Thank you for asking me to present this morning. My name is Mike. I'm a um ST7 registar and I've been doing a fellowship in peroperative care for the last 12 months or so. Um and I'm going to talk uh about the uh updated recommendations from the AGBI on the peroperative management of GLP1 receptor antagonists. um and time permitting I'll just talk a little bit about what the document says about SGLT2 inhibitors as well. So this was the um this was the document which was released in uh published rather in January of this year. Um it's essentially a multi-disiplinary consensus statement. So you can see the um various organizations that were involved in the production of it. Um it includes input from surgeons, anesthetists, uh doctors, pharmacists and they produced a series of recommendations for the management of these drugs uh using a a three-stage modified dely process. Um, so essentially I'd uh I wasn't really familiar of this but basically in in every round the the authors that are involved are given a series of recommendations which they can either agree with, disagree with or uh plan to revise and only recommendations that have more than 75% agreement are able to proceed to the next stage. Uh the recommendations go through this uh process three times uh until they get to a final series of recommendations which are the uh the guidelines that have been published. I've spent a bit of time going through it. It's not not an easy read to be honest. So hopefully what I can try and do is is summarize it and the key points over the next 20 minutes or so. Um I would say I think it's sort of perfect exam foder really for anyone who's planning to do exams. Um I think it would you know really lend itself well to both uh written or revive question and it's clearly clinically relevant because there are far more patients coming through on these drugs now. Um so to take a step back and talk a little bit about the physiology first. um you have both uh GLP1 or glucagon glucagon like peptide one and glucose dependent insulin insulinotropic polyeptide or GIP um and both of those are incrretin hormones um so they're secreted in response to glucose in the gut lumen and they lead to something called the incrretin effect uh which is where you see an increase in insulin secretion in response to oral glucose uh compared to an equivalent amount of glucose given intravenously And what they lead to is a a glucose dependent increase in insulin secretion and they also lead to an increase in insulin sensitivity. I think this diagram summarizes the effects of these drugs quite quite nicely really. It it only includes GLP1 on the diagram uh but GIP has broadly speaking the same effects. They produce weight loss by acting centrally. So they have actions on the hypothalamus to induce satiety and reduce appetite. Um and they also have effects on the stomach where they reduce gastric emptying. Um so what you see is a a slower increase in uh glucose concentrations after a meal. Um and a sensation that the patient feels fuller for longer basically. Um they lead to an increase in insulin secretion and also an increase in insulin sensitivity and GLP1 reduces glucagon synthesis. So overall what you see is an increase in peripheral glucose uptake um an increase in muscle glycogen synthesis and a reduction in hpatic glucanogenesis. GLP1 receptor antagonists and GIP receptor antagonists can or are available for the management of diabetes um as as drug classes on their own. Uh there is another class of drugs called DPP4 inhibitors. Those are the the glyins um that work similarly on this pathway by preventing the breakdown and increasing GLP-1 levels that way. Um and they are used in both the management of diabetes and obesity where patients have been observed to have lower plasma lower plasma concentrations of those hormones. What they also do interestingly is they have cardoprotective effects and those effects can be both direct and indirect. So the indirect effects are related to those effects of the drug that I've already mentioned. So weight loss, uh improved glycemic control, improve triglyceride and cholesterol profiles. They also have naturoretic effects. Um but the drugs also have or the hormones and the drugs also have direct cardoprotective effects because they've been shown to reduce oxidative stress. uh they improve cardiac myioide, glucose utilization and function and they also improve overall endothelial function. So what are the indications? Um so according to NICE GLP-1 receptor antagonists can be used either in the management of type 2 diabetes where they are used uh when the use of three oral agents is ineffective, not tolerated or contraindicated and the patients should also have a BMI of more than 35. Alternatively, they can be used in patients with a BMI of less than 35 where insulin therapy would have significant occupational implications for them. They're increasingly used in the management of diabetes and they've been shown to lead to significant improvements in glycemic control. But interestingly because of those cardiorotrotective effects, they've also been shown to reduce the incidence of major adverse cardiac events. The second indication is in weight management. Um so this is for patients with a BMI of more than 35 and when they have at least one obesity related co-orbidity plus or minus a high risk of cardiovascular disease. Um the second statement