Narrator - Dr. Abel 00:00 Welcome to HelixTalk, an educational podcast for healthcare students and providers, covering real life clinical pearls, professional pharmacy topics and drug therapy discussions. This podcast is Narrator - ? 00:12 provided by pharmacists and faculty members at Rosalind Franklin University, College of Pharmacy. Narrator - Dr. Abel 00:17 This podcast contains general information for educational purposes only. This is not professional advice, and should not be used in lieu of obtaining advice from a qualified health care provider. Narrator - ? 00:27 And now on to the show. Dr. Sean Kane 00:31 Welcome to HelixTalk. Episode 153 I'm your co host, Dr. Kane, Dr. Khyati Patel 00:35 and I'm Dr. Patel. And in this episode number 153 we are going to discuss about a new drug molecule. The title of our episode is, buy one, get one free, learning all about the dual acting GIP and GLP-1 receptor agonist. So all things **tirzepatide** its mechanism, pharmacokinetics, efficacy and safety data for one of its main trials and possible place in therapy, although guidelines are kind of still behind in making any statements regarding this novel Dr. Sean Kane 01:08 agent, Dr. Patel, at least on the inpatient side, diabetes management is fairly straightforward. We just give subcutaneous insulin or maybe even IV insulin, but I know on the outpatient side, it's much more complicated than that, with a variety of different drugs and drug classes that pharmacy students need to learn in order to take great care of those patients with diabetes. So can you tell us a little bit more about kind of the landscape of diabetes meds in general, and where **tirzepatide** might fit into that right? Dr. Khyati Patel 01:35 And you know, you're absolutely right. The landscape is a little bit more complicated. In the recent year, ADA has done a great job delineating what therapies to choose after that primary therapy of metformin based on quote, unquote, compelling indications, such as, you know, kidney disease, or if the patient has risk factors for ascvd, or presence of ascvd, just to name a few. And with the availability of other agents such as the SGLT2 inhibitors and DPP-4s and GLP one receptor agonist, in addition to our traditional agents like Metformin, sulfonylureas, thiazolidinediones and obviously, insulin, it's kind of getting complicated. The focus was years past. You know, you try oral therapy, and it doesn't work. You move on to insulin, but with the availability of injectable agents like GLP, one receptor agonist, you know, the preference has been that we try those first in the eligible patients. I'm referring to type two patients, prior to moving on to insulin. And now with this new agent, which is a combined GLP one gip agonist, we're going to probably see some changes coming in the guidelines to see where it fits in the therapy itself. Dr. Sean Kane 02:56 And just to kind of highlight some of the timeline here, you know, if we go all the way back to 2005 that's where Exenatide (Byetta) made it to the market. And then over the period of many years, we've had a variety of other GLP one agonists make it to the market. And it wasn't really that long ago, in 2019 we actually had an oral GLP one receptor agonist which became available that was semaglutide, brand name Rybelsus. We do have semaglutide as a subcutaneous injection as well, but that was the first oral GLP one agonist on the market. And as you mentioned, Dr. Patel, now we have kind of this, like hybrid molecule that is a GLP one gip agonist. Maybe you can tell us a little bit more about that, right? Dr. Khyati Patel 03:38 So the brand name of tirzepatide is Mounjaro. It was approved by FDA in May 2022, and it's currently approved for treatment of type two diabetes as an adjunct to diet and exercise. And the manufacturer is Eli Lilly. And currently it fits into this, like you said, new category where it has agonistic activity on both the GLP one, which is glucagon like peptide one receptor and GIP receptor. And gip stands for glucose dependent insulinotropic polypeptide. It's a mouthful, so we're going to keep using the acronyms GLP one and GIP as we move forward, Dr. Sean Kane 04:20 and then, not dissimilarly, to the other GLP, one agonists on the market, this is given subcutaneously once weekly, and you can take it with or without food, and also more for tolerance reasons, you're going to start at a lower dose and titrate up. So a typical dose is two and a half milligrams once a week, and then you go up by two and a half milligrams every month, based on blood glucose control, with the max dose of 15 milligrams per week. Dr. Khyati Patel 04:45 Yeah, and it's available as these single dose pens. So a box would include four of the pens as a month supply, and it's available in the increment doses. So you you start from 2.557 and a half, 10. And 12.5 and 15 milligram pens are available. They're supposed to be, obviously stored in the refrigerator, but they could be stored at room temperature for up to 21 days. Dr. Sean Kane 05:10 Dr. Patel, at least when I was in school, Exenatide (Byetta) had just made it to the market. We were kind of learning about GLP-1 agonists, but really, I feel like so much of the physiology is important for understanding how this GLP one gip agonist works. So can you help us understand a little bit more about the mechanism for both of those particular receptors in the body, terms of how **tirzepatide** is going to work for patients with type two diabetes, right? Dr. Khyati Patel 05:38 So both GLP and GIP are peptides, or polypeptides, and these are considered hormone peptides that fall under a bigger umbrella of we call it incretin hormones, or incretin system. You know, they kind of are produced by various cells of intestine. More specifically, the gip is produced by k cell versus the GLP is produced by the L cell of the small intestine. And, you know, we know glucagon like peptide, the GLP one agonist activity has been many fold, such as it increases insulin release when it detects higher level of glucose. So it's kind of like an auto switch on. It reduces that peripheral insulin resistance. It