Why Youre Stuck GLP-1 Plateaus And How to Break Through

0:09 Hey everybody, this is Hunter Williams. I hope you're doing amazing wherever you are out in the world. Today's video is going to be all about GLP-1 plateaus. So does this sound like you? Have you been using a GLp-one? and then have really good results within the first few weeks. And then all of a sudden you start to plateau. As life happens, this is what most people experience because whenever we lose weight, we tend to plato because the body is always going to homeostasis. So what I'm going do today is just walk through all the possible reasons you could potentially be plateauing with your weight loss and not actually getting

0:41 to the desired weight that you want to go to and why in the presence of GLP-1 this might be a little bit different than just the average weight lost. Everyone plateaus when it comes to weight loss usually can start it really fast and if you have a lot of weight to lose usually the weight comes off really So today we're going to be talking about that plateau in the context of a GLP-1 peptide and why that happened. So before I share the screen, thank you guys so much for the like, comments, subscribes, all that good stuff.

1:11 If you want to check out the Peptide Cheat Sheet, that will be down in that link in description below, so you can download that. And if you wanna join the best community on the planet, check it out fully optimized health link also down below for that, So without further ado, I'm gonna share my screen and today, we gonna learn about why you may be plateauing on your GLp-one peptides. All right. I am Hunter Williams. And today we're going to be learning about GLP-1 plateaus. So let's get into it. Before I get in to why we plateau, I just want to review the mechanisms of action real quick. We're gonna be looking at mostly trazapotide and retetrotides because obviously those are the two biggest ones that people are using right now.

1:42 Look at trazarptide. Obviously it's the GLp-one plus the GIP agonism. And it powerfully suppresses appetite, promotes satiety, which makes us feel full, slows gastric emptying, and enhances post-meal insulin secretion. And again, this trisapatite adds the GIP on top of the GLP that semaglutide is. Now with ready-to-true-tide, we take trizapatide and we add the glucagon agonism on to of that, And we're aginizing the glucogon receptors. So this also curbs our appetite but increases energy expenditure even that much more.

2:15 and the dual and triple agonist TERS and RETA in clinical trials have been massively beneficial to weight loss. And we are seeing phenomenal results, usually with people losing around a quarter or 25% of their body mass, which is really crazy when you think about it. So let's look at the kind of trajectory that we're typically looking at when we see this and what's happening. If you've used a GLP-1, you probably know this, most of the agonists you are going to tend to have a rapid early phase of fat loss followed by a slowing

2:46 in plateau. And again, that's really, if you're focused on fat-loss, not that much different than if were doing this without a glp-one. But in trials of triseptide, weight drops most steeply in the first 24 to 48 weeks, or excuse me, 40 weeks. Then it decelerates in analysis from the SRMT-I trial found that by 72 weeks around 90% of patients had reached a plateau, which is defined as less than 5% weight change over a three month interval. So what we are seeing is what would 72 weeks be? That would basically be like 17 or 18 months into the peptide.

3:18 Around 90% of them are reaching a plateau. And a lot of times that's not the weight that they actually want to be at. The median time to plateau, Vary by starting size, so for example, individuals with a lower BMI plateaued sooner, which was around 24 to 36 weeks, whereas those with severe obesity who had much more weight to lose usually plateau around 36-weeks for severe obese is when they plateau. So heavier patients often had a more prolonged weight loss phase before stabilizing, And then the highest groups in their surmount trial,

3:50 which were 10 milligrams and 15 milligrams weekly after Zaptide tended to plateau later than lower doses, Which obviously means that they're doing a higher dose. They're going to get more effects for a longer time. So when we look at semaglutide, and it's just because we have more data on this, it shows a similar timeline. Many patients plateau around one year, just 60 to 68 weeks in therapy. And with TERS, some data suggests plateaus may be delayed slightly further, like we said, 72 weeks. Longer-term data is encouraging, so a three-year extension of the surmount trial reported that substantial weight loss can be maintained up to three years

4:21 with ters, though trajectories diverged between individuals. and some participants around 10% showed an early plateau, while others achieved 20 to 30% weight loss before plateauing much later. So despite the differences in all of these, almost everyone eventually is going to reach an equilibrium where weight-loss stalls. And again, this is really without or with a GOP-1, the GOPs just accelerate it, and essentially where calories in balance, calories out, halting further fat loss. The body is always going reach this calories-in, calorie-out homeostasis.