on this paragraph here was uh correct until a short while ago. Um so previously Munjaro Ampic and Saxenda were all only available on the NHS through uh or prescribed by specialist weight management services. Uh but Munjaro or Tzepide which is a dual agonist at both GLP1 receptor antagonists and GIP can now be prescribed in primary care. Um but there's going to be initially a phase roll out. So the patients who are likely to benefit most are going to be um eligible for it first and there's quite strict eligibility criteria through GP. So uh they need to have a BMI of greater than 40 and they also have to have four obesity related coorbidities. So it might be high blood pressure, type 2 diabetes, sleep apnnea, coronary artery disease, what have you. Another note on Njaro is it does lead to really significant weight loss. Um so studies have reported a mean weight loss of over 20% of initial body weight in 72 weeks. The results of cardiovascular outcome studies for Munjaro are still awaited but it's thought that that will also lead to a similar improvement in cardiovascular outcome profile in the patients taking it. It has been shown to significantly improve surrogate markers of cardiovascular disease. So I think overall we're going to see more and more patients and we already are seeing more and more patients that are taking these drugs not just because they're being prescribed them through the NHS either for the management of diabetes or for weight management but also because patients are now uh there's been a lot of press about it clearly in patients um getting private prescriptions to help with weight management and things like that as well. Um so the potential peroperative benefits then of of continuing these drugs peroperatively are that you know we can see improved glycemic control um and reduce the incidence of complications associated with hyperglycemia such as surgical sight infections problems with wound healing increased length of stay etc. Uh but also if you've got improved glycemic control you're less likely to need posttop uh sliding scale or your posttop insulin requirements will be lower. there's a lower risk of hypoglycemia and all the complications associated with sliding scale insulin as a result of that and as I already mentioned patients potentially will have improved cardiovascular outcomes and a lower incidence of major adverse cardiovascular events and some studies have suggested that even acute use of starting these drugs just a few hours before or after surgery is associated with those benefits including improved cardiovascular outcomes. the concern or the the main issue with continuing these drugs peroperatively is regarding the risk of uh delayed gastric emptying and pulmonary aspiration. So there's been uh several case reports of this. Um but overall there's a a lack of high quality evidence really regarding the the significant of that risk and that's led to a bit of uncertainty and conflicting recommendations about what to do with the drugs peroperatively. Um sorry for the the busy slide here but I just wanted to try and summarize a little bit really about you know what what the evidence says about gastric emptying with these drugs and overall you know studies which are primarily case reports have suggested that there is an association between use of the drugs and an increased risk of pulmonary aspiration uh with a quarter odds ratio of 10.23 two three in the elective setting and there have been case reports of pulmonary aspiration even in appropriately staffed patients who've been having either sedation or GA for for elective elective procedures. Uh but as I say there's it's conflicting really about how significant that risk is. Um and what we don't know is what the risk is in patients who are taking these drugs long term. So most of the studies have looked at what the impact is of starting the drug quite recently rather than long-term use in a perioperative setting. Um it's known that GLP-1 receptor ex GLP1 receptor antagonists display tachilaxis. So there probably is a an effect of tachaphilaxis on gastric emptying and therefore delayed gastric emptying is probably more relevant if the treatment was started quite recently or if the dose was recently increased rather than to patients who are on them long term. And I think it's important to say as well that clearly you know that the presence of gastric content is required for someone to aspirate but it doesn't necessarily mean that they will aspirate. Okay. um is the point that I'm trying to to make. All in all, there are significant potential perioperative benefits to continuing the drugs. There's a poorly defined or potential risk of aspiration which we don't really understand the magnitude of. But there are also several other factors that need to be taken into consideration when deciding, you know, what what to do with these drugs peroperatively. Um, previous guidance released by the ASA in 2023 suggested that we should hold them on the day of the procedure if the patients are having daily dosing or hold them a week before if they're on a weekly dosing um regime. But that was sort of a a widespread recommendation that was given irrespective of the indication for taking the drug whether they're on it for diabetes or weight loss for example also the dose that they're taking the type of surgery that they're having but also it didn't really take into account