How GLP-1 Drugs Support Weight Loss and Their Tradeoffs

Okay, so the next question is something we've not covered yet in any of our Q&As, so this will be fun. It was submitted by Matthew Tanner, who says, how strong is the scientific evidence for or against the relatively new weight loss drugs like Ozempic that are in the headlines a lot? Okay, so let's talk a little bit just about the background of these. So what these are, okay, we're going to start with, it's kind of the basics. So it's incretin. These incretins are hormones. They're special chemicals in our body that come from our gut or our digestive system when we eat. They do help control blood sugar. They signal to the body to release insulin after we eat foods containing sugar or fats, or even to a lesser degree, proteins. There are 2 main types of these hormones.

One is known as GIP, and the other one is known as GLP-1. So GIP is made in the upper part of our gut, while GLP-1 is produced in the lower part. So when we consume foods like glucose, or sucrose, or starch, fats, certain amino acids that are found in proteins, our body will release both of these incretin hormones. And this helps us manage our blood sugar levels after we eat a meal, right? Our postprandial blood sugar levels. So So that's kind of the background. Ozempic connects to incretin hormones by mimicking the action of GLP-1, and it's one of the key incretin hormones involved in regulating insulin secretion and blood glucose levels post-nutrient intake. So it's a GLP-1 receptor agonist. So it's acting like GLP-1, and it's affecting the GLP-1 receptor.

So it basically— causes a natural, like, GLP-1 response to improve diabetes management, right? And it also has additional benefits related to weight loss control and reduced appetite. Okay, so let's talk a little bit about gastric emptying. So both the GIP and GLP-1 are both types— they're both types of hormones in our body that help control blood sugar levels after we eat, right? So we just talked about that. But they do have different effects on how quickly our stomach empties its contents into our intestines. So GIP doesn't really change the rate, like how fast your stomach empties. When GIP is working, it doesn't affect the speed at which food moves in your stomach to your intestines, but GLP-1, on the other hand, does.

So it's basically slowing down how quickly your stomach is emptying food into your intestines. Why does that matter? So when your stomach empties more slowly, because let's, for example, say there's GLP-1 or you're taking a GLP-1 receptor agonist, food takes longer to reach your intestines. And so this means that the breakdown and absorption of nutrients into your bloodstream are going to be delayed. As a result, the increase in your blood sugar levels after eating a meal is going to be more gradual. you're not going to get that really quick spike. You're going to get a slower, steadier rise. And this is beneficial for keeping your blood sugar, your blood glucose levels stable. It also impacts things like mental clarity, or commonly called brain fog.

So having a really quick spike in your postprandial blood glucose levels after a meal can cause problems with mental clarity. So having more stable blood sugar levels makes it, you know, also affects your brain as well, is what I'm trying to get at. There's also an impact on triglycerides. So triglycerides, obviously this is a type of fat circulating in your blood. It also spikes after a meal. So the triglycerides will be more gradual. And so this is also, it's really better to not have a super high spike in triglycerides after a meal as well. Okay, so the type 2 diabetes happens when your body doesn't use insulin properly, so this could be insulin resistance, and also the pancreas can't make enough insulin to meet the body's needs. Another issue in type 2 diabetes is too much glucagon.

So this is a hormone that raises blood sugar, which— so it makes blood sugar control even harder, right? So the incretins are helping lower the blood sugar. And it's been shown to really help treat type 2 diabetes. And these GLP-1 receptor agonists are a group of medications that do act like these natural hormones, and they're really effective in helping manage people with diabetes. So they're stimulating the release of insulin, and they're also reducing the release of glucagon. So those are 2 separate ways that GLP-1 receptor agonists like Ozempic are working. It's suggested as a first line of treatment for type 2 diabetes, especially those who have heart disease and are at a high risk for type 2 diabetes as well. And it's also commonly used in people that don't respond well to metformin.

