Dr. Lauren Vincent discusses various medication options for your patients and how to apply in the clinic.
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great opener. We are now going to turn to Lauren Vincent, who is going to tell us a little bit about medication options for your patients and how to use them in the real world. And just to give you a little bit of background on Lauren. I've been working with Lauren for a couple of years now. She's an adult endocrinologist and trained at the University of California, San Diego, and has been working with us as part of the Script Clinic Medical Group, but really delivering services out in the community and especially communities with underserved populations. So she has been in very challenging situations where you really need to think about what is it that I can offer the patients? What can they afford? What can they manage? Handle? What kind of other support services do they have? So she has a really interesting and good perspective coming into this to give us this update with that. Lauren, I'm gonna let you take it away. Thank you. Thank you so much, Dr Sami Kez for that kind introduction and thank you all for joining us here today. So, as Dr Simic says mentioned, I'll be shifting gears a little bit to take us back to basics covering your medication options for patients with type two diabetes. And hopefully you'll come away from this talk prepared to use these medications in the real world based on our most current guidelines and evidence. So I have nothing to disclose and my objective my objective today or help to help you to determine initial treatment for patients with Type two diabetes and also how to progress therapy in Type two diabetes. So how to add on 2nd and 3rd line options, I'll be covering which agents are preferred in patients with CBD, heart failure and CKD, and I'll also be covering which agents are weight sparing and which agents have lower risk of hypoglycemia. And finally, I'll be covering for each medication class the precautions that you should be considering when using each medication, um, in tailoring your therapies for your patients with Type two diabetes. So I've included this slide toe highlight that there are at least eight distinct path a physiological defects involved in the development of type two diabetes, and this slide also highlights the drugs that we have available to target each of these defects. So this bird's eye view helps to remind us why combination therapy in Type two diabetes, um, is effective on DNA? Not only that, but also often required in order to achieve adequate control. Um, in type two diabetes. So you might have a patient who's on Matt Foreman simultaneously with a GLP one and A T C D. And in SGL t two inhibitor. And that may be what's the most appropriate for your patient. Um, in order to again simultaneously target, um, the defects going on before we get into these specific recommendations and algorithms, I'd like to take a moment to highlight the importance of individualizing your treatment regimens for your patients with type two diabetes. Dr. Simic is already touched on this, but that always begins with individualizing on a one C goal for your patient. Um, you know, you have to decide what your target is before deciding on what medications to use. And in general, older patients with more Cuomo CO. Morbidity is and risks, um, should have a slightly higher a one c goal. Ah, patients. Current health status should also be considered, So if they have concurrent kidney disease, what medications should we not be using. Should we be avoiding or, alternatively, what medications might provide additional benefit beyond the glucose lowering effects for a patient with diabetic kidney disease or cardiovascular disease? Risk factors are important to consider because many of our medication options for Type two diabetes have some of these associated risk factors. So the patient is at additional risk for any one of thes based on other co mobility's, um that also could guide your treatment, um, decision making financial concerns always important to consider. If a patient can't afford medication, it may not be a realistic option for them. The complexity of the treatment regimen that you're prescribing, as well as the patient's mental status, ability for self care and home support is so important to consider, um, in order to come up with a realistic medication regimen for a patient and also language and cultural considerations as well. Then, ultimately, when it comes down to it, um, you know you can have all of the guidelines memorized, ready to employ. But if it comes down to a patient's preference, and so it's just our job to know the guidelines be able, thio use them. But then also apply them to each patient and ultimately honor each patients preferences and goals. So Dr Smith is also brought up this treatment algorithm. It's It's the most recent one that was inthe e a. D a 2020 guidelines on I hope that you'll come away from this talk a little bit more comfortable using the general principles discussed here. I'll be coming back to it multiple times throughout the talk as we go through each medication class, so you know where to find each class on this algorithm. But what I'd like to highlight before moving on here is that metformin is still right at the top of our guidelines. So you should feel comfortable using medication as your first flying therapy for Type two diabetes. And, of course, just will also mentioned the importance of comprehensive lifestyle management as well. When initiating treatment for Type two diabetes, then how do we progress? And so the next arrow, as you'll see here, isn't to assess, ah patients a one C, but instead to consider if the patient before you also has established cardiovascular