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Diabetes Core Update is a monthly podcast that presents and discusses the latest clinically relevant articles from the American Diabetes Association's four science and medical journals – Diabetes, Diabetes Care, Clinical Diabetes, and Diabetes Spectrum. Each episode is approximately 20 minutes long and presents 5-6 recently published articles from ADA journals. Intended for practicing physicians and health care professionals, Diabetes Core Update discusses how the latest research and information published in journals of the American Diabetes Association are relevant to clinical practice and can be applied in a treatment setting. This issue will review: Effects of Patient-Driven Lifestyle Modification Using Intermittently Scanned Continuous Glucose Monitoring in Patients With Type 2 Diabetes Trends in Prescribing Preferences for Antidiabetic Medications Among Patients With Type 2 Diabetes in the U.K. With and Without Chronic Kidney Disease, 2006–2020  Changes in Glucose Metabolism and Glycemic Status with Once-Weekly Subcutaneous Semaglutide 2.4 mg Among Participants with Prediabetes in the STEP Program  Management of Hyperglycemia in Hospitalized Adult Patients in Non-Critical Care Settings: An Endocrine Society Clinical Practice Guideline  Dapagliflozin and Prevention of Kidney Disease Among Patients With Type 2 Diabetes—Post Hoc Analyses From the DECLARE- TIMI 58 Trial  Association of Estimated Time-in-Range Capillary Glucose Levels Versus HbA1c With Progression of Microvascular Complications in the Diabetes Control and Complications Trial    For more information about each of ADA's science and medical journals, please visitwww.diabetesjournals.org. Presented by: Neil Skolnik, M.D., Professor of Family and Community Medicine, Sidney Kimmel Medical College, Thomas Jefferson University; Associate Director, Family Medicine Residency Program, Abington Jefferson Health John J. Russell, M.D., Professor of Family and Community Medicine, Sidney Kimmel Medical College, Thomas Jefferson University; Director, Family Medicine Residency Program, Chair-Department of Family Medicine, Abington Jefferson Health

This week, please join author Sanjiv Shah, Editorialist Evangelos Michelakis, and Associate Editor Justin Ezekowitz as they discuss the article "Latent Pulmonary Vascular Disease May Alter the Response to Therapeutic Atrial Shunt Device in Heart Failure" and Editorial "Atrial Shunt Devices in Patients with Heart Failure and Preserved or Mildly Reduced Ejection Fraction and the Pulmonary Circulation: Promises and Concerns." Dr. Carolyn Lam: Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from The National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health, in Richmond, Virginia. Dr. Carolyn Lam: Greg, I love today's featured article. It's all about heart failure with mildly reduced and preserved ejection fraction, talking about device therapy and the response to therapeutic atrial shunt device. Now, this is a very interesting discussion of how specifically selecting patients based on latent pulmonary vascular disease may hold some answers, but we're going to keep everyone hanging here. You've got to, got to listen to the discussion. But first, we'd like to tell you about some of the papers in today's issue. And I think Greg, you've got one to start us with, right? Dr. Greg Hundley: Absolutely. Carolyn, thank you so much. Well, this first paper comes from Dr. Eliot Peyster from the University of Pennsylvania. And Carolyn, the aim of this study was to leverage computational methods for analyzing digital pathology images from routine endomyocardial biopsies, to develop a precision medicine tool for predicting cardiac allograft vasculopathy, years before overt clinical presentation. Dr. Carolyn Lam: Ooh, interesting. Again, precision tools. So what did they find? Dr. Greg Hundley: Right, Carolyn. So there was a clinical predictive model that achieved modest performance on the independent test set, with area under the receiver operating curve of 0.7. But interestingly, a histopath- predictive model for predicting cardiac allograft rejection achieved good performance, with an area under the receiver operating curve of 0.8. Most importantly, however, a model, incorporating both clinical and histopathologic features, achieved excellent predictive performance, with an area under the receiver operating curve of 0.93. Dr. Greg Hundley: So in summary, Carolyn, these authors found that prediction of future cardiac allograft vasculopathy development is greatly improved by incorporation of computationally extracted histologic features. Their results suggest morphologic details, contained within regularly obtained biopsy tissue, have the potential to enhance precision and personalization of treatment plans for post heart transplant patients. Dr. Carolyn Lam: Aw, that's cool. Makes so much sense, but yet so novel. Thanks. Dr. Carolyn Lam: Well, for the paper I want to talk about, we are going to talk about dapagliflozin. Now we know the SGLT-2 inhibitor, dapagliflozin, improved heart failure and kidney outcomes in patients with Type two diabetes with or at high risk for cardiovascular disease, in the DECLARE–TIMI 58 trial. In the current paper, authors, led by Dr. Wiviott from the TIMI study group, aimed to analyze the efficacy and safety of dapagliflozin stratified, according to baseline systolic blood pressure. Dr. Greg Hundley: Ah, so an interesting question, since SGLT-2 inhibitors are known to reduce blood pressure. And given the concerns regarding the safety of SGLT-2 inhibitors, in patients with low to normal systolic blood pressure. So Carolyn, what did they find? Dr. Carolyn Lam: Nicely put Greg. So in patients with type two diabetes with, or at high risk of, atherosclerotic cardiovascular disease, dapagliflozin reduced the risk for heart failure hospitalizations and renal outcomes, regardless of baseline systolic blood pressure, with no difference in benefit for reduction in heart failure or renal outcomes, among patients with blood pressure from the normal range, all the way to severe hypertension. Moreover, there appeared to be no difference in adverse events of volume depletion, acute kidney injury, or amputations, across the levels of baseline blood pressure. So these results indicate that dapagliflozin provides important cardiorenal benefits in patients with Type two diabetes at high risk, the independent of baseline blood pressure. Dr. Greg Hundley: Oh, very nice, Carolyn. Well, my next paper comes to us from the world of preclinical science, and it's from professor Jeffrey Towbin and colleagues, at Le Bonheur Children's Hospital. So Carolyn, as we know, arrhythmogenic cardiomyopathy is an inherited genetic disorder of desmosomal dysfunction, and plakophilin-2 has been reported to be the most common disease causing gene when mutation is positive. Now in the early concealed phase, the arrhythmogenic cardiomyopathy heart is at high risk of sudden cardiac death before cardiac remodeling occurs, due to mis-targeted ion channels and altered calcium handling. However, the results of pathogenic plakophilin-2 variants on myocyte contraction in arrhythmogenic cardiomyopathy pathogenesis, really remains unknown. So Carolyn, these authors studied the outcomes of a human truncating variant of plakophilin-2 on myocyte contraction, using a novel knock-in mouse model, as well as evaluation of human subjects. Dr. Carolyn Lam: Oh, interesting. So what were the results from this plakophilin-2 knock-in mouse model? Dr. Greg Hundley: Right, Carolyn. So serial echocardiography, a plakophilin-2 heterozygous mice revealed progressive failure of the right ventricle, but not the left ventricle, in animals older than three months of age. Now next, adrenergic stimulation enhanced the susceptibility of plakophilin-2 heterozygous hearts to tachyarrhythmia and sudden cardiac death. Contractility assessment of isolated myocytes demonstrated progressively reduced plakophilin-2 heterozygous RV cardiomyocyte function, consistent with right ventricular failure, measured by echocardiography. Dr. Greg Hundley: And the next, Western blotting of plakophilin-2 right ventricular homogenates revealed a 40% decrease in actin. In contrast, plakophilin-2 heterozygous left ventricular myocytes had normal contraction and actin expression. Dr. Greg Hundley: And finally, Carolyn, Western blotting of cardiac biopsies revealed actin expression was 40% decreased in the right ventricles of end stage arrhythmogenic cardiomyopathy patients. So in conclusion, Carolyn, during the early concealed phase of arrhythmogenic cardiomyopathy, reduced actin expression drives loss of RV myocyte contraction, and that contributes to progressive RV dysfunction. Dr. Carolyn Lam: Wow. Thanks, Greg. Well, also in today's issue, there's an exchange of letters among Drs. Whitman, Ibrahim, and Løfgren, regarding physics at the heart of the matter, referring to the article, “Anterior–Lateral Versus Anterior–Posterior Electrode Position for Cardioverting Atrial Fibrillation.” Dr. Greg Hundley: Right Carolyn. And also in the mail bag, there's an On My Mind piece, from Professor Taegtmeyer, entitled, “The 2022 Beijing Winter Olympics, The Spotlight On Cardiac Metabolism.” Dr. Greg Hundley: Well, how about we get onto that feature article, and learn a little bit more about atrial shunts, and how they may be helpful in heart failure with preserved ejection fraction? Dr. Carolyn Lam: Ooh, can't wait. Dr. Greg Hundley: Well, listeners, we have a very interesting feature discussion today related to hemodynamics pertaining to interatrial shunt devices, in those with and without pulmonary hypertension. And we have, gosh, a repertoire of speakers today. We have Dr. Sanjiv Shah, from Northwestern University in Chicago, Dr. Evangelos Michelakis, from Edmonton Alberta, and our own associate editor, Dr. Justin Ezekowitz, also from Edmonton Alberta. Dr. Greg Hundley: Well, Sanjiv, we're going to start with you. Describe for us, some of the background pertaining to your study, and what was the hypothesis that you wanted to address? Dr. Sanjiv Shah: Great. Thanks, Greg. Thanks for having me today. Well, the background of our study is that, it was a subgroup analysis, or a secondary analysis, of the REDUCE LAP-HF II trial. Now this trial has been in the making for over 12 years, almost 13 years. It started out as an idea that was David Celermajer. David is a pediatric cardiologist in Australia, who had this idea that, in mitral stenosis patients, it's well known that, if there's a concomitant secundum ASD, a congenital secundum ASD, in these patients with mitral stenosis do better. They have a way to unload the left atrium, and distribute that blood to the systemic veins and the right atrium, the right side of the heart. And so could this be helpful in quote, diastolic, heart failure or HFpEF? Dr. Sanjiv Shah: And so, I started working with him about 12 years ago. This started out as a concept. It was studied in animal models, and then in humans, in open label studies, and then, in a first randomized controlled trial. Where we showed, that an intraatrial shunt device, an iatrogenic ASD, so to speak, put in humans with heart failure with risk preserved EF, results in a lowering of exercise pulmonary capillary wedge pressure. And so based on that data, we designed a pivotal trial, a Phase III trial, the largest trial of its kind, of heart failure with preserved and mildly reduced ejection fraction, to see if interatrial shunt device would improve outcomes. And we published that trial earlier this year in the Lancet. Unfortunately, it was a totally neutral trial. And when you have a neutral trial in any condition, but as we see often in HFpEF, the question is, was it neutral overall? Or was there a subgroup that benefited? And what we found in that trial was that, there were three predefined subgroups that came out that seemed like there was a difference. Dr. Sanjiv Shah: First, there was a sex difference. Women did better. Men did worse with the device. Then, there was right atrial volume. Those with bigger right atrial volumes did worse. If you had a smaller right atrial volume, you did better. But the most significant interaction and subgroup was exercise pulmonary artery systolic pressure. Dr. Sanjiv Shah: If the pulmonary artery systolic pressure was greater than 70 at 20 Watts of exercise, so just with a little bit of exercise, those patients did worse. And if PA pressure stayed low, the patients did better. And so we sought to further explore this to say, "Okay, what's exactly going on?" In a post hoc analysis, what's going on with the pulmonary vasculature during exercise, and how does that differentiate how patients potentially respond to the device? And that's what we hope to figure out. Dr. Sanjiv Shah: We hypothesize, that if exercise pulmonary vasculature resistance is lower, then the shunt can actually work, and blood can flow from the left to the right, into the lungs, and the right heart doesn't get too overloaded. And we know, that the normal response of the pulmonary vasculature is to vasodilate with exercise. And so, if patients had retained that response, the ability to do that, that they may benefit. And so, we sought to figure that out with this subgroup analysis. Dr. Greg Hundley: Sanjiv, it sounds like a really elegant, well thought out hypothesis. So what was your study design? And describe your study population. Dr. Sanjiv Shah: Yeah. This was a randomized controlled trial. And so this was 626 patients enrolled at 89 centers across the world. And it was really, heart failure with mildly reduced, so an EF of greater than 40, or preserved EF, and 93% of them had HFpEF. And what was unique about this trial is that we, this is the first trial really, that confirmed that these patients actually had heart failure, with mildly reduced or preserved ejection fraction. Most trials say, well, you have to have an elevated BNP, and you have to have some sign of structural heart disease, and maybe, a history of heart failure hospitalization. In this trial, every single patient had to undergo rigorous noninvasive echocardiography. And then, on top of that, they had to undergo exercise invasive hemodynamic testing. And people thought that it wasn't possible for 626 patients, but we did it. And every single patient had had an exercise pulmonary capillary wedge pressure greater than, or equal to, 25. And so this really was HFpEF. So it's a randomized trial. Dr. Sanjiv Shah: And then, beyond that, we did a subgroup analysis. So we looked on various subgroups, focusing on exercise PVR, and we really looked to see the effect on three outcomes. Number one, a hierarchical endpoint, a combination of cardiovascular death, ischemic nonfatal stroke, recurrent heart failure hospitalizations, and the KCCQ. And then the other two outcomes were just the individual recurrent heart failure hospitalizations, and the KCCQ. We looked at all of these, and tried to figure out if there are certain subgroups that benefit. Dr. Greg Hundley: Great detail. So Sanjiv, what did you find? Dr. Sanjiv Shah: Well, we found that, there's this group of patients, that during exercise, the pulmonary vascular resistance at peak exercise stays above 1.74 Wood units. Now that seems like an arbitrary number, but in fact, in older individuals that are healthy, when you exercise them, the PVR upper limit, the exercise PVR upper limit, is about 1.8. So we're right about the upper limit of where the PVR should be. And if it was above that, the patients actually did worse with the shunt device. They had a lot more heart failure hospitalizations. Their KCCQ got worse, didn't benefit. And if they were below that threshold, meaning they were, sort of compliant pulmonary vasculature, and it stayed compliant, or they vasodilated effectively with exercise, then they benefited from the device. And what we call this concept of exercise-induced pulmonary vasoconstriction, or inability to vasodilate, is latent pulmonary vascular disease. Dr. Sanjiv Shah: And so, if you have that latent pulmonary vascular disease, your win ratio is 0.6. That means you do worse. And if you don't have this pulmonary, this latent pulmonary vascular disease, your win ratio is 1.31. And that means, you do better with the device. And we saw very similar findings with the KCCQ. We saw similar findings with the recurrent heart failure hospitalizations. Dr. Sanjiv Shah: And the final thing is, we found that, we looked at various other subgroups, and it turned out that if there was no latent pulmonary vascular disease and no history of pacemaker, which we found was kind of associated with sex and right atrial volume, those patients, for about 50% of the group, actually did the best. And that was what we called, the responder subgroup. Dr. Greg Hundley: Thank you, Sanjiv. Well, listeners, we're going to turn now to our associate editor, Justin Ezekowitz. And Justin, you have many papers come across your desk. What attracted you to this particular manuscript? Dr. Justin Ezekowitz: So Greg, this paper kind of stood out for a number of different reasons, as I sent you. You're to be congratulated for a variety of reasons. But the number one is, pursuing the data from a neutral trial overall, to understand who might benefit and who might be harmed from a pretty novel device and way to treat patients in such a scale, that's not being done like this before. So it stands out by just the magnitude of number of right heart catheterizations, number of patients enrolled, number of procedures done. And all of those things really lead to us to be able to understand the area much better than I think we can in a human population. Dr. Justin Ezekowitz: Where this sits with other devices that are very similar, is hard to really know, if all devices are going to be the same or different, but your population is quite unique is if they're not all end stage, but they're sick enough to get into your trials. So there's this population we treat actively. And I wondered if you could touch on that continuous nature. And so for readers, there's this beautiful figure, which shows a continuous nature of exercise PVR. And I wonder if you could touch on that. Is this mid group, the group that we should target for our future therapies like this, or this needs further study? Dr. Sanjiv Shah: Well, I think it needs further study. I think the listeners should be aware that this is a post hoc analysis. We did pre-specify exercise PA pressure. This is one trial. But it makes a lot of sense, pathophysiologically. What we're doing here is we're shunting this excessive LA, overloaded LA, shunting the blood from the LA to the RA and into the pulmonary vasculature. Well, if that pulmonary vasculature can't accept that increased flow, the patient's not going to do well. And how can we simulate that? Well, we can simulate it with exercise. As the patient's pedaling on the bike, on the cath lab table, there's increasing blood flow to the pulmonary vasculature, and we're seeing what happens with the pulmonary vasculature. Does it vasodilate, does it not? And so, I think that's why we were excited about this finding. Dr. Sanjiv Shah: I do think that, there are at least seven other companies making shunt devices, interatrial shunt devices or therapies. And I do think, they need to pay attention to this and really look at this. Not all trials are doing exercise and basic hemodynamics, that needs to be done, I think. So it'll be really interesting to see. Dr. Sanjiv Shah: Now, one thing I will say is that, and I've written about this, this is a really interesting trial. Because the BNPs were lower, and so you would think, okay, these are patients that are less sick. And yet, their heart failure hospitalization rate was at least one and a half times higher than pharma Phase III trials. KCCQ was way lower, like 30 points lower. So there are these patients out there that are really sick, and they're the ones that I think, are where their life, their sort of quality of life, their outcomes, are being driven by the HFpEF. And that's what we found in this trial. Dr. Greg Hundley: Very nice. Well, listeners, let's turn now to our editorialist, Dr. Evangelos Michelakis. And Evangelos, two questions. How do we put the results of this substudy, really in the context of the main trial? And then secondly, do you have any, with your expertise in endothelial function, and understanding the mechanisms of pulmonary hypertension, can you describe what you think might be operative as a mechanism here, and why Sanjiv observed these positive results in some patients? Dr. Evangelos Michelakis: Thank you. So the first point is that, I have to also repeat, that it was a remarkable achievement to do all this right heart catheterization on a treadmill in the cath lab. It's a very complex procedure. And it is, they have to be congratulated, the authors, for actually doing this. There is no question that, like Sanjiv said, ongoing trials for future trials will need to include the hemodynamics in the trials, before and after the procedure. Dr. Evangelos Michelakis: So another important thing is that, the authors brought up this, they called it latent pulmonary hypertension, we could call it latent pulmonary hypertension, or probably, early pulmonary hypertension, as an entity. Now that entity, it's newer in the heart failure field. It's not that old in the PIH, the pulmonary interior hypertension field, since it used to be in the guidelines for this disease, that exercise pulmonary hypertension was a diagnostic criterion for that. Because the idea is that, exercise pulmonary hypertension reflects early pulmonary hypertension. So you needed to intervene with therapies early. Dr. Evangelos Michelakis: Now, I'm not sure that this is a fact. But it is very likely that these patients, in Sanjiv's trial, that had the early, that had the sort of enhanced response with exercise, did have at least, endothelial dysfunction in the pulmonary arteries. Not only because this population has a number of endothelial risk factors, diabetes, smoking, you name it. But also, there are newer problems like SNPs polymorphism mutations, that will recognize more into the pulmonary arterial hypertension field, to be more unique to the pulmonary circulation. Dr. Evangelos Michelakis: But the reason I say that is that, the reason that you dilate with exercise, is mostly because of your pulmonary arterial endothelial cells, secreting vasodilatory factors. And also, allowing previously closed capillaries to open up with increased flow. However, the problem is that, if you have pulmonary arterial endothelial cells in vitro, and you expose them to high flow, like in this case, you can actually change their identity. Turn them into cells that are not endothelial cells anymore, are proliferative pro-inflammatory, and they can actually cause structural pulmonary circulation damage. Dr. Evangelos Michelakis: Also, there are animal models and people working in PAH and ASD, where they've shown that, if you have, if you're given endothelial toxin in animals, and then, you do an aortocaval shunt, then you get really severe pulmonary hypertension with structural disease, that is not even reversible if you remove the shunt. Dr. Evangelos Michelakis: So from this trial, the conclusion that patients with pulmonary hypertension should not get the device, is very clear. And probably, the ones with exercise pulmonary hypertension. My theoretical concern is, for those that don't have exercise pulmonary hypertension, or those that do have it, could they get worse after a number of years, and have structural pulmonary vascular disease? And unfortunately, we didn't have a follow up right heart catheterization to prove that, whether this is right or wrong. Which is a thing, is the most important thing to do in the future. So mimic the protocol for this trial from now on, but also add a follow up right heart catheterization, perhaps not just in a year, but longer. In other words, enough time to allow the structural pulmonary remodeling get established, but also, affect the right ventricle, these things don't. So maybe in a few years. It's a very demanding thing for these protocols, but I think, that's what needs to be done before we say this device can actually be beneficial for those patients, or for some patients, or not hurt others. Dr. Greg Hundley: Very nice. And so, a great segue, Evangelos, into what we think the next studies may need to be performed in this particular sphere of research. Dr. Greg Hundley: So Sanjiv, in just 30 seconds, could you share your thoughts first, and then we'll circulate back to Justin, and then finish up with Evangelos. Sanjiv? Dr. Sanjiv Shah: Yeah. I think the key thing is, to do a confirmatory trial. And that's what we're aiming for, is to do a confirmatory randomized sham-controlled trial, but focus in on these patients with an exercise peak PVR of less than 1.75, around there. And I think, that'll help answer the question. The Qp/Qs we get with this device is 1.2 to 1.3. So I don't think it's a high flow. And we actually have open label studies, where we've gone out to three years, with repeat invasive hemodynamic testing, echocardiograms, and we've had patients who've been implanted for seven years. We're not seeing, at least at that point, any sort of worsening of pulmonary vascular disease, or RV function, or anything like that. And so, it remains to be seen. Dr. Sanjiv Shah: The last thing I'll say, which I think is provocative, in the field of HFpEF, all pulmonary vasodilator drugs have failed. And though, we only measure pulmonary vascular resistance at rest. And what we saw in this trial, is that some patients have a high PVR and it comes down. Some people have a PVR that stays low, and is low and stays low. Some people have a low PVR and it goes up. You know? So I think what we need to think about in the field of PH‐HFpEF, is more exercise genotyping, to determine what's the dynamic exercise PVR? And maybe, those with exercise elevation of pulmonary vascular resistance are the ones that respond to pulmonary vasodilators. So that's another thing that I think we can think about taking away from this trial. Dr. Greg Hundley: Thank you, Sanjiv. Justin. Dr. Justin Ezekowitz: Yeah. So my thoughts are mimicking Sanjiv's. But one of the things that we desperately need is, ways in which we can noninvasively assess the exercise PVR, so that we can think about the large scale interventions that might come down the road, if interventions such as this work well. Because the noninvasive scans will really help us look at broader populations. Those are, that don't make it into trials, and those that aren't traditionally in our studies of HFpEF. So I think, that's another area where we can really grow the field, and then, grow our knowledge. Dr. Greg Hundley: Very nice. And Evangelos. Dr. Evangelos Michelakis: So, yes. Of course, like everybody said, we need trials that will have a follow up right heart catheterization, at least address, if not both, like the investigators did. But because the big question is, are these patients having an earlier stage pulmonary hypertension or not? These patients that the authors called, latent pulmonary hypertension, we need to phenotype more their endothelial cells, or their disease. And in the absence of biopsies, the only way we could do that, is perhaps, with molecular imaging, or at least, in some small populations. Or with analyzing pulmonary arterial endothelial cells in the blood, and their molecular phenotype, to see if they are a distinct group, which I suspect they may be. So further genotyping of this exercise induced pulmonary hypertension in this population, will be important as well. Dr. Greg Hundley: Thank you. Well, listeners, we've had a great discussion today, from Dr. Sanjiv Shah, from Northwestern University in Chicago, our editorialist, Dr. Evangelos Michelakis, from Edmonton, Alberta, and our own associate editor, Dr. Justin Ezekowitz from Edmonton, who brought us this study, demonstrating that in patients with heart failure and preserved ejection fraction, or heart failure and mildly reduced ejection fraction, the presence of pulmonary vascular disease, uncovered by invasive hemodynamic exercise testing, identifies patients who may worsen with atrial shunt therapy. Whereas, those without pulmonary vascular disease may, at least in the short term, benefit. And of course, as Evangelos has pointed out, the long term findings really warrant further study. Dr. Greg Hundley: Well listeners, on behalf of Carolyn and myself, we want to wish you a great week, and we will catch you next week on the Run. Dr. Greg Hundley: This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors, or of the American Heart Association. For more, please visit ahajournals.org.