slows down gastric emptying, so you stay fuller for a longer period of time. And it has a satiety effect in the brain receptors as well, where you feel fuller sooner than people who don't have effect of GLP one, and so that kind of helps you lower your caloric intake, and therefore have some impact on weight gain or loss or management as well. Gip is sort of that incretin hormone, slightly different presentation than GLP, and so this one's produced by k cell. There are gip receptors, just like GLP receptors, located in various areas. So we have presence of gip receptors in your pancreatic alpha cells, beta cells, more interestingly enough, gip receptors are also present on visceral adipose tissues, and it gives an additive effect. We'll talk about it in just a moment. But they're also on bone and heart. Interestingly, as opposed to the GLP. Gip doesn't have any impact on gastric emptying. It has similar impact on insulin secretion, so in the presence of higher sugar levels or glucose, it's going to turn on that switch and help release the insulin. The effect on glucagon is a little bit different than the GLP. So when our body has normal blood sugar, or it's experiencing hypoglycemia, it's going to help release the glucagon, which is a good thing. We want glucagon to be released in this that status of low blood sugar, so we can kind of make our sugars go up. Right? However, in the hyperglycemic state, meaning when our bodies experience hyperglycemia, it doesn't affect glucagon secretion at all, versus the GLP would actually go ahead and decrease glucagon secretion in the presence of hyperglycemia. So these are kind of like the nuances and differences between GLP and GIP, and then now we put the two actions together, we kind of get that almost kind of like a designer drug molecule that has favorable effect on insulin and glucagon. Dr. Sean Kane 08:27 So Dr. Patel, it sounds like this, as you said, a designer drug where it's kind of accomplishing these two different mechanisms that should have some beneficial effect in terms of helping with blood glucose, but not dropping your glucose too much by like over exaggerating an insulin response from the pancreas. What can you tell us in terms of some of the net effect of having both GLP one and GIP agonism in this trisepatite? Dr. Khyati Patel 08:55 It's kind of like having best of both worlds of GLP and GIP in this 39 amino acid, peptide molecule. They've kind of added some fatty acids to allow for increased protein binding, like it's 99% bound to our albumin, and increase Half Life. We're talking five days. And so it allows for like that, once weekly dosing. And we kind of can break down its impact on glucose and lipids separately, because how it works and so again, like the word says glucose dependent, really means that this action only occurs when there is higher amount of glucose present. So in in that manner, it increases insulin secretion. And what this also means is that when the patient has either euglycemia or hypoglycemia, it's not going to keep releasing insulin and drop it even further. So the risk of hypoglycemia should be lower with this agent. Obviously, you know, as you use other drugs that causes hypoglycemia, there is always that risk of combined effect. So. However, by themselves, they're kind of very smarter molecule because they're glucose dependent in the periphery. It helps insulin process the blood sugar better. So it improves insulin sensitivity. We kind of talked about it earlier, that it does have this interesting effect on glucagon, where in cases of low sugar, it kind of comes to rescue and helps, you know, increase the blood sugar. Interestingly enough, while as a GI P molecule, you know, there is no impact on glucagon. However, because this has that GLP, one organism two, we have clear data to show that glucagon levels were also reduced, both fasting and postprandially. And so we kind of think that this effect was driven by the GLP one receptor organism. And then, you know, gastric emptying also results and has an impact on blood sugar. What we found with tirzepatide Was that the gastric emptying, or slowing down of gastric emptying was the greatest at the first dose, but the effect kind of diminished over the period of time. We do know that it does help decrease some post meal glucose absorption, and that's another way it helps decrease that postprandial blood sugar. Dr. Sean Kane 11:18 And Dr. Patel at least mentioned that with the other GLP ones, we do see that similar effect in terms of tolerance of kind of feeling nauseous over time, that after you've had several doses of any GLP one the effects on the gastric emptying, and therefore the effects on that feeling of full or even some nausea that can get better over time, Right? Dr. Khyati Patel 11:40 Yeah, that's the same with tirizipatite, too. So great point to bring it up. Dr. Sean Kane 11:44 Yep. What about lipids? So at the end of the day, we're treating diabetes, in part because we want to reduce the risk of cardiovascular endpoints like strokes and heart attacks, and it's always nice if drugs can help with your lipid profile, as opposed to hurt it. Is there any effect on lipids with tirzepatide, right? Dr. Khyati Patel 12:02 So with the gip receptors being on adipose tissues, we do get to see increased lipoprotein lipase activity with tirzepatide action. And what this does is results into increased incorporation and uptake of the circulating fatty acids into adipocytes. And so we will talk about the trial results, but they have been kind of monitoring these as clinical surrogate markers in the studies too. So yeah, we do have some impact. Can't quite say that it translates into cardiovascular risk reduction surrogate versus clinical but yeah, the impact on lipids have been favorable thus far. Dr. Sean Kane 12:45 Should I assume that patients that take tirzepatide are going to have a lower caloric intake per day just because they feel fuller quicker when they eat a meal? Dr. Khyati Patel 12:54 You bet you know this is probably going to be twofold, because both GOP one and GIP does that, so we do see decreased food intake or increased