Man, okay, our next presentation is Dr. Amanda Vest. She's going to be speaking about obesity, heart failure, and beyond, time for revolution and or resolution. Amanda is a expert heart failure cardiologist, is a section head of heart failure at Cleveland Clinic. Well, good evening, everyone. Thank you for staying with us through this evening. It's a real pleasure to be here with you all and the esteemed panel here. I am a heart failure cardiologist. I'm also obesity board medicine certified, so I have the pleasure of working with many patients across the heart failure and obesity spectrum to try and work on both of these comorbidities. And I think you've already got the hang of the app now. If you need a refresher, there's a QR code, and we will have a couple of poll questions as we go through. And I've been asked to share some of the content that we'll actually be presenting in a joint ACC Heart Failure Society of America session at 11 a.m. on Monday. So a quick plug for that, if anyone can join a more expansive discussion on this topic. But here we'll be touching on some brief hits around obesity and heart failure epidemiology and looking at our three main domains of treatment for obesity, specifically as they pertain to the patient with heart failure. So briefly regarding epidemiology, we know there's a very clear and consistent epidemiological link between excess adiposity across the lifespan and the subsequent development of heart failure. But remember, that link is much more clearly established for HEF-PEF, heart failure with preserved ejection fraction, as you see here in some data represented in the most recent iteration of HF stats. We see here the population attributable risk by some demographic groups for HEF-PEF, with hypertension in yellow really driving the way, but obesity in gray coming second as a risk factor for HEF-PEF development, but not such a clear pattern for heart failure with reduced ejection fraction. And this has been observed across a number of similar cohort studies. Keep that in mind as we go through. Now the epidemiology gets a little bit more complex when we move to the discussion of patients with established heart failure. So for individuals who already have HEF-REF or HEF-PEF, as you may well know, there have been a multitude of observational studies describing an obesity survival paradox. I'm gonna have a question around this because I'm really interested to hear your thoughts. So this survival paradox being the observation that individuals with an elevated body mass index, for example, in the 30 to 35 region, may have a more favorable survival than those with a normal range BMI is what has been published across many cohorts. Do you consider this A, fact, or B, illusion? And I'll tell you that the topic is gonna be discussed in much greater detail by Dr. Josephine Harrington during the Monday session, pulling together some of the most contemporary data. But if you think it's a fact, that's A. It's a biological phenomenon and it should impact on our decisions about weight loss in patients with heart failure or not. So this is really interesting because I see great swings in this that I speak at different settings and as I turn in papers for review. And I think you'll find that many of the experts, including Dr. Harrington, aligns with the idea that it's probably illusionary. She's gonna put forward a number of features around the substantial attenuation of any relationship once you put in all the potential confounders, the fact that it seems to be predominantly observed in a BMI analysis and not when you use other anthropometrics like waist circumference. Of course, we know that wasting, which drives down BMI, is a high-risk situation with the development of cachexia. And not only can we not find contemporary data to suggest that obesity protects from death in heart failure, we very consistently see that it drives up heart failure hospitalizations. So her conclusions are shown here. And really, for intentional weight loss in patients with obesity and heart failure, we very much can see some improvements in heart failure status, as we're gonna discuss, and no signal at this time for increased risk of death when it's intentional. So let us talk about those intentional methods. We have three domains of potential treatment, and I'm going to just touch on some data specific to our patients with heart failure in each three of the zones. So we still have very limited randomized controlled trials conducted in patients with baseline HEF-REF or HEF-PEF of the lifestyle interventions, be they calorie-restricted diets, exercise training, or a combination thereof. In fact, of the available data that we have, only three of them actually achieved significant weight loss. But we do see safety, obviously very important, and some signals of improvements in functional status and cardiometabolic health. So of course, lifestyle should be the basis of all of our obesity interventions, but we may think, well, what about bariatric surgery in this population? And even going back a decade, we do have data from a three-state administrative database analysis indicating that those with existing heart failure who undergo a bariatric surgery appear to have a lower rate of heart failure hospitalizations in the 13 to 24 months after surgery, as opposed to the reference periods in the 13 to 24 months before their bariatric surgery. On no note, this was a small cohort, and those individuals who died post-operatively were excluded from analysis. And this is an important point. A few years ago, we looked at the nationwide inpatient sample and were surprised to see that among those who received a bariatric surgery with pre-operative HEF-REF in red or pre-op HEF-PEF in blue, as compared to the rest of the bariatric population having surgery, there were significantly higher rates, at least for HEF-REF, of in-hospital mortality, and then really across many of the potential in-hospital cardiovascular