Circulation February 22, 2022 Issue

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.