4:54 Now what's important to remember about this is that plateau does not mean failure. Weight stabilization is a natural part of the weight loss process. And in clinical terms, reaching a plateau means the intervention's current effect has been maximized under certain conditions. Again, like we said, In the surmount trial, most turzapotite-treated patients hit a new steady weight by 9 to 12 months and maintained it through week 72, so that's really what we're seeing, at least from the data. If the drug is continued, people generally maintain the lost weight with mental regain at the plateau point. And then if the medication is stopped, weight regain is common, highlighting the plateau is an active equilibrium requiring continued intervention,

5:29 not a permanent set point, This is something that everyone is dealing with. So when we look at the reasons, right, the physiological and metabolic reasons are many, and I'm going to go into that. But basically what's happening is this. balance that the body is reaching is due to adaptive physiological responses, which we know as adaptive thermogenesis or metabolic adaptation. I use that phrase all the time, metabolic adaption, because we go through this period of adaptation, whether it's the initial weight loss or it is the plateauing, to where the is trying to reach a state of homeostasis.

6:02 And when you have excess fat, it is going to want to get rid of that fat fast early, but you'll get to a point where it doesn't want it. And it's almost harder for someone to go from like 8% body fat as a man to like 5% of body, fat than it is to from 30% to 18% in some cases, because when we get down lower and lower, it gets harder. So that's what a lot of people are experiencing. Let's look at the first one, which is that our resting metabolic weight drops over time. Losing weight causes the body to burn fewer calories at rest.

6:33 Aside from having a smaller body, the body actively suppresses metabolism below what is expected for the new weight. So this is again, what's known as adaptive thermogenesis, a disproportionate reduction in energy expenditures. The studies show that our resting metabolic rate significantly Falls more than predicted by the loss of mass alone. So the body in effect runs colder conserving energy. so One of the reasons too we could have this mitochondrial activity may shift I'm going to talk about that a little bit later in these slides, which means that uncoupling proteins are going To be less active and cells will extract more energy from every calorie producing less heat so the adjustment

7:11 can slower halt weight loss as Chloric needs drop to match the intake and so basal metabolic rate can decline by 10 to 15 percent more from the expected weight loss contribute more than expected from weight-loss contributing strongly to plateaus. The next one is going to be decreased thermogenesis and efficiency. So along with a lower basal metabolic rate, the body experiences reduced diet induced thermogensis, which means that the fewer calories expended in food digestion absorption and possibly reduced exercise efficiencies were actually going burn less calories from exercise.

7:43 we were doing in the first place. So mitochondria in this process also may become more efficient at ATP production, which means less excess energy is lost as this heat. And while normally this would be good, here it works against further weight loss by squeezing more work out of fewer calories. Adaptive changes can include lower sympathetic nervous system activity and thyroid hormone changes that collectively decrease heat production. So essentially the body is putting the brakes on our metabolism to defend the energy that it has.

8:13 The body has recognizing that, hey, I do not have as much food to run off of. I have to slow down my metabolism because I'm not getting the 5,000 calories a day you were normally feeding me, and I am only getting 1,700. It'd be kind of like if you were used to driving an SUV and you didn't care about your gas mileage and all of a sudden now you are in a place or we're driving further and your really concerned about gas miles because of what you're spending, you would probably change cars. And that's very similar to what the body is doing.

8:43 There's also this idea of the loss of lean mass and weight loss is inevitably, I don't even care which way you cut it. We obviously want to minimize the amount that happens. It's going to include some loss with muscle mass. especially if we're not doing any weight training. So muscle is more metabolically active than fat, so having less lean tissue lowers our daily calorie needs. And if someone loses weight rapidly or without sufficient protein or exercise, a higher proportion might be lean mass significantly cutting our resting metabolic rate. So in the process we lose weight, we loose some of that as muscle, and then that takes our metabolism down even further.

9:16 So even with GLP-1s, studies show that a fraction of the weight loss is lean tissue, partly due to reduced food intake and possibly dehydration, which is a big, big issue. And the resulting smaller, lighter body burns fewer calories during movement as well. Even our exercise we're not burning as much when we are losing weight. Everyday activities also cost fewer calories when you weigh less. So additionally, the body may subconsciously reduce non-exercise activity thermogenesis, otherwise known as NEAT. We'll talk about that a little bit later, which is basically the energy spent on our fidgeting, daily chores, walking around,

9:47 et cetera, that is not considered our exercise. And with less mass to move and an energy conserving brain, people often become less spontaneously active after weight loss. Which makes sense. So a notable finding is that this non-exercise activity thermogenesis can drop by several hundred calories per day after significant weight loss as people unknowingly sit more, move slower or fidget less to save energy as their body is naturally trying to do everything from a subconscious level that it would normally do to expend energy. This also is going to be another reason for the plateau.