disease CKD your heart failure or high risk for established cardiovascular disease. That high risk was added this year, Aziz well, and this goes along with what Dr Sinica's alluded to as well that are. Guidelines were starting to shift from glucose lowering, um, targets Thio pathology driven targets. So if if you're patient falls into one of these categories here, highlighted in red, then you should consider independently of your patients a one C or individualized a one C target whether or not they might benefit from some of the newer medication options that we have that we now have very good evidence for in terms of benefiting patients with underlying cardiovascular disease and and benefiting patients with heart failure, or CKD. And so these two columns here, the Navy column and the Red Column help to guide your therapy. Uh, if you're patient falls into one of those or multiple of those categories, and so if you're patient doesn't fall into one of those categories. You'll go down this side here and then assess the A one C. And if it's above the above, the individualized target you've set, The next decision making process involves assessing whether or not you'd like to minimize hypoglycemia, minimize weight gain or if cost is a major issue for the patient, and then each of those three helps you to determine what will be second line therapy if needed to achieve in a one C target. And so we'll be coming back to this again throughout throughout the talk. Dr Simek is also already mentioned this, but just to highlight our current guidelines, and this is fairly new as well suggests considering GLP one receptor agonist therapy prior to insulin in most patients now, there are certainly exceptions. Some patients are not good candidates for GLP one receptor agonists, and we'll get into the details of that class later on. Um, but for the most part are current guidelines suggest considering GLP one prior to insulin. Um, in most patients now there again are exceptions. You. It would be important to consider the earlier introduction of insulin in a patient with evidence of ongoing metabolism, such as weight loss symptoms of hyperglycemia than a onesie greater than 10 or blood sugar levels over 300. Or, if you're considering that type one diabetes may be a possibility, any of these would support earlier introduction of insulin. So now we'll launch into each of the medication classes again. Hopefully you'll come out of this talk with a comfortable understanding of each and the risks and the potential benefit of each class, so we'll start with Met Foreman. Metformin works by suppressing liver glucose production and also improves insulin resistance by increasing peripheral glucose uptake and utilization. Its efficacy is high, as as mentioned on the prior slide, you can expect a onesie lowering of 1 to 2%. With this medication class, it is not associated with hypoglycemia. The weight change expected with metformin is neutral, but there is a potential for modest weight loss with Met Foreman. With regards to the cardiovascular effect. Um, it's neutral in terms of heart failure may have a potential benefit in terms of atherosclerotic cardiovascular disease. It's a low cost option and Orel in terms of its renal effects, it is important to consider lowering the dose at certain GF are cut offs, which I'll go into more on the next slide. And in terms of additional consideration, G I side effects are common with Met Foreman, such as diarrhea, nausea, abdominal pain, eso. It's important to discuss that those side effects with your patients and, of course, start at a lower dose and gradually increase thio your gold dose with Met Foreman Um, ways to minimize the side effects. Um, are to encourage patients to take metformin with meals and also consider using an extended release formulation. There's also potential for B 12 deficiency with Matt Foreman. Um, no specific guidelines currently on the frequency with which B 12 should be monitored. But you should have a higher clinical suspicion if a patient comes in on Met Foreman with concurrently with symptoms potentially suggesting B 12 deficiency. Thio. Check up B 12 level here. The GF are considerations with metformin above 60. No, um, issues. But once the GF are drops to between 60 and 45 it's recommended to continue the dose, but increase the frequency of monitoring of renal function to every 3 to 6 months. Between 30 and 45 Metformin should be prescribed with caution, and the dose should be reduced, for example, to 1000 mg total daily dose and below 30. Metformin should be stopped. So again, just to reiterate, metformin is the preferred initial pharmacologic agent for the treatment of type two diabetes, and some of you might be wondering, well, when, when should we consider starting metformin, Plus something else at the first presentation of Type two diabetes guidelines currently suggests that if you're presented with a patient who's a one, C is 1.5% or more above their target that you could consider starting dual therapy at the onset. Um, but of course, this needs to be done with consideration of your patient specific circumstances. Um, if they're ready to try more than one therapy at once. So after each class of medications, I'll make sure to come back to our algorithm so that you can see where each class of medications falls on our algorithm. So metformin again, right at the top. First line therapy. Um, and so you should feel comfortable starting metformin. Um, at the onset Type two diabetes. I'll be covering so funny areas. Next. Um, they're an old, old, tried and true class of medication. So many of you probably feel very comfortable using so funny areas. And based on our older guidelines, many people feel most comfortable using cell phone so funny areas as their second line, um, medication