Okay, so thank you guys for sticking around to the very bitter end here, and we have some great questions So I know there's very few minutes remaining, but let me get to those questions here, okay? I know that one of you wants the CME thing posted. I will do that. I promise, but this Question is to Dr. Linkoff and Dr. Taub So I will let you Mike maybe go first, and that is is what is the impact of GLP-1 receptor agonist and SGLT-2 inhibitor and can you use them simultaneously? Can you use SGLT-2 inhibitor and GLP-1 receptor agonist, can you use them simultaneously? So we had no data on that in SELECT because SGLT-2s were not approved for the indications of the heart failure or the renal dysfunction at that time, so we don't have any data from that. The SOL trial which was presented today had over the course of the trial I think up to 50% at some point it had both. I think most believe that it's likely to be complementary and that one wouldn't There's no reason to believe physiologically that they would interfere with each other and they may well be complementary. So we do have data from patients with type 2 diabetes that are often prescribed a combination of SGLT-2 inhibitors and GLP-1 receptor agonist. I think in terms of for patients with obesity, I do have patients with obesity and CKD or obesity and HF-PEF where I clinically use a combination of GLP-1s and SGLT-2s and they work very well together. One of the things that's also nice about SGLT-2s that many people aren't aware of is you get osmotic diuresis and you do also get a little a couple pounds of weight loss with SGLT-2 inhibitors but if there's the indication whether it's CKD or HF-PEF or HF-REF indication or diabetes indication you can use it with a GLP-1. You know what, if you're gonna ask a question, I would ask you to come up to the microphone so that we can all hear you. Okay, so while you're coming up, maybe we can ask this question and that is to Dr. Vest. Can you use GLP-1 receptor agonist to jumpstart weight loss in addition to lifestyle modification and then importantly, can you wean off? Yeah, this is such a tricky question. I'm sure everybody has opinions about this. I think in my experience, there is a subset of patients, maybe it is more those with heart failure with preserved ejection fraction, who sometimes in using the GLP-1 agonist starts to lose some weight, has a lesser appetite, is really able to embrace the exercise and dietary interventions that they've not been able to embrace in the past, can build their lean mass with some resistance exercises, put up their resting metabolic rate and may at a later date do okay when they come off the GLP-1 agonist. But I think that's probably going to be the exception rather than the rule and I agree with the initial comments about making this a lifestyle expectation and a long-term medication plan. Okay, yes. Use your microphone, use the microphone. Yeah, we can hear you. The doctor was saying that you use combination of both medications at times and I specifically want to know about the HEF-PEF because we are always saying and then I want to know how much is the benefit with these two medications. I mean it says it works, right, but how much it is working and is there mortality benefit? Has it been shown? I think SCLT2 inhibitors, they have been shown with, you know, mortality benefit. The other question I had from the doctor, he said about the CRP, all different types of conditions and illnesses, wherever the CRP was high, it was effective. Did the levels go down in those patients? That was my question. Okay, thank you so much. Okay, let's just do two questions because there's so many other questions here. Thank you. I can briefly answer that. So for both patients with HEF-REF or HEF-PEF, as per their several respective studies for SGLT2 inhibitors, we do absolutely know that the composite of heart failure hospitalizations and cardiovascular mortality are reduced with a dipagliflozin or impagliflozin prescription. So unless there's a contraindication, so long as the EGFR is above 20, absolutely, the patient with HEF-REF or HEF-PEF should be on that med before you start thinking about adding on as a second line with GLP-1s. And as for the CRP, the CRP was reduced across the board by about 35% with semaglutide. So Mike, one of the questions here is who would you not start this medication on? Who would you not? So there's been actually a lot of interest. I've had patients say, can I come off my statin and go on to semaglutide, even if their body weight is low. Now again, CRP, as everybody has pointed out, is a poor measurement of adiposity. Nevertheless, I think that although there are some intriguing pathophysiologic mechanisms by which these drugs may actually help cardiovascular health in people who don't have overweight and obesity or diabetes, I think that regardless of your definition, that milieu is where we stand right now. Until and unless we see research pointing otherwise, that's certainly a group. We don't have evidence in overweight and