Circulation Jul 18, 2017 Issue

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.

                                                Now, the SGLT2 inhibitor, empagliflozin, has been shown to improve outcomes in the EMPA-REG OUTCOMES trial. But do these benefits also apply in the real world, and to other SGLT2 inhibitors as a class? Well, we may just have some answers this week in the CVD-REAL study. More soon right after these summaries.

                                                The first original paper this week uncovers the mechanism of beneficial action of T-cells for proper healing after myocardial infarction. Now, the pro-inflammatory danger signal, adenosine triphosphate or ATP, is released from damaged cells, and degraded by the ectonucleotidase CD73 to the anti-inflammatory mediator, adenosine.

                                                Using newly-generated CD4-CD73 null mice, first author, Dr. Borg, corresponding author, Dr. Schrader, and colleagues from Heinrich Heine University of Düsseldorf in Germany, showed that a lack of CD73 on T-cells enhanced tissue fibrosis and worsened myocardial function in the remodeling phase after myocardial infarction.

                                                T-cells migrated into the injured heart and upregulated their enzymatic machinery to enhance the extracellular degradation of ATP to adenosine. T-cells lacking CD73 showed accelerated production of pro-inflammatory and profibrotic cytokines. Finally, the adenosine 2B receptor was upregulated on cardiac immune cells in the remodeling phase.

                                                In summary, therefore, local adenosine formation by CD73 on T-cells appears to be the body's own defense mechanism to control inflammation induced by myocardial infarction. This is a mechanism that might be exploited to promote healing or remodeling by specifically targeting the adenosine 2B receptor in the infarcted heart.

                                                The next paper provides insights on genetic determinants of susceptibility to peripheral artery disease, and specifically puts the spotlight on Bcl-2-associated athanogene-3, or Bag3, which is a cell chaperone protein previously identified in a genetic screen for determinants of tissue loss with hindlimb ischemia.

                                                In the current study, Dr. McClung from East Carolina University, Brody School of Medicine in Greenville, North Carolina, and colleagues, used adeno-associated viruses to show that an isoleucine to methionine variant at position 81 in Bag3 was sufficient to confer susceptibility to ischemic tissue necrosis in BALB/c mice.

                                                In a series of elegant experiments, they demonstrated that Bag3 was a modulator of ischemic muscle necrosis and blood flow. In summary, this study provides evidence that genetic variation in Bag3 plays an important role in the prevention of ischemic tissue necrosis, and highlights a pathway that preserves tissue survival and muscle function in the setting of ischemia.

                                                The next study provides insights into inflammatory atherogenesis by studying psoriasis, a chronic inflammatory disease associated with an accelerated risk of myocardial infarction. First author, Dr. Lerman, corresponding author, Dr. Mehta from the NHLBI, National Institutes of Health in Bethesda, United States, and colleagues, hypothesized that the increased cardiovascular risk observed in psoriasis would be partially attributable to an elevated subclinical coronary artery disease burden composed of non-calcified plaques with high-risk features.

                                                To test this hypothesis, they compared total coronary plaque burden, non-calcified coronary plaque burden, and high-risk plaque prevalence between 105 psoriasis patients, 100 older hypolipidemic patients eligible for statin therapy, and 25 non-psoriasis healthy volunteers. All patients underwent CT coronary angiography, and a sample of the first 50 psoriasis patients were scanned again at one year following therapy.

                                                The authors found that patients with psoriasis had greater non-coronary burden and increased high-risk plaque prevalence compared to healthy volunteers. Furthermore, compared to older hypolipidemic patients, patients with psoriasis had elevated non-calcified burden, and equivalent high-risk plaque prevalence. Finally, improvement in skin disease severity was associated with an improvement in non-calcified coronary burden at one year.

                                                The clinical implications are that patients with psoriasis have similar coronary artery disease risk as hyperlipidemic patients one decade older, and these patients with psoriasis should be screened earlier for cardiovascular disease and educated about their elevated risks. Further investigations focus on the longitudinal impact of psoriasis treatment on high-risk plaque morphology, as well as on the extent of cardiovascular risk mitigation in randomized trials.