satiety as a quote, unquote side effect, but it's a favorable effect if you were to, you know, help patients lose weight in Dr. Sean Kane 13:11 addition to control blood sugar. Well, that's kind of the background of the drug, I'm assuming, given that it was approved this year, we must have at least one clinical trial supporting its efficacy and safety. What can you tell us about some of the trial data for tirzepatide, yeah. Dr. Khyati Patel 13:26 So we have a group of trial labeled surpass, you know? So you can keep labeling, surpass 1234, ongoing. We have data from surpass one trial to kind of summarize this trial was done in type two patients, and patients were inadequately controlled with diet and exercise alone, and were nine to any kind of injectable therapy. This was a 40 week, you know, phase three, randomized, double blind, placebo controlled trial where they compared three different doses of tirzepatide against placebo. Patients were randomized, and, you know, One to One to One to One fashion. And the meantime, in diabetes, for this patient population, wasn't as large 4.5 years, and the baseline agency was 7.95% so let's just say 8% on average, and they were looking at even C reduction from baseline at week 40. And what we found, obviously, you're comparing against placebo, that tirzepatide was superior to placebo. All three doses were in changing, the change of the even C, change of the fasting glucose levels and weight from what we measured at baseline. And so these results were statistically significant. But we're really interested, though, is to kind of use the standard of care agent for comparison to terms of patience, and that's where the surpass two trial comes in. Dr. Sean Kane 14:50 Then how was surpass two different in terms of patient population? Dr. Khyati Patel 14:54 So surpass two trial was patients who were inadequately controlled. Controlled on Metformin monotherapy, so they looked at, obviously, diet and exercise, but these patients were almost always on Metformin and still uncontrolled in terms of maybe even C reduction or rate weight control. Again, these were type two patients, but the more different, or the drastically different, thing about this trial was that they had an active comparator, which was semaglutide. This was also a 40 week phase three trial. It was apparel group design, and because of the administration and blinding issues, this trial was kept open label. Dr. Sean Kane 15:38 Okay with surpass two. We're comparing to semaglutide, a GLP one agonist, versus in surpass one, it was just against placebo, and that's a fairly easy bar to hit, so I would assume that in surpass two, that it's a little harder for the drug company to show that the drug is better, because now they're comparing it to an actual drug, and actually a fairly commonly used GLP one agonist as well, right? Oh yeah, absolutely. Dr. Khyati Patel 16:01 The standard of care, as I kind of mentioned earlier, too, is, before moving on to insulin therapy, we want to try an injectable therapy. And we know, up until tirzepatide came in the market, you know, our GLP one receptor agonists were the injectable agents, and semaglutide, having that cardiovascular benefit, is the right agent for a lot of patients who need that acvd risk reduction. And so it was fair for the tirzepatide manufacturer to compare their drug with quote, unquote, standard of care, semaglutide. Dr. Sean Kane 16:33 So as you mentioned, these are type two patients that were not adequately controlled on Metformin. Their baseline a 1c was around seven to 10 ish, and they all had BMI of at least 25 and had to have stable weights for the past three months. And one of the reasons for that, I would assume, is that they were interested in seeing how much weight loss occurred in this trial, right? Dr. Khyati Patel 16:53 You bet. Yeah. Weight outcomes were used as a secondary outcomes for this trial. Yeah. And then, as we know, we don't use GLP one in type one patient. So exclusion criteria was that they couldn't have type one diabetes, that their renal function was decent. So anybody with the EGFR of less than 45 and those those who had more severe outcomes with GLP one, such as pancreatitis or maybe non proliferative retinopathy, non proliferate nephropathy or maculopathy, these patients were also excluded. Dr. Sean Kane 17:29 So in terms of interventions, they gave three doses of tirzepatide, just like in the previous trial, we talked about 510, or 15 milligrams that was given once weekly, and it was blinded, and then they compared that to semaglutide at one milligram subcutaneously once a week. And again, this is a one to one to one to one randomization. And then just for background, Dr. Patel is, can you give us context in terms of one milligram of semaglutide? Is that a low dose, a high dose? Where does that kind of fit right? Dr. Khyati Patel 17:59 And so I think this is emerging as one of the critique of this particular trial is that the trial ended up using one milligram of somacotide, while now, FDA has approved somagotide to be used as two milligram maximum dose. And I think the you know, the investigators realize that this is probably a critique or drawback of the study design, but they admit that at the time of randomization, FDA label for somagotide had only included one milligram as the max dose, and so they could only use that. And so it's possible that in future, a trial is done with terzipatide and an appropriate comparative dose of somagotide, which would be two milligram. Dr. Sean Kane 18:42 So then 40 weeks, plus four weeks of safety follow up, and then they did stratify it to make sure that they had a good representation of those with higher versus lower a one C's. And I guess we should have mentioned that on both arms, they escalated the doses, kind of as we talked about that you titrate the dose every four weeks, and they did not allow for dose de escalation. So once you get to whatever dose, you kind of stay there. And if they were still not controlled, it was okay, in an open label fashion, to add on other anti diabetic medications to help with blood sugar, right? Dr. Khyati Patel 19:16 