10:18 When we look at this metabolic adaptation, it means that an initial period of caloric deficit and weight drop, the body adjusts its energy expenditure downwards to reach this new equilibrium. So the built-in response is basically an ancestral thing that when our ancestors had famine, their body learned to adapt to it because the ones that didn't ended up dying. And it obviously is not good for us for fat loss over time. So trisapatite, a recent modeling study found in the journal Cell Metabolism confirmed that as weight loss approached the plateau, metabolic counter-regulation ramped up offsetting the drug's effects on energy expenditure.

10:51 We do know this is happening. And basically, trizapatide did not completely override the body's adaptation. Weight loss slowed as the bodies fought to preserve its new lower state. So that's really big, but another big thing that no one really talks about, we all kind of understand those physical dynamic things, is the hormone adaptation. So weight loss triggers cascade of hormone adaptations, and there's probably more than you think about that we're going to talk. in regards to, in this part of the presentation, but it's often coming from this starvation response that the body is going through.

11:21 So let's look at the first one, which is leptin. Leptin is called the satiety hormone. It's produced by fat cells and signals the brain, specifically the hypothalamus, about energy stores. High lepton normally promotes satiated feelings of fullness and higher metabolism, whereas low lepton triggers hunger. Remember, this is an inbuilt response to being in starvation mode. If you're in Starvation Mode, your brain is going to signal, hey, we need you to eat because you are starving to death. So when you lose fat, leptin levels plummet, especially if you loose weight really fast.

11:52 This basically informs the brain that energy reserves are shrinking. In the context of weight loss, falling lepton removes its appetite suppressing metabolism boosting effects. So the brain, when it sees that leptin goes low, it ramps up hunger to tell you to eat. And then it also conserves energy. So this is a major reason people feel hungrier at a lower weight. When they were 300 pounds, maybe now there are 200 pounds and they are hungrier because they're getting these lepton signals, uh, increased because lepton is actually going down.

12:22 Individuals with obesity often start with lepin resistance, which means that their lepiton is chronically high. And the body ignores it, but even so relative leptin declines during weight loss, exacerbate appetite. So studies have shown that after weight lost, administering low dose lepton actually can reverse some metabolic adaptation, preventing the sharp drop in metabolic rate in thyroid hormones and actually like help kickstart the metabolism after it slowed down from rapid weight. Basically, the way it works is we have less fat on our body equals less leptin, equals more hunger, and then less energy coming out of our bodies.

12:54 So, GLP-1 agonists do not stop lepton from falling. If anything, as fat mass decreases, lepton drops proportionally. Even on Terzereta, body experiences a lepin decline that encourages a plateau. Though the GLPs are causing this fat loss, we are having this lepetin effect that is actually trying to stall us from losing fat. This is also too why a lot of people after 12, 16 weeks, like I just don't feel the appetite suppression anymore. It could be that the drug is working just as strong. However, our leptin levels are going down, which is then increasing hunger to go up.

13:31 I also put on here that females and trials tend to lose slightly more weight than males. And one reason may be hormonal differences. Women often have had a longer time to plateau potentially related to leptin sensitivity because males and females have different lepton sensitivity. So ghrelin is the hunger hormone. is mostly produced in the stomach, which rises before meals to stimulate appetite. So with caloric restriction of weight loss, ghrelin levels climb higher, driving stronger hunger signals. Low leptin, high ghrelin equals more appetite, so this is the body's way of trying to get you to eat more and regain weight.

14:05 In long-term diet studies, participants had significantly increased ghrellin even after a year after initial weight-loss, coinciding with persistent hunger. GLP-1 agonists initially blunt appetite so strongly that patients reported reduced hunger and cravings. Interestingly, some short-term studies suggest GLPs can lower ghrelin acutely. However, as we go through this longer phase of weight loss, the underlying biology still nudges ghrelin upward because we are reducing body mass.

14:35 So the transition to plateau correlates with increased appetite likely from hormones like ghrelin rising. So basically an increase in the hunger hormone ghrelin combined with decreases in satiety hormones leads to our appetite going up or stalling out or causing fat loss to stall out. Even if you didn't feel hungry during the first months on trisapatite or retrotritide, you might notice hunger creeping back closer to the plateau phase, which a lot of people say is the peptide not working. but we are also creating this hormonal cascade with leptin and ghrelin that is affecting as well.

15:05 So higher ghrelin can make it harder to further cut calories and may cause slight intake increases that stall weight loss and also have you not respond to the peptide as one. The next one's going to be insulin. Insulin, ghrellin, and lepton are all interrelated, but let's talk about insulin so insulin is the If not one of the most anabolic hormones in our body, it helps cells uptake glucose and promotes nutrient storage. And in obesity, insulin levels tend to be chronically high and there's often insulin resistance in the body. This is why I always look at someone's fasting insulin more so than I look it their fasting blood sugar, because how much insulin the bodies pumping out

15:41 will tell me how insulin resistant or insulin sensitive they are. But waist loss, especially with GLP-1 drugs, dramatically improves our insulin sensitivity, which is a good thing. It also lowers fasting insulin levels. And this is beneficial for health and indicates the body's becoming less storage oriented. So lower insulin can slightly favor fat burning. However, very low insulin might also permit more muscle protein breakdown if the diet is inadequate. GLp-I agonists themselves stimulate insulin after meals. That's why they work so well. They help the pancreas secrete insulin better to help bring down our blood sugar.

