a meaningful physiological response. So that means with the orforglipran, the person doesn't have to worry about the absorption enhancer. They don't have to worry about taking it on an empty stomach. There's no waiting period. They can take it any time of the day with any amount of food. Okay, now Let's just revisit the metabolic actions here. Of course, no surprise with you knowing what you do about me, I need to talk about insulin. But that's because we're talking about drugs that induce weight loss. So it's not inappropriate to bring up insulin because insulin is the master metabolic hormone that controls the growing and the shrinking of fat cells. So what happens to insulin and other related metabolic outcomes? There is a 26-week trial in adults with type 2 diabetes that compared this. It compared orforaglipron against placebo and against an injectable GLP-1 drug. Markers of insulin sensitivity improved with the standard fasting index of insulin resistance falling by up to about— it was about a quarter, about 25% at week 26. And also adiponectin which is a very friendly hormone. It's released from healthy fat cells that improves insulin sensitivity, also increased. Now let's get into some additional studies. Um, there are other studies that have looked at— they've expanded the results and done more direct drug comparisons. Um, but when I mention these, I just want to help you understand some of the scientific record-keeping that happens here in these kinds of studies. There are 2 ways the scientists can track and analyze the results. One way counts everyone who was randomized, whether or not they stayed on the drug. The other will count only what happened in the people who stayed on the drug. So the first number is always going to be more modest, but it's also— it's more conservative, but it's also more reflective of a real-world population because sometimes people get off the drug. So I'm going to rely on that one. All right, so the main obesity trial enrolled a pretty significant number of people, about 3,000 adults with obesity, um, and, and without diabetes, and they ran for 72 weeks. Weight fell by 7.5% at the lowest dose, 8.5% at the middle dose, and just over 11% at the highest dose, um, against A loss of just about 2% on placebo, and then among people who stayed on the highest dose, the figure was a little over 12%. So it was it was a bit more. Now there's also a head-to-head trial in type 2 diabetes where orforglipron, the small molecule, was tested against the oral semaglutide, and orforglipron won on blood sugar and on weight. But the dose wasn't totally comparable. The oral semaglutide doses in that trial were the seven and the the 14 milligram dose, which are the diabetes doses. As you know, I've articulated this before, semaglutide has been traditionally used at lower doses when it was just used for controlling diabetes, but its obesity dose is, is more significant. So the dose approved for obesity is 25 milligrams. So the trial did not test the 2 drugs at a dose that people would normally be taking for weight loss. When you look at the obesity trials instead, each drug against the against placebo in people with obesity and without diabetes, the oral semaglutide at the obesity dose produced about 13.5% weight loss, and the orforaglipron produced about 11%. So so pretty good, pretty comparable weight loss. The peptide one in that case, the semaglutide with its absorption enhancer, did beat that out. But you could say it was it was still close. Um, however, in this case, interestingly, these— the negative side effects, the tolerability were a little more negative on the orforglipron. And those— that's the same side effects that you'd see with semaglutide: the nausea, the vomiting, the diarrhea. So I think the summary here would be that the small molecule performs better on blood sugar in, in diabetes at the doses that were tested in that one study. So a more modest semaglutide dose. The peptide produces a little more weight loss when it's head-to-head at, at weight loss dosing. But the small molecule is a lot easier to take, and so maybe it has a higher real-world adherence. Okay, there's one more. Researchers took nearly 400 people who had completed a long course of injected semaglutide or injected tirzepatide, and they'd reached a stable weight. And then they moved them off the injected peptide and then moved them either onto orforglipron or onto placebo for a year. So they started on the injected peptide, then they switched them over to the small molecule or placebo. The people that were switched to the small molecule held up about almost 80 to 90% of their weight loss. They, they kept it. But the people switched to placebo, they kept only half that weight loss. So in other words, they gained about half back. So let me say that all another way. The people that were on the injectable and switched over to the oral small molecule gained back about 10%-ish of their weight, but the other group switched over to placebo, gained back about half of their weight. And so they, uh, that's pretty, pretty meaningful. And it might be powerful in light of, of my final point here, um, which is the, the timing of all this thing. So we have a molecule that survives the stomach, it's absorbed about 80 times more efficiently as the peptide version. You don't have to worry about fasting, you can take it with food. That is a very convenient advancement, and the convenience I think is relevant because it may determine whether someone stays on the drug. But there are still these fundamental—not not a but—I would just say nevertheless, we need to keep the fundamental metabolic rules in mind. Insulin still governs whether fat cells are shrinking or growing. As long as insulin is elevated, stored fat stays stored. No amount of GLP-1 drug can change that physiological biochemical cell. Biology. What the drugs do is lower insulin directly, especially by changing how much a person eats and how much that what they eat is getting into the blood. Now, when I say what the person eats, refined carbohydrate is the most powerful