This week, our very own Carolyn Lam is in the author role along with author Vlado Perkovic, Associate Editor Naveed Sattar, and Guest Editor John McMurray as they discuss the articles "Efpeglenatide and Clinical Outcomes With and Without Concomitant Sodium-Glucose Cotransporter-2 Inhibition Use in Type 2 Diabetes: Exploratory Analysis of the AMPLITUDE-O Trial" and "Effect of the Glucagon-Like Peptide-1 Receptor Agonists Semaglutide and Liraglutide on Kidney Outcomes in Patients With Type 2 Diabetes: A Pooled Analysis of SUSTAIN 6 and LEADER Trials." Dr. Carolyn Lam:             Welcome to Circulation on the Run, your weekly podcast, summary, and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley:           I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr. Carolyn Lam:             I have a confession. I am nervous because right after this, Dr. Greg Hundley is going to interview me and, thank goodness, not just me, but really, really interesting other authors and editors with feature papers, all about GLP-1 receptor agonists and the SGLT-2 inhibitors. Very, very, very hot topic. Do listen up! But for now, Greg, you're going to be nice, right? How would you start? Dr. Greg Hundley:           Well, thank you, Carolyn. I am really looking forward to that. Maybe we'll have a few quiz questions in there. Before we get started, how about we grab a cup of coffee? I am going to bring to our listeners a paper from the world of preclinical science. It's from Professor Vincent Christoffels from Amsterdam. Carolyn, there's a pathogenic variant in the fifth exon of TBX-5 entitled PG125R. It's found in a Dutch atypical Holt-Oram syndrome family with early onset atrial fibrillation. These investigators modeled this in a mouse. Carolyn, this is the first human pathogenic variant based on a patient family in this key cardiac transcription factor that's been explored in an in-vivo animal model. Dr. Carolyn Lam:             Wow, that's interesting. So, what did they find, Greg? Dr. Greg Hundley:           Right, Carolyn. The investigative team identified widespread electrophysiological transcriptional and epigenetic changes including coding and non-coding RNA, chromatin accessibility, and H3K27ac associations in the atria of TBX5-PG125R heterozygous mice distinct from the changes in the atria of TBX5 insufficient animals. Dr. Carolyn Lam:             Okay. Could you give us the clinical take home message, Greg? Dr. Greg Hundley:           Right, Carolyn. What these authors really have found is that the characterization of the TBX5-BG125R mouse model... it indicates that a patient-specific pathogenic variant in TBX5 induces changes in regulatory element activity, an altered balance in the regulatory network of atrial cardiomyocytes, and clinically relevant changes in cardiomyocyte function. So therefore, Carolyn, this work may provide insight into the epigenetic changes and transcriptional underpinning of arrhythmias in the general population caused by small increases in TBX5 expression also caused by common variants predisposing ones to atrial fibrillation. Dr. Carolyn Lam:             Wow. Thanks Greg. Well, guess what? I've got an interesting mouse model to share about as well. This next paper comes from co-corresponding authors, Drs. Chen, Fu, and Wu from UCSD. What they do is provide insights into possible underlying factors in a molecular mechanism responsible for left ventricular noncompaction cardiomyopathy. Now, we know this condition, but... It was discovered half a century ago, yet owing in part to the lack of a suitable mouse model that faithfully mirrors that selective left ventricular vulnerability in patients, the actual mechanisms underlying susceptibility of the left ventricle to dilatation dysfunction in this condition actually remain unknown. Well, until now. Dr. Greg Hundley:           Wow, Carolyn. So, what actually did this investigative team do, and what did they find? Dr. Carolyn Lam:             At the basis of their study is a transcription factor. This is PRDM16. This transcription factor has previously been implicated in this condition through characterization of defects associated with the 1P36 syndrome. What the authors did this time, though, is they generated two new conditional knockout mouse models of PRDM16. Their subsequent characterization of the phenotype is a tour de force of gene expression analysis that uses a myriad of functional genomic approaches, including RNA-seq, ChIP-seq, single cell RNA-seq spatial transcriptomics. What they found is cardiomyocyte specific ablation of PRDM16 in mice indeed caused left ventricle specific dilation and dysfunction, as well as biventricular non-compaction. In other words, fully recapitulating the left ventricular noncompaction syndrome in patients. Mechanistically, PRDM16 functions as a compact myocardium enriched transcription factor which activated compact myocardial genes while repressing trabecular myocardial genes in the left ventricular compact myocardium. Consequently, PRDM16 knockout cardiomyocytes shifted from their normal transcriptomic identity to a transcriptional signature resembling trabecular myocardial cardiomyocytes and/or neurons and chamber specific transcriptional regulation by PRDM16 was in part due to its cooperation with left ventricular and rich transcription factors. Dr. Greg Hundley:           Carolyn, wow. Mechanistic understanding now for cardiovascular noncompaction. This is really exciting research. Clinically, how can we interpret this work from this animal model? Dr. Carolyn Lam:             Thought you may ask. This study provides a unique left ventricular noncompaction mouse model for developing therapeutic interventions for any person with a left ventricular dilation and dysfunction, which emerge as the most important disease features in this condition. Improper specification of compact or trabecular cardiomyocytes is likely the common mechanism in the pathogenesis. Spatial single cell gene expression profiles in normal or disease conditions can be shown in this example to facilitate future studies for identifying new targets. This paper is accompanied by an editorial by Drs. Mably, Joe Wu, and Dr. Wang. Dr. Greg Hundley:           Very nice Carolyn. Well, there are some other articles in this issue, and before we get to that feature forum let's go through those with our listeners. First, Carolyn, I've got a Research Letter from Professor Cornel entitled "Long Term Efficacy of Colchicine In Patients With Chronic Coronary Disease With Insights From LoDoCo2." Dr. Carolyn Lam:             Wow. There's an exchange of letters between Drs. Wang and Ji regarding the article "Histidine Triad Nucleotide Binding Protein-1 Attenuates Cardiac Hypertrophy Via Suppressing Homeobox A5 Expression," Global Rounds paper by Dr. Indolfi on the universal healthcare system and cardiovascular disease burden in Italy. There's a cardiovascular case series by Dr. Raber on a pacemaker red herring and a hypertrophic cardiomyopathy copycat. Finally, there's a Perspective piece by Dr. Drakos on a mechanical bridge to recovery as bridge to discovery learning from few and applying to many. Dr. Greg Hundley:           Well, Carolyn, I can't wait to get to this feature forum discussion, and I get a chance to interview you. Dr. Carolyn Lam:             Ah! All right, let's go. Dr. Greg Hundley:           Welcome listeners. We have on this February 22nd a forum feature discussion where we have two papers that we are going to present, and oh, what an honor it is. Guess who I get to interview first? Dr. Carolyn Lam from the National Heart Center of Singapore, along with a guest editor, Dr. John McMurray from Glasgow University in Scotland, followed by another paper from Dr. Vlado Perkovic from the Georgia Institute for Global Health in Sydney, Australia. Then lastly, Dr. Naveed Sattar, one of our associate editors who also comes to us from Glasgow, Scotland. Welcome to all of you. Well, Carolyn, we're going to start with you today. I know you've got a paper combining the use of GLP-1 receptor agonists with SGLT-2 receptor antagonists. Can you tell us, Carolyn, a little bit about the background that went into this study? What was the hypothesis that you wanted to test? Dr. Carolyn Lam:             Happily, Greg. First of all, what a pleasure to be sitting on the opposite side of the mic, if I might say so, and a real privilege to be speaking on behalf of the AMPLITUDE Executive and Steering Committee about this paper. The whole idea is that we know that SGLT-2 inhibitors and GLP-1 receptor agonists are the rage being recommended for their reduction in cardiovascular events in patients with Type 2 diabetes. However, they appear to do this by complimentary mechanisms. That really raises the tantalizing question of, "Can we combine them?" Now, What do I mean by that? Well, GLP-1 receptor agonists are known for their reduction in the risk of atherosclerotic ischemic events, particularly like stroke, that benefit being greater, whereas a relatively modest effect on kidney function, perhaps heart failure. Whereas SGLT-2 inhibitors more impressively reduce the risk of heart failure, kidney function decline, kidney outcomes, and so on with a modest effect on myocardial infarction and perhaps no effect on stroke. So, you see, very complimentary. The whole question was, "What would it be like to combine these treatments?" And, in the absence of a trial that actually does a two by two randomization perspective or anything, we decided to look back at the AMPLITUDE-O trial, which was a large multinational trial of patients with Type 2 diabetes randomized to the GLP-1 receptor agonist efpeglenatide versus placebo, but was unique in including the largest proportion thus far of concurrent SGLT-2 inhibitor use in these prospective GLP-1 receptor agonist trials to date. Dr. Greg Hundley:           Very nice. And so, you've told us a little bit about your study design. How about specifically your study population? And then, Carolyn, what did you find? Dr. Carolyn Lam:             All right. So, of the 4,076 participants in the AMPLITUDE-O trial, 618 reported SGLT-2 inhibitor use at baseline. They were fairly similar to those not receiving SGLT-2 inhibitors. They had similar age and body mass index, but were less likely to be women, they had a longer duration of diabetes, similar history of cardiovascular disease, but lower prevalence of prior heart failure and lower blood pressure, HB A1C, LDL cholesterol, and albuminuria, but similar GFR. When we looked at the effect of efpeglenatide in the presence or absence of baseline SGLT-2 inhibitor use, we basically found no difference. The P for interaction for each of these outcomes was basically not significant, whether we were looking at MACE and expanded MACE, which included revascularization and angina on top of standard MACE, whether we were looking at a renal composite or a composite of MACE and death, or whether we were looking at heart failure hospitalization. Which, by the way, all of these were significantly reduced by efpeglenatide, and so, similarly, whether or not there was a baseline SGLT-2 inhibitor. Very importantly, side effects were also similar whether or not patients were on an SGLT-2 inhibitor concurrently. This bodes really well for the combination. Dr. Greg Hundley:           Very nice Carolyn. Well, John, as a guest editor to Circulation, several papers often come your way each year. What in intrigued you about this particular manuscript? Dr. John McMurray:       Well, exactly as Carolyn said, Greg, this asks a question and gives some of an answer to a question that all of us are asking which is, "Should we be using these two drugs together? Do they have complimentary additive benefits, or are those benefits independent of each other?" I think, as Carolyn said, her data from the AMPLITUDE-O trial, which was a fantastic trial, go some way towards addressing that. And, Carolyn, I wondered... Maybe to give some more context to these really interesting data... I think this question was asked the other way around. I think our colleagues in the DECLARE–TIMI 58 trial looked at it in reverse. They were able to look at adding of an SGLT-2 inhibitor to the subset of patients who were in a GLP-1 receptor agonist. What... Can you remind us what they found, because I think that's an interesting alternative approach to this? Dr. Carolyn Lam:             Excellent point, John, thank you. Because DECLARE was so big a trial that even though the percentage of patients on a concurrent GLP-1 receptor agonist was a bit smaller if you look at percent, it was still a very large subgroup. Thankfully, those results were extremely consistent with what we are seeing, too. In a trial of an SGLT-2 versus placebo, the SGLT-2 inhibitors benefits were regardless of concurrent GLP-1 receptor agonist, and we showed the mirror image of that. Again, I think with the totality of evidence, it's very reassuring and also very important because to truly answer this, we would need a huge prospective randomized two by two trial, or... Which, I think will not be feasibly accomplished except in a pragmatic trial. Dr. John McMurray:       Carolyn, maybe one very last point to make again about context, which Greg asked about. Here, we're talking about the primary, secondary prevention of cardiovascular events. You mentioned heart failure, which we're both very interested in. That's intriguing, because it looks to me like the heart failure was largely the prevention... perhaps the incident heart failure. I think there is still a question mark about the role of GLP-1 receptor agonists as a treatment for prevalent heart failure. Do you agree? Do you think that's still an unanswered question? Or, do these results in some way make you more comfortable about using GLP-1 receptor agonists in patients with established heart failure? Dr. Carolyn Lam:             Wow. Again, an excellent question. These data reassure me that if I had a patient with Type 2 diabetes who developed heart failure and still required glucose control I would be very comfortable continuing a GLP-1 receptor agonist, because many of these patients in this trial who got heart failure obviously didn't drop out of the trial. They continued on the GLP-1 receptor agonist and the safety profile looks okay. However, I do not agree that the GLP-1 receptor agonists have become a treatment for heart failure the same way the SGLT-2 inhibitors have. That would require, in my mind, evidence in a prospectively defined validated population of heart failure, with known ejection fraction or not. And, to be even more provocative, I suppose, even perhaps without diabetes. Now, that would really put the nail in the coffin, if I may. Basically exactly what you did, John, in DAPA HF. Dr. John McMurray:       All right, to finish on a provocative comment for the audience just before we leave this segment, it may of course depend on the heart failure phenotype type as well. In all of these trials, we're never really sure whether the patients have HFpEF, HFrEF, or a combination. So, lots of questions still. Dr. Greg Hundley:           Very nice. Well, thank you so much, Carolyn and John. Listeners, next we want to turn to our second feature article. This one is from Dr. Vlado Perkovic. Vlado, welcome. You have a paper involving GLP-1 receptor agonists and focusing on renal disease. Can you describe for us a little bit about the background pertaining to your paper, and what was the hypothesis that you wanted to address? Dr. Vlado Perkovic:         Thanks so much, Craig, and thanks for having me here. It's such a joy to be part of this conversation. Our paper was a post hoc analysis of two completed clinical trials, the LEADER and SUSTAIN trials that looked at liraglutide and semaglutide, respectively, compared to placebo in people at high cardiovascular risk. We wanted to ask the question of... in more detail, the effects of these agents collectively and individually on important kidney outcomes to try and understand whether the GLP-1 receptor agonist, which, as Carolyn says, have clearly had significant benefits for MACE in particular, might also have the sorts of benefits that we've seen, for example, with SGLT-2 inhibitors on renal outcomes recognizing the massive burden of ill health, premature mortality, morbidity, economic, and social costs that go along with kidney disease as a complication of diabetes. What we've done here is we've pulled the data from the two trials and looked at them collectively and individually to try and unpack the effects of GLP-1 receptor agonists on a range of kidney outcomes. We've looked at different thresholds of loss of kidney function. Traditionally we've used doubling of creatine, which equates to a 57% loss of kidney function. More recently, we've moved to a 40% loss of kidney function as being a good outcome in kidney trials. There's been a push for 30 and 50% outcomes to be used. Here we wanted to look really comprehensively at all of those outcomes, as well as the outcomes of change in albuminuria and change in EGFR slope, where we had more power, perhaps, to detect differences between the agents. Our hypothesis was that GLP-1 receptor agonists would have evidence of kidney protection. We thought up front that the likelihood was the kidney protection would be consistent at different levels of kidney function and might be similar between different agents. But, that wasn't what we ended up finding. Dr. Greg Hundley:           Very nice. So, you mentioned the SUSTAIN and the LEADER trials. Can you describe for us a little bit more, and some of the specifics, perhaps, to your study population? And then, walk us through your study results. Dr. Vlado Perkovic:         Yeah, so very happy to do that. Thank you. As I say, these trials were primarily cardiovascular outcome trials that were designed to assess the cardiovascular effects of the GLP-1 receptor agonists and therefore the populations reflect that intent with people who had preexisting cardiovascular disease primarily. What we found when we looked at the results was evidence of perhaps modest reduction in some of the renal outcomes based on different thresholds of loss of kidney function of the order of 10 to 20% overall when we looked at the pooled study population. Of course, that compares to a much more significant 30 to 40% reduction in the risk of these same outcomes when we look at drugs like SGLT-2 inhibitors. Overall, they didn't appear to be quite as effective. But, we were somewhat surprised when we started to dig into the data in more detail in that we found that people who had reduced kidney function based on a lower EGFR, particularly an EGFR below 60, or those who had either micro or macro albuminuria, the benefits of treatment appeared to be greater in absolute and proportional terms. It also was much clearer, such that in people who had both had reduced EGFR and an increased level of albuminuria, there were reductions in the risk of the constant renal outcomes of approximately 40%, suggesting that these drugs may be particularly effective in people with established kidney disease, which... there's a novel finding today. We were able to dig into that in more detail, looking at albuminuria and EGFR slope and effectively found consistent results for those outcomes as well, giving us some confidence that the findings perhaps were more likely to be real. We, in addition, looked at the different drugs and found some evidence that high dose semaglutide... in particular, one milligram weekly dose, and appeared to be more effective than the lower dose of semaglutide or liraglutide for some of those intermediate markers, if you like. Dr. Greg Hundley:           Very nice. Naveed, now, as the associate editor, what intrigued you about this particular study? What drew your attention to it and caused you to bring it through that review process to our readers? Dr. Naveed Sattar:          Yeah. Thanks Greg, and thanks Vlado. Now, I think this is a lovely study. I think we've been familiar with the effect of GLP-1 and albuminuria for a long time. I think that's fine, but not... that doesn't really float everyone's button. You know, albuminuria is not necessarily a hard endpoint. But, EGFR and EGFR slopes are becoming something that people are starting to become interested in as a marker of future diabetic kidney disease in end stage kidney disease. Vlad could probably comment on that. I think there was a suggestion if you meta-analyze all the GLP-1 trials, which we did recently on the back of efpeglenatide, both Carolyn and John were co-authors.... that there's a suggestion that GLP-1 may actually improve hard kidney outcomes. This paper, on the back of that, with a detailed look at EGFR slopes and different thresholds, does further support the fact that liraglutide and semaglutide do slow kidney outcome progression, particularly in those who've already got a degree of kidney damage. Now, the context of that is actually really important in the sense that Vlado and colleagues and nephrologists around the world are very excited about the SGLT-2 inhibitors. But, also having another drug on top of that would might further slow kidney damage is excellent, particularly in a population which also has more atherosclerotic cardiovascular disease. These drugs could therefore have a double benefit, not only slowing kidney damage, but also preventing atherosclerotic cardiovascular disease and the population at high risk of both conditions. Of course, the future then also, as John mentioned, will be, "what about the benefit on top, and going forward in heart failure as well?" I think this study looks... well, adds to the support that GLP-1 receptor agonists actually improve hard kidney outcomes. I think that's the realization. But, going back to Vlado, I'd be interested to get his comment of, "Well, does this study and associated evidence now lead you to think when should we be using these drugs in our patients with chronic kidney disease?" That probably is the question, Vlado. Dr. Vlado Perkovic:         Yeah. That's an important question. I think, Naveed, for us as a community. I think one of the nice things is that we can use these drugs in people with kidney disease already. They're approved, and we don't have the same sort of EGFR restrictions as we've had with SGLT-2 inhibitors. But, what we really want to know is, "What are the benefits that we're offering to our patients, and at what price might that come? Is there an increased risk of adverse events in this very sensitive population?" Of course, the only way to answer those questions is to test it prospectively, which we're now doing in the FLOW trial, where we're randomized three and a half thousand people on semaglutide and placebo. So, over the next couple of years we will answer that question more definitively I hope. We're particularly focused on people with kidney disease in that trial. But of course it also... These data, if they're confirmed in that trial, raise important questions, I think, about the mechanism of the renal effect that needs teasing out. If they're truly more effective in relative terms, as well as absolute terms, in people who've got established kidney disease what does that tell us about the way that they might be providing that renal benefit? And its relative interaction, not only with SGLT-2 inhibitors, but also with mineralocorticoid receptor antagonists, which have recently additionally been shown to be beneficial on the kidney in the FIDELITY and the FIGARO trials. Dr. Greg Hundley:           Very nice. Well, Naveed, you have led us and Vlado into our next very quick rapid fire question for our listeners, in working through each of you, both as authors and editors, what do you see is the next study to be performed in this sphere of research? Carolyn, we'll start with you, then John, then Vlado, and then Naveed. Dr. Carolyn Lam:             Well, I think I alluded to it a little bit earlier that what we'd, of course, really love is a prospective randomized trial looking at the combination of the treatments versus placebo and versus one of each only. That sounds like pie in the sky, though. Maybe a pragmatic trial. Maybe an... Oh, John, shut your ears, but maybe looking back at real world data to look at this a little bit better. We're going to need a little bit more, at least I think, also to reassure ourselves that the combination is really safe in these patients. Dr. Greg Hundley:           John? Dr. John McMurray:       I think we need to know about GLP-1 receptor agonists in patients who don't have Type 2 diabetes because I think it's going to be critically important going forward to know whether this is just about dysglycemia and glucose lowering, which it seems probably isn't. Because my interest is in heart failure, of course, I would like to see these drugs tested in patients with symptomatic heart failure and both the major heart failure phenotypes with and without Type 2 diabetes. Dr. Greg Hundley:           Vlado? Dr. Vlado Perkovic:         Yeah, I'd support what John says and add people with and without diabetes in kidney disease as well to that group, as we've seen with DAPA-CKD study. I think the other really big opportunity for us here that's been highlighted by work done by John and others is the possibility that we might dramatically reduce the prevalence of these terrible complications of diabetes by using combination therapy and multi-drug combination therapy. Potentially, we've got not just the GLP-1 receptor agonist and the SGLT-2 inhibitors, but we've got MRAs and other drugs, depending on which outcome we're talking about. If these drugs are truly independent, as Carolyn's important work suggests, we could have a major impact at a population level on the prevalence of these terrible disorders in our patients. Dr. Greg Hundley:           And finally, Naveed. Dr. Naveed Sattar:          Yeah, thanks. I'm glad I'm not the only one who upsets John McMurray now and again, but it's probably good for him. What I would say is I agree with all the comments thus far. I would love the fact that with the newer stronger GLP-1s giving us additional weight loss, and, perhaps, with the combined GLP-1 GIP drugs, I would love if we could test them early in diabetes, actually, to actually reverse diabetes, as it were. And, can we delay these complications for 5-10 years, and perhaps with combination SGLT-2? Of course, we can't really do that now because of the costs, but going forward... And, John and I have had lots of conversations about multi-morbidity and obesity is being a big driver to all of that. Now we've got class of drugs coming that actually could cause significant weight loss and improve multiple outcomes that we've discussed: kidney, heart failure, atherosclerotic cardiovascular disease, and also possibly improve patients quality of life, particularly if the weight loss is quite substantial. I would love if we target that, but I think that's partly linked to some of the answers that've already been heard. Dr. Greg Hundley:           Well, listeners, we want to thank our investigators, Dr. Carolyn Lam and Dr. Vlado Perkovic, and also our editors, Dr. John McMurray and Dr. Naveed Sattar for bringing us these two papers. The first highlighting that the efficacy and safety of GLP-1 agonists appear independent of concurrent SGLT-2 inhibitor use. And the second paper, emphasizing that GLP-1 receptor agonists offer renal protection, particularly in those with advanced renal disease. Well, on behalf of Carolyn and myself, we want to wish you a great week and we will catch you next week On The Run. Speaker 7:          This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors or of the American Heart Association. For more, please visit AHAjournals.org.

