Dr. Karl Nadolsky reviews pharmacotherapy, individualized therapy, and the latest FDA approved drugs.
Our next speaker is Dr Carl Niedowski. He's an endocrinologist at spectrum health in grand rapids michigan. He's also clinical assistant professor of medicine at michigan State University. He served in the Navy for nine years. He graduated from michigan State University with a degree in kinesiology. And for those of you who are familiar with. Ace, that's one of the major endocrine organizations societies. He was actually one of the authors of their obesity guidelines and he is the chair of their disease state network. So we are very excited to hear you talk, carl. Go ahead. All right, thank you. Great job Alex, that was perfect segue into medications because he talked about how complicated obesity is and even got into some questions at the end, intermittent fasting metabolism, all that stuff. Well, the biology is working against us. So sometimes we have to use some medications and surgeries to help people out. So I don't have any disclosures quickly. Go through some objectives here. Uh First of all, we want to review Win to even consider pharma co therapy for obesity. We want to define diagnose and stage the severity of obesity because the treatment intensity will be based upon that disease severity and we'll go through the medications, the mechanism of action a little bit, a little bit about the efficacy, the dozing and response, continuation guidance and depending on time, I'll try to go quickly where necessary. Um maybe we can get to the end. I have some slides on uh one of the rare uh obesity pharmacology, medications that that we should at least be familiar with. Just going back to the complications of this complicated nature of this energy balance that leads to excess and a posse de and animosity based chronic disease that we'll talk about. Like Alex said, it's still an energy balance, It's calories in calories out to some degree, but there are a lot of complexities that are adversely affecting our individual patients. And so the severity of obesity is on a continuum. So I actually stole this concept from thyroid cancer and I really liked it because I think it fits in with obesity. So severity is on a continuum treatment, intensity for all diseases is generally on a continuum. And so the treatment should match the disease severity. So we're going to talk about obesity severity and how that should help us with our treatment intensity as far as medication. So this is going back to 2016 and hopefully we'll revise this a little bit for people. But basically think about staging Uh you know, kind of the metabolically healthy stage zero where there's still a risk of harm from excessive pomposity all the way to mild complications or severe complications like type two diabetes. And so that can help us decide how urgent or how intense we need to be with our therapy, including pharmacologic therapy and surgery. And so then when we think about, well, what kind of goals do we have for these patients and, you know, Alex also touched on uh you know, when they lose a few pounds, we need to be very encouraging and supportive of that. That that requires some positive feedback because we've all heard 3% weight loss does some good 5% does some good. Well, when we really have disease, like at a possibly based type two diabetes diss lady mia, we need a little bit more, but these are pretty reasonable goals that everyone is probably familiar with that. 10% is a sort of magical number. 15%. And now we're going to start talking about some 20% and putting diabetes into remission. So when should we think about using these medications? Well, if patients truly have excess an apostrophe and they're otherwise pretty healthy and they don't have any complications that sort of that stage zero. And so while I don't like to say we should use it when people fail lifestyle there, they actually don't like that term. They haven't responded yet because we're going to talk about response to therapy. So they're trying but they haven't responded yet. Well, we know that even metabolically healthy obesity is not really a benign state, it's going to progress, especially depending on their genetic milieu. So we need to then start thinking about acting with pharma co therapy in that case if they have mild to moderate complications, sort of that stage one, you know, sort of in between give him a chance but we need to have maybe a little bit more sense of urgency. and then that stage two, a little bit more severe disease. Type two diabetes, multiple components of metabolic syndrome, severe sleep apnea. We need to be pretty aggressive early on and and start thinking about using medications right away of their severe complications of that animosity, the obesity. So just to quickly go through, what medications do we have currently approved for chronic weight management. And again, I'm not going to jump to the to the one for one of the mono genic obesity's unless we have time. But we've had oral stayed around for a while. We'll talk about the mechanisms of action. Lord Catherine. We actually don't have around anymore that got taken off the market and I don't know if you guys can see these slides. I'm a little concerned about this but I don't see it that well. But laura go tide is still around the extended release fundamental pyramid combination, the extended release combination of naltrexone be appropriate on. We now have something the trade name is called Planete. It we'll get to that. It's kind of a new thing. I'm gonna count it as a medicine even though it's not