any of the patient characteristics or anesthetic techniques and finally it didn't take into account the potential negative effects of stopping the drug which this guideline has tried to address. The recommendations from this guideline really are that essentially giving a single recommendation about when to stop the drug is probably not sufficient to manage peroperative risk in this patient population. And the key thing that they recommend is that we should be doing an individualized aspiration risk assessment for all patients. Taking to it taking into account drug factors, which I'll talk about in a second, but also patient factors, procedural factors, and weighing all of that up against the potential negative effects of stopping the drug, which would be deterioration in glycemic control and the consequences of that, but also potentially an increase in the risk of major adverse cardiac events peroperatively. Thinking about the drug first of all it's important to consider the pharmacocinetic and the phicodnamic profiles of the drugs clearly and and I think really the most important thing to to highlight here and I'll go to this table for this which is again a really busy slide but you've got all of your GLP-1 receptor antagonists from left to right and then you've got Mojaro on the far right which is a dual agonist at both GLP1 and GIP. The two that we're seeing most frequently for weight loss would be um Zmpic and also um Nunjaro and they both have quite a long halflife. So five and seven days respectively but also there's quite a significant variation in the dose that patients might be prescribed depending on whether they're on the drug for diabetes or weight loss uh the roots and whether they'd be receiving it once daily or once weekly. So while the longer that they're stopped for, you know, if we stop these drugs for a longer period of time, there probably is a lower risk of residual gastric content, the guideline highlights that even stopping them for a week is probably not a sufficient duration to reduce the risk of pulmonary aspiration because there are some studies that suggest that stopping them even for up to 3 weeks is still associated with an increase in gastric volume. So, if we were just looking at stopping the drugs on their own, we'd have to stop them for a really significant period of time or or much longer than a week probably, and then we're going to expose the patients to the potential negative impacts of that. So, what they suggest that we do instead of that is to look at other factors, come up with an individualized risk assessment for patients, use shared decision- making when we're having conversations with patients peroperatively, and use strategies to to mitigate risk. So moving on from the drug, the patient profile, I think universally probably all patients who are on these drugs will be at high risk for aspiration anyway, not only because they're on the drug, but because they have either diabetes or they're obese and they might have other conditions or drugs that delay gastric emptying as well. the procedure. You know, clearly with emergency surgery, there's a higher risk of aspiration, but also if they're having procedures in which sedation or or no tracheal incubation would normally be used or planned, it might be sensible to adjust that technique or or consider an alternative. In summary, this slide hopefully helps to summarize the strategies that the guideline recommends, which first of all is to continue the drugs peroperatively, accepting that there may be an increased risk of pulmonary aspiration, but the potential benefits probably outweigh that risk and taking strategies with the patient involving them in shared decision m shared decision-m conversations to to try and mitigate risk. And it's fairly intuitive really what they've recommended. There are several strategies that they recommend which you know first of all adhere to fasting guid guidance that's quite straightforward but might not always be possible in an emergency setting for example to consider a regional anesthetic technique to use an RSI with or without crycoid pressure where you might not choose to do so otherwise to intubate the patient instead of using an LMA manage them in the headup position or put an NG tube in before or um before they go off to sleep or just before you wake them up. The other strategies it mentions would be to use pro kinetics which is not something that I typically use or have used in my uh practice or experience. But they also talk about using uh or the role for gastric ultrasound in assessing um risk in these patients. And I thought that would be an interesting point for discussion because it's not something that I really have much experience with or or of. Um I don't know how I was talking to um Dave Evans about this yesterday, but I don't know how uh reliable that would be in obese patients and I also don't know whether you know in this situation where you have a patient who's potentially at high risk of aspiration whether I would you know hang my hat on my ability to perform that with limited training or limited experience um and be uh reassured by that. But I know it's an option they recommended as an option um and it's something discussed to see what uh what people think. Um so the guideline also talks about the management of SGLT2 which I think SGLT2 inhibitors rather which I think is something that