Insights from DECLARE-TIMI 58 Trial

Part Ten: Trial Review, DECLARE-TIMI

Following the last episode focusing on GLP-1 RAs, we are now turning to SLGT2 inhibitors. Which patients would benefit most from an SGLT2 inhibitor, and who should we avoid offering one? To help answer these questions, we're joined by Dr Kevin Fernando, GP Partner and Scottish Lead for the UK Primary Care Diabetes Society. For more free education, visit the DKIP website, follow us on Twitter (@dkipractice) or connect on LinkedIn. Funding statement: This independent educational activity is supported by an educational grant from Eli Lilly, Merck Sharp and Dohme Corp. and Novo Nordisk A/S. The educational content has been developed by Liberum IME in conjunction with an independent steering committee; the financial supporters have had no influence on the content of this education. Disclosures: Dr Kevin Fernando declares the following: Advisory Board Member - Lilly, Napp, Boehringer Ingelheim Speaker Honorarium - Lilly, Napp, Boehringer Ingelheim References: - Zinman B et al. N Engl J Med. 2015;373(22):2117-2128 [EMPA-REG OUTCOME]. - Neal B et al. N Engl J Med. 2017;377(7):644-657 [CANVAS]. - Wiviott SD et al. N Engl J Med. 2019;380(4):347-357 [DECLARE-TIMI 58]. - Cannon CP et al. N Engl J Med. 2020 Oct 8;383(15):1425-1435 [VERTIS-CV]. - Perkovic V et al. N Engl J Med. 2019;380(24):2295-2306 [CREDENCE]. - McGuire D et al. JAMA Cardiol. 2021; 6(2): 1–11 [CVOT meta-analysis]. - Heerspink H et al. N Engl J Med. 2020 Oct 8;383(15):1436-1446 [DAPA-CKD]. - Packer M et al. N Engl J Med. 2020 Oct 8;383(15):1413-1424 [EMPEROR-Reduced]. Funding statement: This independent educational activity is supported by an educational grant from Eli Lilly, Merck Sharp and Dohme Corp., and Novo Nordisk A/S. The educational content has been developed by Liberum IME in conjunction with an independent steering committee; the financial supporters have had no influence on the content of this education.

SGLT2 inhibitors are the new drugs which have been approved for heart failure with reduced ejection fraction (HFrEF). After the landmark EMPA-REG_OUTCOME, DECLARE TIMI 58, EMPEROR REDUCED and DAPA HF trials, empagliflozin and dapagliflozin have found a place in the management of HFrEF or heart failure. Lets discover what makes them special drugs in heart failure.