for type two diabetes. So if that is your current practice, if you are presented with a patient with Type two diabetes that's not well controlled on metformin, and your go to is to start us off on a Korean next. I challenge you thio reconsider. Um, that practice, because, as hopefully you'll come away from this talk with that is a bit outdated, Um, in terms of what our current guidelines suggest. So um, the salon erase that we have are most commonly and use their glide your ID blip aside and dilemma pride. They work by increasing endogenous insulin secretion from pancreatic beta cells. They last 24 hours and important side effects to consider hypoglycemia, especially glad you're right, which is a longer duration of action. So it's actually never used medication in the Medicare population there associated with weight game, which is also very important to consider. Their efficacy, though, is high, with expected, a onesie lowering of 1 to 2%. They're absolutely associated with hypoglycemia and weight gain neutral in terms of their cardiovascular effects, and their cost is low. Their aural andan terms of using them in patients with kidney disease. Um, they should be used conservatively to avoid hypoglycemia. So where do you soften areas fall if we have a patient on metformin and and we're considering Sealfon area as our second line agent in a patient who's a one. C is above target. They're on Lee way over here. If cost is a major issue and that's really what's driving your decision making process, then you could consider so funny area as a second line therapy. But in all other situations, um, it really shouldn't be your second line go to because of some of the risks and side effects I just discussed moving on to our T C D S P, a good his own and rosiglitazone. They work by decreasing insulin resistance in muscle, liver and adipose cells by activating the peop are gamma nuclear receptors. They may take 4 to 6 weeks to see full effect, so it's important to have warn patients of that who may get impatient and feel that they're not working. Side effects include weight gain, fluid retention and increased risk of fractures. The side effects air greater at higher doses, so it's recommended to really use the lower doses. Um, for example, Paola his own at 15 or 30 mg max, um, really little added benefit of going up to the full 45 mg dose but increased risk of side effects. Their efficacy is high, with also agency lowering potential for 1 to 2%. They're not associated with hypoglycemia. They dio cause weight game, their cardiovascular effects. So it's very important to mention that they are associated with an increased risk of heart failure. And there's actually a black box warning for that. PEO Goodison may have a potential cardiovascular benefit. The cost is low and their aural, um no dose adjustment is technically required in patients with kidney disease. But they're generally not recommended in renal impairment to present prevent fluid retention. Already mentioned is CHF black box warning. Due to the fluid retention, they have a benefit to Nash. Um, but unfortunately, a risk for bone fractures and also this potential risk for bladder cancer, which I know was ah, really kind of more in the forefront, Um, maybe a few years ago. But it seems that this risk may be less than was prior thought. Um, and so more and more people are feeling more comfortable using this class of medication despite that risk. But I know that it continues to be um, the forefront of many people's minds when considering this class of medication on patients as well. So where do T CDs fall? If we're considering them a second line therapy, they fall into this middle category. If you are wanting to minimize the risk of hypoglycemia with your second line agent, So T. C. D s again do not cause hypoglycemia. And they also are great to consider if cost is a major issue. So T C. D s, um, tend to be relatively cheap. Where they do not fall is in the heart failure category because of that black box warning, and they do not fall in the weight, um, the weight loss category, either because they are associated with weight gain. All right, let's move on to the STL t two inhibitors. Canada flows in dahe pickle flows and ethical flows in an article flows in. They work by blocking the re absorption of glucose in the proximal tubules of the kidney, causing more glucose to be released in the urine again. Here are the four that we have. Um, I think it's important to mention how to use these medications so it's recommended toe start at the lower dose and try the lower doses to see if you can achieve your A one C targets and then after a certain period of time, say, three months increased to the higher dose. Um, before moving on to another medication category so really should be maximizing the doses for whichever one you're using before trying and moving on to another medication. SGL Teaching inhibitors have intermediate efficacy with a onesie lowering benefits of 0.1 toe 1%. They're not associated with hypoglycemia. They can cause weight loss, which is so important to so many of our patients. It's important to highlight that and was even more exciting is that we currently in the past five years have so many studies that have come out to support additional cardiovascular benefit for many medications within this class. Specifically, both chemical flows in an empirical frozen have excellent data to suggest that they prevent cardiovascular death in patients who have underlying cardiovascular disease. And in addition to that, they also both canticle flows and ethical flows in and dad pickle flows and also have been proven in these cardiovascular outcome trials to have a benefit in patients with CHF to prevent hospitalizations and also death from heart failure. Their cost