And I think what this also allowed is to look at tolerability data, and so if, if the patient did not tolerate the drug, the answer wasn't to lower the dose that they can tolerate it. The answer was that then they would probably discontinue the medication. So therefore this de escalation wasn't allowed for the dose. Dr. Sean Kane 19:36 And in true new diabetic med fashion, the primary endpoint here was change in a 1c from baseline to week 40, as we've kind of talked about a number of times. You know, it's great if you're a 1c changes, but we're much more interested in cardiovascular endpoints. But from an FDA standpoint, this is the bar that all new diabetic drugs have to meet in terms of an A 1c reduction. Dr. Khyati Patel 19:58 Yeah, you bet. And then there. Was a slew of secondary endpoints that they were looking at. And as you mentioned earlier, Dr. Kane, with the impact on food or appetite, they were definitely interested in looking at change in weight from baseline to week 40 as well. And then they looked at lot of other parameter, you know, how many of these patients achieved a particular A and C goal, whether it be, you know, less than 7% 6.5 or less than 5.7 same thing, categorical weight loss goals, those who achieve it, these 510, or 15% of weight loss, and then many other blood markers. So fasting, glucagon levels, lipid levels, you know, BMI and all of those things. Dr. Sean Kane 20:38 But also looked at, and then, from a side effect standpoint, of course, they looked at side effects. They looked at things like pancreatitis related side effects, and those were adjudicated, where they were evaluated by a third party, typically, who was going to be blinded. They looked at tolerability, how often were the drugs discontinued? They even looked at hypersensitivity reactions, changes in vital signs, issues with hypoglycemia, all sorts of other safety oriented endpoints as well. Dr. Khyati Patel 21:07 Yeah. And one of the things that struck out to me is that they were really interested in the serum calcitonin level. None of the GLP, one studies that I recall looking at looked at calcitonin levels, and so I was interested to see why that was the case, and we're going to tie it to one of the warning that the drug has from FDA, and we'll talk more about why the study decided to look at calcitonin levels. Dr. Sean Kane 21:30 So in terms of a statistical analysis, this was actually a non inferiority study. So they were looking at the two higher doses of transeptide, 10 and 15 milligrams compared to that semaglutide dose, and they have specific boundaries in terms of what met, not inferiority. Obviously, they figured out what their dropout rate would be, what their sample size needed to be, and it was a modified intention to treat analysis Dr. Khyati Patel 21:54 patient population wise. So looking at baseline characteristics in this trial, we had patients who had diabetes for 8.6 years, almost nine years, a little bit more than surpass one trial. Their mean a, 1c, as you mentioned earlier, Dr. Kane, was somewhere between seven to 10% as a range, but the average was somewhere around 8.28% and then the mean baseline body weight was 93.7 kilogram. Dr. Sean Kane 22:19 So Dr. Patel, we mentioned the primary endpoint was change in a 1c over a 40 week period. What did the results show in terms of how good these lower and higher doses of tricepatide are compared to semaglutide? Dr. Khyati Patel 22:33 What we found is that all three of the different doses of tirzepatide were superior to the somagotide one milligram dose in terms of that even C reduction, we're looking at 2.1% point reduction in even C with five milligram up to 2.3% even see reduction in that 15 milligram terms of petite group versus in somagotype group, it looked At 1.86% reduction. Now you may ask, you know, clinical significance versus statistical significance, so macrotide, having that 1.86% reduction is still considered clinically meaningful reduction in A and C and so then you can ask yourself, how much more is 1.86 and 2.3 how much more of the difference we are bringing it here? And so looking at the difference. And so this is a difference between five milligram of tricepatide and that one milligram of somagotide, we saw about point 15% ANC difference. With that 10 milligram, we saw about point 39% even C reduction difference. And then with that 15 milligram, we saw about point 45% even see reduction difference. Now all of these differences were statistically significant. However, again, you asked yourself, you know, what is that? Even C reduction that is clinically meaningful, usually we say point five to point 6% and so was this different? That drastically different than somagatide. You could question that. Dr. Sean Kane 24:07 And again, just to highlight originally, it was designed as a non inferiority study. Once they proved non inferiority, they moved to the superiority analysis, and they did show superiority, but I would agree with you. Dr. Patel, two things stand out to me. One, even with semaglutide at one point, we'll call it 1.9% a 1c reduction. That's still a very large reduction in a 1c remember the mean a 1c was 8.2 so these patients are going from on average 8.2 all the way down to almost 6.2 6.3 something like that. So we're seeing really big reductions, even with semaglutide. And I agree, is the extra point one five to point four reduction in a 1c with transepitide that big of a deal? Probably not. But it would be interesting to look at some of the other endpoints to help inform that Dr. Khyati Patel 24:56 Absolutely and you know, we gotta strike a balance between efficacy and. Safety. So how much are we pushing these patients to get to that a 1c reduction? Dr. Sean Kane 25:05 So with respect to a 1c sometimes clinical trials will look at the mean change, but they'll also look at a dichotomous in point, terms of did patients achieve a specific threshold, yes or no. So if you look at how many people got to an A 1c less than 7% it was basically similar. So tracepatite, 82 to 86% of patients got below 7% versus semaglutide, 79% and we saw slightly better results with a threshold of six and