you know people are more familiar of. We we sort of got a fairly um clear way of working with those but I thought I would just touch briefly on what the guideline says about those as well. And again just going back to to the physiology just I think it gives some context to the potential risks associated with these drugs. So SGLT2 inhibitors in inhibit glucose reabsorption in the the proximal convoluted tubule. So you end up with glucose in the urine and that leads to a reduction in insulin secretion and an increase in glucagon secretion. Um you get an increase in lipolysis as a result of that with free fatty acid liberation and beta oxidation of free fatty acids leads to ketone production. So you get an increase in plasma ketone bodies uh without necessarily uh hypoglycemia and the result is glycemic DKA. Um, normally the time taken for ketone levels to increase is long enough to allow for adequate respiratory and renal compensation. So you don't see an acidosis. But if you have any increase in physiological stress such as fasting or surgery that drives further production of those hormones, it drives further ketone production and essentially the speed of ketone production increases and it overwhelms the ability to compensate leading to acidosis. Um the indications for SGLT2 inhibitors are uh in diabetes they're currently co- firstline with metformin. Uh for patients at high cardiovascular risk or those with existing cardiovascular disease, heart failure or CKD and they're also used in the management of heart failure and CKD in patients without diabetes because they lead to they cause an osmotic diaresis and you get a reduction in circulating volume. Um, previously I think it was thought that the risk of keto acidosis in these patients was probably just in patients with diabetes because patients taking them for heart failure might have sufficient insulin concentrations uh to prevent ketone production or keto acidosis but that's now been challenged and that there is a risk in both cohorts of patients although it's probably greater in patients with diabetes. Um the studies unfortunately it's difficult to use them really to inform or change practice because they're fairly limited in their um uh presentation and there you know the the authors in this guideline particular comment that there's you know risks of confounding and bias with the studies but the risk has been quantified in the studies that are available as being um one per thousand patients versus 0.69 69 per thousand patients in patients who are not on these medications and as you would expect the risk is higher in patients having emergency surgery. Um but again you know it's always a balance of risk. So clearly there's a risk of keto acidosis but that needs to be balanced against the risks of stopping the drug including hypoglycemia and worsening heart failure. With these drugs what I thought was interesting is that they've all got a halfife of about 12 hours but the effect on glucose excretion persists for quite a lot longer than that. So um your half life is 12 hours but glucose excretion will persist and therefore ketone generation will persist for longer than that. Um currently our advice is to admit them the day before surgery. So if you take the patient who has the drug in the morning they admit it they emit it sorry the day before and they come in on the morning of surgery they should have had a 48 hour gap. But there have been reports of ketoacidulosis even when patients have withheld the drugs for more than 72 hours. So we shouldn't again be reassured totally by that. you know there's not a defined cut off or a defined threshold where the risk of keto acidosis is eliminated entirely or reduces to zero entirely and on that basis the guideline recommends again that we should be taking strategies to to mitigate risk essentially. So while the drug should be admitted the day before uh we should also be having again shared decision-m conversations with patients about the risk of stopping the drugs and the reasons for that and taking strategies to mitigate the risk of ketone production during their starvation period. So trying to keep them hydrated by avoiding long starvation times and considering glucose containing fluids if there are periods of unplanned or unavoidable prolonged fasting. Um, what I thought was interesting and again another talking point potentially from this guideline was it recommends adequate glucose and ketone monitoring peroperatively but it doesn't give any guidance about how often or how uh frequently we should be doing that and basically puts the ball back in our court and says we should do it according to institutional capability which I thought was a little bit of a copout. Um so overall there's really a lack of high quality studies and a bit of uncertainty regarding the best way to manage these drugs fairly limited evidence base and then recommendations from this which I tend to agree with really are pragmatic but it focuses a lot on shared decision-m individualized risk assessment and taking strategies to mitigate risk accepting that recommendations on what to do with the drugs alone probably not sufficient to reduce the risk of both aspiration um decay in these patients. Um but overall going forward the rest the recommendation is to continue GLP1 and to emit SGLT2 the day before. Um if anyone has any questions be very happy to try and answer them.