FDA 批准超速效赖脯胰岛素治疗糖尿病Diabetes Care 1型糖尿病业余运动员：9天中高强度自行车训练意外的升高血糖Nature Review Cardiology SGLT2抑制剂：除血糖控制外的心血管益处机制Annals of Internal Medicine SGLT2抑制剂与糖尿病酮症酸中毒风险Cell ALK基因功能下调可以减肥超速效赖脯胰岛素（URLi）超速效赖脯胰岛素（URLi），在短效赖脯胰岛素的基础上改良的一种起效更快、持续时间更短的胰岛素，更大程度上模拟生理条件下、餐后胰岛素的释放曲线。超速效赖脯胰岛素与赖脯胰岛素相比，达到50%最大功效的时间分别为12.8分钟和25.4分钟，两者30分钟内的总暴露量分别为99.3pmol*h/L和34.8pmol*h/L。超速效赖脯胰岛素20分钟达到峰值，持续6小时。2020年6月，超速效赖脯胰岛素（LyumjevTM）已经被FDA批准上市。《PRONTO-T2D研究：超速效赖脯胰岛素与赖脯胰岛素在长效胰岛素基础上治疗2型糖尿病的3期临床研究》Diabetes Care，2020年6月 (1)评价赖脯胰岛素与超速效赖脯胰岛素（URLi）比较，在长效胰岛素基础上治疗2型糖尿病的疗效和安全性。共673位患者，在优化的、长效甘精胰岛素或长效德谷胰岛素的基础上，联合餐前赖脯胰岛素治疗8周后，患者随机分入餐前0-2分钟注射超速效赖脯胰岛素组、或普通赖脯胰岛素组。两种短效胰岛素均能改善患者糖化血红蛋白，治疗结束时糖化血红蛋白分别为6.92%和6.86%。在控制1小时和2小时餐后血糖的变化方面，超速效赖脯胰岛素优于赖脯胰岛素：餐后1小时两组差异为0.66 mmol/L，2小时两组差异为0.96 mmol/L。接受超速效赖脯胰岛素治疗的患者餐后30分钟至4.0小时内，餐后血糖偏移明显减少。两种治疗方法之间的总体治疗紧急不良事件，包括低血糖，发生率相似。结论：在2型糖尿病患者中，餐时注射的超速效赖脯胰岛素与餐前注射的赖脯胰岛素在控制糖化血红蛋白方面效果相当，但在餐后血糖控制方面优于赖脯胰岛素。《PRONTO-T1D研究：与赖脯胰岛素相比，超速效赖脯胰岛素改善了1型糖尿病患者餐后血糖控制》Diabetes Obesity Metabolism，2020年8月 (2)在一项为期26周的III期临床试验中，评估了超速效赖脯胰岛素（URLi）与赖脯胰岛素在成人1型糖尿病患者中的疗效和安全性。研究发现超速效赖脯胰岛素在控制糖化血红蛋白方面，不劣于赖脯胰岛素。餐时注射超速效赖脯胰岛素在减少餐时1小时和2小时餐后血糖方面明显更优秀：1小时两组血糖差异为1.55mmol/L， 2小时两组差异为1.73 mmol/L，餐后4小时低血糖发作降低37%（P = 0.013）。其他的不良反应发生率相似。结论：在1型糖尿病中，超速效赖脯胰岛素提供了良好的血糖控制，餐后血糖控制优于赖脯胰岛素。1型糖尿病的运动管理规律的运动对1型糖尿病儿童和青少年具有重要的健康和社交益处，应鼓励。有氧运动（步行、骑车）通常可降低血糖浓度，而无氧运动（全速跑、曲棍球、举重）通常会升高血糖，许多团体运动（足球、篮球、棒球）包含有氧和无氧运动。低血糖可能发生在运动期间或运动后不久，或者延迟至运动后数小时或睡眠时。高血糖可能发生在运动期间，或情绪激动时。建议运动前、运动30分钟、运动恢复期和睡前监测血糖。《1型糖尿病运动后血糖控制与残留的β细胞功能有关》Diabetes Care，2020年10月 (3)研究旨在评价剩余β细胞功能对1型糖尿病患者运动后血糖的影响。研究招募30名、1型糖尿病病史≥3年的参与者，首先盲法进行7天的自由生活数据采集；然后进行3小时混合餐试验评估C肽和胰高血糖素水平。使用C肽峰值将参与者分成极低C肽组（C肽浓度200 pmol/L）；最后，参与者完成45分钟在60%VO2峰值的运动，然后再进行48小时的连续血糖检测。在运动后12小时和24小时，高C肽组参与者中葡萄糖正常的时间显著高于其他两组的参与者（高C肽组：12小时 73.5%，24 h 76.3%；低C肽组：12小时43.6%，24小时52.3%；极低C肽组12小时40.6%，24小时 51.3%）。而且，高C肽组参与者中高血糖的时间显著低于其他两组，血糖的波动也更小（P < 0.01）。从运动前到运动后24小时连续血糖检测的结果发现：高C肽组的参与者血糖控制得更好了（正常血糖的时间增加了12.1%），但另外两组的血糖控制得更差了（正常血糖的时间减少了9.1%和16.2%）。结论：剩余的β细胞功能可能部分解释了1型糖尿病患者运动后血糖的个体间差异，量化C肽有助于为患者提供个性化、针对性的运动支持。《1型糖尿病与有氧运动：在长效基础胰岛素基础上，运动前单次口服果糖可降低运动性低血糖的风险》Diabetes Care，2020年8月 (4)虽然调整胰岛素是降低1型糖尿病患者运动相关性低血糖风险的既定策略，但对超长效基础胰岛素治疗的患者来说，这并不容易实现。目前的研究确定了1型糖尿病患者在运动前摄入果糖是否能降低因运动引起的低血糖的风险。研究中14名参与分别完成了两次60min的有氧自行车运动，一次在运动前30min服用20g果糖，一次不服用果糖。摄入果糖的情况下，患者60min平均只发生1次低血糖事件，而对照组在运动的约30分钟内发生6次低血糖事件，果糖将运动时低血糖的风险降低了87.8%。服用果糖的运动期间平均血糖为7.3mmol/L，对照组为5.5mmol/L。摄取果糖后30分钟内休息时，患者的乳酸水平较高，但运动期间即回到基线。结论：对于使用超长效胰岛素的1型糖尿病患者而言，运动前摄取果糖是一种简单可行、有效且耐受良好的策略，可以减轻运动引起的低血糖风险，同时避免高血糖。《1型糖尿病业余运动员：9天中高强度自行车训练意外的升高血糖》Diabetes Care，2020年8月 (5)1型糖尿病中，心率变异性（HRV）降低可能是早期的自主神经功能障碍的一种表现；1型糖尿病患者，尤其是剧烈运动和长时间运动时，血糖会急剧变化，从而对心率变异性产生负面影响。本研究中，20名患有1型糖尿病的业余运动员9天骑行1500公里。研究出乎意料的发现，骑行的距离越长，高血糖时间越长，低血糖时间越短，同时夜间心率变异性越低；这可能和副交感神经张力降低有关。而且在这一过程中，胰岛素的使用没有改变，从饮食中摄入的碳水化合物也没有变化减少。结论：在患有1型糖尿病的运动爱好者中，长时间中高强度运动加重了高血糖，而高血糖与副交感神经及心脏功能相关；考虑潜在的对心脏的有害后果，未来的工作应该集中在理解和管理运动引起的高血糖现象。《1型糖尿病与中高强度运动：在运动前，采用长效胰岛素和胰岛素泵混合方案》Lancet Diabetes & Endocrinology，2020年6月 (6)使用持续皮下注射胰岛素泵（CSII）的1型糖尿病患者通常会在长时间运动前移除泵，但这种方法可能会增加高血糖和酮症的风险。该研究目的是评估一种混合方法的有效性和安全性，即通过胰岛素泵混合德谷胰岛素qd（一种长效胰岛素）提供每日必须的基础胰岛素治疗。这是一个单中心、开放标签、概念验证、随机交叉试验中，招募了平时规律使用胰岛素泵的1型糖尿病患者，开放标签分入单用胰岛素泵组和胰岛素泵联合长效胰岛素治疗组中，两组患者均在运动前60分钟停止胰岛素泵，运动后立即重新连接。与通常的胰岛素泵方案相比，混合胰岛素泵方案的参与者在中高强度运动后6小时内，血糖稳定（4-10mmol/L）的时间显著延长；在家运动时的高血糖持续时间更短。两种干预措施低血糖时间和低血糖事件方面没有显著差异。结论：清晨注射一次长效胰岛素和胰岛素泵的混合方案似乎对有规律运动习惯的1型糖尿病成人更加安全有效的。小羽点评：1型糖尿病病患者的残余β细胞功能和自主神经功能障碍均会影响患者运动后的血糖。β细胞残余功能越差，血糖波动越大；长时间中高强度的运动，副交感神经张力降低，引发高血糖。为了更高的减少运动后高血糖，可以采用长效胰岛素和胰岛素泵混合方案；为了减少运动相关低血糖时间，可以在运动前服用果糖。2型糖尿病的药物治疗-SGLT2抑制剂钠-葡萄糖协同转运蛋白2（SGLT2）表达于肾近端小管，介导约90%的滤过葡萄糖的重吸收。SGLT2抑制剂促进肾脏对葡萄糖的排泄，因此可降低血糖、降低血压和体重，通常不会导致低血糖。SGLT2最常见的副作用为外阴阴道假丝酵母菌感染及低血压。对于合并糖尿病肾病、心力衰竭和冠心病的患者，可考虑优先使用。在《内分泌科星期五 Episode 5》中，我们聊到了SGLT2抑制剂在1型糖尿病患者中的应用，不知道各位听众是否还记得。由于SGLT2抑制剂有增加1型糖尿病患者酮症酸中毒的风险，因此欧洲仅批准了SGTL2抑制剂用于BMI>27kg/m2的1型糖尿病患者。《队列研究：SGLT2抑制剂与糖尿病酮症酸中毒风险》Annals of Internal Medicine，2020年9月 (7)研究旨在评估SGLT-2抑制剂与DPP-4抑制剂相比，是否增加2型糖尿病患者酮症酸中毒的风险。研究纳入20757名新使用SGLT-2抑制剂的患者和20757名新使用DPP-4抑制剂的患者。在370 454人年的随访中，共发生了521例酮症酸中毒。与DPP-4抑制剂相比，SGLT-2抑制剂与酮症酸中毒风险增加相关。其中，达格列净的风险比为1.86；恩格列净的风险比为2.52；卡格列净的风险比3.58。这种关联性与年龄和性别无关，在曾接受过胰岛素治疗的人群中，这种风险风险似乎更低。结论：SGLT-2抑制剂使用后酮症酸中毒风险增加近3倍，不同药物的风险比略有不同。《SGLT2抑制剂：除血糖控制外的心血管益处机制》Nature Review Cardiology，2020年7月(8)SGLT2抑制剂除了控制血糖，也可以改善心血管和肾脏结局，且获益扩展到有射血分数降低的心功能不全的非糖尿病患者中。其中的机制可能包括：（1）早期尿钠与血浆体积减少、随之而来的血细胞比积升高、血管功能改善、血压降低和组织钠的变化都可能发挥作用；（2）减少脂肪组织介导的炎症反应和炎性细胞因子的生产，心脏和肾脏转向酮体代谢，减少氧化应激，降低尿酸，减少肾小球渗透压和蛋白尿，抑制晚期糖基化产物生成。《EMPEROR-Reduce研究：恩格列净治疗心衰患者的心血管和肾脏结局》New England Journal of Medicine，2020年8月 (9)这项双盲试验中，随机分配3730名II、III或IV型心衰、射血分数≤40%的患者，除推荐治疗外，随机接受恩格列净10mg qd或安慰剂治疗。随访16个月，恩格列净组和安慰剂组中，主要终点事件（心血管死亡和心衰住院）的发生率分别为19.4%和24.7%（风险比0.75，P < 0.001）。无论是否患有糖尿病，结果是一致的。两组中肾小球滤过率下降的幅度分别为-0.55ml/min和-2.28ml/min（P < 0.001）。应用恩格列净无并发症的生殖道感染发生率更高。结论：无论是否合并糖尿病，射血分数≤40%的心力衰竭患者加用恩格列净可以降低心血管死亡或心衰住院的风险。《DECLARE-TIMI 58研究的探索性分析：达格列净与2型糖尿病患者的心脏、肾脏和四肢的预后的关系》Circulation，2020年8月 (10)有研究显示SGLT2抑制剂增加2型糖尿病的截肢的风险。在这项探索性分析中，纳入了DECLARE-TIMI 58研究中的、17 160例2型糖尿病患者，6%患有外周动脉疾病PAD。主要疗效结果为MACE(心血管[CV]死亡、心肌梗死、卒中)、CV死亡/HHF和肾脏疾病进展。截肢、外周血管重建和肢体缺血不良事件由盲的审稿人进行现场报道和分类。患有外周动脉疾病的患者，死亡、心肌梗死、卒中（风险比1.23）、心血管死亡、心衰住院（风险比1.60）、肾脏疾病进展（风险比1.60）和截肢（风险比8.37）的风险显著升高。无论是否患有外周动脉疾病，服用达格列净后，心血管死亡、心衰在入院的相对风险均降低（风险比 0.86和0.82，p=0.79），肾脏疾病进展相对风险也降低（风险比0.78和0.76，P=0.84）。随访过程中，共记录到了560例患者的肢体缺血事件、和407例截肢事件。总体而言，使用达格列净与安慰剂相比，肢体缺血不良事件和截肢的风险没有统计学差异（风险比1.07和1.09）。结论：有外周动脉疾病的患者发生心血管死亡、心衰入院和肾脏结局的风险更高，使用达格列净能够获益；但与肢体缺血不良事件没有显著相关性。《VERTIS CV研究：埃格列净对2型糖尿病、冠心病患者的心血管事件结局的影响》New England Journal of Medicine，2020年9月 (11)这项多中心、双盲试验中，随机将8246名患有2型糖尿病和冠心病的患者，分配至埃格列净5mg qd、埃格列净15mg qd或安慰剂组。平均随访3年半，埃格列净组和安慰剂组均有11.9%的患者出现了不良心血管事件。埃格列净组和安慰剂组，分别有8.1%和9.1%的参与者死于心血管疾病或因心衰恶化住院（P=0.11），肾脏原因死亡、肾脏替代治疗或肌酐水平上升2倍的发生率也没有统计学差异。结论：在患有2型糖尿病和动脉粥样硬化性心血管疾病的患者中，埃格列净在主要不良心血管事件方面并不逊于安慰剂。胖基因《基础研究：在瘦的人群中定义ALK基因》Cell，2020年6月 (12)为研究肥胖的遗传易感性，但我们对健康的瘦的人群（BMI值最低的6个百分位数）进行了全基因组关联分析研究（GWAS），发现间变性淋巴瘤激酶（ALK）是一个候选的“瘦”基因。下丘脑神经元中的表达的ALK，通过交感神经对脂肪组织分解作用的影响，来控制能量的消耗。ALK突变可以增强机体的分解代谢能力，从而有效抵抗体重增加。在果蝇中，RNAi介导的ALK基因敲除，可以降低甘油三酯水平。在小鼠中，ALK基因缺失导致瘦的动物对饮食诱导的肥胖、和瘦素突变诱导的肥胖，均具有显著的抵抗能力。结论：这项遗传和机制实验确定ALK是一个胖基因，参与抵抗体重增加。小羽点评：ALK抑制剂已经用于癌症的治疗了。如果在可以关闭ALK或使ALK基因功能下调，那么是否能够帮助我们保持苗条，甚至减重呢？参考文献1.Blevins T, Zhang Q, Frias JP, Jinnouchi H, Chang AM. Randomized Double-Blind Clinical Trial Comparing Ultra Rapid Lispro With Lispro in a Basal-Bolus Regimen in Patients With Type 2 Diabetes: PRONTO-T2D. Diabetes Care. 2020.2.Klaff L, Cao D, Dellva MA, Tobian J, Miura J, Dahl D, et al. Ultra rapid lispro improves postprandial glucose control compared with lispro in patients with type 1 diabetes: Results from the 26-week PRONTO-T1D study. Diabetes Obes Metab. 2020.3.Taylor GS, Smith K, Capper TE, Scragg JH, Bashir A, Flatt A, et al. Postexercise Glycemic Control in Type 1 Diabetes Is Associated With Residual β-Cell Function. Diabetes Care. 2020;43(10):2362-70.4.Kosinski C, Herzig D, Laesser CI, Nakas CT, Melmer A, Vogt A, et al. A Single Load of Fructose Attenuates the Risk of Exercise-Induced Hypoglycemia in Adults With Type 1 Diabetes on Ultra-Long-Acting Basal Insulin: A Randomized, Open-Label, Crossover Proof-of-Principle Study. Diabetes Care. 2020.5.Lespagnol E, Bocock O, Heyman J, Gamelin FX, Berthoin S, Pereira B, et al. In Amateur Athletes With Type 1 Diabetes, a 9-Day Period of Cycling at Moderate-to-Vigorous Intensity Unexpectedly Increased the Time Spent in a State of Hyperglycemia, Which Was Associated With Impairment in Heart Rate Variability. Diabetes Care. 2020.6.Aronson R, Li A, Brown RE, McGaugh S, Riddell MC. Flexible insulin therapy with a hybrid regimen of insulin degludec and continuous subcutaneous insulin infusion with pump suspension before exercise in physically active adults with type 1 diabetes (FIT Untethered): a single-centre, open-label, proof-of-concept, randomised crossover trial. Lancet Diabetes Endocrinol. 2020;8(6):511-23.7.Douros A, Lix LM, Fralick M, Dell'Aniello S, Shah BR, Ronksley PE, et al. Sodium-Glucose Cotransporter-2 Inhibitors and the Risk for Diabetic Ketoacidosis : A Multicenter Cohort Study. Ann Intern Med. 2020;173(6):417-25.8.Cowie MR, Fisher M. SGLT2 inhibitors: mechanisms of cardiovascular benefit beyond glycaemic control. 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FDA 批准超速效赖脯胰岛素治疗糖尿病Diabetes Care 1型糖尿病业余运动员：9天中高强度自行车训练意外的升高血糖Nature Review Cardiology SGLT2抑制剂：除血糖控制外的心血管益处机制Annals of Internal Medicine SGLT2抑制剂与糖尿病酮症酸中毒风险Cell ALK基因功能下调可以减肥超速效赖脯胰岛素（URLi）超速效赖脯胰岛素（URLi），在短效赖脯胰岛素的基础上改良的一种起效更快、持续时间更短的胰岛素，更大程度上模拟生理条件下、餐后胰岛素的释放曲线。超速效赖脯胰岛素与赖脯胰岛素相比，达到50%最大功效的时间分别为12.8分钟和25.4分钟，两者30分钟内的总暴露量分别为99.3pmol*h/L和34.8pmol*h/L。超速效赖脯胰岛素20分钟达到峰值，持续6小时。2020年6月，超速效赖脯胰岛素（LyumjevTM）已经被FDA批准上市。《PRONTO-T2D研究：超速效赖脯胰岛素与赖脯胰岛素在长效胰岛素基础上治疗2型糖尿病的3期临床研究》Diabetes Care，2020年6月 (1)评价赖脯胰岛素与超速效赖脯胰岛素（URLi）比较，在长效胰岛素基础上治疗2型糖尿病的疗效和安全性。共673位患者，在优化的、长效甘精胰岛素或长效德谷胰岛素的基础上，联合餐前赖脯胰岛素治疗8周后，患者随机分入餐前0-2分钟注射超速效赖脯胰岛素组、或普通赖脯胰岛素组。两种短效胰岛素均能改善患者糖化血红蛋白，治疗结束时糖化血红蛋白分别为6.92%和6.86%。在控制1小时和2小时餐后血糖的变化方面，超速效赖脯胰岛素优于赖脯胰岛素：餐后1小时两组差异为0.66 mmol/L，2小时两组差异为0.96 mmol/L。接受超速效赖脯胰岛素治疗的患者餐后30分钟至4.0小时内，餐后血糖偏移明显减少。两种治疗方法之间的总体治疗紧急不良事件，包括低血糖，发生率相似。结论：在2型糖尿病患者中，餐时注射的超速效赖脯胰岛素与餐前注射的赖脯胰岛素在控制糖化血红蛋白方面效果相当，但在餐后血糖控制方面优于赖脯胰岛素。《PRONTO-T1D研究：与赖脯胰岛素相比，超速效赖脯胰岛素改善了1型糖尿病患者餐后血糖控制》Diabetes Obesity Metabolism，2020年8月 (2)在一项为期26周的III期临床试验中，评估了超速效赖脯胰岛素（URLi）与赖脯胰岛素在成人1型糖尿病患者中的疗效和安全性。研究发现超速效赖脯胰岛素在控制糖化血红蛋白方面，不劣于赖脯胰岛素。餐时注射超速效赖脯胰岛素在减少餐时1小时和2小时餐后血糖方面明显更优秀：1小时两组血糖差异为1.55mmol/L， 2小时两组差异为1.73 mmol/L，餐后4小时低血糖发作降低37%（P = 0.013）。其他的不良反应发生率相似。结论：在1型糖尿病中，超速效赖脯胰岛素提供了良好的血糖控制，餐后血糖控制优于赖脯胰岛素。1型糖尿病的运动管理规律的运动对1型糖尿病儿童和青少年具有重要的健康和社交益处，应鼓励。有氧运动（步行、骑车）通常可降低血糖浓度，而无氧运动（全速跑、曲棍球、举重）通常会升高血糖，许多团体运动（足球、篮球、棒球）包含有氧和无氧运动。低血糖可能发生在运动期间或运动后不久，或者延迟至运动后数小时或睡眠时。高血糖可能发生在运动期间，或情绪激动时。建议运动前、运动30分钟、运动恢复期和睡前监测血糖。《1型糖尿病运动后血糖控制与残留的β细胞功能有关》Diabetes Care，2020年10月 (3)研究旨在评价剩余β细胞功能对1型糖尿病患者运动后血糖的影响。研究招募30名、1型糖尿病病史≥3年的参与者，首先盲法进行7天的自由生活数据采集；然后进行3小时混合餐试验评估C肽和胰高血糖素水平。使用C肽峰值将参与者分成极低C肽组（C肽浓度200 pmol/L）；最后，参与者完成45分钟在60%VO2峰值的运动，然后再进行48小时的连续血糖检测。在运动后12小时和24小时，高C肽组参与者中葡萄糖正常的时间显著高于其他两组的参与者（高C肽组：12小时 73.5%，24 h 76.3%；低C肽组：12小时43.6%，24小时52.3%；极低C肽组12小时40.6%，24小时 51.3%）。而且，高C肽组参与者中高血糖的时间显著低于其他两组，血糖的波动也更小（P < 0.01）。从运动前到运动后24小时连续血糖检测的结果发现：高C肽组的参与者血糖控制得更好了（正常血糖的时间增加了12.1%），但另外两组的血糖控制得更差了（正常血糖的时间减少了9.1%和16.2%）。结论：剩余的β细胞功能可能部分解释了1型糖尿病患者运动后血糖的个体间差异，量化C肽有助于为患者提供个性化、针对性的运动支持。《1型糖尿病与有氧运动：在长效基础胰岛素基础上，运动前单次口服果糖可降低运动性低血糖的风险》Diabetes Care，2020年8月 (4)虽然调整胰岛素是降低1型糖尿病患者运动相关性低血糖风险的既定策略，但对超长效基础胰岛素治疗的患者来说，这并不容易实现。目前的研究确定了1型糖尿病患者在运动前摄入果糖是否能降低因运动引起的低血糖的风险。研究中14名参与分别完成了两次60min的有氧自行车运动，一次在运动前30min服用20g果糖，一次不服用果糖。摄入果糖的情况下，患者60min平均只发生1次低血糖事件，而对照组在运动的约30分钟内发生6次低血糖事件，果糖将运动时低血糖的风险降低了87.8%。服用果糖的运动期间平均血糖为7.3mmol/L，对照组为5.5mmol/L。摄取果糖后30分钟内休息时，患者的乳酸水平较高，但运动期间即回到基线。结论：对于使用超长效胰岛素的1型糖尿病患者而言，运动前摄取果糖是一种简单可行、有效且耐受良好的策略，可以减轻运动引起的低血糖风险，同时避免高血糖。《1型糖尿病业余运动员：9天中高强度自行车训练意外的升高血糖》Diabetes Care，2020年8月 (5)1型糖尿病中，心率变异性（HRV）降低可能是早期的自主神经功能障碍的一种表现；1型糖尿病患者，尤其是剧烈运动和长时间运动时，血糖会急剧变化，从而对心率变异性产生负面影响。本研究中，20名患有1型糖尿病的业余运动员9天骑行1500公里。研究出乎意料的发现，骑行的距离越长，高血糖时间越长，低血糖时间越短，同时夜间心率变异性越低；这可能和副交感神经张力降低有关。而且在这一过程中，胰岛素的使用没有改变，从饮食中摄入的碳水化合物也没有变化减少。结论：在患有1型糖尿病的运动爱好者中，长时间中高强度运动加重了高血糖，而高血糖与副交感神经及心脏功能相关；考虑潜在的对心脏的有害后果，未来的工作应该集中在理解和管理运动引起的高血糖现象。《1型糖尿病与中高强度运动：在运动前，采用长效胰岛素和胰岛素泵混合方案》Lancet Diabetes & Endocrinology，2020年6月 (6)使用持续皮下注射胰岛素泵（CSII）的1型糖尿病患者通常会在长时间运动前移除泵，但这种方法可能会增加高血糖和酮症的风险。该研究目的是评估一种混合方法的有效性和安全性，即通过胰岛素泵混合德谷胰岛素qd（一种长效胰岛素）提供每日必须的基础胰岛素治疗。这是一个单中心、开放标签、概念验证、随机交叉试验中，招募了平时规律使用胰岛素泵的1型糖尿病患者，开放标签分入单用胰岛素泵组和胰岛素泵联合长效胰岛素治疗组中，两组患者均在运动前60分钟停止胰岛素泵，运动后立即重新连接。与通常的胰岛素泵方案相比，混合胰岛素泵方案的参与者在中高强度运动后6小时内，血糖稳定（4-10mmol/L）的时间显著延长；在家运动时的高血糖持续时间更短。两种干预措施低血糖时间和低血糖事件方面没有显著差异。结论：清晨注射一次长效胰岛素和胰岛素泵的混合方案似乎对有规律运动习惯的1型糖尿病成人更加安全有效的。小羽点评：1型糖尿病病患者的残余β细胞功能和自主神经功能障碍均会影响患者运动后的血糖。β细胞残余功能越差，血糖波动越大；长时间中高强度的运动，副交感神经张力降低，引发高血糖。为了更高的减少运动后高血糖，可以采用长效胰岛素和胰岛素泵混合方案；为了减少运动相关低血糖时间，可以在运动前服用果糖。2型糖尿病的药物治疗-SGLT2抑制剂钠-葡萄糖协同转运蛋白2（SGLT2）表达于肾近端小管，介导约90%的滤过葡萄糖的重吸收。SGLT2抑制剂促进肾脏对葡萄糖的排泄，因此可降低血糖、降低血压和体重，通常不会导致低血糖。SGLT2最常见的副作用为外阴阴道假丝酵母菌感染及低血压。对于合并糖尿病肾病、心力衰竭和冠心病的患者，可考虑优先使用。在《内分泌科星期五 Episode 5》中，我们聊到了SGLT2抑制剂在1型糖尿病患者中的应用，不知道各位听众是否还记得。由于SGLT2抑制剂有增加1型糖尿病患者酮症酸中毒的风险，因此欧洲仅批准了SGTL2抑制剂用于BMI>27kg/m2的1型糖尿病患者。《队列研究：SGLT2抑制剂与糖尿病酮症酸中毒风险》Annals of Internal Medicine，2020年9月 (7)研究旨在评估SGLT-2抑制剂与DPP-4抑制剂相比，是否增加2型糖尿病患者酮症酸中毒的风险。研究纳入20757名新使用SGLT-2抑制剂的患者和20757名新使用DPP-4抑制剂的患者。在370 454人年的随访中，共发生了521例酮症酸中毒。与DPP-4抑制剂相比，SGLT-2抑制剂与酮症酸中毒风险增加相关。其中，达格列净的风险比为1.86；恩格列净的风险比为2.52；卡格列净的风险比3.58。这种关联性与年龄和性别无关，在曾接受过胰岛素治疗的人群中，这种风险风险似乎更低。结论：SGLT-2抑制剂使用后酮症酸中毒风险增加近3倍，不同药物的风险比略有不同。《SGLT2抑制剂：除血糖控制外的心血管益处机制》Nature Review Cardiology，2020年7月(8)SGLT2抑制剂除了控制血糖，也可以改善心血管和肾脏结局，且获益扩展到有射血分数降低的心功能不全的非糖尿病患者中。其中的机制可能包括：（1）早期尿钠与血浆体积减少、随之而来的血细胞比积升高、血管功能改善、血压降低和组织钠的变化都可能发挥作用；（2）减少脂肪组织介导的炎症反应和炎性细胞因子的生产，心脏和肾脏转向酮体代谢，减少氧化应激，降低尿酸，减少肾小球渗透压和蛋白尿，抑制晚期糖基化产物生成。《EMPEROR-Reduce研究：恩格列净治疗心衰患者的心血管和肾脏结局》New England Journal of Medicine，2020年8月 (9)这项双盲试验中，随机分配3730名II、III或IV型心衰、射血分数≤40%的患者，除推荐治疗外，随机接受恩格列净10mg qd或安慰剂治疗。随访16个月，恩格列净组和安慰剂组中，主要终点事件（心血管死亡和心衰住院）的发生率分别为19.4%和24.7%（风险比0.75，P < 0.001）。无论是否患有糖尿病，结果是一致的。两组中肾小球滤过率下降的幅度分别为-0.55ml/min和-2.28ml/min（P < 0.001）。应用恩格列净无并发症的生殖道感染发生率更高。结论：无论是否合并糖尿病，射血分数≤40%的心力衰竭患者加用恩格列净可以降低心血管死亡或心衰住院的风险。《DECLARE-TIMI 58研究的探索性分析：达格列净与2型糖尿病患者的心脏、肾脏和四肢的预后的关系》Circulation，2020年8月 (10)有研究显示SGLT2抑制剂增加2型糖尿病的截肢的风险。在这项探索性分析中，纳入了DECLARE-TIMI 58研究中的、17 160例2型糖尿病患者，6%患有外周动脉疾病PAD。主要疗效结果为MACE(心血管[CV]死亡、心肌梗死、卒中)、CV死亡/HHF和肾脏疾病进展。截肢、外周血管重建和肢体缺血不良事件由盲的审稿人进行现场报道和分类。患有外周动脉疾病的患者，死亡、心肌梗死、卒中（风险比1.23）、心血管死亡、心衰住院（风险比1.60）、肾脏疾病进展（风险比1.60）和截肢（风险比8.37）的风险显著升高。无论是否患有外周动脉疾病，服用达格列净后，心血管死亡、心衰在入院的相对风险均降低（风险比 0.86和0.82，p=0.79），肾脏疾病进展相对风险也降低（风险比0.78和0.76，P=0.84）。随访过程中，共记录到了560例患者的肢体缺血事件、和407例截肢事件。总体而言，使用达格列净与安慰剂相比，肢体缺血不良事件和截肢的风险没有统计学差异（风险比1.07和1.09）。结论：有外周动脉疾病的患者发生心血管死亡、心衰入院和肾脏结局的风险更高，使用达格列净能够获益；但与肢体缺血不良事件没有显著相关性。《VERTIS CV研究：埃格列净对2型糖尿病、冠心病患者的心血管事件结局的影响》New England Journal of Medicine，2020年9月 (11)这项多中心、双盲试验中，随机将8246名患有2型糖尿病和冠心病的患者，分配至埃格列净5mg qd、埃格列净15mg qd或安慰剂组。平均随访3年半，埃格列净组和安慰剂组均有11.9%的患者出现了不良心血管事件。埃格列净组和安慰剂组，分别有8.1%和9.1%的参与者死于心血管疾病或因心衰恶化住院（P=0.11），肾脏原因死亡、肾脏替代治疗或肌酐水平上升2倍的发生率也没有统计学差异。结论：在患有2型糖尿病和动脉粥样硬化性心血管疾病的患者中，埃格列净在主要不良心血管事件方面并不逊于安慰剂。胖基因《基础研究：在瘦的人群中定义ALK基因》Cell，2020年6月 (12)为研究肥胖的遗传易感性，但我们对健康的瘦的人群（BMI值最低的6个百分位数）进行了全基因组关联分析研究（GWAS），发现间变性淋巴瘤激酶（ALK）是一个候选的“瘦”基因。下丘脑神经元中的表达的ALK，通过交感神经对脂肪组织分解作用的影响，来控制能量的消耗。ALK突变可以增强机体的分解代谢能力，从而有效抵抗体重增加。在果蝇中，RNAi介导的ALK基因敲除，可以降低甘油三酯水平。在小鼠中，ALK基因缺失导致瘦的动物对饮食诱导的肥胖、和瘦素突变诱导的肥胖，均具有显著的抵抗能力。结论：这项遗传和机制实验确定ALK是一个胖基因，参与抵抗体重增加。小羽点评：ALK抑制剂已经用于癌症的治疗了。如果在可以关闭ALK或使ALK基因功能下调，那么是否能够帮助我们保持苗条，甚至减重呢？参考文献1.Blevins T, Zhang Q, Frias JP, Jinnouchi H, Chang AM. Randomized Double-Blind Clinical Trial Comparing Ultra Rapid Lispro With Lispro in a Basal-Bolus Regimen in Patients With Type 2 Diabetes: PRONTO-T2D. Diabetes Care. 2020.2.Klaff L, Cao D, Dellva MA, Tobian J, Miura J, Dahl D, et al. Ultra rapid lispro improves postprandial glucose control compared with lispro in patients with type 1 diabetes: Results from the 26-week PRONTO-T1D study. Diabetes Obes Metab. 2020.3.Taylor GS, Smith K, Capper TE, Scragg JH, Bashir A, Flatt A, et al. Postexercise Glycemic Control in Type 1 Diabetes Is Associated With Residual β-Cell Function. Diabetes Care. 2020;43(10):2362-70.4.Kosinski C, Herzig D, Laesser CI, Nakas CT, Melmer A, Vogt A, et al. A Single Load of Fructose Attenuates the Risk of Exercise-Induced Hypoglycemia in Adults With Type 1 Diabetes on Ultra-Long-Acting Basal Insulin: A Randomized, Open-Label, Crossover Proof-of-Principle Study. Diabetes Care. 2020.5.Lespagnol E, Bocock O, Heyman J, Gamelin FX, Berthoin S, Pereira B, et al. In Amateur Athletes With Type 1 Diabetes, a 9-Day Period of Cycling at Moderate-to-Vigorous Intensity Unexpectedly Increased the Time Spent in a State of Hyperglycemia, Which Was Associated With Impairment in Heart Rate Variability. Diabetes Care. 2020.6.Aronson R, Li A, Brown RE, McGaugh S, Riddell MC. Flexible insulin therapy with a hybrid regimen of insulin degludec and continuous subcutaneous insulin infusion with pump suspension before exercise in physically active adults with type 1 diabetes (FIT Untethered): a single-centre, open-label, proof-of-concept, randomised crossover trial. Lancet Diabetes Endocrinol. 2020;8(6):511-23.7.Douros A, Lix LM, Fralick M, Dell'Aniello S, Shah BR, Ronksley PE, et al. Sodium-Glucose Cotransporter-2 Inhibitors and the Risk for Diabetic Ketoacidosis : A Multicenter Cohort Study. Ann Intern Med. 2020;173(6):417-25.8.Cowie MR, Fisher M. SGLT2 inhibitors: mechanisms of cardiovascular benefit beyond glycaemic control. Nat Rev Cardiol. 2020.9.Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, et al. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. New England Journal of Medicine. 2020;383(15):1413-24.10.Bonaca MP, Wiviott SD, Zelniker TA, Mosenzon O, Bhatt DL, Leiter LA, et al. Dapagliflozin and Cardiac, Kidney, and Limb Outcomes in Patients With and Without Peripheral Artery Disease in DECLARE-TIMI 58. Circulation. 2020;142(8):734-47.11.Cannon CP, Pratley R, Dagogo-Jack S, Mancuso J, Huyck S, Masiukiewicz U, et al. Cardiovascular Outcomes with Ertugliflozin in Type 2 Diabetes. N Engl J Med. 2020;383(15):1425-35.12.Orthofer M, Valsesia A, Magi R, Wang QP, Kaczanowska J, Kozieradzki I, et al. Identification of ALK in Thinness. Cell. 2020;181(6):1246-62 e22.