16:15 They reduce overall insulin demand as weight and resistance drop. So the net effect of this is a healthier metabolic profile. That's why these drugs are the greatest anti-aging medications of all time, because we have a healthier metabolic profiles which causes aging and causes disease. So it's not necessarily a direct cause of plateau. If anything, lower insulin is helpful for continued fat loss. However, insulin, leptin, and ghrelin interact in very complex ways. And some research that you can look up suggests that the combination of low lepton plus low insulin and high ghrelin after a weight loss period creates

16:48 a potent drive to refeed, which again, when we look at appetite suppression and food cravings and the drive eat, this is why after long time people are stalling out on these or they're noticing their appetite comes roaring back. So on the flip side, improved insulin sensitivity means less chronic hyperinsulinemia, which originally promoted fat storage in this adaptation is generally positive for body composition. Again, what's going on with insulin is good for the body, but when you combine that with a low leptin and the high ghrelin, it can potentially drive people to eat more.

17:20 I think that's why a lot of people will have this rebound weight gain when they go off of them. Now, let's look at thyroid hormones, because thyroid are rarely talked about in the presence of GOP-1. So, the thyroid gland controls the body's metabolic speed. During calorie restriction, body turns down thyroid hormone output, particularly T3, to conserve our energy. A lower T-3 slows our metabolism and reduces heat production in body, and weight loss is consistently associated with declines in T 3 levels, sometimes a slight rise in reverse T three, indicating a metabolic slowdown at the hormonal level.

17:53 So this is part of the adaptive thermogenesis we're talking about. Less thyroid activity means fewer calories burn. And one classic study found a significant drop in circulating T3 after losing weight contributing to around 15% reduction in metabolic rate beyond what weight change alone would predict. So GOP1s don't fully prevent this even as trans-appetite patients lose weight, their thyroid hormones likely dip, though detailed data in GOp1 trials aren't widely reported. And there is some hope that gradual weight loss as opposed to rapid weight-loss causes a smaller thyroid drop than crash diets.

18:24 Again, I think this is why it's important not to do like crash-diets, but to like have manage weight loss to where you're gradually doing this at a very controlled rate. But regardless of that, a sluggish thyroid axis, which is lower T3 and maybe slightly reduced T4, is known to be a plateau contributor. So it's one reason that people get cold intolerance, fatigue, and other signs of slow metabolism. as they get further along into the diet and into GOP-1 use. And then leptin is also partly responsible here. So lepton signals the hypothalamus to support thyroid output.

18:55 Low lepton after weight loss can lower TSH and T3. Experiments giving lebtons to people after loss prevented the usual decline in T-3 and resting energy expenditure, which I actually found fascinating in researching this. We also have cortisol, and I think it's important to address cortisol. Although probably not as important, still important. So cortisol is a stress hormone, as you probably know, it often rises under conditions of calorie deficit or psychological stress. And dieting can be a very physical stressor and chronic stress or poor recovery may elevate our cortisol levels as we're diet and calorically restricted.

19:29 And so also it can trigger muscle breakdown and then promote visceral fat deposition because the body's like, hey, I'm in a stress state. I need to store fat. It's also linked to increased appetite and cravings in some individuals, often for calorie dense foods. And if someone is over restricting calories or not sleeping well on GLP-1 therapy, cortisol might chronically increase and impede weight loss progress. So cortisol opposes insulin and can lead to blood sugar swings that some interpret as hunger. And then obviously, too, we have psychological stress alone has been shown to potently raise ghrelin as well, which could compound our hunger signaling.

20:02 So you have cortisol plus ghrelin. And when we irritate those two hormones through our weight loss and through psychological stresses, it can cause a lot of issues. Then lastly, sex hormones. Again, if you could give people the gift of testosterone on a GLP-1, that would solve so many of their problems. and they make their weight loss experience so much better. But weight-loss typically improves testosterone levels in obese men. At GLP-1 therapy, men with obesity or type 2 diabetes has been associated with significant increases in testosterone as they lose weight.