and other organ complications. So picking patients correctly for bariatric surgery and optimizing them for that procedure in combination with our metabolic bariatric surgery colleagues remains an area of further study and ongoing learning. Having said that, we do now have a few observational cohort studies indicating reductions in mortality and also heart failure hospitalization after a bariatric surgery, specifically in individuals with baseline heart failure. So here are a couple of administrative databases that were analyzed, and in individuals who were admitted with heart failure and a prior history of bariatric surgery, a lower rate of mortality as compared to matched patients with heart failure who had not had a bariatric surgery. Then a couple of small subgroups, 142 and 247 patients, observed to have bariatric surgery with pre-existing heart failure who show a lower hazard ratio for mortality over the medium term of about four to five years and also lower odds ratios of hospitalization. So some helpful data there, but no granularity about HEF-RAF versus PAF phenotype and little information about how stable were these patients preoperatively. So we're gonna move now into our third domain of obesity management, which is anti-obesity medications, and firstly dive into the HEF-RAF situation. So as you've already heard, we have loraglutide, somaglutide, tizepidide, all with our FDA indications for obesity. But specifically, if we're talking about patients with HEF-RAF, which of these individuals would be appropriate for using one of these medications to manage obesity? Would it be A, the 64-year-old man with BMI 37, heart failure hospitalization last week and 3B symptoms awaiting transplant? A 52-year-old woman with a BMI of 35, HEF-RAF with NYHA class two symptoms and no prior admits? Or a 28-year-old male with BMI 45 and prior ventricular tachycardia who has declined a defibrillator? There's also option D, which is all three of the above patients. So I'll give you a moment with this. So all of these individuals in the vignettes have HEF-RAF, PF less than 40%, symptoms of heart failure, but who would you pull out that prescription for to manage obesity? This is really very interesting. And I don't think there's a right or wrong here, and I'd love to hear if my colleagues have opinions on this. For me, I would have answered B. And the reason for that is we have to think about the safety profile, obviously, in everything we do. And as I'm gonna show you, we have a couple of older studies pertaining to loraglutide in patients with HEF-RAF, which do raise some concerns about the safety of the GLP-1 agonists in the advanced HEF-RAF setting. And so although in my clinical practice within the multidisciplinary metabolic heart failure clinic that I run with some PharmD colleagues, I would ultimately, with appropriate counseling, probably offer the medication to patients A and B. I personally would not offer this medication to patient C unless they received a defibrillator. And I actually encountered this just last week, and the young lady has a defibrillator now. And I'll show you why. Maybe you'll think I'm overcautious. But the FITE-HF study, going back now a decade, was a study of treating patients with advanced HEF-RAF, hospitalization within the last 30 days, really sick cohorts, with loraglutide, 1.8 milligrams, versus placebo. This was not an obesity study, though about half of the population did have an elevated BMI. This and its European counterpart, Live, which looked at a similar setup, both raised some safety concerns. Although FITE-HF was neutral on its hierarchical endpoint analysis, if you look here at the Kaplan-Meier curve of mortality or heart failure re-hospitalization, you do see that loraglutide arm in the dark line, non-statistically significantly, trends towards a higher event rate than placebo. And just a couple of years ago, the investigators dove back in to look at the details here. And you see, versus the placebo group, the loraglutide group does trend towards more deaths. Now this was particularly notable in those with a baseline NYHA 3-4 status, or no pacemaker defibrillator. And as you see, the arrhythmic events, again, not a significant P, but numerically in excess. And this was a split of both atrial fibrillation and a significant number of V-fib events, V-T events, including one death. So I think we do have to respect this data. And although this was not a weight management study, and we don't know if this is a loraglutide-specific issue and maybe not a class effect, I am cautious around these meds. And we just published our initial experience in a metabolic heart failure clinic in Jack Heart Failure. And as you'll see in there, small numbers. But we have had a couple of patients who seem to have decompensated with very advanced stage D HFREF. So those patients do raise some warning signs. Fortunately, though, courtesy of Dr. Linkoff and colleagues, we do have some reassurance from the SELECT study. So about a quarter of participants in that large randomized controlled trial did have baseline heart failure. And recently, the group has published their outcomes by heart failure status. And so we see here on the left side, MACE and then a heart failure composite. Comparing placebo in red to the semaglutide arm in blue with both the HFREF and HFPEF comparisons. And you can see a significant reduction in the major adverse cardiovascular event rate, both for the HFREF and PEF patients, non-significant reductions for the heart failure composite. But remember, 90% of these patients were NYHA 1 to 2. They were a very stable group of patients with HFREF and not the likes of the advanced patients we were seeing back in FITE and Live. Now turning, of course, to HFPEF, which has been an area of great exploration over the last couple of years. Stormy Gale is a pharmacist at Atrium Health. And in Monday's session, she'll be presenting this data in more detail. As you're likely