technically medicinal. And then of course now we have some magnetite and hopefully spend most of our time talking about that because that's the newest. Although probably fairly familiar to everyone who is here watching a lecture or a series on diabetes. So let's talk about this jealous ist Hydrogel, otherwise known as plenty. So it's it's available now the mechanism of action basically it's it's kind of like a super fiber. You take it before lunch and dinner and it it causes a matrix of volume feeling in your in your stomach to help improve satiety. And there you can see some pictures. This is from the actual website of it and and then the planete particles are degraded in the colon and it gets re absorbed and then you pass it through and eliminated with a bowel movement. So what you do is you take three capsules 20 minutes prior to lunch and dinners. How it's indicated. Obviously there's going to potentially be some side effects generally it's going to be fairly mild gi related effects. As you can imagine. Maybe some distention bloating, some irregularity potentially. Yeah. And obviously, you know, it's not really a medicine so it's not it doesn't have a lot of contraindications or safety concerns to be honest. But we do have to always think about some things with these. All right, we'll get into efficacy. So so here's one of the trials. It was a 24 week placebo randomized controlled trial and you can see patients with the B. M. I. 27 to 40 if they were less than 30 they had an impossibly based disease, dislike anemia metabolic syndrome, type two diabetes et cetera. And you know, pretty modest efficacy. Um you know we start getting 4567% weight loss in the placebo group. That means they had a pretty good lifestyle arm. So 2% more than that is pretty good. But as we talk about all these medications, it's all about early response to therapy to see who's going to stay on it and who's going to get the longer term benefits. So going back to this um with the weight loss responders, you can see that pretty good weight loss compared to placebo. Yeah. And when we look back at the early response, 3% weight loss at eight weeks was very predictive of getting more than 5% weight loss. And 80% of the patients got that at 20 weeks. And you can see here that this really does predict better outcomes. So if patients get that early response to therapy on this, then that means they're going to do well with it. They're going to get. Around the average of 10% weight loss is where we really start to see the clinical benefits. That's what really matters. It's what's on the inside that counts. Right, So moving on to the fundamental Pierre made. Now these slides that you see here from the 2016 8 algorithm, so they're a little bit busy, but there's more for a reference. Okay, the mechanism quickly. So up in the arcade nucleus that controls our appetite and satiety area, The fender mean, works on that palm sea area to improve uh second order neuron appetite suppression and the tapir make combination works up in their synergistically with the fender mean, and it's pretty good for cravings and satiety. And as you can see the dose, you start with a baby dose 3.75 23 mg every day for a couple of weeks. And you go up to the usual dose of 7.5 slash 46 mg daily. And most people do pretty well with that. And you should get a 3% weight loss response at 12 weeks in order to to continue on. If you don't meet that, then you can go up to the next dose and ultimately the full dose, which is 15 92 mg or consider different alternatives. Uh Slew of potentially common side effects. But I'll tell you most people uh if they respond to it, they don't mind these, you know, a little bit of paris these days, and the fingers usually not too much insomnia if you take it at the right time of day. Um Some dry mouth that patients feel like they just drink more water and it's a good part of their dietary plan. Um And taste change I think is important because uh I don't know if we're supposed to be doing off label discussion but to appear made itself can help people get off a soda pop and contraindications, sort of the main ones. No medication is approved for use with pregnancy because we don't want active weight loss. This one specifically is is very important. And you're supposed to even monitor pregnancy tests because of the toe pyramid. Obviously we probably shouldn't be given it to people with untreated hyperthyroidism. There's also a concern of acute angle closure, glaucoma. So, those are the patients we don't want to give it in. And uh and there are a few things to monitor very rarely. Uh these things will cause us to not be able to continue on. I've had one patient have some issues with depression that we had to stop. So just things to talk to the patients about and say, you know, be a little aware of this and and let you know. All right, so quickly. Uh hears from one of the big trials. I think I may even skipped over one. But I want you to start thinking about how much these categorical wait categorical weight loss these medications can help patients get because that's where we really need to start thinking about. And so look at the percentage of patients Uh in the big trials for this, who who got over 10% weight loss. Over 50% of people were achieving 10% weight loss. And that's pretty darn good. And there was a decent number who got over 15% weight loss. And that's where we start to see really good clinical benefits. So that's important to think about as we move forward with these medications. So I'm gonna move on to the naltrexone be appropriate extended release and