is unfortunately high. They are Orel and then in terms of the renal effects. We also in the past several years have renal outcomes. Trials that have come out just show that canticle flows in empirical flows in and capital flows in all have benefits in terms of preventing the progression of diabetic kidney disease. Um, for example, outcomes that were looked at included doubling of the creatine in, um, death due to renal disease, or the the time to initiation of dialysis outcomes such as those all were improved in patients on these medications. Um, the capital flows in study was just recently published last month, and it had to be ended early because of the benefit. Because of the positive outcomes. There are dozing considerations with the G FRS, and I'll cover that on the next slide. And finally, in terms of additional considerations, there was a black box warning that was removed since these guidelines were published, um, in January. So there used to be a black box warning on the risk of amputation with chemical flows in the black box. Warning has now been removed, however, there still may be an increased risk, so it's still something important to discuss with patients. But I do think it's exciting that the black box warning was removed. There may be an increased risk of bone fractures with Canada flows in, and there's also an important DK a risk to consider, um, in all of the agents within this class. So in practice, I do not use this class if I'm concerned that a patient might have type one diabetes or if they're a onesie, is very high. For example, around above 10, they're also associated with an increased risk of genital urinary infection infections related to the increased glucose that's excreted in the urine. And there's also risk of dehydration and volume depletion. So I remind all patients on this class of medications to stay well hydrated and consider avoiding this class in any patient who has a risk for hypertension or volume depletion. There is a slight increase in LDL cholesterol in this class of medication and also, unfortunately, a risk of Fournier's gangrene so very important to discuss good hygiene with patients on this, this class of medications I've had, I've put all together some of the GF are cut offs and considerations because I know that this could be hard and practice to know which cut offs to use. And I'll just summarize by saying it's definitely a moving target. As more of these renal outcome trials air coming out, in which patients are being included in the studies with G f R is down to 30 down into the twenties, we're seeing that these medications are not only safe but efficacious in terms of preventing the renal outcomes even down into the low G f r s. The the flip side to that is that this class doesn't work as well in terms of the glucose lowering benefits with the lower GF are so if less glucose is getting filtered through the kidneys, Um, there's less benefit potential benefit for blocking the re absorption. So down in these lower g f R s. Um, what's important to consider when deciding on using these medications is whether or not there's also potential benefit in terms of the renal outcomes. Um, uh, which excitingly it seems that there is. So where did SG lt two inhibitors fall? Um, let me just pull a few things up so again, if you have a patient already unmet. Foreman, who potentially has had a heart attack before, has evidence of atherosclerotic cardiovascular disease and SGL T two inhibitor with proven CBD benefits such as M Poko flows and mechanical flows, and would be a great second line option if you have a patient with a history of heart failure or CKD. M. Pickle flows in Canada flows and adaptable flows and all have evidence, um, in terms of reducing heart failure and or CKD progression. And so it would be, um, great options for second line therapy as well. Three. SGN lt two inhibitors also fall here because they do not cause hypoglycemia and they also cause weight loss. So they're great medication options to consider a second line. If you're trying Thio, promote weight loss in your patients as well. So finally I'll be covering the in cretins the DPP four inhibitors and the GLP one receptor analysts ag agonist Analog Excuse me, They work by blocking so DPP four enzyme in the body breaks down endogenous GLP one and G I p. And so DPP four inhibitors block that breakdown. Onda helped to potentially eight ones endogenous GLP one and G. I. P GLP. One receptor analyst Act analog. Excuse me. They directly stimulating protein receptors, and that's how they work. So comparing the mechanisms of action, the GOP one receptor agonists have added benefits specifically decreasing food intake and slowing gastric emptying. And that helps to explain the weight benefits of this class of medication. In addition to the glucose lowering benefits DPP four inhibitors, the four listed here, the ones most commonly in use, increase the concentration of endogenous GLP one by two fold. And so the a onesie lowering benefit is intermediate. Really, you can expect in a onesie lowering of 0.62 point 8% for this class of medications. They do not cause hypoglycemia. They are neutral in terms of the weight change expected. They are neutral in terms of the cardiovascular benefits. Unfortunately, no cardiovascular benefit has been proven in the studies done to date, and there's a potential risk with sacks of leptin in patients with CHF. Their cost is high. They are oral medications, andan terms of the renal effects. What is nice is that there are options within this class for patients with reduced G f R and one of the medicines in this class, Linux. Clifton is not cleared by the kidney, so it can be continued without those adjustment. Even in patients on dialysis, there is a potential risk for acute