already aware, STEP-HFPEF was the first large randomized controlled trial of a weight intervention for patients with heart failure and obesity of any nature. And in this study, randomization to semaglutide 2.4 milligrams versus placebo in individuals with an EF of 45% and above, BMI of 30 and above, and also an abnormal Kansas City cardiomyopathy questionnaire score did show co-primary endpoints of an improvement in KCCQ as well as the weight loss as shown here. Now this was followed up by the SUMMIT study last year looking at tezepidide in a similar population. And this was a study really set up to look at the clinical endpoints with a composite of cardiovascular death or heart failure events shown here. And as you'll recall, the study did meet its endpoint and showed a significant reduction with a hazard ratio of 0.62 as illustrated. Perhaps a trend towards a stronger effect in those with the lower NT-proBNPs down at the bottom, but certainly across the BNP group, a consistent improvement in Kansas City cardiomyopathy questionnaire summary score. So our patients appear to be feeling better, doing better in terms of their patient-reported metrics. And this is so important, and I really like the way that Stormy has laid this out for her talk on Monday in which she's put the KCCQ clinical summary score changes seen in the recent HF-PEF studies alongside the obesity-related HF-PEF findings from STEP, HF-PEF, and SUMMIT. And you can see that the effects that we get from treating obesity medically are quite beyond that which we've seen with some of these other heart failure therapies in the HF-PEF setting. So this really sets us up for a question. Does GLP-1 agonism meet that threshold for being a GDMT-type therapy in obesity-related HF-PEF? And if we follow through that thought, do we have to then bring in that BMI cut point of 30 into our heart failure guidelines in their next iteration to help determine who would get these medications? And the reason why that makes me shudder a little bit is because BMI is already noted as a very imperfect tool for the obesity entity that we're trying to distinguish here. Of course, not only does it fail to acknowledge the relative amounts of lean mass versus fat mass, but in this heart failure population, of course, the fluid mass as well, which may be shifting. Furthermore, BMI was created as an insurance metric really based amongst white men and doesn't perform well across race and sex groups. And so we really do have some difficulties here, especially with people who are maybe in that sort of 27 to 35 range to understand what is the metabolic health and the actual consequences of obesity in those individuals. And this is what led the Lancet Diabetes Endocrinology Collaborative to put together their new proposal of how to define clinical obesity. So if you're not familiar with this, they take that elevated body weight or BMI as a first step, as a screening factor, and then ask for clinical confirmation of abnormal fat mass. This could be using a waist circumference or a waist-hip ratio, waist-height ratio, or using a DEXA scan to determine fat versus lean mass. Then the individual could be classed as not having obesity. Maybe their fat mass is not elevated because they have more of a muscular phenotype. But if fat mass does indicate obesity, then we have to assess for clinical obesity, which the collaborative describes as an obesity-related organ dysfunction, limitations of daily living, or both. If those are present, then an individual has clinical obesity, if not preclinical obesity. And here I've tried to think through, well, what does this mean if we're taking a population of patients with heart failure who may or may not have obesity? Well, we can screen on that BMI. I think for individuals perhaps with a BMI of over 35, maybe it's less controversial what's going on, and we don't need to waste the resources of doing DEXAs and spending more time in the diagnostic algorithm. But we come through and get to that point of confirming fat mass and saying, yes, an individual has obesity. Now let's cast our minds back to that epidemiology. And I would posture that if the individual meets the universal definition of heart failure for HEF-PEF, then we would say that's an obesity-related end-organ damage, and that's clinical obesity. Maybe also if they had HEF-REF with an etiology that was pathophysiologically linked to obesity, but probably not if they have HEF-REF for some other cause, maybe genetic cardiomyopathy, in which case they would fall into that preclinical category. So more for us to figure out and learn here. And to conclude, this is at least where I am currently thinking along with my colleagues with whom I research and do clinical practice in the area in terms of what's the approach to overweight and obesity in patients who have established heart failure. So if there's overweight, we don't have any evidence that weight loss itself is beneficial, but of course a healthy lifestyle is important. For obesity class one, the HEF-PEF population, we know get benefits from the anti-obesity medications. And for example, in STEP-HEF-PEF, we saw that specifically that lowest group of BMI was a category of patient that benefited. For HEF-REF, I think we still have to individualize based on other patient factors as noted here. Whereas for individuals with symptomatic heart failure and BMI of 35 and above, certainly for HEF-PEF, we have the data on safety and efficacy. For HEF-REF, we do have to be mindful of how advanced is their heart failure syndrome. Although in carefully selected patients who are closely monitored, I personally interact with these patients at least over telehealth every four weeks during up titration, then GLP-1 agonism or perhaps even bariatric surgery may be appropriate, especially as a pathway towards transplant in otherwise eligible patients. Thank you so much. Thank you.

obesity

heart failure

bariatric surgery

GLP-1 agonists

HFPEF