obesity outside of patients with pre-existing cardiovascular disease. The Surmount MMO will have high-risk primary prevention. I think we all expect it will work, but you could argue that that's maybe a lower priority group. Not that I would consider it absolutely contraindicated. I would also add, based on the label, I wouldn't give it to patients with pancreatitis or the MEN, the endocrine syndromes with a specific type of thyroid cancer. In addition, I would be very careful in patients with known eating disorders like anorexia or bulimia. I just want to say that MEN, it was in one animal species. It's never been duplicated. It's probably entirely a false signal. Granted, it's in the label, but so much is made of it. You see all these listings of looking for this, and I think it's complete nonsense. I think most people, the science behind that is nothing. Martine, there's a question for you. We at the Cleveland Clinic, we do shared medical appointment because our volume is overwhelming. It's overwhelming. We have so many patients. They get started, and the biggest part is actually not filling out the pre-op form, which I know that's painful, and we got our lovely pharmacist to do that for us, so thank you, but our biggest pain point has been dose titration. And so because we have overwhelming number of patients, we decided to do shared medical visits. So, and how do you do it? Because the numbers are overwhelming, I'm sure, at your practice. So I started that metabolic clinic at the end of, in the winter of 2023, so my clinic is not, I'm the sole provider. They refer me all the patients in my, it's a big private group, so we don't do shared group visits, but I have trained one of the nurses who takes the calls in between when the patients have complications, and they just reroute to me whatever they think needs to be addressed. Let's say side effects, if they need to address the side effects, and I do a lot of telehealth visits. And the patients have access to me via email, they email me all the time with questions and all that stuff. Because I think one of the pain points of this drug, which is an amazing drug, as those, anybody who's ever prescribed this drug knows, besides the horrific pre-coverage issue, is the dose titration, and the enormous patient-initiated questions, because there's so much as you dose titrate. And, but once they get used to it, it sort of becomes very easy. So Mike and Pam and Amanda and Martine, what do you think is the weight benefit of this drug, this is a final question before we end the session, versus the class effect? So even if you don't, because Mike, one of the most sort of significant things I've learned from Select is that even if you lose, don't lose a lot of weight, you still get the benefit. So tell us what you think is weight, and what you think is the class effect. We start with Mike, and then we go all the way. So to be brief, I think that there are different effects on different endpoints. So for ischemic endpoints, I think it's very weakly related to weight. But for heart failure, for example, for at least the functional benefits for heart failure, there seem to be a very strong association. And I think, you know, the bone effects and other things that people are looking into. So I think it really depends on the endpoint. I'll leave it at that. No, I agree with Mike. But in general, I think there's a lot of pleiotropic benefit. I mean, just when you look at these drugs mechanistically, what they do to inflammation, what they do to oxidative stress, and all of these other important pathophysiologic mechanisms, I think it's beyond weight loss. But I do think for certain conditions, such as HFPAF, the weight loss does play a significant role. Yeah. Also in the HFPAF studies, of course, CRP did come down. And pro-BMP came down as well, despite the inverse relationship, usually, between pro-BMP and BMI. So I think there are metabolic things going on. But as mentioned, there was a bit of a tighter coupling between improvement in functional status and amount of weight loss in those studies. So it probably does play in more. But what weight being lost? And many think it may be that paracardiac adiposity, which came out in the MRI sub-study of summit, as seemingly being important. I agree with all of you. What I've seen, I definitely think there's a class effect. Because I've seen a lot of my patients, before they start losing weight, their numbers are getting better. Their cholesterol getting better. I've seen LDL drop significantly, even before they start losing significant weight. And on the select trial, I think the patients had less weight loss than the actual weight loss trial. And their cardiovascular benefits were there. So this is my experience. Fantastic. And thank you so much for staying until the bitter end. And the CME credits, can you guys put up that slide one more time for our audience? But thank you so much.

GLP-1 receptor agonists

SGLT-2 inhibitors

type 2 diabetes

cardiovascular mortality

inflammation reduction