Ouça dica rápida com o Dr. Bruno Rezende Passos.

This week’s episode includes author Charlotte Andersson and Associate Editor Naveed Sattar as they discuss familial clustering of aortic size, aneurysms, and dissections in the community. TRANSCRIPT: Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast, summary, and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke national University of Singapore. Dr Greg Hundley: And I'm Greg Hundley, director of the Pauley Heart Center at VCU health in Richmond, Virginia. Well, Carolyn, our feature this week has to do with aortic size, aneurysms, and predilection to dissection. But before we get to that, how about if we grab a cup of coffee and go through some of the other articles in the issue? Dr Carolyn Lam: I got my coffee, Greg, and you know what? I'm going to start with quiz for you. Dr Greg Hundley: All right. Dr Carolyn Lam:  True or false, in the setting of obesity and/or diabetes, cardiac substrate metabolism shifts towards increased fatty acid oxidation, while lipid accumulates in the heart? True or false? Of course, you're right. Oh, but there's a part two. Can you guess, by increasing fatty acid oxidation, will we induce or prevent obesity-induced lipotoxic cardiomyopathy? Dr Greg Hundley: I'm going to say, because you asked it in the way you asked it, prevent. Dr Carolyn Lam: Wow. All right. Well, the truth is we didn't really know before today's paper. The specific link between cardiac metabolism and lipotoxic cardiomyopathy was elusive and there was no specific therapy available for this condition. And these authors, Dr Rong Tian from University of Washington and colleagues, hypothesized that cardiac pathology-associated obesity would be attributable to the imbalance of fatty acid supply and oxidation. So using a diet-induced obesity model in the current study, they demonstrated that enhancing fatty acid oxidation through deletion of acetyl-CoA carboxylase 2, was sufficient to prevent obesity-induced cardiomyopathy. So, increasing cardiac fatty acid oxidation alone does not cause cardiac dysfunction, but instead protects against cardiomyopathy in chronically obese mice. The cardiac-protective effect of increasing fatty acid oxidation and obese mice is through maintenance of Parkin-mediated mitophagy, and thus preventing mitochondrial dysfunction. These findings indicate that impaired mitophagy contributes to mitochondrial dysfunction in obese mice, and that targeting the Parkin-dependent pathway is a viable therapeutic intervention for obesity-induced cardiomyopathy. Dr Greg Hundley: Very nice. Carolyn. Dr Carolyn Lam: I'm going to be greedy and go on to my next paper. So Greg, do you think cardiac regeneration is possible? Dr Greg Hundley: Well, Carolyn, I would have said, several years ago, no, but that trip that we took to China with Joe Hill and Hesham Sadek, our Associate Editor and our Chief Editor, convinced me otherwise. So I'm going to definitely answer yes on this one. Dr Carolyn Lam: Oh, Greg, you're just too smart. And speaking of China, this next paper is from there, from co-corresponding authors, Dr Nie and Hu, from Fuwai Hospital National Center for Cardiovascular Disease and Chinese Academy of Medical Sciences and Peking Union Medical College. So, using seven genetic mouse lines, they identify that Oncostatin M is the top upregulated cytokine during neonatal heart regeneration. Oncostatin M is a pleiotropic secretory protein that belongs to the interleukin 6 family, and associates with the pathological process of dilated cardiomyopathy. And these authors found that macrophages promote heart regeneration by secreting Oncostatin M, which promotes cardiomyocyte proliferation via a co-receptor, gp130. Employing RNA-seq and functional screening, they further found that Src-mediated gp130 triggered cardiomyocyte proliferation by activating the downstream signaling pathway involving Yap, with Y357 phosphorylation independent of the Hippo pathway. So the last thing that they did was show that gene therapy with adenovirus-associated virus and coding this activated gp130 improved heart regeneration and pumping function, thus serving as a potential therapeutic target. An amazing paper. Dr Greg Hundley: Very nice, Carolyn. What a great summary and so much detail. Well, Carolyn, I'm going to turn our attention to catecholaminergic polymorphic ventricular tachycardia. And this article comes to us from Dr Jason Roberts, from the Western University. Carolyn, genetic variants in calsequestrin 2 can cause an autosomal recessive form of catecholaminergic polymorphic ventricular tachycardia, though isolated reports have identified arrhythmogenic phenotypes among heterozygotes. So in this study, a total of 112 individuals, including 36 catecholaminergic polymorphic ventricular tachycardia probands, 24 were homozygotes for compound heterozygotes, and 12 were pure heterozygotes, against 76 family members possessing at least one presumed pathogenic calsequestrin 2 variant. These were all identified. Dr Carolyn Lam: Wow, a very precious cohort. So what did they find, Greg? Dr Greg Hundley: This international multicenter study of calsequestrin 2 catecholaminergic polymorphic ventricular tachycardia really redefined its heritability and confirmed that pathogenic heterozygous calsequestrin 2 variants may manifest with a catecholaminergic polymorphic ventricular tachycardia phenotype, indicating a need to clinically screen these individuals. Among individuals heterozygous for a pathogenic calsequestrin 2 rare variant, medical therapy and exercise restriction are likely not necessary in the absence of the catecholaminergic polymorphic ventricular tachycardia phenotype. Though, you have to be certain over time, an intermittent clinical screening to ensure they remain phenotype-negative should be obtained. Dr Carolyn Lam: Wow, Greg, clinically important study there. Well, I'm going to go back to the basic science world and talk about calcineurin. Now, calcineurin has long been implicated in the induction of pathological cardiac remodeling but has not been therapeutically targetable for the prevention of heart failure because of its pleiotropy and our lack of understanding of its specific protein-protein interactions and compartmentation within the cardiomyocyte. Dr Greg Hundley: Okay. Carolyn, do you want me to give background on calcineurin? Dr Carolyn Lam: No, Greg, you're off the hook. I'm going to give you some background on calcineurin. So, calcineurin is the calcium-calmodulin-dependent phosphatase that exists as a heterodimer, consisting of a catalytic subunit and a regulatory subunit. Now, of the three catalytic subunit isoforms, alpha, beta, gamma, it's the beta isoform that appears to be the most important for the development of cardiac hypertrophy. Binding of calcium to the calcineurin regulatory subunit enables binding of the calcium-calmodulin complex, thereby releasing auto-inhibition and freeing the enzyme to dephosphorylate downstream substrates. That's the background. Now, in today's issue, we have this great paper from co-corresponding authors, Dr Kapiloff from Stanford University, and Dr Nikolaev from University Medical Center Hamburg. And, with their colleagues, they described the discovery of a calcineurin catalytic subunit beta binding protein Cdc42-interacting proteins 4, and I'm going to call that CIP4, which functions as a scaffold to sequester the pool of calcineurin near the sarcolemma of cardiomyocytes, where it regulates pro-hypertrophic signaling. These findings have really important implications for understanding how cardiac calcineurin is selectively activated by stress signals, as opposed to the pleiotropic second messenger, calcium, that really floods the cardiomyocytes during each contractile cycle. Furthermore, the data provide proof of concept for an innovative therapeutic approach, whereby CIP4-anchoring activity is selectively inhibited to block the action of a small pathogenic pool of calcineurin as a means of treating heart failure. How about that? This is really discussed in an elegant editorial by doctors, Woulfe, Travers, and McKinsey. Dr Greg Hundley: Very interesting, Carolyn. Sounds like another possibility for treating and managing heart failure. Well, let me share with you some of the other findings in our mailbag this week. First, I've got, from Professor Lang Li and Stephen Wiviott, they swap research correspondence regarding the prior publication entitled, Effect of Dapagliflozin on Atrial Fibrillation in Patients with Type 2 Diabetes Mellitus, Insights from the DECLARE-TIMI 58 Trial. And then Professor Laszlo Littmann has a nice ECG challenge for us related to a high-risk ECG that exposed some downstream worrisome vital signs. Dr Carolyn Lam: In addition, there's a perspective piece by Dr Nambi discussing the fact that a zero-calcium score is desirable, but isn't enough to defer therapy, given that up to one-third of events will occur in this group. There's also an In Depth paper by Dr Borlaug, entitled, “Altered Hemodynamics and End Organ Damage in Heart Failure, The Impact on the Lung and Kidney,” and oh boy, this one is so beautifully illustrated. Just a must read for the understanding of the hemodynamics in the lung and kidney and heart failure. Next is a research letter by Dr Loeys on enrichment of rare variants in the Loeys-Dietz syndrome genes in spontaneous coronary artery dissection, and not in severe fibromuscular dysplasia. And finally, another research letter by Dr Arora on racial differences in serial NT-proBNP levels in heart failure management with insights from the GUIDE-IT Trial. What a rich issue, but let's move on to our future discussion, shall we? Dr Greg Hundley: You bet, Carolyn. Well, listeners, we're now getting to our feature discussion and it's very interesting this week where we're going to evaluate aortic aneurysms. And we have with us one of the lead authors of this paper, Dr Charlotte Andersson from Boston Medical Center, and our own Associate Editor, Naveed Sattar from Glasgow, Scotland. Charlotte, welcome to our feature discussion. Could you tell us a little bit about the background and the hypothesis that you put forward with this study? Dr Charlotte Andersson: The background for this study was based on clinical work and what we observed in clinic. We had a few patients where we had been stricken by the fact that they came in with an acute aortic syndrome and they had a first-degree relative themself with the condition, but they did not look syndromic at all. And we started to wonder, what is the actual risk in the community, in people without obvious syndromic features of suffering from an aortic event itself. And although there are quite a few studies out there that have, to some degree, focused on the familial clustering of aortopathies, there is not a lot of information based on communities and whole entire populations. So we wanted to, frankly, estimate what is the incidence rates of aortic dissections and aortic aneurism in the community if you have a first-degree relative that has suffered from the disease themselves. Dr Greg Hundley: How you organize your study and what was your population and what was your design? Dr Charlotte Andersson: This study was actually based on two independent samples. First, we used the Framingham Heart study population that is very densely phenotypes over many years of spanning three generations of participants, where we looked at people who had at least one parent who had an aortic size in the upper quartile index to body-surface area and adjusted for age and sex. And we saw what's the risk of you, as a child, having an aortic size in the same upper quartile. And second, we looked in the general Danish population, the Danish healthcare system is, as you probably know, governmental funded and we have very good registries of all hospitalizations, all outpatient visits, and so we were able to link more hard clinical events in people with and without a first-degree relative. What we did was we started time when people had an aortic dissection, we identified all the first-degree relatives in these people, and we matched them with up to 10 sex and age match controls from the general population without a first-degree relative with the disease. Dr Greg Hundley: What did you find? Dr Charlotte Andersson: We found that in the Framingham sample, if you had at least one parent who belongs into the upper quartile of aortic size, you had an odds ratio of two to three, adjusted for various clinical risk factors, such as hypertension and smoking yourself. And in Danish population, we found that if you had a first-degree relative with an aortopathy, the hazard rates for you developing the disease yourself was almost a tenfold-increase compared to age and sex match controls. And importantly, seemed like hazard ratios use were, more or less, unchanged when we start adjusting various known risk factors, such as bicuspid aortic valve, Marfan syndrome, and Ehlers-Danlos syndrome, normally those kinds of things. And we also found that the younger your proband were at the time of an acute event, the higher was your relative risk yourself. So among people who were below the age of 50 when they suffered an event, the hazard ratios were up to a 50-fold increase. Dr Greg Hundley: Very nice. Naveed, what attracted you to this article as it was coming through the editorial process? And then second, how do we take the information that Charlotte's just conveyed and will be published here today, how do we take this in the context of what we already know about aortic aneurysms? Dr Naveed Sattar: I think it's a beautiful study, so well done, Charlotte. I think it's a beautiful fusion. As Charlotte said, an in-depth cohort study, which has got very well-measured parameters of systematic points and a fantastic population-based data set from Denmark, which Sweden shares and Scotland shares and relatively small countries like us share. So small countries like Denmark punch above their weight in these kinds of studies, which is fantastic. But there's a rich seam of research that comes from these, and this is one of them. So I think that fusion of two data sets with different strengths and limitations combined giving off same signals is good. I think, as Charlotte said, this is the first major population study to look at this question. So there's been people around the world who have got this sense that the aortic aneurism may well be familial, this provides, probably, some of the best data to suggest, yes, it definitely is. Now the questions going forward is, okay, at what point do you screen everybody's got a family history with a proband, or do you screen those who've got a family history of younger probands? And I think what Charlotte and the team and other people around the world thar are going to look at this say, "Okay, we now think, in addition to screening, for example, in the UK and the US we probably screen just men above 65, where most of the disease is, do we also then implement screening in younger people with family histories? And who do we screen, and when and how? And do we need to develop some kind of risk score?" And then when we do that screening, what do we do about it? Is going to be the questions and I'm sure Charlotte and her colleagues have thought about these things and it'd be interesting to see what her view is on those things. But I think it was a beautiful study in every sense. Dr Greg Hundley: So Charlotte, he's really set you up nicely, what study do we need to perform next in this area? What are you and your group thinking about? Dr Charlotte Andersson: Yeah, I think there are two implications of this study. First, clinical, as Naveed says. They already had a sense that aortic diseases were heritable, and I think these data definitely support that we should probably screen first-degree relatives. And I think, at some extent, this is what the guidelines already encourage us to do. So I'm not sure it would be feasible to randomize people or do a clinical trial where we screen some but not others. I'm not sure that would be ethical. I think the evidence is too strong for familial clustering and that we should probably screen these people. But I think also, our estimates, they are so strong that I suspect that there are likely more genetic variants associated with non-syndromic aortopathies that we are not aware of just yet. So I think the next step would be to try to disentangle the genetics a little bit more. I have seen some preliminary analysis based on the UK Biobank, for instance, and I think there are more genetic variants to come up with also, more common genetic variants, at least, that we are not aware of just yet. So that would be the next step as I see it. Dr Naveed Sattar: And that might particularity in younger probands. Dr Charlotte Andersson: Right. Dr Naveed Sattar: Those with the younger probands, because it looks like, as you said, the hazard ratio, the risks, are so high, it could also potentially be monogenic, but anyway. Dr Charlotte Andersson: I agree. Dr Greg Hundley: Well, Charlotte, Naveed, we really appreciate your time and taking this opportunity to discuss these really interesting findings and helping us understand that, truly, there may be a familial component to understanding this disease process, particularly in patients with aortic aneurysms that may go on to develop aortic dissections. Well listeners, we hope you have a great week and on behalf of Carolyn and myself, catch you on The Run next week. This program is copyright, the American Heart Association, 2020.  