a half percent. So the percent of people who were less than six and a half or 5.7% all of these tended to favor true zapit over semaglutide in terms of the dichotomous endpoint of where you're above or below, the kind of somewhat arbitrary a, 1c thresholds Dr. Khyati Patel 25:47 and then similar outcomes first seen, you know, looking at fasting blood glucose reduction. So mean fasting blood glucose was 173 we know goal is between 80 to 130 so obviously this was high, and all three groups of tricepatide reduce the fasting blood glucose more than somagotide. No, I would say there was no clinical difference here, because even that somacotide Group patients achieved fasting blood glucose of about average of 124 after 40 weeks of trial Butch, 124 Well, it's between 80 and 130 I'll call that at a goal too. Dr. Sean Kane 26:22 We see a similar pattern with postprandial glucose reduction. So in both groups, we saw a pretty good reduction intercept. Petite was just a little bit better, but I would argue, probably not clinically relevant in terms of that difference. Yeah. Dr. Khyati Patel 26:34 More interestingly enough, people are looking forward to the weight outcomes trials, but this child looked at weight outcomes as a secondary results. So they were looking at baseline weight and then how much more weight was reduced at 40 weeks. And we found all Tera zapatide groups, again, were superior to somagotide in that weight loss. And so if we talk about that weight loss, five milligram group, for example, showed 7.6 kilogram weight loss. 10 milligram group showed 9.3 kilogram. 15 milligram showed 11.2 kilogram. So this was a dose dependent effect. If you compare that to that somacotide group, we saw weight loss of about 5.7 kilogram. Dr. Sean Kane 27:19 And if we just kind of target the max dose of torzepatide, 15 milligram, those patients then lost 5.5 more kilograms than the semaglutide group. Just think about that for a second. Normally in weight loss trials of drug x versus placebo, a 5.5 kilogram weight difference would actually be pretty good versus placebo, we're seeing that 5.5 kilogram weight loss versus an active drug, semaglutide, which is one of the best weight loss drugs that we already have on the market. So this is actually pretty impressive and kind of exciting, that now we have a drug that as long as it's tolerable, and we'll get to the side effect profile in a second, but this is basically beating out in a very clinically relevant way, the weight loss of semaglutide with that higher dose of Teresa petite in particular. But really, all three doses were better than semaglutide. Dr. Khyati Patel 28:08 Yeah, it's that star mount one child Dr. Kane would really show the right head to head comparison between the Tera zapatide and the higher dose of somagotide, which we use and approved for weight loss in form of big ov and we'll see. You know, what weight loss difference are we really getting when we are really comparing it to the right dose of somagotide in terms of how we categorize, you know, clinically meaningful weight loss, we say anywhere between five to 10% of the weight loss is considered clinically meaningful. And so this child kind of looked at groups of patients who received at least 5% 10% 15% weight loss, and the results were very similar to that mean weight loss change at 40 weeks, where patients in terms appetite groups did far better than patients in some semaglutide groups. And then, Dr. Sean Kane 29:00 if we want to get really fancy, and this is almost certainly an endpoint that the drug company knew that they were going to win out on, they had an end point of, did the patient in the trial have an A 1c less than six and a half percent, and did they lose at least 10% of weight? So kind of both a 1c oriented goal and also a weight loss goal, and this was between 30 and 60% with trazepatide met both of those two criteria, versus only 22% with semaglutide. So again, we're seeing good a 1c reductions, good weight loss reductions. And I should mention also this was without clinically significant hypoglycemia or severe hypoglycemia. So again, adding a component of a safety endpoint in there. Yeah. Dr. Khyati Patel 29:40 And then, just like clinical trial design wise, Dr. Kane this, this composite endpoint, which seems very designer and very specific. It's very interesting. Usually, these type of analyzes used to be done as a post hack analysis, and nobody really wanted to pay attention to what came out of post hoc analyzes. But it's. Very nice for manufacturers to now kind of consider some of these endpoints early on and include that as a as a secondary endpoint, rather than post hack analyzes. Dr. Sean Kane 30:10 So Dr. Patel, we mentioned earlier that because of the gip component, that there may be some changes in lipids that happen with tursepatite. What did we see in this trial? Dr. Khyati Patel 30:20 Yeah, so true to the effect on the adipose tissues, as we talked about earlier, we did see lowered triglycerides and the very low density lipoprotein, the VLDL, and actually favorable effect on High Density Lipoprotein suits so higher HDL. These differences weren't statistically significant, but at least it was nice to see that it was trending in that direction, and we found that the difference in the total cholesterol and LDL between the groups was not significant. Dr. Sean Kane 30:53 Interesting. And you know, every trial has limitations, and we've kind of alluded to many of these. Dr. Patel, what are some of the biggest limitations that you would like the audience to think about before they go out and get really excited about this particular trial. That, at least for weight loss, seems like a pretty big slam dunk for tirzepatide, right? Dr. Khyati Patel 31:11 So every trial has this limitation. We kind of talked about how this had to be kept open label, because, you know, two different manufacturers make two different pens, and also there is difference in how the doses are titrated. So for somagothe, it's a different titration, and it's a different titration. For tripatide, for that reason, you know, you couldn't, you couldn't blind the child. So that