driver of insulin, since it's flour, sugar, and the processed starches that are built from them that push insulin higher and hold it up longer than anything else the person is going to eat or drink. So if a drug is making it easier to eat less, the thing to eat less of is refined carbohydrate. This is something I've discussed previously. Researchers 30 years ago compared women with obesity to lean women matched for age, and they gave both groups an oral carbohydrate load and on one occasion a big fat load. So they had a high-carb meal And a high— and then a low-carb, high-fat meal. And following the gut, they, they looked at the gut response over 3 hours, how much it produced GLP-1. In the women with obesity, the GLP-1 response to carbohydrate was essentially nonexistent. It was markedly blunted, we would say in scientific terms, but it didn't reach a point of statistical significance at all. But the response to fat was more robust, and it tended to follow similar, more in line with the lean women. So the impairment to GLP-1 response was unique to the carbohydrate in some of these women. The macronutrient that raises insulin the most is therefore also the one that has stopped producing a satiety signal in the form of GLP-1 in the people eating the most of it. Remember, it was just the women with obesity. That had this effect, so they would want to eat more carbohydrates. The hormone that would normally help them regulate that, the GLP-1, was blunted. It wasn't working so well. A GLP-1 drug gives in in the pill. I think what it can help do is restore the GLP-1 response. So just to keep this in mind, whether it's the oral delivery or whether it's an injectable, we want to keep in mind. That the drug should be used not for weight loss per se, even if that is the foundational justification for it. It should be used to help someone learn to control their cravings for carbohydrates. And I also think there's a window in which that can work better. In the— there's a 2-year semaglutide trial, and they measured cravings for sweets and refined starches and sugars, and they found that at about 6 months, cravings were significantly blunted. At one year, the cravings were still blunted, and then at about two years, the cravings had returned to normal despite ongoing and even escalation of the dose of the GLP-1 drug. In other words, the reduced pull or cravings of the sweet food—it faded even while the person was still on the drug. This is what an economist may refer to as diminishing returns. So there's roughly a year. Maybe a little more, during which sugar and foods built on that sugar exert measurably less temptation than they otherwise would. And that period is, I think, the window. Someone who spends that time eating smaller portions of the same food will lose weight and leave all the other habits though unchanged. And when the cravings start to return, they go right back to them. So what they need to do during this time when the, when the cravings for these refined carbohydrates is turned down is use that as an opportunity to build new habits. And when you do eat, you're focusing on foods like fat and protein, and then you're not having to worry about the diminishing returns of this turned-down carb craving. When that, when the cravings would start to come back, well, hopefully they don't, that the, because the person has learned a little bit of discipline. This, I think, might It will be interesting to see how studies come out in the next years, but this idea of someone being on the injectable and then switching off the injectable to the oral small molecule, I can't help but wonder whether that allows the person to more effectively cycle off and, and help retain a higher efficacy or a higher sensitivity to the drug. But remember, all of it is with the purpose. It should be with the purpose of learning to control your habits. No one wants to stay walking around with a crutch. They hurt their knee. Well, they're on a crutch until that knee is strong enough to carry to get them off it. I think the same thing should be done with these GLP-1 drugs. They're a crutch. No one wants to be on a crutch forever. You shouldn't need to. You should be learn. You should learn. Or you should be hoping to get strong enough to walk again on your own. That to me, I think, is the best view with these GLP-1 drugs. You need a little help to control your cravings for carbohydrates. You've not been able to do it on your own because, dare I say, you have an addiction. It can be difficult to break an addiction on your own. The drug can help break that addiction where you are now using it more strategically With, again, with the intention being this is helping me control my cravings for carbohydrates. You learn what that feels like, what that looks like, and then someday you have an off-ramp on that drug where maybe about a year in or so you say, I know I'm going to start losing some efficacy here. I need to be thinking of my habits changing. Maybe that gives you an opportunity to reduce the dose and then eventually get off the drug. Just like someone with a knee injury wants to get off the crutch. All right, let's wrap this up. Oral semaglutide is close to the thing that people imagine when they say Ozempic you can swallow, quote unquote. It's the same peptide; it's just escorted through the stomach with some clever chemistry, with some absorption enhancing. But it's at the cost of some convenience. It's a very strict routine of what you can eat or drink. Around it. But the small molecule is different, or foraglipron. It's not a peptide. It has a different way of activating GLP-1, a different way of getting into your blood that makes it a lot more convenient. But it does appear to have slightly more of the negative consequences, like the nausea and the vomiting. So the chemistry can change between the molecules, but even still, the metabolic rules do not. These must be, or ideally they are used as a way to help lower your insulin by helping you learn to control your cravings. Class dismissed. Until next time, more knowledge, better health.