This week’s episode of Circulation on the Run has 2 Feature Discussions. Associate Editor Ntobeko Ntusi discusses the article "Prevalence of Infectove Encocarditis in Streptococcal Bloodstream Infections is Dependent on Streptococcal Species." Then, author Anumpam B. Jena and Associate Editor Sandeep Das discuss trends in new diagnoses of atrial fibrillation after the release of an ECG-capable smartwatch. TRANSCRIPT: Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to The Journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley: And I'm Dr Greg Hundley, associate editor from the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, our feature this week involves infective endocarditis and looking at that in streptococcal bloodstream infections. Are they dependent on the different species of streptococci? But before we get to that, how about we grab a cup of coffee and start off and discuss other papers in the issue. You want to go first? Dr Carolyn Lam: Sure, Greg. I got my coffee, but I want to start with a quick question. So do you think it's safe and efficacious to prescribe SGLT2 inhibitors to patients with Type 2 Diabetes and concomitant peripheral artery disease? Dr Greg Hundley: Ah, Carolyn, very good question. I don't know if it's right or wrong. A little bit of controversy here. Dr Carolyn Lam: Let's explain that controversy. So patients with peripheral artery disease are at heightened risk of cardiovascular complications. However, there's also an increased risk of amputation that was observed with canagliflozin in one prior trial. Now, the SGLT2 inhibitor dapagliflozin was shown to reduce the risk for hospitalization for heart failure and kidney events in patients with Type 2 Diabetes in the DECLARE–TIMI 58 trial. So authors Dr Bonaca from University of Colorado School of Medicine and colleagues examined the cardiovascular and kidney effects and the risk of limb related events in patients with and without peripheral artery disease in the huge DECLARE–TIMI 58 trial, including more than a thousand patients with peripheral artery disease. Dr Greg Hundley: So this could be really helpful to answer this question. What did they find, Carolyn? Dr Carolyn Lam: Well, patients with versus without peripheral artery disease were indeed at higher risk of major adverse cardiovascular events, cardiovascular death, or heart failure, hospitalization and kidney events. They also had consistent benefits for the outcomes of cardiovascular death or heart failure hospitalization as well as progression of kidney disease with dapagliflozin. Now ,patients with peripheral artery disease also had a higher risk of limb events, but there was no consistent pattern of incremental risk observed with dapagliflozin. So the take home, diabetes patients with peripheral artery disease are at risk of heart failure and kidney events and dapagliflozin is beneficial with no patterns of increase limb risk. Dr Greg Hundley: Very nice, Carolyn. Boy, that is very helpful and a nice take home message for all of us administering these agents. Well, Carolyn, my first study comes from Professor Magnus Bäck from the Koralinska Institute. And the aim of this study was to identify the role of omega−3 polyunsaturated fatty acids, derived specialized pro resolving mediators, or SPMs, in relation to the development of aortic valve stenosis. The synthesis of specialized pro resolving mediators are potent beneficial anti-inflammatory agents. They have pro resolving and tissue modifying properties that are useful in managing patients with cardiovascular disease. Dr Carolyn Lam: Interesting. So what did these authors find? Dr Greg Hundley: This study showed that human stenotic aortic valves contain decreased levels of n-3 PUFA, and that n-3 PUFA treatment decreased aortic valve calcification, and aortic valve leaflet area in murine models’ concomitant with improved aortic valve hemodynamics. The pro resolving lipid mediator, resolvin E1, which is derived from the n-3 PUFA enoic acid, or EPA, exerted protective effects on valvular interstitial cell calcification and valvular inflammation through its receptor, chemR23. And therefore Carolyn, further clinical evaluation of n-3 PUFA treatment may open up novel therapeutic opportunities for preventing the progression of aortic valve stenosis. Dr Carolyn Lam: Wow, really interesting, Greg. Just more and more data on these omega−3 PUFAs, huh? So cool. Well, the next paper is kind of related in the lipid world. Do you think treating to a low LDL cholesterol target of less than 70 milligrams per deciliter may impact carotid plaque evolution? Dr Greg Hundley: I would think so. It seems like that target is beneficial in many ways. Dr Carolyn Lam: Well, good guess, Greg. But I'm going to tell you about a study that actually looked at that. First of all, recall that the treat stroke to target, or TST trial, showed the benefit of targeting an LDL cholesterol concentration of less than 70 in terms of reducing the risk of major cardiovascular events in 2,860 patients with ischemic stroke with atherosclerotic stenosis of the cerebral vasculature. Now, today's paper describes results of the parallel TST plus study, which included 201 patients assigned to an LDL cholesterol concentration of less than 70 versus 212 patients assigned to a target of a hundred. To achieve these goals, investigators led by corresponding author, Dr Amarenco from Bichat Hospital in Paris, France, allowed investigators use the statin and dosage of their choice, and added ezetimibe as needed. After certification of ultra-sonographers, carotid ultrasound examinations were performed at baseline and at two, three, and five years, and blindly analyzed at a central core laboratory. Dr Greg Hundley: Very nice, Carolyn. So what did they find? Dr Carolyn Lam: After a median follow-up of 3.1 years, patients in the lower target group had a similar incidence of newly diagnosed carotid plaque compared to the higher target group, but significantly greater regression of carotid atherosclerosis as measured by the common carotid intima media thickness. So this really further strengthens the concept that the lower the LDL cholesterol, the better the clinical and atherosclerosis outcomes. Dr Greg Hundley: Very nice, Carolyn. Another study emphasizing that very important point. Well, Carolyn, my next study comes from Professor Abdelkarim Sabri from the Temple University School of Medicine. So studies suggest that cardiac rupture can be accelerated by thrombolytic therapy, but the relevance of this risk factor remains controversial. In this study, the authors analyzed protease activated receptor or PAR4 expression in mouse hearts with myocardial infarction, and investigated the effects of PAR4 deletion on cardiac remodeling and function post demise by echocardiography, quantitative immunohistochemistry, and flow cytometry. Dr Carolyn Lam: Oh, okay. What did they find, Greg? Dr Greg Hundley: Three things. First, PAR4 deficiency leads to cardiac hemorrhage and increases the rates of cardiac rupture following chronic myocardial infarction. PAR4 deficiency in neutrophils, but not in platelets, impairs inflammation resolution and myocardial healing after myocardial infarction. And finally, adoptive transfer of neutrophils can be used as a novel therapy to modulate the inflammatory response and improve cardiac remodeling and function following myocardial infarction. Dr Carolyn Lam: Okay, what's the take home message? Dr Greg Hundley: It's a little tricky. So acute transient administration of par four inhibitors may provide a new approach to prevent early inflammation and myocyte loss immediately after ischemic injury. The keyword is immediately. But importantly, prolonged P4 inhibition strategies could impair myocardial healing and increased cardiac hemorrhage and the rates of myocardial rupture following infarction. PAR4 inhibition therapies should be limited to the acute phases of the ischemic and fault, and it should be avoided for the chronic treatment post myocardial infarction. Really intriguing, Carolyn. Dr Carolyn Lam: Very nice and elegant results, kind of like yin and yang, huh? Dr Greg Hundley: You bet. Dr Carolyn Lam: All right. Let's sum up with the other papers in the issue. There's a white paper by Dr Psotka on challenges and potential improvements to patient access to pharmaceuticals with examples from cardiology. There's a perspective by Dr Armstrong comparing the benefit of novel therapies across clinical trials, and that provides important insights from the VICTORIA trial. There's an ECG challenge by Dr Chu regarding a young male with incessantly alternating tachyarrhythmias. Dr Greg Hundley: Very nice, Carolyn. Well, in my mail bag, I have an on my mind piece from Dr Jamil Tajik relating to, our favorite, the art and science of occultation. Well, Carolyn, how about we get on to that feature article and talk a little bit more about those little devils, the streptococci? Dr Carolyn Lam: Yeah, let's go, Greg. Infective endocarditis is the topic of our feature paper today. Now, we all know it's a life threatening disease, and despite its relative rarity, it's still consumes a disproportionate share of healthcare resources, and its annual mortality is still really high, exceeding 20%. Now, I think we all recognize that improved outcomes are critically dependent on a timely diagnosis and early investigation. The problem is the clinical presentation is less and less likely that classical textbook presentation, and the clinical suspicion is often triggered after microbiological identification of potential causative organisms in the blood. And while we as a medical community are usually aware of the dangerous of staphylococcal bacteremia, I think there's a lot less appreciation of the propensity of different streptococcal species to cause infective endocarditis. Greg, my dear partner, greatest friend, and colleague, do you agree? Dr Greg Hundley: Yes, Carolyn. So this paper and this feature addresses bacterial endocarditis and focuses on streptococcal infections just as you've described. Now, streptococci I frequently cause infective endocarditis. Yet, the prevalence of infective endocarditis in patients with bloodstream infections caused by different streptococcal species is unknown. So in this study, Dr Shamat and associates aim to investigate the prevalence of infective endocarditis at species level in patients with streptococcal bloodstream infections. Dr Carolyn Lam: Now, we're taking a lot of pains to describe this paper, Greg and I, because we didn't manage to get hold of the authors this time. We certainly have our editor who managed the paper and that's Ntobeko Ntusi from University of Cape Town. So welcome Ntobeko, and thank you so much for discussing this paper with us. But before we get to that, I think Greg and I are going to try to, in our usual fashion, get to the bottom of describing. Here's something I learned that I didn't know before. That the ESC guidelines for example, are primarily based on the modified Duke criteria, which include blood cultures, mentioning viridians streptococci. Remember those? Viridians streptococcus, or strep bovis, as a diagnostic major criterion for streptococcal infective endocarditis. And yet, the term viridians is based on bacterial culture using green hemolysis on blood agar plates, which is outdated. So I didn't realize that. It's outdated and inconsistent because some of the included streptococcal species do not even cause hemolysis, and other species are able to produce different kinds of hemolysis. And thus, we really need more details on specific streptococcal types that are much more current. And when we face these different streptococcal species, they're not mentioned in the guidelines and so we need more data. So that's why this paper is so important. So Greg, now over to you. Do you mind to describe what the authors did? Dr Greg Hundley: Sure, Carolyn. So these investigators identified and assessed all patients with streptococcal bloodstream infections from the period of time of 2008 to 2017 in the capital region of Denmark. And data were cross-linked with Danish nationwide registries for identification of concomitant hospitalization with infective endocarditis. In multi-variable logistic regression analyses, the authors investigated the risk of infective endocarditis according to some of those species that you just mentioned. And they adjusted their analyses for age, sex, greater than or equal to three, positive blood culture bottles, native valve disease, prosthetic valves, prior episodes of infective endocarditis, and whether or not they may have had an implanted cardiac device. Dr Carolyn Lam: Great, great. So tell us the results, Greg. Dr Greg Hundley: So Carolyn, they had 6,500 plus cases with streptococcal bloodstream infections. And the average age of the patients was 68 years, and a little more than half. So 52% to 53% were men. The prevalence of infective endocarditis overall was 7%. Now, the lowest infective endocarditis prevalence was found with strep pneumoniae and strep pyogenes, ranging from 1.2% to 1.9%. the highest infective endocarditis prevalence, and that was found with strep mitis or oralis at 19%. Streptococcus gallolyticus, formerly known as strep bovis, at 30%. Strep sanguinis at 35%, and strep mutans at nearly 50%, at 48% overall. So in multi-variable analysis, using the strep pneumonia at 1.2% as a reference, all species except strep pyogenes were associated with a significantly higher infective endocarditis risk. Again, the highest with the odds ratio of strep gallolyticus is at an odds ratio of 31 ranging up to straight mutans with an odds ratio of 81.3. Dr Carolyn Lam: Whoa, Greg, that was beautifully summarized, and frankly, beautifully pronounced. I don't think I could have done that with all the species. That is so cool. And in case everyone didn't get it, I strongly suggest you refer to figure three of this beautiful paper. It shows the prevalence of infective endocarditis in bloodstream infections with the different streptococcal species, all in one figure. And Ntobeko, with that introduction, if you may, by both Greg and I, could you please let us behind the scenes? Tell us what you first thought when this paper came across your desk and perhaps what the editors’ thought was so important about this paper. Dr Ntobeko Ntusi: Thank you very much, Carolyn and Greg. So this is an important paper coming out of circulation. And while infective endocarditis may not be so harmonic in North America and western Europe, in many parts of the world, including where I come from in Sub-Saharan Africa, with a high prevalence of rheumatic heart disease, it remains an important cause of morbidity and mortality. And we forget that it's a disease with very high inpatient mortality of up to 50% in many countries. And of course in those with rheumatic heart disease, streptococcal bloodstream infections remain an important cause of infective endocarditis. So when I saw this paper, I very much enjoyed reading it. I thought it was well written and beautifully illustrated. In some ways, even though I say it's an original paper, it has a feel of a review because the discussion, as well as the figures and tables, are quite instructive. And the comments from the reviewers were very much aligned with my own thinking that there were a number of important new learnings coming out of this paper. The first important message for me was that the distribution of streptococcal infections in the population was not uniform and I had assumed infections to be broadly the same across the population. And contrary to what I thought, the risk of infective endocarditis was inversely related to the frequency of streptococcal bloodstream infections in the population. In other words, the most common streptococcal blood infections that are very low prevalence of infective endocarditis. And that leads to the second important learning from this paper, which is that if you are a clinician evaluating a patient with suspected infective endocarditis, the risk of infective endocarditis should be evaluated on a species level, as the species from Greg's description is probably the most important determinant of the likelihood of developing infection. And then the other important, I think, take home message from this paper, I'm looking at the results of multivariate regression analysis, is that it confirms much of what we know from studies with older patients studies focusing primarily on staphylococcal bloodstream infections as well as studies focusing on device therapies. And that message is that the risk of developing infective endocarditis, even with streptococcal blood infections is related down to presence of native or valve disease. Those with trust that tech devices, intracardiac devices, and of course, the number of fat blood culture bottles that are positive, which is something that is well accepted and established in clinical practice. Thank you, Carolyn. Dr Carolyn Lam: I just love those three take home messages. So beautiful. And I really also love that you invited this fantastic editorial, Dr Prendergast, Dr Allen, and Dr Klein. I thought it was wonderful the way they summarized the paper, put it into context, and perhaps, I could borrow their words and also explaining that they pointed out that we do need to be cautious about interpreting this being a retrospective series classified by diagnostic coding. And of course, by design, because of that, we can't fully attribute causal associations. They also pointed out that this paper, I believe did not include echocardiographic data as one of the variables. And so of course, that could be something that could be further explored in future studies. And I'd love your thoughts on what they also said about before we extrapolate regional data, I mean, it's all from Denmark after all, to other regions, this work should probably be considered something that should inspire extension of further studies and prospective evaluations in other areas, and yet never losing sight of the fact that this informative paper will of course be of considerable interest to not just cardiologists, but also infectious disease specialists, because we're often called to sort of assess, "All right, how much do you need to work up for infective endocarditis if you see this specific streptococcal bacteremia?" And this paper definitely puts us strides ahead in this area. Would you agree with that, Ntobeko, and anything to add? Dr Ntobeko Ntusi: Indeed, Carolyn. So I was delighted that the review, the editorial, was co-authored by cardiologists and infectious disease specialists. We might view as they balanced in as one of the modifications to the original submission. We actually posed that question to the office that how can we be certain in the absence of echocardiographic data that the diagnosis was in fact infective endocarditis in patients? And so they went back and performed a sensitivity analysis and triangulated the principle diagnosis of infective endocarditis with the treatment of patients in the duration in hospital. And that sensitivity analysis in fact strengthened our believe that this wasn't fit the diagnosis of infective endocarditis. And I think your point is well taken that similar studies need to be conducted in different regions of the world and this field will be strengthened by large amount of prospective studies on top of the plethora of retrospect data that we have. Dr Greg Hundley: Well listeners, we have a second feature discussion this week. A very interesting article pertaining to the use of smartwatches and detection of atrial fibrillation. And to present this work, we have Dr Bapu Jena from the Harvard Medical School, and our own associate editor from University of Texas Southwestern Medical Center in Dallas, Dr Sandeep Das. Welcome gentlemen. And Bapu, perhaps, could you tell us a little bit about the hypothesis and the background of this material? Dr Anupam B. Jena: Sure. So you probably are aware that in December of 2018, Apple released this new watch and this watch made a lot of buzz in part because it featured this single lead EKG that the company said would be able to detect atrial fibrillation. And there was this question among many, at least certainly among clinicians, as to whether or not we would see a large increase in atrial fibrillation diagnoses after this watch was released onto the market. And then the second question was, would we be picking up worrisome cases of atrial fibrillation that we needed to act on, or would we be picking up cases that patients probably would have been okay living with and would never have known that they were living with? We were lucky to be able to work with a company called Athenahealth. Athenahealth is a nationwide cloud-based healthcare information technology company. What that allowed us to do was to do a very early analysis of the change in atrial fibrillation diagnosis after the Apple Watch was approved on the market. So that's the data we use is from small physician practices. It's not nationally representative, but these practices are all across the US. The data from Athenahealth have been used in other studies, including some by myself and other colleagues. In terms of the method that we applied; it was pretty straight forward. So what you basically want to see is before and after December of 2018, do we see a market spike in the diagnosis for atrial fibrillation? Again, these are diagnoses that physicians who are in these offices would be making and that we would be seeing in the electronic health records of their practices. Now, the problem is, is suppose over time, atrial fibrillation diagnoses are going up. So if we looked at the first six months of 2019 compared to the last six months of 2018, and we saw an increase, we obviously wouldn't want to attribute that solely to the Apple Watch because atrial fibrillation diagnoses may be going up for a lot of other reasons. What we said as well, let's at least try to account for the possibility that there are seasonal trends at play in the diagnosis of atrial fibrillation. Dr Greg Hundley: Very nice. What did you find? Dr Anupam B. Jena: So the basic finding is as follows that we didn't really see a differential increase in atrial fibrillation diagnoses. So for example, in the months before the watch was released, in this population, about 0.4% of all visits had an atrial fibrillation diagnosis. 0.4%. If you look at the year after the app release, about 0.4% of visits have the diagnosis. If you look one year back, you also find that one year before in the pre period, there is about 0.36% of visits were for atrial fibrillation, and that increased the 0.39%. So the difference in difference change is basically about zero. Meaning, we found that there was no increase in atrial fibrillation diagnoses. The second thing that we did is we looked at high income zip codes, and we looked at zip codes with the population of individuals would be such that we might expect an increase. And we found no changes in either one of those two subgroups. Dr Greg Hundley: Very good. Well, Sandeep, help us put this in the context of using these watches and then also using these watches to identify patients with atrial fibrillation. Dr Sandeep Das: Absolutely. So let me first just add a comment that Bapu was a little too modest to blow his own horn, but he's really built a lovely research program of identifying and answering really interesting questions in large datasets. So the fundamental question here about whether the use of the Apple Watch and these detection algorithms would be associated with a big spike in diagnosis of atrial fibrillation was extremely important or is extremely important. So that was really the hook. I knew it was going to be something interesting. In our heart of hearts, we're all a little worried that people are going to have wearables. There's going to be an 8 million people presenting with abnormal findings on their watch and it's going to break medicine. So that was really kind of the context and the key for what made it interesting to us. Dr Greg Hundley: Very nice. And so what do you think, maybe start with Babu, and then come back to Sandeep. What do you think will be the next study in this area using these devices as they pertain to patients with atrial fibrillation? Dr Anupam B. Jena: Yeah. Great question. So I think there's two things that come to mind. So first is this was really an early analysis. I do expect that as the Apple Watch grows in popularity and as other similar such devices get introduced to the market, that we probably will pick up patients with atrial fibrillation who otherwise wouldn't have been diagnosed. I think that's less likely, but would be diagnosed earlier than they otherwise would have. So I think that if we look a couple of years out, we probably will find different answers that we found here. But as Sandeep said, at least in the first year after the watch was introduced to the market, we didn't break the bank. So I think this first natural question is to look longer out. And I think the second thing, which is particularly interesting to me at least, is that this potentially gives us a nice natural experiment to understand whether or not all patients with atrial fibrillation or what are the other factors that we should be thinking about in terms of benefits? Dr Greg Hundley: Very good. Sandeep, do you have anything to add? Dr Sandeep Das: So I agree with that answer entirely. I think that one of the things that really is going to be the $64,000 question is what does wearable diagnosed atrial fibrillation mean? So we were pretty good. As Bapu said, we have well established history of understanding what to do with patients that have atrial fibrillation that we diagnose in conventional ways. People either present with symptoms or are diagnosed externally in the hospital. But what does it mean if you're perfectly fine and you just have a watch that gives you an alarm? What are the implications of that? Because there are therapies generally revolve around anticoagulation in a large fraction of patients with atrial fibrillation. And that's the big deal. If we're going to commit people to lifelong anticoagulation, based on what they're watch told us, is that the right thing to do? So I think that to me, the most important question going is what does a diagnosis of a-fib by wearable mean for downstream treatment implications and outcomes? And then the larger scope is also how can we then incorporate the data that we're going to continue to get from wearables into practice? So studies on sort of the practical downstream implications of wearable technology on utilization are also going to be super important and interesting. Dr Greg Hundley: Very good. Well, I want to thank you Bapu, and also thanks Sandeep for your time today. And just sharing this new research using Apple smartwatches and trying to diagnose atrial fibrillation and compared it at least in this first year to, I guess, historical controls, not an overabundance or mass increase in the diagnosis of atrial fibrillation. And as you both have identified more to come with research on using these watches in the future for management, and then how we might improve therapeutic interventions through the use of these devices. Well, listeners, we hope that you have a great week and we look forward to catching you on the run next week. Take care. This program is copyright of the American Heart Association, 2020.  