20:32 Go figure. The leaner you are, the higher your natural testosterone will be, although you should still supplement with testosterone. So higher testosterone can benefit weight lost by helping preserve lean muscle tissue and boosting our mood and energy. And in many cases, this is favorable hormonal change, not a cause of the plateau. However, if weight lose is extreme, In a lot of cases it is with the GOP-1 testosterone can drop as part of the body's energy saving strategy. So you can send the bodies so much so into starvation mode that it does not want to produce testosterone any longer.

21:02 Not something we really need help with in society today as most people are not producing hardly any testosterone relative to our ancestors. With the more moderate sustained deficits under GOP-1 treatment, severe hypogonadism is less common than in crash diets. At most, TERS and RETA patients see improved hormonal balance once the weight loss happens, but in the process of losing weight, they still can have massive swings and drops in their sex hormones, particularly testosterone, which is not good for muscle maintenance and fat loss as well.

21:32 The sex hormone changes on GOP1 therapy are generally beneficial or mild, so they are not primary drivers of plateaus, but I did want to throw that out there that your GOp1 journey will be so much better in the presence of optimized hormones. And that's one thing we'll just keep saying until the cow's home home. Now, There are some other ones we can look at. Amalin, you've probably heard of coagulantide, it's an amalin analog. Amylin is co-secreted with insulin, so it helps signal satiety and may be reduced when eating less. So some researchers are exploring analogs like Cagri to supplement GLP-1 drugs for this reason.

22:03 In the brain, we also have this neuropeptide Y, known as MPY, and AGRP, which is a Gaudi-related peptide. And they're hunger-stimulating neurotransmitters. So these increase during caloric restriction, which powerfully drives appetite and reduces energy expenditure. And GOP1 agonists act on the POMCCART neurons to suppress eating, but the body can push back via the MPYAGRP neurons if it senses prolonged deficit. So essentially the longer and more weight you lose, the more the the hormonal milieu shifts towards a pro eating energy conserving state,

22:37 which is kind of like a tug of war between the medications effects and homeostatic counter hormones. The weight plateau is the truce point where you wave the right wave, the white flag. Now let's look at some behavioral and lifestyle contributions to plateaus. Cause I think that's important to, like I said, to reduce non activity exercise, adaptive thermogenesis neat for short. So When we have weight loss, we stop this spontaneous physical activity, which is like walking, fidgeting, doing things that we would normally do when

23:08 we had a decent amount of energy. So you might find you don't do these things as much or you're simply moving a lighter body with less effort. The decrease in calorie burn can be significant for people that are eliminating this from their kind of daily routine because they don't have as much energy, they're losing weight. So for example, someone who's lost 50 pounds might burn 100 to 150 fewer calories per day just from the movement of day, even without realizing it. Even if a person is completely sedentary, but they lose weight, The calories that they burn from the little things that do is going to be less than it

23:42 was before, just as calories from exercise, but we're really looking at this for the context of obese people, what it's doing. So, on GOP1, some patients report low energy or mild fatigue, especially if they're not eating that much, which could further reduce the willingness to active. Together, these shifts mean the calorie deficit shrinks over time, contributing to plateau, and again, is why people stop losing weight, because they are not burning as many calories as they were before for that same activity. Then we have calorie creep. So humans are notoriously poor at estimating calorie intake and caloric misreporting can increase over time.

24:13 Early in the weight loss program, one might be very strict with diet tracking or portion control. However, as people go through their weight-loss journey, they tend to be less adhesive because it's not fun to count calories. I think this is why something like the sugar diet could be beneficial for a lot of people. And so you have a shrinking calorie deficit because of what the body's burning. And then you also have people too, over time it just becomes harder and harder to comply with a diet to where they're feeling restricted. So dietary adherence tends to decline over the time for individuals. Again, this is why we see GLP-1s, people stalling out because even if they are really, really strict on their diet, it becomes hard to adhere to the same

24:47 diet if it's very restrictive. We also have psychological fatigue. So weight loss obviously requires sustained effort. I don't know what I would have to do if I had to lose a hundred pounds, I'd figure out a way to it. But that person has to work a lot harder than I do to loose the same amount of weight in a lotta cases. After an initial dramatic drop, hitting a plateau can be psychologically demotivating, so some people get discouraged. And then stress or emotions can also play a role. GOP1s have the advantage of reducing physiological cravings, but they don' eliminate emotional eating or habit-driven eating.