was open label. That could be a limitation there shorter duration we talked about earlier. This was 40 week, which, if you think about with including that titration up to the desired dose, you had about 16 weeks, weeks of steady state dosing. So again, 40 weeks might be okay for FDA to approve it. But you know, do we have long term data? And hopefully the CBOT childs will tell us that you already touched this point. Dr. Kane earlier, if you're looking at surrogate endpoints here, we're looking at A and C, it doesn't really translate into long term morbidity or mortality. And here, in terms of diabetes, those micro and macro vascular data. And again, we're probably going to wait for the CBOT trials to kind of give us some of that information. Dr. Sean Kane 32:20 A couple other things to just mention. So there were fewer black patients, and probably we would like to see in a clinical trial. We kind of already mentioned that the semaglutide dose was only one milligram, but now the FDA label has two milligrams as an option, but again, at the time of the trial, that wasn't part of the FDA labeling. So just food for thought in terms of there are some nuances here of why semaglutide may not have performed as well as probably the manufacturer of semaglutide would have liked it to perform. So there are some nuances there that we see this with all clinical trials, especially phase three, where a drug company is trying to make their drug look as good as possible. So I think we covered Dr. Khyati Patel 32:58 efficacy points really well. Dr. Kane from this trial, it's very fitted to talk about some safety concerns. And then coming from this trial, particularly, there were a similar number of patients reporting ADRs in either of the groups. There were some more serious side effects in the tirzahpatide group compared to the somacotide group, and those that most serious of all side effects was covid, 19 related pneumonia. Dr. Sean Kane 33:24 In terms of kind of more common side effects, we already talked about gi oriented side effects, primarily nausea, maybe diarrhea, vomiting, having a low appetite, or anorexia, being constipated, all of that kind of stuff. Typically, this is mild to moderate and fairly transient, and during that dose titration period. So once a patient got to a dose, after some period of time, they typically developed a tolerance to these side effects, and they weren't as troublesome. Dr. Khyati Patel 33:49 And the other thing to look at was clinically significant hypoglycemia. And so we saw a few patients, more in the tirzahpatite groups, having hypoglycemic events compared to somagotide, and the most of it was in the 15 milligram group of tricepatide. So it is a dose dependent effect. And obviously you're paying attention. You know, outside of the trial, when you're using it for your patients who already on an agent that causes hypoglycemia, the effect might be compounded. Dr. Sean Kane 34:16 And you know this to provide context, yes, there were numerically more patients with hypoglycemia, the clinically significant hypoglycemia in that highest dose of **tirzepatide**, but eight patients out of 470 in that arm. That's still a fairly low number. And almost certainly, as you mentioned, Dr. Patel, this is confounded to some degree, because oftentimes, even with GLP one agonist, and would expect the same with terms appetite, but usually it's just that you have another drug that causes hypoglycemia and that risk is magnified, as opposed to the drug itself, the GLP one or two zapit type causing hypoglycemia on its own right. Dr. Khyati Patel 34:55 I appreciate that perspective, as we talked about earlier, the release of insulin is. Really, you know, glucose dependent. So it's almost this very neat auto switch turn on type mechanism that helps actually lower the cases of hypoglycemia. Dr. Sean Kane 35:11 And similarly, in terms of severe hypoglycemia, we saw a couple events with tirzepatide and none with semaglutide. And they're going to continue safety monitoring in the trial. And then on the converse side of that, you know, we did see greater a 1c reductions with tirzepatide. So it shouldn't be surprising that terms of the need for rescue, anti hyperglycemic so adding other medications for diabetes, it was a little bit more common with semaglutide versus tirzepatide. But really in both groups, it was fairly rare, roughly one and a half percent with tirzepatide versus roughly 3% with semaglutide. Dr. Khyati Patel 35:45 Yeah, and these were kind of common side effects that we expected with this incretin based drug, in terms of some of the rare side effects. Now they were monitoring pancreatitis cases, and to have, you know, fairly equal amount of cases in tirzepatide versus somagot group, there were some cases of cholial diasis noticed in tirzepatide group. So four cases versus two. And so there is some warning coming out or precautions coming out in the label as well. They didn't notice any changes in calcitonin levels, or medullary thyroid carcinoma. And this brings a point of why they measured calcitonin levels as the safety monitoring point. They were just trying to see if there were any cancer markers, and calcitonin being one for the medullary thyroid carcinoma, they decided to measure levels in this trial. Dr. Sean Kane 36:40 They did look at diabetic retinopathy, and they saw a couple cases with **tirzepatide**, again, fairly rare, none with semaglutide. Interestingly, they saw a slight bump in heart rate, so between one and four to five beats per minute with **tirzepatide**, really wasn't significantly different, but kind of an interesting side effect. And then in terms of blood pressure, they did see a slightly lower blood pressure with tirzepatide versus semaglutide. Dr. Khyati Patel 37:07 Yeah, again, not clinically significant, but like, kind of trending in that direction. The trial that we have shortlisted in our reference section the handout can provide you more details on how much you know, SPP versus DPP reduction was seen, but it's something to kind of keep in mind. And then some other things to consider, you know, hypersensitivity reaction we noticed