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley: I'm Greg Hundley, associate editor from the VCU Pauley Heart Center in Richmond, Virginia. Dr Carolyn Lam: Greg, amyloid cardiomyopathy is the rage. I cannot tell you the number of discussions I've had on the topic. Of course, it was tafamidis, the amazing results with that trial that really made us realize we need to pick this up. But have you ever thought about the cost effectiveness of tafamidis for amyloid cardiomyopathy? Well, guess what? We're going to have a whole feature discussion just about that. But first let's go to our summary, shall we? Dr Greg Hundley: You bet, Carolyn. Well, let me get started. I'm going to talk about regulation of cell cycle growth as well as division in regard to cardiac regeneration. My first paper comes from Dr Lior Zangi from the Mount Sinai School of Medicine. Well, Carolyn, have you ever wondered why the adult mammalian heart has limited regenerative capacity? Dr Carolyn Lam: All the time, Greg. Dr Greg Hundley: Well, of course you have. It's mostly due to postnatal cardiomyocyte cell cycle arrest. In this study the investigators evaluated the effect of pyruvate kinase muscle isozyme 2 and cardiomyocytes through models of loss, that is cardiomyocyte specific PKM2 deletion during cardiac development or gain using cardiomyocytes specific PKM to modified mRNA to evaluate PKM to function and regenerative effects post-acute or chronic MI in mice. Dr Carolyn Lam: Nicely described. What did they find, Greg? Dr Greg Hundley: What they found is that PKM2 is expressed in cardiomyocytes during development and immediately after birth, but not during adulthood. Using cardiomyocytes PKM to modified RNA, they found that cardiomyocyte targeted strategy following acute or chronic MI resulted in increased cardiomyocyte cell division, enhanced cardiac function, and improved long-term survival. They found that PKM2 regulates the cardiomyocyte cell cycle and reduces oxidative stress damage through anabolic pathways and beta-catenin. Dr Carolyn Lam: Cool, Greg. Man, this cardiac regeneration really, really is a hot area. Dr Greg Hundley: Carolyn, that is so insightful because these results really impact research toward unlocking pathways that could be involved in induction of myocyte cell division and regeneration in those sustaining MI or conditions like MI. Dr Carolyn Lam: Nice. Well, Greg, I'm going to change tones here and ask you, can we prevent atrial fibrillation with treatments for diabetes? Well, guess what? We have a paper next. It's from Dr Wiviott from the TIMI Study Group and his colleagues who really reason that since atrial fibrillation is associated with hypertension, obesity and heart failure in patients with diabetes and SGLT2 inhibitors have been shown to lower blood pressure, reduce weight, and reduce hospitalization for heart failure in these patients, perhaps SGLT2 inhibitors may also reduce the risk of atrial fibrillation. They explored the effect of Dapagliflozin on the first and total number of atrial fibrillation and atrial flutter events in patients from the DECLARE-TIMI 58. As a reminder, they had type two diabetes with either multiple risk factors for or known atherosclerotic cardiovascular disease. Now importantly, atrial fibrillation events were identified by a search of the safety database using these MedDAR preferred terms. Now what they found was Dapagliflozin reduced the risk of atrial fibrillation events during follow-up as well as the total number of atrial fibrillation events in patients with type two diabetes. These reductions were consistent across major subgroups including sex, presence of atherosclerotic cardiovascular disease, history of atrial fibrillation, history of heart failure, history of ischemic stroke, HBA1C groups, body mass index groups, blood pressure or EGFR. They looked at all these subgroups because these are all clinical factors, well established, with associations with the risk of atrial fibrillation. Dr Greg Hundley: Wow, Carolyn. Another sort of feather in the cap for the SGLT2 inhibitors. What does this mean for clinical practice? Dr Carolyn Lam: Ah. I'm not going to answer it here. I am going to say everybody has to read the excellent editorial by Dr Granger from Duke University and Dr Mahaffey from Stanford University School of Medicine. But what I will tell you is their concluding sentences. They said, "This report provides evidence that Dapagliflozin appears to reduce atrial fibrillation events in patients with diabetes and coronary disease and multiple risk factors. It also raises the issue of how to determine when effects on a secondary outcome, particularly one collected without the rigor of systematic collection using perspective definitions and case report forms, whether or not these are reliable." So must read. Dr Greg Hundley: Absolutely. Carolyn, my next study comes and evaluates arrhythmogenic right ventricular cardiomyopathy and is really investigating the concept of auto immunity, looking at associations of circulating anti heart and anti intercalated disc auto antibodies with disease severity and family history. The paper comes from Professor Alida Caforio from the University of Padova. Again, looking at the role of auto antibodies in patients with ARVC. An interesting topic. Dr Carolyn Lam: Yeah, that's really novel. What did they find? Dr Greg Hundley: They investigated ARVC pro bands, so those that sort of started with the disease process in a family and noted an increased frequency of serum organ specific anti heart autoantibodies and anti-intercalated disc autoantibodies in a sizeable arrhythmogenic RVC cohort as compared to controls. They found that positive AHA status. Dr Carolyn Lam: Anti-heart antibodies. Dr Greg Hundley: Yep. Was associated with lower left ventricular ejection fraction, a higher frequency of cardiac symptoms and implantable cardioverter defibrillator implantation. Positive AIDA was associated with lower ejection fractions in both the right and the left ventricle. Dr Carolyn Lam: AIDA being the anti-intercalated disc auto antibodies. Wow. That is interesting. But what are the clinical implications? Dr Greg Hundley: Well, the presence of both these organ specific AHA and AIDA antibodies provides evidence of autoimmunity in the majority, so 85% of familiar, and almost half, 45%, of sporadic ARVC. In programs and in effective relatives, these antibodies were associated with the disease severity features. So really a link with this auto immunity and ARVC. Dr Carolyn Lam: Yeah. I never thought of ARVC as an autoimmune disease. Very interesting. But let me also tell you what else is in this week's issue. There are letters to the editors, one from Dr Kaski regarding the mag STEMI randomized control trial questioning whether improving coronary vasal motion can be equated to restoring patient's cardiovascular health. Interestingly with a letter in response from Dr Sabatine. There's also a research letter by Dr Alahmad on the cardiovascular mortality and exposure to heat in an inherently hot region and where they were was Kuwait. They also drew some implications for climate change. Very interesting piece. There's also an ECG challenged by Dr Verma describing conduction abnormalities and ischemic cardiomyopathy in an 84-year-old man. Dr Greg Hundley: Very nice. Carolyn, in the mailbag, there's a nice research letter from Dr Nicholas Leeper from Stanford University School of Medicine. It's entitled “The 9p21 locus promotes calcific atherosclerosis.” Our own Josh Beckman has an on my mind piece regarding “The Big Mac Attack on Peripheral Arterial Disease.” Dr Carolyn Lam: I love that. I just love the titles Josh comes up with. Dr Greg Hundley: Then finally Bridget Kuehn has a very nice sort of correspondence on Cardiovascular News regarding cardiac imaging on the cusp of artificial intelligence. What a revolution we have ahead, Carolyn, and I know that's a topic that's true to your heart. Dr Carolyn Lam: It is. I loved her paper. Dr Greg Hundley: Okay. Carolyn, how about we get onto that feature article? I'm waiting to hear about the cost effectiveness of tafamidis. Dr Carolyn Lam: Me too. Dr Greg Hundley: Well listeners, we have got a great discussion for our feature publication today and we have Dr Dhruv Kazi from Beth Israel Deaconess in Boston and our own associate editor, Dr Justin Ezekowitz from University of Alberta. Well, as we get started, Kazi, can you tell us a little bit what was the hypothesis that you wanted to test with this study and maybe even before that a little bit of background with transthyretin amyloid and tafamidis? Dr Dhruv Kazi: Yeah. Transthyretin amyloidosis is a subgroup of patients who present with heart failure with preserved ejection fraction, which we know is a heterogeneous condition that has been pretty resilient to effective guideline directed therapies over the past decade. It's a subgroup of patients generally presenting in their 70s with slowly declining quality of life and a median survival of about three years. It hadn't had an effective therapy before and so when tafamidis, which is a stabilizer of transthyretin and prevents its deposition in the myocardium, was developed and tested in a randomized clinical trial that showed an improvement in survival, a reduction in heart failure hospitalizations and a slowing of decline and quality of life. It was viewed as a really big win for the heart failure community. What came as a surprise though is the pricing. It was launched in 2019 at $225,000 a year. We set out to ask, given that this is a severe disease without alternative treatments, is this price tag generating enough value? Is this a cost-effective therapy? The background here again is that oncologic therapies have had a long history of very high prices for rare diseases and severe diseases. But this is the first time we're seeing this in cardiology. Can we think more broadly about how we're going to tackle this issue? Not just for tafamidis but also for other drugs that come down the pipe. Dr Greg Hundley: Wow. $225,000 per year. Tell us what was your study design, and how did you go about evaluating this issue? Dr Dhruv Kazi: We started off with the one phase three trial of the drug that has been published and simulated in a mathematical model the population that would be eligible for this therapy, reproduced the events, heart failure hospitalizations, debts, quality of life that were seen in the trial for the first three years, and then extrapolated beyond the trial based on what we know about HFpEF and what we know about transthyretin amyloidosis. It's a mathematical model that first reproduces what was seen in the trial and then extrapolates beyond what we think is the best guess of what happens to these patients. We tested a variety of scenarios whether the drug continues to be effective, whether the effectiveness declines over time or the effectiveness ceases immediately after three years. Dr Greg Hundley: What did you find? Dr Dhruv Kazi: What we found was interesting and it surprised us a little bit, which is that in the base case, which is assuming that the drug stays effective beyond three years, the drug is actually very effective in the traditional sense. It added 1.3 quality adjusted life years. For context here, this is about twice the effect size you expect to see with Entresto, and the HFpEF patients. So here's a drug that we've accepted and HFpEF has part of guideline directed medical therapy. Tafamidis in that best-case scenario is about twice as effective, but it is not cost effective. Because you're paying $225,000 for every year that the patient is on the medication, its incremental cost effectiveness ratio compared with usual care was $880,000, so well above what we would consider value for money. That's the best-case scenario assuming that the drug is permanently effective, if the drug's effect wanes over time, which is very likely as these patients get older and sicker, then the drug gets even less economically attractive. Dr Greg Hundley: You've pointed out in your article, if you had 120,000 transthyretin patients in the United States, that would translate to how many dollars? Dr Dhruv Kazi: We estimate that if all of those 120,000 patients received tafamidis, the healthcare spending would go up by $32 billion a year and most of it is towards the drug. But the caveat is that we think 120,000 patients in the US is a very conservative number because the diagnostic technology for amyloid cardiomyopathy has improved substantially over the last five years so that we no longer need biopsies. We can use nuclear scans to diagnose the disease and we have pretty good to genetic testing to identify the genetic variant of the disease. We think that number is probably closer to 200,000 or even higher because the healthcare expenditure is almost entirely driven by drug costs. The more patients we diagnosed, the bigger the budget's impact on healthcare spending. Dr Greg Hundley: Oh my. Well Justin, for our listeners, Justin resides in Canada. Justin, what do we do with these results? I mean this is quite a sticker shock for probably an important therapy for this patient population. Dr Justin Ezekowitz: Greg, it's a great issue and Kazi, thank you very much for this terrific, easily understandable manuscript that I think everybody should read as it's very well written and easy to understand for us non-health economists. The sticker shock is a bit of a tricky one because we always want to do what's best for our patients. When we look at that budget impact analysis, the challenge is what do we think internationally? The US is critical in terms of understanding this, but then for the rest of the world, there's certainly almost no willingness to pay at this threshold and with an uncertain incidence of amyloidosis globally, but also within the US and Canada and the difficult in diagnosis already, I think we're going to have to realize what can we do for our patients and who benefits the most with this drug given its importance and its efficacy? Kazi, you mentioned another thing which I think is critical is what happens after 30 months if the effect wanes and where does that take us for the impact on cost and effectiveness over time but also the budget impact analysis? Because the second drug or third drug may very well come along that may fill that niche. Dr Dhruv Kazi: Justin, that's a really good question. I mean the study only goes to 30 months and that's the only one randomized trial for tafamidis that we're working off of. So there's substantial uncertainty about what happens to this drug beyond 30 months. It's reasonable to assume that some of the effect persists, that as patients get older, get sicker, that effectiveness will wane over time. Which ties very closely to the cost effectiveness. So if the patients continue to take the drug but it's not as effective as you can imagine, it becomes less cost effective. This also has implications for other drugs coming down the pike, which may or may not be more effective than tafamidis. They may or may not be tested head to head with tafamidis. Physicians are going to be left with the question, very clinically relevant question, of which drug to start with, how do you switch on them the next generation or more expensive drugs that come down the pike? We'll have to rely on both real-world evidence and to some extent mathematical modeling to use our best judgment on developing a treatment strategy for these patients. But rest assured that our current regulatory framework means that the drugs coming down in the future will be more expensive than tafamidis and hence, this is a good time to have the conversation about cost effectiveness and our willingness to pay for innovation. Dr Greg Hundley: What needs to happen next to help either lower cost or develop some sort of competition in the treatment of this disease to lower the cost? Dr Dhruv Kazi: I can take a stab at that. Greg, I think the findings of this particular drug in transthyretin amyloidosis is illustrative of the challenges that lie ahead. I think there are clinical research and policy implications. As clinicians, it's really important for us to know that this high cost of the drug is not a theoretical challenge. It's a practical challenge for our patients. The majority of these patients are going to be on Medicare part D. We estimate that the out of pocket costs is going to be in the range of $8,000 to $9,000 a year even with Medicare part D, which is a big amount of money for our fixed income seniors. I encourage our clinicians to have this conversation about out-of-pocket costs with patients, not just when you start the therapy but throughout the year. We know that the Medicare part D copays change over the course of the year based on where they are in the insurance plan. Having this conversation may help preclude costs related non-adherence. We might be able to identify patients early or at risk, put them into patient support programs or switch them to alternate therapies that may not be as effective but at least are likely to offer the patient some support. From a research perspective, we really need to figure out what subgroup of patients are more likely to benefit. Let's say we have 200,000 patients with transthyretin amyloidosis in the US. We need more research, and the company is not going to be vested in doing this research, it's going to have to be NIH funded research to identify subgroups of patients who benefit most from this drug, both in the short term and over the long term. From a policy perspective, what this drug pricing issue is telling us is that we provided incentives for companies to innovate in the rare disease orphan drug program. These incentives are working. More than half of the drugs that are coming out now or have in the past year are under this rare disease umbrella. But these drugs, once they're approved, are super expensive. We need to figure out a regulatory framework where we continue to incentivize innovation for rare diseases for orphan drugs, but at the same time tie those incentives to the final pricing to ensure that the patients get access to the drug and not just the wealthy patients who can afford the copays, but all patients who would benefit from the drug. One of the things that comes to mind as clinicians and researchers is that particularly in cardiology, we are obsessed with innovating, with regards to new molecules and new technology. I would like us as a community to focus not just on molecules but also on markets because the innovation is not meaningful if our patients cannot have access to them. This year being the presidential election year, we're going to hear a lot about drug pricing. What I hope that this example shines a light on is that drug pricing is complicated and trying to figure out the right framework to incentivize innovation while it's still ensuring access is going to take thoughtful interventions, regulatory interventions, and clinicians should very much be a part of that process. Dr Greg Hundley: Well listeners, we've heard a wonderful discussion here highlighting a new therapy for a disease process that's being increasingly diagnosed with our aging population and new technologies, magnetic resonance, echocardiography that identify this condition. But then how are we going to afford some of the therapies that are moving forward and design a system that emphasizes not only scientific discovery, but cost effectiveness? We want to thank Dr Dhruv Kazi from Beth Israel Deaconess and also Justin Ezekowitz from the University of Alberta. We hope you have a great week and look forward to speaking with you next week. This program is copyright the American Heart Association 2020.

This week's View discusses the accuracy of coronary computed tomography angiography to identify coronary artery disease in patients with non-ST-segment elevation acute coronary syndrome and summarizes the 5-year outcomes of the PARTNER 2A trial and new results from a substudy of the DECLARE–TIMI 58 trial.

In this interview, Spencer King and Marc Bonaca discuss insights from the DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58) trial, specifically dapagliflozin and outcomes in patients with peripheral artery disease.

An overview of new and recent data presented during ADA 2019. This includes: REWIND - the CVOT for dulaglutide CARMELINA - the CVOT for linagliptin CAROLINA - an active comparison CVOT studying linagliptin vs glimepiride PIONEER 6 - the CVOT for oral semaglutide DECLARE-TIMI 58 - the CVOT for dapagliflozin Featuring an interview with Professor Steve Bain. This independent educational activity is supported by an educational grant from Novo Nordisk A/S. The educational content has been developed by Liberum IME in conjunction with an independent steering committee; Novo Nordisk A/S has had no influence on the content of this education.