25:19 You can only blast so much true tapdide, but even if you do or read a true tab, even it doesn't really cure like the emotional need to eat. And what I mean by that is like being with family, like, you know, it really sucks is if you're on turzapotide or retrotide and you go to a Superbowl party and it's like all the best food in the world there and he can't eat it because you are so nauseous that you can eat to enjoy it. It's actually even more depressing because he wanted to because have like this emotional wiring with food and then you cant do it to get the pleasure out

25:51 of life that he used to before. And on top of that, you kind of feel nauseous. So we can also look at sleep deprivation is another factor that accumulates. When people have inadequate sleep, it increases hunger hormones. And again, if you're not sleeping right, then the GLP-1 is not going to work as effective and then you are going plateau. Research shows that short sleep duration associated with lower leptin and higher ghrelin, which is what we want. We want the reverse of the higher lepton and lower ghrellin if we're trying to lose fat. If someone's sleep quality is worsened or they started sleeping less, they could biologically and behaviorally promote a plateau,

26:24 We also have diet quality so obviously people don't really understand food groups and the right foods to eat so if protein intake isn't kept high enough during the weight loss loss of muscle may accelerate. Now I'm not going to say what that is because there's all this stuff coming out with the sugar diet of like how much protein do we really need or even if we don' t need less protein we need the same amount of protein like when do I eat it to time up the best to help encourage my weight Alongside that, if one was doing a very low calorie intake, initially the body might adapt by inducing strong cravings for energy dense foods,

26:58 which leads to a lapse because you start with the the bodies going to want those really energy-dense foods like pizza or high fat, high carbohydrate foods. And that's kind of like where people get their craving. Obesity treatments recognize the environmental factors like food availability and behavioral fatigue contribute to plateaus. So again, it's just, as you go through the GLP-1, it becomes less than effective for all these reasons. Plus, you have people that feel like they were restricted. The longer you feel restricted from something, the harder it is going to be to adhere to it. Another big thing is hydration.

27:28 So, in a lot of cases, what looks like a plateau might be shifts in water balance or body composition. For example, if one starts strength training while on a GLp-I, they might gain a bit of muscle even as they lose fat, resulting in scale weight plateaus but continued fat loss. And that's why we say it's more important to look at how much body fat you're losing, not how weight. Unfortunately, it is just a lot easier to measure your weight, so people will just look up the scale. And depending on your situation, that might not be a bad thing, but I think it it important and monitor how muscle you are either losing or maintaining in the process. Also high sodium intake or hormonal fluctuations can cause water retention and mask fat loss on the scales.

28:03 It's worth ensuring a plateau is truly no fatloss via be a body measurements or body fat scans and not just a scale illusion. And then plateaus usually indicate the factors above have equalized intake and expenditure. So again, just make sure you're hydrating and then also too, when you are measuring that stuff, you actually getting good measurements. Now let's look at the pharmacological tolerance and dosing issues that can come up. Obviously we have this idea of receptor desensitization.

28:34 I've talked a lot about that, but with chronic stimulation of the GLP-1 receptors, they can down-regulate and become less responsive, especially when flooded continuously. And so this could create a feedback loop that triggers mechanisms that dampen the signal that we want to get, which is fat loss and appetite suppression. So in animal studies and some human data, chronic GLP-1 exposure leads to a blunted effect on gastric emptying and possibly reduced anoretic signaling compared to initial use.

29:04 Specifically, the gastrix slowing effects of tachyphalactis, initially drugs like SEMA or TERS markedly delay stomach empting. which contributes to that feeling of fullness. But after a few weeks, the stomach partly adapts and emptying speeds up a bit despite continued therapy. So this is due to vagal nerve adaptation. The consequence is that one mechanism of weight loss, which is prolonged fullness from slow digestion, becomes less pronounced over time. And patients often notice that early on they could eat a small portion before they're feeling stuff, but months later they can eat somewhat more. That doesn't mean the drug isn't working, But the magnitude of the effect can lessen over the time because of this receptor desensitization,

29:40 because we're constantly flooding the receptors. We also have these appetite pathways, so GOP1 and GIP both act in brain areas to suppress appetite. Over time, the brain can counteract this by altering other neurotransmitters. For example, it might increase expression of orexigenic signals like MPY to offset the heightened POMC-CART, satiety drive, and this is akin to tolerance, fullness or appetite control from medication might not be as strong as month 12 as it was in month three, because the brain's feeding circuits have basically adjusted.

30:10 Again, his body is always going back to homeostasis. So some people report that after a year on CMAR or TERS, their appetite is a bit higher than during the first months. They're still lower than pre-medication, which makes sense. And I think a lot of times, too, people come off of medication and their appetites goes back where it before, but because they've normalized to a lower appetite, they think that their back, which may be true. It's definitely roaring back from being lower. But in a lot of cases, I think it's just where it was before. And they have become normalized to it being lowered than it normally is.

30:42 So the central adaptation is hard to measure, but it aligns with the idea that multiple redundant systems regulate appetite and blocking one pathway long-term may lead to others to step up and cause the body. The body's going to figure out a way to get your appetite back. We look at GIP and glucagon. So, there's a debate about how GIP contributes. So paradoxically, G.I.P. is an obesogenic in some contexts, but the G-I-P activation seems to enhance weight loss alongside J-O-B-1. Basically, it's theorized that G I P signaling in the brain may synergize with J O P 1 to improve metabolic profile or counteract some adaptive responses.