pancreatitis. Um, no clear positive effect has been established to date, but it is important to consider, and joint pain is a potential side effect. The DPP force fall, um, right here in the middle. So if you're considering using a medication that will minimize hypoglycemia. Second line The DPP four is one of your four options, but its high cost. So it is not over here on the right. It is neutral in terms of weight loss and no evidence to suggest benefit in cardiovascular disease. Heart failure. CKD. So finally, I will be covering the GLP one receptor agonists. I've listed those currently in use here, and what's exciting is that we now have an aural options. Some glue tied Orel just came out last year, but for the rest of them, they are sub Q GLP one receptor agonists have high efficacy, a onesie lowering of 1 to 1.5%. They're not associated with hypoglycemia, and they cause weight loss, which again is a very important factor to consider and usually very important to patients in terms of the cardiovascular effects. We also just like the SG lt two inhibitors in the past five years have, um, cardiovascular outcome trials that suggests that multiple medications within this class, which I will get into on the next slide which ones have benefit in terms of preventing cardiovascular events and death? Um, in our patients that Type two diabetes there's neutral data on CHF. The cost is high there mostly sub Q. Except for the aural semi glue tied and then in terms of the renal effects lira glue tied, which is Victoza, seems to also have a benefit in terms of preventing the progression of diabetic kidney disease. And in terms of dozing considerations, um, renal does is adjust renal. Those adjustments is required for Exanta tied and Lexie's Anna tied. Um, and caution should be used for all of the medications in this class when using um in the lower G f R ranges. But there's no specific cutoffs. The current recommendation recommendations just say to use caution. There is a black box warning for the risk of thyroid see cell tumors. These were seen in rats that hasn't been seen in humans, but it is important to assess for risk a family history of thyroid cancer, specifically medullary thyroid cancer M E n. Before starting any of the medications within this class, G I side effects are common, and that's why when starting these medications, it's recommended to start at the lowest dose. Most of the medications in this class have a lower dose option to start at for the first month to minimize the side effects before increasing to the full treatment dose and escalating. Beyond that, the injection site reactions specifically with Exanta tied the initial formulation caused nah, jewels under the skin that benign and usually go away that can be quite upsetting for patients. That's been better with the more recent formulations of Exanta tied, and they're also maybe an acute pancreatitis risk again, not clear evidence to support this, but important to consider if you're patient has had pancreatitis so again coming back to our algorithm, we have a patient who might be on that Foreman. Andi has had a heart attack before. Ah, GLP. One receptor agonist is an equally good second line option if it has been shown to have a proven CVD benefit. Um, those are Lyra glue tied sema glue tied and do a glue tied or Victoza is epic and treeless city. Um, so that would be an equally good second line option to consider. Um, if a patient, for whatever reason, doesn't want to take, it s guilty, too. And then coming down the red side here. If a patient, um, is on that Foreman has heart failure or C k d. And for what? For whatever reason, cannot taken SGL t two. Then the next option should be a GLP one with proven CBD benefit again. Those same three. If a patient doesn't fall into any of those categories of GLP, one is a great option for a patient in whom you're trying toe, minimize hypoglycemia or minimize waking. And the GOP one with the best wait benefit is, uh, semi glue tied on. And I think that this, um, will be, uh, changed in the next set of guidelines. Eso look out for that. So just like toe to summarize here because I think it can be a little bit confusing about which option to consider if you end up going down one of these two algorithms. So again, if you have a patient on Matt Foreman with a history of atherosclerotic cardiovascular disease or high risk for atherosclerotic cardiovascular disease as your second line therapy, you could consider either GLP one or an s guilty to. There is no clear benefit of one over the other. So then it comes down to those patient's specific factors. If a patient doesn't want an injection, then maybe An s guilty to would be a better option. If a patient is more interested in weight loss than probably a GLP, one would be a better option because the weight loss with the GLP one is greater than what's seen with the S guilty too. On the other hand of heart, failure of CKD predominates. The guidelines do suggest picking an SGL T to over a GLP one, specifically ones with evidence for benefit. And those air M pickle flows in canticle flows and adaptable flows in. But if for whatever reasons, the GF are cut off insurance limitations you cannot using s guilty to then the G l. One of these three GLP ones would be the next best option. So, um, just to go over some of the conclusions that I hope you'll take away from my talk. Hopefully, I've driven home that the initial diabetes treatment for Type two diabetes still includes education, lifestyle changes and met Foreman. And it's important early on to consider indicators of high risk or established atherosclerotic cardiovascular disease, CKD or heart failure. When considering your second line therapy for Type two diabetes, it's important to consider wait, sparing agents and medications