this medication is a little bit more of a uh, I think a little annoying to take because you have to start with one pill a day for a week and then ultimately titrate up to two pills twice a day. Um it has a 5% weight loss early response to therapy on 12 weeks on the full dose common side effects. I do feel like are a little bit more common and uh due to some degree cause people to stop this medication more than others, including headache and nausea. Um it has a whole variety of contraindications as you see. Um mostly just because of the individual medications like anorexia um and seizure disorder, because of the appropriate on um I don't see the alcohol withdrawal naltrexone is used for alcohol addiction And obviously if someone really needs opioids for their pain treatment, you can't give naltrexone because it's an opioid antagonist. So here are, here is the mechanism back up to that are cute nucleus and the palm sea area to be appropriate in is going to help work on that. While the new truck zone actually block some of the negative feedback of the beta endorphin to help it work better. And also this works pretty well on that sort of dopamine meso limbic system. So people have cravings and there's some studies that suggest that yeah, this when people really describe that sort of food addiction, Carb addiction, sweet addiction, whatever it is, then this medication does seem to perhaps fit in line with that a little bit better. All right, a little bit of the efficacy. So this slide shows you four of the big phase three trials for the naltrexone buPROPion and these are the complete er So you have to understand that all these medications are, are studied and reported out as overall and then the complete ear's and the computers are the ones both placebo and on trial that that finished the trial. So usually they're going to do better. And I have circled here the behavior modification one. Remember I mentioned when we start seeing placebo arms that have like 67% that's in line with really good lifestyle intervention. But even there with the addition of naltrexone be appropriate on, there was over a 4% greater placebo subtracted improvement in overall weight loss and that 12%. That again, that's getting really good for our clinical outcomes. And going, here's a graph of that in fact. So you can kind of see the the uh the basic trial is over 9% versus 5%. But the complete ear's they're the ones that do well and they're the ones that of course we're going to, we're going to continue on these therapies. And so when we look at all these trials again, going back to the early response to therapy when you lose 5% at 16 weeks or 12 weeks on the full dose. Then across the board, they were getting about that average of 12% at one year. And that's important to remember. So we don't just keep people on the medicines if they're not having good clinical response because um, we can change it up and do something different for them. All right now, moving on to our list at now, this is everyone's favorite because it blocks the essentially the hydraulics of triglyceride to thus decreased lipid absorption. So it comes with a lot of fun side effects that people love and what you do is you take these before each meal. So you're supposed to do it three times a day. So again, a little bit of a logistical issue. There isn't over the counter version with the trade name of ally. Um, and the side effects if you don't have a low fat diet. So going back to Alex's low carb, low fat doesn't matter. We need to personalize the therapy. Probably not going to be a good one to use with the folks doing a keto diet and high fat because they're going to have a lot of steel, battery, a fecal or incontinence, oily spotting all that stuff, you know, no matter how much they like. It probably not going to be a great idea in those patients. So, um, again, contraindications, pregnancy, breastfeeding important can't have it on those, be aware of male absorption issues. Um, and vitamin uh fat soluble vitamins and so here's one of the biggest trials. Endorse randomized controlled trial with over 3000 patients. And if you look earlier on again, the placebo group had a good lifestyle arm and they were over 6% kilograms and percent are often uh similar in these trials by the way, because they're usually about 100 kg. But there was a 4% greater than placebo weight loss with orlistat in the lifestyle at about one year. But just like with all obesity trials, people tend to start to regain because of that a little bit of that metabolic adaptation that Alex talked about and also the biology of the body that drives weight regain back to that quote set point or so. But they're maintained in this trial over several years. Um more weight loss in the orlistat group. And that's important. And it also had benefits for diabetes in a lot of its trials. So I'm gonna move on to laura go to because there's one trial that overlaps these two. So everyone is very familiar with this for type two diabetes. And uh and probably maybe a little bit more familiar with this than the new some magnetite for obesity. And uh we know that this is a GLP and again it goes up to that argument nucleus and works on the anorexia genic system to help us with our food intake. Ultimately, that energy balance and Alex talked about and so here is a trial that that includes orlistat. If you see down here in the green, along with placebo and then a variety of doses of Nicaragua tied and they went 20 weeks and then one year, some people got to extend it and then they switched all the placebo and laura got tight groups to 