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Hey everyone, it's Mikki here. You're listening to Mini Mikkipedia on a Monday. And today I want to share a bit about what I've been recently diving into with regards to obesity pharmacotherapy. Specifically the newer generation of weight loss medications that are getting a huge amount of attention right now, both in clinical circles and in the media. And I want to get practical with you about it today. More and more people are starting on these medications and

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whether it's you personally or someone in your life or clients you're supporting, understanding how these drugs work, what to realistically expect and how to actively manage the experience is genuinely important. So that's what today is all about. And I have several clients now, either members or people I work personally with and just other people I know in my life who have either taken these medications or are thinking about it. And I think this information is super worthwhile.

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So we're going to start off with a quick, clear explanation of what these medications actually are and how they work. And then we'll talk about their effectiveness, the numbers from the clinical trials. And I know that I've already done this, but I think it was maybe two years ago. So a bit of a refresh on that data. And then we'll spend the bulk of the episode on the practical stuff, which I haven't really covered a lot about, the managing the side effects.

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protecting your muscle and bone, which I know you know a lot about anyway, and a few things you may need to know going in. So let's start from the beginning. The medications I'm talking about today fall into two main categories. You've got your GLP-1 receptor agonists and the newer dual GLP-1 GIP receptor agonists. And the main players right now are semiglutide, known by the brand names of

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Ozempic for diabetes and Wigovie for weight management and Terzepatide, which is Monjaro for diabetes and ZetBound for weight management. Although in New Zealand, it's Monjaro actually. And this has actually just been released, I think, at the start of March or late February as an alternative to the semaglutide or Wigovie. So that's pretty exciting for people who are interested in the space.

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And both are given as weekly subcutaneous injections, meaning a small injection just under the skin, and both have become genuinely transformative tools in obesity medication. Whether or not you quote unquote agree with the method, there's no denying how effective these can be. I will just add actually that there is in North America, or at least in United States, there is now the oral semi-glutide as well. But I'm not really diving into that today. So let's chat about what they actually do.

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just to refresh you. GLP-1, a glucagon-like peptide-1, is a hormone that your small intestine naturally produces after you eat. It has a few key jobs. It tells your pancreas to release insulin in response to glucose. It suppresses glucagon, which would otherwise raise blood sugar. And critically for weight management, it slows gastric emptying and acts on receptors in the brain, particularly the hypothalamus, to increase satiety and reduce appetite. If you feel full faster,

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stay full longer, you just simply want less food. Semiglutide works by, I would say mimicking, but it does way more than that with that GLP-1 hormone because it has a much longer half-life than the natural version, meaning it stays active in the body for around a week and it raises the levels of GLP-1 in the thousands. So that is one of the reasons why it can be dosed just once a week. Terzepatide adds another layer.

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It activates both the GLP-1 receptor and the GIP receptor. GIP, glucose-dependent insulinotropic polypeptide, is another gut hormone involved in insulin secretion and fat metabolism. Researchers at UAB have described this dual receptor activation as synergistic. When you activate multiple receptors expressed in different tissues, including the brain, fat cells, and pancreatic beta cells, you don't just

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add effects, you get a multiplied response. That's a big part of why tuzepatide tends to produce greater weight loss than semaglutide in head-to-head comparisons. It's also worth saying, because I do think it matters, that these drugs reinforce something really important about obesity. It is not a willpower problem. It's a complex biological condition involving hormones, brain signaling, genetics, and metabolism. These medications work precisely because they intervene at those biological levels.

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So how effective are they? I think it's worthwhile to talk numbers because this then helps people set realistic expectations in both directions. For semaglutide at the 2.4 milligram weekly dose used for weight management, the step one trial showed a mean weight loss of around 15 % body weight over 68 weeks in people without type 2 diabetes. For context, behavioral interventions alone typically yield about 5 to 8 % at best, which...

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is actually enough to show meaningful improvements in metabolic health, but it's quite a lot lower than what semaglucide can produce. Tuzepatide pushes this even further. In the CIMMUNT 1 trial, participants achieved a mean weight losses of 15 to 21 % over 72 weeks, depending on the dose, with the highest dose, 15 milligrams, reaching roughly 20 to 21 % mean weight loss. And in the CIMMUNT 5 trial, which directly compared the two drugs,

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Two zepportype produced a mean weight loss of around 20 % versus approximately 14 % for semiglutide at 72 weeks. An important nuance is if you have type 2 diabetes, you can expect approximately 5 to 10 % less weight loss than someone without diabetes on the same drug. This is a consistent finding across the trials and is worth factoring into expectations. These numbers are means of course. Individual responses vary considerably.