actually, you know, 1.7 to 2.8% in transeptide group and 2.3% in somagotite. And none of these reactions were serious in either of the groups. These agents are injectable, and so you have to look out for injection site reactions. And we found that the instances were a little bit more interceptite group compared to the somacatide group. And then the worst thing we fear out of any trial is ultimate adverse outcome, which is death. And so overall, in this study, they found 13 deaths in the tirzepatide group, six of this that occurred due to covid, 19. Obviously, there was that independent monitoring group that also certified that the these deaths were not due to the study drug in itself, for additional deaths happened because of cardiovascular reasons. And then two other deaths were kind of went under undetermined. And then there was additional that occurred in somagotide group. Again, this was also not believed to be related to the study drug. Dr. Sean Kane 38:33 And Dr. Patel, just to kind of highlight that a little bit recall that the whole point of doing this treating diabetes is to prevent cardiovascular endpoints that will eventually potentially eventually potentially cause death, right? So it's somewhat concerning that the death rate was higher with trazepatite, but it's also really small numbers, and it doesn't take that many kind of chance things to kind of numerically increase the rate of death in this case of tricepatide. I also wanted to highlight too that the injection site reaction, it was semaglutide point 2% versus tricepatide roughly two to four ish percent. So that's like a 10 to 20 fold difference between the two arms. So it would appear that the injection site reactions are quite a bit worse with tirzepatide. But in most cases, these are fairly mild, and patients acknowledge them, but it doesn't mean that they won't take it once a week. Typically, it's not so bad that they would not continue therapy. Dr. Khyati Patel 39:26 Yeah, good points to stress out and again, patient education on proper injection technique and location can also help abate some of the injection site issues. Dr. Sean Kane 39:35 Well, Dr. Patel, I would assume, because you mentioned the calcitonin and thyroid cancer risk and things like that, I would assume that tirzepatide carries the same warnings that all of the other GLP-1s contain as well. Is that correct? Dr. Khyati Patel 39:48 You bet Yes, there is a C cell thyroid tumor box warning. They saw some data with tricepatide in rat models, but to this day, no human cases have been known. But just like GLP ones, you know, it's the same thing in there too, they've included that warning there. It is obviously contraindicated to be used in those who have family history of medullary thyroid carcinoma, obviously personal history of medullary thyroid carcinoma, or the men two syndrome, which stands for multiple endocrine neoplasia syndrome, type two, these patients are at higher risk of having neoplastic endocrine based neoplastic conditions and then kind of following that pancreatitis flag. There are some warnings to watch out for and educate patients on to watch out for pancreatitis related symptoms, hypersensitivity reactions. We saw cholial diasis, so yeah, acute gallbladder disease, looking out for diabetic retinopathy, complications, again, minor instances were noted. There is no cause relationship established out of these outcomes, but patients should be following up for regular eye exam once a year anyways, when they have diabetes. And so these things could be caught earlier on. Acute kidney injury is possible, and that's possibility with the GLP one receptor agonist too. So it's not surprising that this one carries that warning as well. And then in cases of you know, severe gi illness. And so it's common to have, as you mentioned, Dr. Kane, nausea and vomiting. And it's common to have these things when you're titrating the dose, you know, in that dose titration ranges, but most patients tolerated it well, and some patients didn't tolerate so well, and so they had to discontinue the drug. And so this is possibility as well. Dr. Sean Kane 41:41 In terms of special populations, GLP ones are not recommended in patients who have diabetes, who are pregnant and actually tirzepatide showed fetal harm in animal studies. So of women who are of childbearing potential, the recommendation is that they use a contraceptive method, but because of a drug interaction, they should not use oral contraceptives, but they should switch to non oral contraceptives so that could be injectables or use barrier methods in addition to oral contraceptives for four weeks after initiation of the trucepatite and for four weeks after every dose escalation of tirzepatide, right? Dr. Khyati Patel 42:16 And I think there is this delayed gastric emptying based drug interaction with oral contraceptives that's cited in the package insert, and in my discussion with the rep to they really like honed on this, you know, drug interaction and making sure you're taking care of your patients contraception sense. So you can kind of say it's a special population flag, but also a drug interaction flag to be kept in mind, no interaction in terms of non oral contraceptives. So you could always give that option to the patient too, and then going along the route of drug interaction, drugs that have narrow therapeutic windows, the label indicates to kind of look out for and monitor that closely. One example includes, it's included is warfarin. Dr. Sean Kane 43:01 So Dr. talters appetite seems like a fairly exciting drug, but we do need some more data at a minimum. Some of that cardiovascular outcome data would be really nice. A big deal in the GLP one area is also weight loss. So are there trials coming out? I assume there are that are looking at some of these other endpoints, and we'd love to see what your drugs for patients with diabetes. Dr. Khyati Patel 43:23 Yeah, you bet you know these manufacturers, they do couple of trials, submit the NDA to FDA to get that initial approval, and then continue their quest. So we do have surpass four trial that compares **tirzepatide** with basal