2.4 and ultimately three mg and they kept the orlistat group on orlistat. And so Look here, I think that did a circle of the 20 week results And here's the about the one year mark. And you can see over 11 kg or percent weight loss with the three mg of arugula tied. And we'll compare that to orlistat, which similar to the trials, you saw a little bit over seven kg or 7% compared to placebo, which is a little bit over four. And so that's looking pretty good for laura got tied more than orlistat, but orlistat was doing better than placebo. So now on to the big scale trial with almost 4000 people randomized to Laura go tighter placebo and ultimately, there was on average a little bit more than 5% weight loss, placebo subtracted and nearly two thirds got that 5% weight loss and a third achieved 10% weight loss. And so here you can see that categorical weight loss, that's so important. And here's the graph. But I'm gonna move on to this because I want to see the early responders. So 77% of you look in these these pie graphs in the upper right hand corner. Got that early response to therapy with laura got tight, it's 4% and now only 30% of placebo got it. But you can see that even the placebo group who did get that response to therapy, they did pretty darn well down here in these solid lines going across. So the laura gloated responders got about 11% the placebo responders got 8%. So that's important to remember response to therapy to anything is very important to think about. But then those who didn't respond didn't do very well at all. And so this is going to slide us into some magnetite because at least we have some comparisons of some magma tied with laura got tied because it's the same company. So they wanted to see how it did. And so this was a phase two trial mostly for dozing. This was before they decided to stick with the weekly dozing that we're familiar with uh with the one mg for type two diabetes. And you can see over on the far right as our placebo and that's that little more than Two% 8-9 with Laura got tied. And then look at all these different doses of some agility. These are the daily doses you can see as it goes on and this is getting closer to what ultimately was approved. You can see a remarkable amount of weight loss compared to even Laura got tight and certainly compared to placebo. So that brings us to the Phase three trials that were published last year. And I suspect a lot of people are familiar with it because we were so excited about this and everyone was ready to, you know, to get it into our patients who needed it. And I see my camera, okay, don't look at my face because it's paused. Um But and then the company didn't have enough. They weren't even prepared because we knew that this was coming. So here's a glance at the step program. So we're gonna talk about step 123 and four. And obviously there are others coming including a cardiovascular outcome trial. And so here is step one. Nearly 2000 patients with a BMI over 30 or 27 plus add a posse based chronic disease. They randomized 2 to 1. This was worldwide over 68 weeks. And the tea tray shin 680.25 mg weekly for four weeks and then tie traded every four weeks. Mhm. And so you're not gonna be able to see this, but I'll try to point out some of the important characteristics. So everyone the average age was about 46-47. Um it was about 73% in the magnetite group for female sex. The average body mass index was about 38. And you can see because we'll talk about the prediabetes almost half 45% in the democratic group and 40% in the placebo group had uh what was diagnosed as pre diabetes. And here just some blood pressure and lipid levels to think about. And over here on the right you can see our efficacy graphs. And so what was really remarkable compared to the other trials especially is that 94% of the participants actually completed this trial, over 90% had a body weight assessment. So in the other trials, one if the treatment arm didn't do as well then um you know, people tend to drop out and then of course side effects tended because people to drop out. But also the placebo arms have a lot of drop out in the other trials. And so what you see here is especially with the observed on treatment data, more than 14% placebo subtracted weight loss. And then down on the bottom right, when we talk about that categorical weight loss, look at how many people were getting over, You know, 10, 15 and even 20% weight loss where we're really seeing really good clinical outcomes that we actually care about. Um for type two diabetes, metabolic syndrome, remission, sleep apnea, etc, fatty liver. Alright, going on to step two. And now this is patients with type two diabetes. And this actually compared to the one mg of some agua tied and you can see here that some of the baseline characteristics again, about that 100 kg across the border, as I mentioned earlier and a one c of about 8% here. The medications they were on. Obviously most people on Metformin. I can't I don't understand why so many people are and it's so funny to Rias anymore. A quarter of them were on SCL T two inhibitors. Yeah. And so here what you see basically is again that kind of same old placebo amount of weight loss about 2.5 3%. The one mg of magnetite that we're all used to doing well with had a 4 4.5% more weight loss than the placebo. And then with the full dose some magnetite 2.4 mg, we had another 3% weight loss compared to the one mg. Mhm. The A one C reduction wasn't that great compared to the one mg. And that's why the company is struggling with their two mg request for FDA approval. So