And there are several different GLP-1 receptor agonists that are approved. So there's a variety of them. I'm not going to talk about all of them, but probably the most well-known one is the semaglutide, which is known as Ozempic. And I think that is probably the one that's, again, most well-known, but there are a variety of others, and they all seem to end in -glutide or -tide in general. I don't want to get into every single one of them, but they're working in very similar ways. They also affect appetite and food intake. So GLP-1, I mentioned this, it's a hormone. It does play a role in controlling how much food we eat.

So, when our bodies are making GLP-1, whether, you know, it's directly being administered to us through a medication or it's happening after we eat a meal, it helps us feel fuller faster and eat less. So what's happening is it's signaling and working on specific areas in our brain, specifically the hypothalamus, which is a crucial part of the brain that is involved in appetite regulation. So the ability of GLP-1 to make us feel full and eat less, and why medications that mimic its action are able to do so, do help people lose weight because they are feeling satiated. So separate from GLP-1, there's GIP. We were talking about this, you know, at the start of this section.

It's also— it wasn't originally known to help people with weight loss, but there's new types of medications that are hybrid peptides. So they're not only mimicking GLP-1, but they're also mimicking GIP. And they're a hybrid between these 2 different types of medications. So these new treatments are aiming to boost both weight loss more effectively than GLP-1 alone, but they're also involved with blood glucose regulation as well. So they're further decreasing appetite, they're increasing weight loss, as well. And so let's talk about some of these. These are— there's some studies comparing just GLP-1 alone, so semaglutide or Ozempic, Wegovy, as well. And there's been a lot of different studies done. So there was a large study that combined the results from 6 different trials.

So there was almost 4,000 different overweight or obese people in this trial that did not have diabetes. And they were taking semaglutide, sold as Ozempic. It significantly reduced their body weight. On average, people taking the semaglutide lost about 11.8% of their body weight and about 12.2 kilograms or 26.9 pounds. Okay. So that was compared to placebo. In one of these studies, this was a popular trial. It was called the STEP 5 trial. It lasted for 2 years, included about 300 different participants. It showed that people taking semaglutide lost an average of 15.2% of their initial body weight compared to just 2.6% in the placebo group. And over 70% of the participants in the treatment group lost at least 5% of their body weight. The study also found that the weight loss was maintained.

It levels off— well, it levels off at about 60 to 68 weeks. But the weight, the reduced weight was maintained for several months as long as the medication was continued. So the medication needed to be continued. There wasn't, but there wasn't such a dramatic loss in weight after about 60 to 68 weeks. It was just sort of maintained after that level, after that time. So there's these large studies that have really significantly shown reductions in body weight with semaglutide. It's thought that the reductions in body weight are largely attributed to a loss in fat mass, but not all studies were, you know, directly measuring changes in muscle mass. So, you know, there are— some studies use DEXA scans, which do— DEXA scans are sort of a widely used method for assessing body composition.

They include bone mineral density, fat mass, lean body mass, which includes muscle mass. It's considered a reliable and valuable tool in clinical research, but it does not directly— it's not directly, you know, accurately measuring muscle mass. So it is an indirect measurement. And so for that reason, you know, doing lean body mass, you know, it's— People are saying, oh, lean body mass, and saying, yes, this means muscle mass, but it doesn't necessarily— they're not necessarily the same thing. So lean body mass includes muscle, but it also has other nonfat tissues like organs. It has connective tissues, and it can be influenced by the hydration status of the individual. So lean mass measurements are affected by water content in the body.

And so DEXA assumes a constant hydration level of lean tissue. But, you know, there's a lot of— you could point out a lot of flaws with DEXA measurements as an actual measurement of muscle mass. I don't want to turn this into a podcast about DEXA. The point I'm trying to make is that the GLP-1 receptor antagonists— sorry, agonists, the semaglutide drugs, do reduce appetite. And if you are reducing appetite, you are going to decrease your overall food intake, which is what happens, and that includes protein. So there could be some implications for reductions in muscle mass as part of that weight loss, particularly in people that are not taking in enough protein and are not engaging in resistance training and resistance exercise.