                                                Well, those were your summaries. Now for our feature discussion. Now, we've heard of the EMPA-REG OUTCOME trial, that prospective randomized, controlled trial, showing a substantial reduction in cardiovascular death and hospitalization for heart failure with the sodium-glucose cotransporter 2, or SGLT2 inhibitor, empagliflozin, and that's, remember, that was in patients with type 2 diabetes and established atherosclerotic cardiovascular disease.

                                                Well, our paper today really extends our knowledge and tells us a bit more about the role of SGLT2 inhibitors in real-world clinical care. And I'm so please to have with us the first and corresponding author, Dr. Mikhail Kosiborod from Saint Luke's, Mid America Heart Institute, as well as Dr. Gabriel Steg, associate editor from Paris, France, joining us today. Hello, gentlemen.

Dr. Gabriel Steg:               Hello.

Dr. Mikhail Kosiborod:   Hi. Good morning, Carolyn.

Dr. Carolyn Lam:               Mikhail, I am going to say what I said to you at the ACC and at the ESC Heart Failure: Congratulations on CVD-REAL. Please tell us about CVD-REAL.

Dr. Mikhail Kosiborod:   Right, well, we know, as you just mentioned, that the EMPA-REG OUTCOME trial showed substantial reduction in cardiovascular death, and hospitalizations for heart failure in patients with type 2 diabetes and established cardiovascular disease. We were all very excited once that data got presented in September of 2015 in Stockholm, but there were several very important questions that weren't really addressed, and truly, could not be addressed, in EMPA-REG's trial.

                                                The first, actually, and probably the most important is, we all know that clinical trials, while we regard them as the gold standard of evidence, as we should, they do have their own set of limitations, the most important of which is that they examine a relatively small sliver of patients; and many patients we see in the clinic, in the hospital, don't look like patients in clinical trials. I think the most important questions we tried to address was, "Will this translate to real-world clinical practice?"

                                                The second was, as you recall, again, all patients on EMPA-REG had established cardiovascular disease, so we wanted to know whether the benefits associated with the use of SGLT2 inhibitors could potentially extend to lower-risk patients with type 2 diabetes without established cardiovascular disease, a much broader spectrum of patients.

                                                And finally, and also very importantly, I think, the third question was, "Is it an empagliflozin-specific effect or is it a class effect?" These are all the critical questions we tried to address in the CVD-REAL study.

Dr. Carolyn Lam:               Great. Could you give us the topline results, please?

Dr. Mikhail Kosiborod:   Right. So, just as a reminder, we collected data from well-established registries in six countries, so the United States and some five countries in Europe, Sweden, Norway, and Denmark, and also, the United Kingdom and Germany. And really, the inclusion/exclusion criteria for the study were quite broad, you just had to have type 2 diabetes and be newly started on either an SGLT2 inhibitor or any other glucose-lowering medications, which was the comparative group.

                                                And after we did the one-to-one propensity match to make sure, comparable samples, we ended up with about 154,000 patients, and each treatment group, over 300,000 patients overall. What we actually observed was a marked and highly significant reduction in the risk of hospitalization for heart failure that was associated with use of SGLT2 inhibitors versus other glucose-lowering drugs.

                                                In fact, the magnitude of reduction in risk that was associated with SGLT2 inhibitors, so that outcome was quite similar, about 39% relative risk reduction, quite similar to what we see in the EMPA-REG OUTCOME trial. But this, of course, was for the entire class of SGLT2 inhibitors, so patients in the study were treated primarily with canagliflozin and dapagliflozin, with a small proportion being treated with empagliflozin.

                                                We also saw dramatic and highly significant associated reduction in the risk of all-cause death with SGLT2 inhibitors versus other glucose-lowering drugs, about a 51% relative risk reduction, and the composite of those two outcomes, obviously, there was significant associated reduction in risk as well.

                                                So, again, the hazard ratio estimate that we saw for these outcomes were quite similar, and in some cases, almost identical to what we've seen in EMPA-REG, but for a patient population that was much broader, in fact, about 90% of patients, close to 90% of patients in our study did not have established, documented cardiovascular disease. And, of course, as I mentioned before, important implications to these findings, in my opinion.

Dr. Carolyn Lam:               Yeah, that is just remarkable. Gabriel, could you share some of the discussions that happened among the editors about this paper?