31:17 Makes sense, and then that's obviously why stop time works better. But whether tolerance develops to the GIP component isn't well known. And as for retinotide's glucagon agonism, chronic glucagon activation could, in theory, lead to receptor downregulation or the body adjusting gluconeogenesis pathways. So glucogon raises metabolic rate, but the buddy might attenuate that effect over time. Long-term data isn' available yet, But phase three trials of RETA are ongoing to see if weight loss continues beyond 48 week or ends up plateauing as we have seen. in a lot of cases with turzapotide, or maybe it goes further and people plateau less.

31:52 So early indications suggest weight might keep dropping up to around 18 months with triple agonist, but it's likely a plateau. And again, it is so hard to avoid the plateau, especially when you're not hitting this from multiple half ways. We have this idea of a dose ceiling, so each medication has a maximum dose beyond which there's no significantly greater effect. I probably think mine, what I would say, is lower than what pharmaceutical companies say. But for triseptide, the 15-milligram mark is the top of the approved range, because after that, they don't really see that much more benefit.

32:23 Probably a lot more detriment, but anyway, I've seen people on way more than 15. So if a patient reaches a plateau at that dose, one simply cannot increase the dose further, at least not with off-label prescription. And then in retrutide trials, went up to 12 milligrams weekly, and if the patient's plateau is in part because the drug effect isn't as potent as needed, then dosing limitations mean you may have hit the drugs ceiling. So in the SRMT1 trials higher doses yielded greater total weight loss, makes sense, in a longer time to plateau on average. And this suggests that for someone plateauing on a lower dose, uptightering to the max dose could reignite weight loss.

32:55 So I'm not going to sit here and tell you that going up to a higher dose isn't going make you lose fat faster. It definitely will, but you just have to know what you're doing because that can be a dangerous game. Some patients do plateau because they cannot tolerate higher doses due to the nausea or side effects and have to remain at a moderate dose. In these cases, the plateau might reflect a suboptimal dose for maximum weight loss. And then we do have novel delivery methods coming out. So we've got oral and higher dose formulations that may be explored in the future and we'll see how those play out in population.

33:27 We might have an oral GLP very, very soon. I'll just say that, but What are some strategies? So we need to know what to do about this, right? The first one is going to be re-evaluate caloric intake. We can adjust the calorie deficit, which is obviously makes sense, right? Like see how many calories I'm eating, go down if I need to. We could look at how much protein we're eating. we can look about how carbohydrate and fat. In a lot of cases, I think people are eating too much fat and not enough carbohydrate. You can also use fiber rich foods and we could also track our food to intake. I thinks it's important too, this is another point about the sugar diet, is to understand that you could potentially use something like the Sugar Diet

34:02 to help drive metabolism up and use food increase our metabolism. which is a good thing because then we can eat, we don't feel like we're restricted and then were driving our metabolism higher and we lose fat in the process. So I think that's important. We can increase physical activity so we could obviously burn more calories. Obviously there's so many people that are taking GLP-1s and they don' exercise. Some of them are in my family and I know, cause they take GLPs and they just refuse to exercise. So we can burn more calories through exercise, obviously resistance training should be mandatory component of using a GLP.

34:33 You should handcuff to a gym or handcuffed to cardio equipment machine or both if you're taking a GOP and so I recommend adding in cardio or HIIT workouts and then also include walking throughout the day this idea of neat of having activity throughout the day that is not specifically considered exercise could be good. Sleep is very important. So I want people to sleep for seven to nine hours. Reducing stress is important, journaling, yoga, all those things, and then making sure that you're recovering is really important to overcome.

35:03 One thing too is checking biological factors. Any time someone is slowing down, it's almost the first culprit to me is going to be the thyroid function. Checking thyroid functions, even if it is low, like considered out of the range. It still could be low and you could still benefit from using desiccated thyroid and thyroid support there. And also to look at other medications you may be taking, cause they could, be working against you. For instance, an SSRI could working you because it's going to suppress testosterone even that much more, and then you're not going feel good.

35:33 Then it can be harder to lose weight. So the list goes on. Also to just make sure you are smart with tie trading. Remember the goal is to LOSE FAT. not necessarily weight. There's other things we can do. Some of this pharbontological add-on. So a lot of people have been adding in LDN. I use this intermittently with my GLP, not because it can resensitize you to it, which it will, but because of the way that it helps modulate the hypothalamus and reward system. It helps with the cravings or emotional eating.