there is a trial that was published in Lancet I think last year. And it just wasn't isn't that much more bang for the buck for the actual glycemic control but more patients were able to to get off medication. So if we think about, you know those trying to get off insulin uh you know, maybe we get with the 2.4 than the one mg. But either way uh Samantha tie does a good job and it's ushering in that new air I think. And here's the step three and again, this is the type of, you know, these two slides that we're going to go over our right from jam because they do a nice job of that. Um but this is the intensive behavioral modification. So if we look over here on the right, it's a smaller trial with 600 patients in a 2-1 manner. And uh that placebo group got around that 6% weight loss because they had a real actual behavioral intensity that we expect. And then those randomized to some magma tied got 16% so 10% more than placebo even with intensive behavior modification. But what some people are quick to point out is that if you notice the absolute amount of weight loss compared to the other trials. Now, these were not head to head, but it wasn't like a lot more. It was just that the placebo arm did a lot better. This group still did better. But the placebo arm did a lot better. So some magnetite in general just really must be helping people stick to their caloric deficit dietary plan. And here's just the graph that again, nearly 6% weight loss with lifestyle therapy is pretty darn good And more than 10% with the same magnetite more than Placebo also very good. But again, the absolute amount similar to these other trials. Now, here's step four is a fun trial because what they did was that everyone got some some magnetite first and then they were randomized to placebo. And so I'm just gonna go right to the graph because we run out of time here. And what you see here in the same magnitude running group over 20 weeks is pretty darn good. Weight loss. Have it down here in percent weight change there and then they were randomized to placebo or some magnet tied. And unfortunately, like you see in all these trials, is that when you get randomized back to placebo, you start to slowly regain your weight. But what is great is that the people who stayed on some magnet tied got even more weight loss and some waist circumference loss. Okay. To that categorical weight loss again, this is this is outstanding. So look at these these darker bars. Look at how many patients, what percent? We're getting more than 10%. 15% over 60%. And look that 40% of people were getting 20% weight loss. I mean, that's that's remarkable. That's knocking on the door of surgery there. All right now to that early response to therapy again, this is yet to be published for what that's worth In step 48 over, 80% of participants achieved 10% weight loss on some ago tied And nearly 90% were early responders what they called 5% weight loss during that run in phase. And then even the early non responders achieved clinically relevant weight loss by week 68 if at least they were continued on the same ago tied. And so over here you can you can see this. I don't know if I have any cartoons. So I just want to talk about these early responders here. Look at that 20% weight loss. If they were that early response to therapy group. Mhm. So benefits safety tolerance. Certainly improved waist circumference and jealousy me across the board, lipids, blood pressure and physical function has been noted in these trials. And really the best part is that similar adverse event rates really kind of overall. And so that's gonna be hard for me to read this. But you know, people are always so concerned about these but this really did not lead to discontinuation of the drug or placebo as much as you might think. And as we all know, nausea, diarrhea, some of that G. I. Stuff is what the side effects were and certainly more common in the same magnetite group but again not not causing them to discontinue the drug which is which is remarkable. And then down here I I point out that uh you know, people have been worried about the pancreatitis with G. Lps but we've seen the meta analysis of this and and it really doesn't look like G. LPS cause pancreatitis. Um And and in this it was really negligible and hard to say there was really any issue going on because there are other risk factors for pancreatitis. Yeah. All right. And here's the titillation plan, Month 1.25 mg each week for for four weeks. And then you just go up 2.51 that we're all used to. And then 1.7 and 2.4 mg weekly as the full bills. and so here is just a little this is from 2016. So this is this is a network meta analysis looking at the odds of getting weight loss versus the odds of uh I think discontinuing the medication for adverse events. And so you can see placebo up here. Not a lot of weight loss, but not a lot of adverse events. And it goes down to your list at what I erased here was the Lord Catherine. And over here you can see the naltrexone be appropriate on the arugula tied and Fetterman to a pyramid. Now, what I'm about to show you is not published. This is only my guess because I did not do the statistics. I'm just sort of throwing it out there. But I think that if we just sort of compare these other two medications that are not on here yet. I would guess that some ago tide would be way down here and that perhaps the planet E. Would be around there where the where the Lord Catherine was just based on their their current data Treat capacity-based type two diabetes, treat the underlying obesity and uh, think about these goals.