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Some people are what clinicians call super responders and lose considerably more, others get less. But these are the benchmarks the science gives us. One critical point, this is often debated, but from what we understand in the research right now, these medications need to be understood as long-term treatments, not courses. When people stop taking them, the data is very clear. Weight regain happens and quite rapidly. On average,

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people regain around two thirds of lost weight within a year of stopping. That is significant. The biology underlying obesity doesn't go away and the drug was doing real metabolic work. And again, this isn't a failure of willpower. It's pharmacology behaving as expected. It's the same reason somebody with hypertension takes their medication indefinitely. Unless of course they make real diet change and that diet change has an impact on their blood pressure. What I would also...

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just like to highlight here is that not all research shows this complete weight regain. And if you take care of some of the dietary factors, which I talk about a lot in podcasts and everywhere, and of course I've talked to guests about including Dr. Spencer Nadolski, we can protect that weight loss success by optimizing lifestyle along with the drug itself. So I did just want to add that caveat. Beyond weight loss, semiglutide has a cardiovascular disease indication.

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The SELECT trial showed a 20 % reduction in major cardiovascular events in people with obesity and established cardiovascular disease. Tuzibitide has been approved for obstructive sleep apnea. Both show promise in metabolic associated sciatohepatitis, MASH, previously called NASH, and chronic kidney disease. This is not just a weight loss drug class. These drugs, they're cardio metabolic drugs. So what about the side effects then? This is where I want to get practical.

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The most common side effects with these medications are gastrointestinal, nausea, vomiting, constipation, and diarrhea. I would also say that the loss of appetite, complete loss of appetite is also a side effect. For most people, these side effects are mild to moderate and transient, but they're the number one reason people discontinue treatment. So knowing how to manage them is genuinely important. First, just to frame it and understand why these side effects happen, this can actually help people

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tolerate them better. The mechanism, slowed gastric emptying and activation of satiety signals in the brain is exactly why the drugs work for weight loss. The nausea, the early fullness, the GI changes, these are an expected consequence of that mechanism, not a sign that something is wrong. Counselling people on this upfront makes a real difference to their experience. Most GI side effects are front loaded.

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They tend to be worse in the first four weeks starting the medication or after each dose escalation. And they typically improve substantially over time. In a real world study of over 300 participants on either semaglutide or tuzepatide over 12 months, the proportion reporting no side effects at all increased from around 42 % to 60 % in the tuzepatide group and from 54 % to 68 % in the semaglutide group. So you can see that those

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Side effects diminish the longer you're on a drug. Now for nausea specifically, the most effective strategies are eat smaller meals more frequently rather than large meals, avoid fatty, fried, spicy or very sweet foods while you're getting started, stay well hydrated, this is key, and identify and limit individual triggers. Common ones include strong odours, alcohol, coffee,

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dairy and carbonated beverages. If nausea is significant, then some short term anti-nausea medication can be used. Now constipation is actually the most common side effect reported with these medications and it stems directly from slowing of gastric motility. The approach is to aim for 1.5 to 2 litres of fluid per day, introduce a fibre strategy gradually, starting with a small amount of psyllium husk, just a teaspoon to avoid bloating.

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and prioritise 30 minutes of physical activity daily, which supports colonic motility, which obviously is also going to help with the muscle and bone loss. But we'll talk a little bit about that in a minute. So if lifestyle measures aren't enough, osmotic laxatives such as Macragol or Lactulose are a reasonable first step, followed by some stimulant laxatives like Bicicodyle or Senna if needed. And obviously these are under the

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the recommendation of your doctor or physician. Now with diarrhea, you want to identify and avoid triggers like fatty foods, artificial sweeteners, coffee, alcohol, spicy food, and consider a low residue diet in the short term, focusing on lean protein and hydration and eat smaller meals more frequently. And there are some prescribing tips to be mindful of that you might want to chat to your doctor about as well.

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Gradual dose escalation is one of the most effective tools for minimizing these GI side effects. Both semaglutide and tuzepatide are started at low dose and titrated up slowly. The escalation schedules exist for a reason and there's no benefit to rushing them. If someone is struggling, slowing that titration or reducing the dose temporarily is a completely reasonable strategy. And I'd also say that if you're getting success on a low dose,

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There's no reason to immediately go up just because in the schedule it is just hydration up. I've had clients that have just stayed for several weeks at the lower dose rather than just the four weeks as scheduled. And this is what their doctors advise as well. So this isn't against their medical advice, but it's just a reminder that more isn't always better and you're not going to achieve better outcomes just by...

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by getting an increased dose. So be mindful of that. And an underrated practical tip might be to consider changing the timing of your injection. If someone experiences more intense side effects in their 24 to 48 hours after their dose, giving the injection on a Friday evening or at the weekend means the worst if it lands on days when they might not be at work or managing a demanding schedule. It's a simple thing to think about, but it's effective. So think of how the timing of that works for you.

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And I'll just add in a note here about eating because I know the very common side effect is that people just simply don't eat. All I will say is the medication is allowing for you to lose weight, but it's not going to help you keep it off in the long term, particularly if you want to come off it. You need to learn how to eat. So it is important to manage these symptoms effectively. So you're still eating three times a day and you're still trying to hit a relatively reasonable protein intake. And so you're able to do the physical activity that's important.