36:07 There's also coagulantide, and I'm a big fan of doing this. If you feel like you're stopping or you are hitting a plateau with your fat loss and appetite suppression, a lot of times coargulentide can come in at a really tiny dose and just give you that extra added conqueror of food noise. So I really like that. And then there's also going to be other things in the future that probably can be paired with retitrutide. I'm sure there are already research companies are doing like retritrutides blends with coagulantide because you can do that. So there're other thing like leptin analogs, which could be pretty cool because if we increase leaptin, that can help with appetite and it can also help

36:44 that loss because of stimulating the thyroid too. And also too, we want to look at different pathways. GLP-1 and GIP and glucagon is cool, but what about some of these other pathways that work really well to help fat loss? And that's what I'm going to talk about in a second. Another one could be metformin. I think everyone should be taking met formin, even if it's just 500 milligrams a day alongside your GLp-2 to get the benefits. We also have mitochondrial interventions. So we have BAM-15, which is a mitochondria. Coupler, we have SLU PP332, which is another mitochondrial stimulant.

37:18 We've got MOTC, We got SS31. So I always recommend people, hey, before you take your TERS or RETA dose from two to five milligrams, why not throw in BAM15 and SLUP? Why not through in Motsi or SS 31? Because it's going to attack the fat loss from a different pathway and the process make you healthier too. You don't have to use injectable carnitine. That's another great one. you can do the sauna. that's great too, especially if you're someone that has trouble exercising or injured or there's too fast to exercise or whatever it is, the sauna can be very, very beneficial to increase energy.

37:48 There's also this idea of cycling. So I'm a big fan of this and you don't see this in the clinical trials, but I think going on and off periodically is a good thing. Because not only does it allow us to resensitize to the GLP, but it also gives us this like calorie break. Meaning if I cycle off the glp, maybe I go back to a higher calorie amount that I'm eating for the day, or maybe i do the sugar diet or some of these things. but it actually can help me reset because I'm, again, resetting my metabolism. So if we take the body out of homeostasis, it's going to have to adapt to get to homeoseasis again which is, in the process,

38:23 going make us lose more fat. We want to convince the bodies it is not starving so that when we resume, the deficit responds better. There's obviously mixed evidence on this if you look into the studies, but it obviously in practice works really well. So we don't want to overdo it. We don' want it to go to the Chinese buffet three times a day when we get off our GLP-1, But we can potentially, maybe we lose 20 pounds. Okay. Let me take like a week break to where I can kind of get back into homeostasis, kind not be in such a caloric deficit and then resume my GLPs,

38:53 resume, my aggressive fat loss. Given that GOPs often blunt hunger, many patients find it feasible to skip breakfast or dinner and compress eating into a window, which is where you're going to do fasting. This is why I love alternate day fasting or even intermittent fasting, I think alternate is better. But we can use fasting as a tool and then In the process, we also want to make sure that we're still meeting our nutritional needs. So even though we are in a calorie deficit, you still want make we want getting enough protein. We still wanna make that sure we get enough micronutrients.

39:23 All these things, cycling, refeeds, again within context, within reason, can be very, very beneficial to our weight loss on a GLP-1. And a lot of people just think, okay, take the dose up, and that's not always the smartest thing to do. That is it for the slides. And that is my comprehensive review of all the things that could potentially making you stall with your GLP-1 peptide. So, like I said, this really, you could take the GLp-one out of this conversation.

39:55 It really is a weight loss thing in general. it's just the GOP ones accelerate weight-loss. When we accelerate weigh- loss, all of these things I talked about today are going to become much more pronounced. so it is important to keep that in mind as you are losing weight that this is going happen. And you saw it in almost no cases did anyone not plateau. For some people, it's faster than others, but almost in all cases after a year, people plateaued on their weight loss. So it was going to happen. The question is, what are you going do about it and how are we going approach it? What strategy are going use if you do need to keep losing weight to help keep pushing through those plateaus.

40:30 I'd love to hear your feedback on this one. Let me know how you guys liked it. Doing a little bit more of a GLP theme for these next couple of videos. So hopefully that has helped you, guys. Obviously, GLPs ones are all the rage right now. But just close out every video. Thank you so much for liking, commenting, and subscribing. I cannot thank you enough for all of the overwhelming amount of support I get. And the channel is continuing to grow. Everything is continue to growth. so thank so you much. It is my mission to keep bringing you the best, most helpful, insightful content around all peptides. and biohacking related things.

41:01 So thank you guys so much, truly, from the bottom of my heart, I mean that. And hopefully that comes across in my material and what I bring to you, guys. It means a lot to me that wherever you are in the world, that you're supporting. Thank you so guys much and I'll talk to the next one. Peace.