And that is a consideration, you know, for people that are taking these drugs, the semaglutide drugs, because they likely are reducing their overall protein intake. And I don't know what percentage of people are not engaged in resistance training, but there's a large percentage of the population in general that does not engage in resistance training. So these are important considerations, particularly when people are taking any kind of drug that is in some ways sort of increasing a fasting state, right, by reducing appetite and reducing food intake. Now, there's also some data on these dual GIP and GLP-1 receptor agonists. And these are called tirzepatide, so Mounjaro or Zepbound, I guess, is what they're called. Sorry if I butchered their names.

But there was one large study that looked to see how well people lost weight and managed that weight loss. And this included over 4,000 people. Some people did have type 2 diabetes, some people did not that were part of the trial. And these combination drugs were really good at helping people lose weight compared to a placebo. Depending on the dose, people lost between 7.7 kilograms to almost 12 kilograms more than people who did not take the medication. So this is anywhere between 8.1% to 12.4% of their total body weight. In another part of the study called the SURMOUNT-3 trial, people who already lost 5% of their weight through diet and exercise were also given tirzepatide or a placebo.

And those in the treatment group lost an additional 18.4% of their body weight, while those on the placebo actually gained back 2.5%. So it really shows that these drugs are effective at weight loss. And the weight loss did level off a little bit later than the semaglutide. So they leveled off about 68 to 72 weeks. And the study didn't last long enough to see if the weight loss would stay off in the long term. Now, there wasn't a head-to-head comparison of the semaglutide to the tirzepatide. But when those trials were sort of just looked at separately, it was found that the combination the tirzepatide, was actually more effective than the semaglutide with respect to weight loss. So what about after discontinuing treatment?

There was one— there was a 1-year after withdrawal of once-weekly subcutaneous semaglutide treatment that found people did regain 2/3 of their weight after they had had prior weight loss after discontinuing the semaglutide. And I think it's pretty clear now from a variety of studies that in order to maintain the weight loss, those drugs need to be continued. And so that's a major, obviously a major drawback with some of these drugs. Now, the combination drug, the tirzepatide, it seems as though weight was also gained back, but to a lesser degree. I think both those medications are effective for weight loss. When they're combined, it's more effective. However, stopping the medication leads to weight regain.

So there are some adverse effects as well, in addition to obviously stopping the medication and regaining back the weight. There's some stomach-related side effects like nausea, diarrhea, constipation, vomiting, all those sorts of things, burning in the stomach, and, generally speaking, the side effects seem to be more common, obviously, in people that are taking the actual drug versus a placebo. For the semaglutide, the chances of experiencing these were 2.6 times higher than those taking a placebo. For the combination drug, the tirzepatide, it was up to 4.6 times higher. So it seems as though some of the side effects were even higher with the combination drugs.

Some of the studies suggest that these negative side effects, the stomach-related ones, actually don't last that long, and they generally improve in less than 2 months. So it's like the first couple of months are the hardest with respect to some of those side effects. And then some people have more serious side effects, like a risk of very low blood sugar, acute pancreatitis, which is inflammation of the pancreas, is another one, and then some people can experience some psychiatric disorders, but those are more rare than the more common stomach-related issues.

So generally speaking, I think that, you know, these medications can be very helpful for people that are overweight and obese to, you know, to get to lose a healthy amount of weight and control their blood sugar levels, particularly if they're doing resistance training and trying to take in enough protein as well to make sure they're not losing a lot of muscle. The problem then becomes, okay, is this going to be a lifelong medication, or can you keep that weight off by dietary and lifestyle changes? Probably you will regain some of that weight back because just simply you're going to not be as satiated. So you will— calories in, calories out will— calories will be coming in more readily when you stop the drug. And so, that is something to consider. We don't really know what the long-term effects of these drugs are over the case of like, you know, 2, 3, 4 decades, right? So that's a whole other question.