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to help preserve muscle and bone mass loss. So it is the dietary strategies and the behavioral strategies that you put in place because of the medication that will keep this momentum and it will allow for sustainable fat loss. So you're way less likely to have that weight regain. Now I do just want to chat through a few bigger side effect concerns and this was off the back of a medical lecture that I was listening to and I thought it would be quite worth just talking about.

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briefly and they are more serious considerations and they're worth covering. So gallbladder disease and including gallstones is a known risk with these medications and the risk increases with prolonged use, rapid weight loss and higher doses. This isn't unique to GLP-1 drugs. Rapid weight loss from any cause increases gallstone formation. So patients should be warned to stop the medication and seek immediate medical attention if they experience intense or persistent

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abdominal pain. Acute pancreatitis is rare but serious adverse event and again sudden severe abdominal pain is a red flag. this falls into the category of rare but serious rather than a common concern when you're looking at clinical reviews or the scientific literature. Bowel obstruction has been reported in some cases.

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particularly in those with pre-existing GI conditions. There are also considerations around anesthesia as well. The slowed gastric emptying, meaning aspiration risk is higher if someone hasn't disclosed they're on these medications before a procedure.

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But of course, if your clients are having any kind of procedure requiring anesthesia, they are going to be working with a surgical team. They'll let them know, remind them to let them know that they're on a GLP-1 medication. Now we have talked considerably about protecting muscle and bone. So I will uh note that. And with some of these studies of people on GLP-1 medications,

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suggests that roughly 25 to 40 percent of total weight loss may come from fat-free mass, which includes muscle and bone. Researchers, though, have emphasized that this lean mass appears largely adaptive, so it's proportional to what we'd expect with the magnitude of weight loss, rather than these sort of side effects of the drug themselves. And they are similar to what we see with bariatric surgery. So this does mean that there is something we can do about it, yet we need to be proactive.

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So protein intake, briefly ensure you're aiming for at least 1.2 grams of protein per kg of body weight per day distributed across meals, breakfast, lunch and dinner, rather than having it skewed to later in the day. So this will help protect the muscle that you've got. And of course, resistance training. So this is the most potent non-pharmacological stimulus for preserving muscle mass during weight loss. So make sure that you're...

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doing the resistance training and even if you start with 10 to 20 minutes of squats, of lunges, of press ups off a wall, that is something at least and hopefully you're working out ways to build this into your long term health plan. For bone health, this is particularly relevant for older adults or anyone, perimenopausal woman. Impact and weight bearing activity matters. Walking with pace, stair climbing, squats.

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lunges and again at 10 to 20 minutes a day will make a real difference to bone remodeling signals. And for older, more frail adults, there may be a case for slowing down the rate of weight loss, extending titration intervals, doing a thorough nutritional assessment, makes sense to me, and considering dexa scanning to track the body composition. So if you're at risk of any sort of bone related or muscle related

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problems, then you do not want to rush through that dose escalation. And I think it's worth noting as well that if you work with or you are a reproductive aged woman, weight loss may improve ovulation, particularly if you have polycystic ovarian syndrome. So this is a good thing for

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people wanting to conceive, but it also means fertility can increase unexpectedly in women who previously have had irregular cycles. So anyone on these medications who is not trying to conceive does need reliable contraception. The recommended washout period of trying to conceive is about one to two months, and these drugs are not recommended during pregnancy or breastfeeding because we don't have the safety data there. Now, there's also an important drug interaction with tuzepatide specifically.

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It reduces the bioavailability of oral contraceptive pills. So women onto Zepatide, and that is Monjaro here in New Zealand, who are using oral contraception need to switch to a non-oral contraception method. Implant, injection, IUD, condoms, for this reason. Semiglutide and other GLP-1 receptor agonists don't have the same interaction with oral

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contraceptive absorption. But if someone is experiencing significant vomiting or diarrhea, the missed pill rules still apply. So be mindful of that as you're going in. So in summary then, these medications clearly they represent a genuine step change in what's possible for people living with obesity. But they are not passive tools. The people who get the best outcomes and who maintain them are ones who actively protect their muscle.

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through protein and resistance training, manage the GI symptoms with practical strategies rather than just stopping the medication or stopping eating, and understand the biology of why the drug needs to be continued long term if it's working. So if you are supporting clients on these medications like I am, or thinking about whether or not they might be right for you, I hope this gives you some sort of foundation to sort of...

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Think about it. And of course, as always, these decisions should involve a qualified prescriber who knows your individual history and situation. Chat to your doctor. So hopefully that was helpful. If you've got any questions, comments, or anything like that, hit me up over on Xthreads or Instagram @mikkiwilliden, Facebook @mikkiwillidenNutrition, head to my website, mikkiwilliden.com. All right, guys, thanks for listening. You have a great week. See you later.