insulin. We have similar GLP one comparison to basal insulins in the past. So it was no brainer that, you know, the tirzepatide manufacturer was going to do that we have a surpass CVOT trial in action right now, where it's actually comparing with the lactate as an active comparator. And then we have surmount one trial, so different than surpass trial. The name is different, I suppose, because they're going for that weight loss indication, and so they're looking in patients who are either overweight or obese, and this one is in comparison to placebo. So the time will tell what the results of these trials are, and if any additional changes in labels and use will be made. Dr. Sean Kane 44:18 So then at this point, Dr. Patel, without having those new trials out yet, where do you think the role or the place in therapy is for **tirzepatide** in 2022 prior to some of these, what could be landmark trials coming out? Right? Dr. Khyati Patel 44:33 You know, I haven't seen much buzz from major guidelines like the ADA or the ACE guidelines. We know ADA updates their guidelines every year or so. We're hoping something will be included in the January 2023, update. So what I'm about to say is very much a personal opinion of how I would use tirzepatide, and I've thought about it since the reps coming in and, you know, in the clinic, where would I use this drug? And so while I put tirzepatide has a slightly additional benefit in glycemic control, but much more benefit in weight reduction than our GLP one receptor agonist. You know, we're looking to use it in patients who either didn't meet their goals of a 1c or weight loss with proper use of GLP one, and we just need to push them a little bit more. That's where I see tirzepatide being used. Not kind of like, yeah, first line go to but you know, if they the GLP-1s didn't work, then move it to tirzepatide. That's my current state of opinion. It will change, hopefully, or maybe not, when we see the results of the future Childs. One of the other things to consider, Dr. Kane is the cost. You know, we were just having a conversation earlier about inpatient use of these agent versus outpatient use, buck stops, you know, prescription stops, when the insurance says, Nope, I'm not going to cover it. And so if you kind of compare the AWP cost, I know this is not the patient cost. Each pen, which is just one dose, one week dose, a WP is about 300 so you're looking at a month cost AWP of about 1200 which is drastically more expensive than your insulin therapy or even the GLP one therapy, which we thought were the most expensive therapy for diabetes? Dr. Sean Kane 46:22 Yeah, and at this point, given how new it is, I can't imagine very many insurance companies are going to have this on a favorable tier for patients. So it is difficult to say what the actual cost for the patient would be. Certainly, 1200 a month would be the maximum, and it will likely be lower than that. It could be a copay. If you have a really good insurance company that has it on a favorable tier, but probably it's not going to be something that you could immediately get without a prior authorization or some other reason why you're favoring this over any of the GLP ones. So Dr. Patel, we've kind of covered A to Z of tirzepatide, what are some key points that you think the audience should take home from today's episode. Dr. Khyati Patel 47:02 I think the most exciting thing is how novel of an agent it is, where it's combining that gip and GLP, one receptor agonistic activity, where the end result is, you know, glucose dependent increase in insulin secretion, and then it still helps us suppress that glucagon secretion, so helps lower or balance blood glucose. Dr. Sean Kane 47:27 Number two is that this is super new. So FDA approved May of 2022, lots of new trials that are coming out that we don't have results for yet. What we do know is that currently it's approved for type two diabetes only as an adjunct to that exercise. It's a long acting, once weekly injection pen, and it's given subcutaneously. Yeah. Dr. Khyati Patel 47:48 And like we said, Dr. Kane, more studies are coming out, but current efficacy data comes from a couple of 40 week trial, one with placebo and one with active comparative like somagotide, where it showed that tirzepatide was superior to somacotide, and even C reduction, and more people achieved that clinically significant weight loss from baseline when compared to somacotide. Dr. Sean Kane 48:12 And then finally, not surprisingly, because it does have that GLP, one activity in addition to the gip, but tirzepatide Side effects are going to be gi oriented primarily, so we're thinking nausea, vomiting, anorexia, diarrhea, and there is a signal of a little bit more hypoglycemia, especially when you're combining this with other diabetic drugs that do cause hypoglycemia. So it is a concern, but again, it's a trade off of a 1c reduction versus risk of hypoglycemia, so that is a consideration when selecting therapy of true zapit type versus some other diabetic medication. So I think that rounds out today's episode quite nicely. If you want to see Show Notes and references that's available on our website at HelixTalk.com and again, this is episode 153 if you like clinical pearls in your Twitter feed, you can find us on Twitter, at HelixTalk. We also have a mailing list, so if you want to get an email every time New episodes come out with those clinical pros, you can sign up for our mailing list again at our website, HelixTalk.com, and then finally, we love the five star reviews and iTunes or Apple podcast, so keep those coming. So with that, I'm Dr. Kane Dr. Khyati Patel 49:18 and I'm Dr. Patel, and as always, study hard. Narrator - Dr. Abel 49:22 If you enjoyed the show, please help us climb the iTunes rankings for medical podcasts by giving us a five star review in the iTunes Store. Search for HelixTalk and place your review there Narrator - ? 49:33 to suggest an episode or contact us. We're online at HelixTalk.com thank you for listening to this episode of HelixTalk. This is an educational production copyright Rosalind Franklin University of Medicine and Science.