with lower risk of hypoglycemia when possible on when you're advancing therapy. And hopefully, now you know which medications those are. And as you progress therapy and type two diabetes, Um, it's important to consider all of the patient specific factors that we discussed and ultimately so critical to include the patient in the decision making process. So thank you all so much, and I'll be happy to entertain any questions. Lauren. Thank you. That was fabulous. It's a daunting topic to be ableto encompass all the medications that are really available out there for diabetes and 30 minutes and ma'am, you you did it. So thanks for that we have time for just a couple of questions. We remind people that there is that box that you can enter your questions. I have a couple for you. That I was wondering about. One is you are in this environment where it might be a little bit more restricted and access to medications. But you just presented these really nice outcomes for cardiovascular disease. Heart failure. I'm just curious. What is the access? Like, uh, in your environments There in the community, health centers or underserved communities eyes it. Getting any better toe. Have access to some of these medications that really can make a difference in the outcomes of someone's diabetes. And e. Yeah, that's such a great question in such an important thing, Thio Consider. So, luckily, in the community health centers where I work, we do have excellent options for patients, even who are self pay without any insurance. Um, specifically, if you happen, thio work in the San Diego area, we have the 3 40 b assistance program, So certain pharmacies, um, are able Thio through programs, um, sponsored by the federal government. Offer s guilty to inhibitors GLP one receptor agonists at very low cost 20 to $30 a month. Thio to some of these patients. So yes, um, we are luckily able thio utilize some of these great medications even in patients with significant financial restrictions, so that I have a follow up question for you. Let's say you, um, add an injectable on someone in times of cove it How does that work? How are you able Thio guide someone through starting something like that? Sometimes there's a fear associated with an injection. What are you doing? Tell me a little bit about that. That is a great, great question and important consideration. So of course it's patient specific addressing a patient's concerns and comfort level with doing injections. And I do have many patients who are are comfortable for whatever reason, maybe already on insulin, or have family members doing injections who I've talked through over the phone, Um, some of these medications. And luckily, um, you know, many online resource is on each of the medications respective websites, great videos, which I've do utilize, um, in these situations because we don't want to delay due to Kobe, Um, you know, achieving appropriate management in these patients that that very clever What can I say? I have one last question before we head to the break from Emily, and I think it's an interesting one. How do you address uncontrolled patients with a one sees over 9% that are on aural agents. So metformin Genovia Cell phone in your real life style, financially restricted and needle phobia. What might you do next on these patients? I mean, that is, ah, challenge. And, you know, you really addressed a little bit that there is more access to some of these new medications. Eso they might utilize some of that. Is there anything else that you would consider this a tough situation? Absolutely. So the specific case that was brought up. It looks like a patient with an A one c F nine on metformin, Genovia, Stefanie Korea and financial restrictions as well as needle phobia, very realistic situation. So multiple things to consider and different options available. So I would the first that comes. First thing that comes to mind would be, um, addressing that needle phobia many of the GOP ones. Actually, I have patients who can still manage it. So one option would be thio. Replace that Januvia with the GLP one using some of the assistance programs that are available out there. Another option if the assistance programs are available to help with those financial concerns, to consider adding on a nest realty to both of those options helpful with with regards to wait and finally, if if those options aren't available considering a TZ d you know, um, they're very effective medications. The cost is low, are associated with weight gain, but again, there are benefits to using it as well. Yeah, that's great. Good. Very good comments. Thank you. And you know, there is again this that cost consideration might play a role. But Orel So Magda tied you. Also mentioned is now out there, and it's been shown to be quite effective as well. So, um, maybe not specifically, if if they can't get access to it, but certainly in some with needle phobia, if you can't manage to get them over it, that could be an option. So I am going to have Thio cut it off. For now, I see a few other questions, but some of these can be answered, uh, in our upcoming sessions related to SCLC two inhibitors and some kidney questions. So I'm going to save some of those far nephrology session with that. I'm gonna thank you. Lauren, Thank you so much for a great talk. And we are going to move to the break when we get back from that. My co director, Dr Samantha Harris, is going to take over the moderation and the introductions before we then head off to lunch after that. So go grab a cup of coffee. A bathroom break. We will be back at. Let me just check my schedule here. 10 o'clock sharp. Will have Dr David on at that time talking about new technology. Very exciting, eh? So we'll see you back right at 10 o'clock sharp. Thanks so much.