How will the findings of the REWIND trial and the DECLARE-TIMI 58 renal outcomes analysis affect treatment decisions for high-risk diabetes patients without overt cardiovascular disease? medwireNews asks Kamlesh Khunti. Find more on Medicine Matters diabetes

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and it's editors. We're your co-hosts, I'm Dr Carolyn Lam, associate editor from The National Heart Center and Duke National University of Singapore. Dr Greg Hundley:             And I'm Greg Hundley, associate editor for Circulation and director of The Pauley Heart Center at VCU Health in Richmond, Virginia. Dr Carolyn Lam:                Guess what Greg? Right after this we have a double feature discussion. It is all about dapagliflozin with some really, really important self-analyses from the DECLARED-TIMI 58 trial and about heart failure in Type 2 Diabetes with dapagliflozin. But, all of that coming right up only after we have our chat. So Greg, what do you have for us today? Dr Greg Hundley:             My first article is going to be from Dr Mintu Turakhia at the VA Palo Alto healthcare system at Stanford University and is going to discuss the practice variation in anticoagulation prescription and outcomes after device-detected atrial fibrillation. It's a study that has insights from the VA Health Administration. This study evaluated the relationship between oral anticoagulant prescription practice variation in response to new device detected atrial fibrillation and the association to outcomes.                                                 As you know Carolyn, there are no clearly defined thresholds of AF burden, for which to initiate oral anticoagulation. Dr Carolyn Lam:                Interesting, so what did they find, how did they do this? Dr Greg Hundley:             Carolyn, the investigators performed a retrospective cohort analysis using data from the Veterans Health Administration linked to remote monitoring data that included day level AF burden. They included patients with cardiac implantable electronic devices and remote monitoring from the years 2011 through 2014. A CHA2DS2-VASc score of greater or equal to 2, and no prior stroke or oral anticoagulant receipt in the preceding 2 years. They determined the proportion of patients prescribed oral anticoagulants within 90 days following new device-detected AFib across a range of AFib thresholds. Greater than or equal to 6 minutes, all the way up to greater than 24 hours. And they examined sight variation in oral anticoagulation prescription. Dr Carolyn Lam:                And so? What did they find? Dr Greg Hundley:             Well, you ask among 10,212 patients with defibrillators, proportion receiving oral anticoagulation varied based on device detected AF burden. For example, for those greater than or equal to 6 minutes, it was roughly 13% of individuals, for those greater than 24 hours, 27% of individuals received oral anticoagulants. Importantly, there was a substantial sight variation in oral anticoagulation prescription after device-detected atrial fibrillation, for example, greater than one hour. The median was 16%, but it ranged from as low as 3% up to highs of 67%. And so, in adjusted models, oral anticoagulant prescription after device-detected AFib of greater than 24 hours was associated with reduced stroke risk and has a ratio of 0.28, p-value's 0.02, although, the propensity adjusted model was significant when AFib lasted at least 6 minutes.                                                 So, in conclusion, among veterans with implanted devices, device-detected atrial fibrillation is common. There is large practice variation in 90-day oral anticoagulation initiation after new device-detected AFib with low rates of treatment overall, even for episodes greater than 24 hours. Remember, we said that rate was 27%. The strongest association of oral anti-coagulation with reduction in stroke was observed after device-detected Afib of greater than 24 hours. And what this study shows, is that randomized trials are needed to perform these observational findings.                                                 So, Carolyn, how about your next study? Dr Carolyn Lam:                Well, from anti-coagulants to anti-hypertensives. I'm going to tell you about the 6-month results if the RADIANCE Hypertension Solo Trial. Dr Greg Hundley:             Oh, so, what was the RADIANCE Hypertension Solo Trial? Can you remind us? Dr Carolyn Lam:                Glad you asked. So the trial was the one that demonstrated a greater reduction in daytime ambulatory systolic blood pressure at 2 months by endovascular ultrasound renal denervation compared with a sham procedure among patients who were not treated with anti-hypertensive medications. So the current paper, led by Michel Azizi from Université Paris-Descartes and colleagues, now report the 6-month results following the addition of a recommended, standardized, stepped-care anti-hypertensive treatment to the randomized endovascular procedure under continued blinding to the initial treatment.                                                 Now, remember these were patients with uncontrolled combined systolic and diastolic hypertension who were initially off medications for two months following randomization. Now, between two and five months, if the monthly measured home blood pressure was more than 135/85, the stepped-care antihypertensive treatment approach was recommended and consisted of sequential addition of, for example, amlodipine 5mg a day, then a standard dose of an angiotensin-converting-enzyme inhibitor, or an ARB, and hydrochlorothiazide at 12.5mg a day, followed by sequential uptitration of the hydrochlorothiazide and amlodipine.                                                 So, what did they find? At 6 months, 65% of the patients in the original renal denervation group were being treated by this stepped-care approach, versus 84.5 in the sham group. And the average number of antihypertension medications and defined-daily doses were all less in the renal denervation group than the sham group.                                                 Now, despite less intensive antihypertensive treatment, the renal denervation group had reduced daytime ambulatory systolic blood pressure to a great extent than the sham group. Importantly, there were no major adverse events in either group through 6 months. The blood pressure lowering effect of endovascular ultrasound renal denervation was maintained at 6 months with less prescribed antihypertension medications compared with the sham control. And what this means is if safety is maintained in larger studies with longer follow-up, renal denervation could be a promising adjunct therapy for patients with hypertension. Dr Greg Hundley:             Wow, so we're getting back toward renal denervation? How about that?                                                 Carolyn, my next paper jumps into the world of basic science. This is a study from Kari Alitalo at the University of Helsinki, and it involves endothelial cells and how they regulate physiological cardiomyocyte growth versus VEGFR2 mediated paracrine signaling. The study evaluates the role of bidirectional endothelial cells and cardiomyocyte cross-talk via cardiokine and angiocrine signaling as it pertains to the regulation of cardiac growth and homeostasis in pathological cardiac hypertrophy. The expansion of the cardiac vasculature to maintain adequate supply of oxygen and nutrients is a key determinant of whether the heart grows in a physiological compensated manner, or a pathological decompensated manner.                                                 Understanding how an excess of angiogenesis induces cardiac hypertrophy and how endothelial cells regulate cardiomyocyte homeostasis, could provide novel therapeutic targets for heart failure. Dr Carolyn Lam:                Ah, this is something very close to my heart. So Greg tell us, how did they establish the link between the endothelial cells and cardiomyocytes? Dr Greg Hundley:             The investigators demonstrated that both endothelial cell deletion of vascular endothelial growth factor receptor 1 and AAV-mediated delivery of the VEGFR1's specific ligands, VEGF-B or BGIF, into the myocardium increased the coronary vasculature and induced cardiomyocyte hypertrophy in adult mice.                                                 The resulting cardiac hypertrophy was a physiological as indicated by preserved cardiac function and exercise capacity and lack and pathological gene activation. Also, the investigators demonstrated that the reported changes were mediated by increased VEGF signaling via endothelial VEGFR2 and found that the notch and ERBb pathways are involved in transducing signals for endothelial cell cardiomyocyte cross-talk in response to angiogenesis.                                                 So clinically, the relevance of the findings are highlighted nicely in an editorial by professor Issei Komuro at the University of Tokyo Hospital. First, he emphasizes that cross-talk between the endothelial cell VEGFR2 and cardiomyocyte ErbB signaling pathways coordinates cardiomyocyte hypertrophy with angiogenesis and contributes to physiological cardiac growth. And understanding whether factors could modify this process may impact the treatment down the road of pathologic hypertrophy. Dr Carolyn Lam:                Oh interesting! Well you know what, Greg, I've got a preclinical one for you too, and this time looking at the role of inflammation in atherosclerosis and specifically at the role of the adaptive immune response and T-cells.                                                 So, Greg, let me remind you that when we looked at CANTOS and Canakinumab we were actually looking at the role of the innate immune response. And here is where I had planned this very nice, complicated quiz for you, Greg, about the innate versus the adaptive immune response in the various cells. Would you like to take the quiz? Dr Greg Hundley:             You know what? I think I'm going to pledge that I'm already going to get a D or an F, so why don't you enlighten us? Dr Carolyn Lam:                Now alright, remember that the CD4 T-cells are assumed to be activated by our antigens derived from modified proteins such as oxidized LDL, and these are presented via MHC class II molecules in the context of cytokine signaling, remember those? What I didn't realize is that it hadn't been assumed that atherosclerosis involves a loss of tolerance against these modified self-antigens, generated in response to hypercholesterolemia and that presentation of such antigens on these MHC class II cells, then lead to activation of proatherogenic Th1 cells. So, that was the assumptions, but this was really studied in detail by the authors, Dr Wigren from Scania University Hospital and Lund University in Sweden and their colleagues, who addressed the role of CD4 T-cells in a real novel, unconventional way. And they did this by crossing MHC class ii deficient mice with atherosclerosis-prone ApoE-deficient mice.                                                 Now the result of these double deficient mice was almost complete void of CD4 T-cells. However, despite the lack of these T-cells and inflammation, these mice developed larger atherosclerotic lesions in the aortic root area of the heart than their ApoE-deficient counterparts. Cell transfer and blocking antibody studies also, then supported these findings and suggested that loss of regulatory T-cells is the most important cause of aggravated atherosclerosis in the double-deficient mice.                                                 So, overall these observations demonstrate that deficiency of activation of the adaptive immune responses through MHC class ii is associated with increased development of atherosclerosis, and the findings have important implications for our understanding the possible risks and benefits of immunosuppressive therapy in patients with cardiovascular disease. Now this is discussed in a beautiful editorial by Dr Slütter and Kuiper and they are from Leiden, the Netherlands.                                                 So, Greg, interesting stuff, huh? Dr Greg Hundley:             You bet! Let's go on and here a little bit more about diabetes. Dr Carolyn Lam:                And dapagliflozin coming right up.                                                 Today's feature discussion is all about SGLT2 inhibitors both in heart failure and atherosclerotic disease. A huge discussion because we have two papers, and they're all coming from the DECLARE-TIMI 58 trial. I am so pleased to have the corresponding author, Dr Stephen Wiviott from the TIMI study group at Brigham Women's hospital in Boston, Massachusetts, as well as the first author of one of the papers, and that is Dr Eri Kato, who was at the TIMI study group and is now at Kyoto University, as well as the editorialist for these two papers, Dr Subodh Verma from University of Toronto, and our deputy editor, Dr Darren McGuire from UT Southwestern.                                                 All-star cast, all-star papers. So, Steve, could you start by telling us about the DECLARE-TIMI 58 trial, just to set the background please? Dr Stephen Wiviott:        So DECLARE, for people who don't know, was a large, randomized trial of 17,000+ patients with diabetes, comparing the SGLT2 inhibitor dapagliflozin to placebo. And the patients could be enrolled if the patients had either an established cardiovascular disease, meaning secondary prevention, or simply risk factors for cardiovascular disease with primary prevention.                                                 Patients that were treated with dapagliflozin or placebo were followed for a period of just over 4 years and there were co-primary endpoints. Those were cardiovascular death and hospitalization for heart failure, and the second co-primary endpoint was MACE, major adverse cardiovascular events, a combination of cardiovascular death, MI, or stroke.                                                 And what we saw, initially, this was a safety trial to demonstrate the safety of this diabetes agent according to worldwide guidelines. We saw that there was certainly non-inferiority for MACE, so it was safe with regard to MACE, but we did see a statistically significant reduction in cardiovascular death and hospitalization for heart failure driven predominantly by a large reduction in hospitalization for heart failure, and we also saw consistent with the other SGLT2 inhibitors, a significant reduction in the progression of renal disease. And so we had the opportunity to follow up with a couple of important papers that were published in circulation. Dr Carolyn Lam:                Thanks, Steve. And at this point I would love to invite Eri to tell us, because we just heard that the heart failure hospitalization signal is very strong. What did you do in your analysis? Dr Eri Kato:                         So previously, SGLT2 inhibitors including dapagliflozin have shown to reduce hospitalization for heart failure, now we wanted to take a step further and explore those who are at high risk. So, the aim of our study was to evaluate whether the clinical benefit of dapagliflozin is greater in patients with HFrEF, heart failure with reduced ejection fraction, compared with patients without HFrEF.                                                 So, we used data from the DECLARE-TIMI 58, which you just heard, which included a broad spectrum of patients with Type 2 diabetes, and was also unique that it is the only SGLT trial to date that has detailed the information of these ejection fractions. So, for this study, for our study trying to find patients by the presence or absence of HFrEF, which was defined as having ejection fraction less than 45%, which is pre-specified ejection fraction couplings, and the key outcome in each was cardiovascular death or hospitalization for heart failure, its components, and of course, mortality. But we also additionally looked at MACE and renal composite endpoints.                                                 There are several interesting findings. First, is that dapagliflozin reduced the risk of hospitalization for heart failure regardless of ejection fraction, including those with preserved ejection fraction.                                                 Second, is we have observed lower rates of cardiovascular death in all-cause mortality with dapagliflozin in patients with HFrEF, but not in those without HFrEF.                                                 So, in patients with HFrEF, there was a significant 45% reduction in cardiovascular death, and 41% reduction in all all-cause mortality with dapagliflozin. And I'd like to highlight that these were achieved on top of high-proportional use of conventional evidence-based heart failure therapies, and that it did not increase any adverse events.                                                 And third, and finally, there were lower rates of renal composite endpoints with dapagliflozin regardless rejection fraction, and once again, it improves patients with preserved rejection fraction.                                                 So, to summarize, our results showed a robust mortality benefit in patients with HFrEF, but also showed that dapagliflozin is beneficial in full spectrum patients with diabetes, regardless of ejection fraction. Dr Carolyn Lam:                Thank you Eri, that's beautifully summarized, but could I just clarify? These were patients not just with a reduced ejection fraction, but with heart failure? And how was that determined? Dr Eri Kato:                         We collected data at the baseline and the heart failure was collected based on the medical record. Dr Carolyn Lam:                So, I just wanted to clarify that it wasn't just rEF, but HFrEF, but the HF part was a medical record. So, Darren, I know you thought a lot about this stuff, so what do you think? Is there still equipoise for these heart failure trials, or how do you think this adds? Dr Darren McGuire:        First, as deputy editor of Circulation, I'm thrilled that were attracting these excellent diabetes-related publications, we've had a track record of several years now of capturing many of the key analyses and certainly these two papers we're talking about today qualify among the very best we've had, and I've also had the privilege of working with these investigators on the executive committee at DECLARE. And to the investigators and the credit of the sponsor, we observed these heart failure signals in other trials as DECLARE was ongoing, and we actually made a modification during the trial to begin to collect as much as we could pre-randomization ejection fraction data. And we were able to capture on roughly one-third of the patients, pre-trial EF data and we took any way it was measured and any time of when it was measured, and there are some limitations to that, but this now represents the largest data set where we can stratify the outcomes by some measure of ejection fraction.                                                 And I have to say I was really surprised by these results; that the cardiovascular death benefits were amplified in patients with heart failure with reduced ejection fraction, but not in those with heart failure with preserved ejection fraction, as these medications are relatively modest, diuretic agents I anticipated the opposite, honestly, that heart failure would preserve ejection fraction that is much more volume-sensitive may have incremental benefits from these medications.                                                 So, I was surprised by this, it was a little bit upside-down from what I expected. I know Subodh and Carolyn you've both thought a lot about this as well, I'd be interested in your opinions. Did you expect that heart failure with reduced ejection fraction would drive these clinical results? Dr Carolyn Lam:                Subodh, I'm going to let you go first. Dr Subodh Verma:           First and foremost, I appreciate the opportunity the circulation gave both myself and Professor McMurray to write the editorial to these very important pre-specified analyses from DECLARE.                                                 I actually see the results not only as interesting and tantalizing as you already discussed, but I actually see a lot of consistency between the two phenotypes, if I may, in that there is a heart failure signal or reduction in heart failure hospitalizations that appears to be consistent between the two groups, right? People with an EF of less than 45 with or without heart failure and then on the other side, people without reduced ejection fraction. They're both responsive in terms of reductions in heart failure hospitalization, so it brings into question that is this differences that we're seeing with respect to mortality, a reflection of a difference in phenotypic responsiveness to an SGLT2 inhibitor, or is this simply a reflection of increasing placebo event rates and a response based on baseline of entry in one group versus the other.                                                 So, as has been nicely outlined by the authors, the placebo event rate for CB death and heart failure and the placebo group would have pass, if I may, was about 5 times lower than those with heart failure with reduced ejection fraction. And it might be that as we go up the pyramid of risk, whether that risk is defined based on a TIMI risk score, whether it's based on a post-MI versus stable CAV risk score, or whether it's defined based on GFR, or whether, finally, it's defined based on the event rates for CV death and heart failure, that the higher the event rate, the higher the probability of demonstrating a CV death benefit, but that old strategies are actually demonstrating a consistent benefit on the overall driver of that outcome, which in this case, is a reduction in heart failure.                                                 So, that's what we sort of said in the editorial as well that we think that it may be a bit premature at this point to reach a conclusion that one group is responsive, and the other group is not responsive. But, as you rightfully said, Darren, it is entirely feasible through these analyses to hypothesize that one of the alternative hypotheses could be that there is a greater responsiveness in HFrEF compared to HFpEF. I actually don't understand the mechanisms of it, if that was the pieces I would have a difficult time explaining it based on the overall biology and sort of current understanding of these agents.                                                 But, I would say let’s wait: dapa heart failure is just around the corner. That trial will enroll people with documented heart failure with reduced ejection fraction. I think 4,774 patients that are being randomized on top of base, on top of RNA, on top of MRA, etc. who still have heart failure and who have a BP that's elevated so the definitive proof for this, at least from a rough standpoint, will be forthcoming. And then there are numerous HFpEF studies that are ongoing. There's Emperor Preserve and there's Deliver, and they have characterized the HFpEF population with a little bit more granularity and clarity. And I think we will be able to then look at, specifically, is there a HFpEF group that has the same event rate for CV death and heart failure, and compare that population to a HFrEF group at the same level of risk and whether there is differences in the responsiveness to be definitive about whether this is a matter of risk, threshold, or whether this is a true representation phenotypically. Dr Carolyn Lam:                Subodh is a hard act to follow. So, I will answer your question directly, but maybe not with so many words, because it's already been said, Darren. And I'll just say I expected this benefit to be in both, I wouldn't have said one versus the other, but because we do know that in trials and with prospective studies that HFpEF outcomes are lower, especially mortality is lower, compared to HFrEF. I do wonder if it's a power issue, but the most important message--and this is coming from me also being on the steering on the committee of both DELIVER and EMPEROR Preserve--that please, this doesn't mean that we don't need the trials. I really really think that there's equipoise there still and we need to look at the DEDICATED HFpEF trials.                                                 But, moving on from the concept of risk stratification, I would like to go on and talk about the next paper. About the DECLARE sub-study of those with a prior MI. So, Steve, could you tell us, why did you do this, and what did you find? Dr Stephen Wiviott:        I think that what we've seen as a pattern across the three SGLT2 inhibitor trials including CANVAS, EMPEROR, Outcome, and DECLARE, was that there seems to be, as Subodh has said, reductions that are relatively consistent in heart failure and renal outcomes. But there was what appears to be ischemic outcomes, the MACE outcomes, cardiovascular death, MI and stroke.                                                 In fact, in a meta-analysis that we published at the same time as the primary paper for DECLARE, we demonstrated that there was an interaction between the primary prevention in the population, those without established cardiovascular disease, and the secondary prevention population as it relates to MACE, where the benefits for MACE seem to be in the secondary prevention population.                                                 So, this was seen in DECLARE as well, and so we hypothesized that the population of patients who had myocardial infarction as their entering condition may be particularly at high risk for MACE and it may potentially be that that was driving the benefit. And so, what we did was we stratified the patients based on history of prior myocardial infarction versus none, turned out that there was about 3,500 patients in the trial who had had a prior myocardial infarction. As would be expected from what's known about the conditions, the event rates for those patients in the placebo arm were much higher, about 2.5 times higher than patients without myocardial infarction for MACE, also true for CV death and hospitalization for heart failure.                                                 And then what we saw when we looked at the treatment outcomes was that there tended to be a greater reduction in MACE for patients with prior myocardial infarction. In fact, for the MACE outcome, we saw about a 16% reduction in MACE with patients with prior MI compared to reduction with patients without prior MI. And so, the combination of this higher risk, also a tendency towards a greater relative benefit lead to a much greater absolute benefit, where, in fact, we saw about a 2.5% reduction in MACE over the four-year period for patients with prior MI, compared to a 0% reduction for patients without prior MI.                                                 And, in fact, when we broke this down to three groups: patients with prior MI, patients with atherosclerotic cardiovascular disease without prior MI, and then patients with no atherosclerotic vascular disease, essentially, we saw the same thing, which is that patients with MI were the ones who had the greatest benefit in terms of MACE. And this was almost entirely driven by reductions in myocardial infarction.                                                 Now, I would say in contradistinction, as we look at heart failure reductions, the relative benefits for heart failure were similar among these groups, but because the risk was higher in the patients with prior MI, and of course the absolute benefits were greater in the MI population, and similar for renal outcome. So, I think that this sort of extends what we have previously known that patients with atherosclerotic cardiovascular disease were at higher risk intended to have greater benefit with the SGLT2 inhibitors on MACE events that the core of that appears to be those patients with myocardial infarction. Dr Carolyn Lam:                Thanks, Steve, that was just so clearly explained. Darren, in the last couple of minutes could I ask you to give us the take-home messages from these two studies, and maybe just, what next? Dr Darren McGuire:        I think the take-home message from these two studies in the context of the overall field of SGLT2 inhibitor data, I think the picture's becoming relatively clear and Subodh stated in eloquently before and is reviewed in the editorial is that I think across the board, and independent of how you define higher versus lower risk subsets, this class of medications in general and dapagliflozin, and these studies appear to have augmented benefit, the greater the risk. Whether that greater risk is defined by prior myocardial infarction, or heart failure with reduced ejection fraction, or decreased EGFR, these are all states where various sub studies have consistently shown across the three compounds where we have outcomes data that the treatment benefits are amplified in the higher risk patients.                                                 And it's not just an absolute risk reduction that's augmented based on baseline risk, but there appears to be an interaction where the relative risk reduction is also amplified. And so, it's really a remarkable field and it's providing therapeutic options in these really high-risk subsets of patients where we've really been handicapped up until now with these antihyperglycemic therapies for type ii diabetes. Dr Carolyn Lam:                Thank you everybody for joining us today. This was truly a bonanza feature discussion, didn't I tell you?                                                 You've been listening to Circulation on the Run, thank you for listening today and don't forget to tune in again next week.                                                 This program is copyright American Heart Association 2019  

In this interview, Gerald V. Naccarelli and Stephen D. Wiviott discuss the DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58) trial.

In this special episode of Eagle’s Eye View, Dr. Peter Block, Dr. Kim Eagle, and Dr. Deepak Bhatt discuss highlights from Day 3 of ACC.19, including IRAD: Acute Aortic Dissection: Lessons Learned From 9000 Patients, REDUCE-IT: Reduction in Total Ischemic Events With Icosapent Ethyl, DECLARE-TIMI 58 HFrEF: Dapagliflozin on HF and Mortality in T2D Based on EF, and SAFARI-STEMI: Femoral Access vs. Radial Access For Primary PCI in STEMI.