Dr. Gabriel Steg:               We were really excited by this paper. I think this is truly a landmark paper for a number of reasons. It's a very large, multinational study, but even more than the size, I think what's interesting here are a couple of key aspects. First of all is data on all-cause mortality, which is a highly reliable outcome when you look at many of the observational studies.

                                                Non-fatal outcomes can easily be skewed or biased in ascertainment or assessment, but this is relatively reliable. And here, we have a very large multinational cohort that finds benefits on death, heart failure, and their composite, which are remarkably consistent internally, consistent across countries, and consistent with the randomized trial data evidence from the EMPA-REG OUTCOME trial.

                                                So that is striking, and this is consistent across six countries using a very large sample size. But again, the size of the sample is not the most important thing, because in observational studies, you often have very large sample sizes, but if you have bias in your observational study, the bias is just replicated times the size of the study.

                                                The consistency here between the treatment effects across the various countries, the consistency with the efficacy assessed in randomized clinical trials is really a crux in the quality of the data and how believable the results are. Another key aspect that got us really excited is the fact that only a minute fraction of the data is related to use of empagliflozin.

                                                Most of the data was acquired using other SGLT2, and we still only have results now with empagliflozin, we don't have outcome trial data with the other agents. They are pending, but pending the availability of these trials, the fact that this large study sees a consistent benefit, in terms of heart failure and mortality, of the other agents in the class suggests that this is a class effect.

                                                And likewise, the fact that we're seeing these benefits in a population that is much, much broader than the population of EMPA-REG OUTCOMES is also very, very intriguing, and exciting, and makes us really want to see more data not only from the randomized trials that are upcoming, but also from this study.

                                                Because now, what we would like to see is, see the detailed cardiovascular outcomes in these cohorts, and I know that Mikhail and his colleagues are working very, very actively on preparing these analyses. I think this is going to be exciting. This is the first of a series of landmark papers from a model observational study.

                                                There are many issues with observational studies. This is almost as good as it can ever get, and I want to compliment Mikhail and the consortium that's with him, because this is a tremendous effort, across several countries, on achieving this. I think it's very exciting for our readership and for clinicians around the world.

Dr. Carolyn Lam:               I couldn't agree more, and I share your compliments for Mikhail. Perhaps, Mikhail, could you give us a sneak peek at the future and the ongoing work?

Dr. Mikhail Kosiborod:   We frequently think of, and I think perhaps mistakenly at times, think of clinical trials and observational real-world data as competing with one another. In many cases, they're really complementary, and I think if you really, kind of, think of interventions that we consider as those gold standards enshrined in clinical guidelines, or something we absolutely should be doing for our patients.

                                                Just to pick one example, statins for secondary prevention after a cardiovascular event, for example, there is data from both sources suggesting that these drugs are highly beneficial, right? So it is very important to have data from both sides, and I think, as Gabriel mentioned, I look at CVD-REAL as a model, in many ways, of how compelling the data from non-randomized, large, real-world observational studies can be when done well.

                                                In terms of a sneak peek for the future, there are many, many things going on. We are carefully examining the outcomes that we are reporting in circulation, including heart failure and all-cause mortality in various subgroups. We are, of course, as Gabriel mentioned, intently looking at other outcomes, including myocardial infarction, stroke, cardiovascular death, and a composite of major adverse cardiac events.

                                                We're also examining some of the diabetes, one could argue, maybe, diabetes-specific outcomes, such as hypoglycemia rates. We, of course, as cardiologists tend to concentrate on cardiovascular outcomes, but it's also important to remember that there are other important outcomes that could be associated benefits.

                                                So these medications may be associated with marked reduction of cardiovascular events, such as death and heart failure, but they may also reduce hypoglycemia rates and, of course, that's important from a quality-of-life standpoint for patients with diabetes, so some of that work is ongoing.

                                                And I would say, importantly, one of the other things that we're hoping to be able to do in the future is to go beyond cardiovascular outcomes, and perhaps blood glucose-specific outcomes, such as hypoglycemia, and start looking at events such as renal disease events, which I think are very important, of course. Interact quite a bit with, I suspect, in many ways, with some of the cardiovascular benefits that we're observing with those agents, both in the clinical trials and, now, in large observational studies.

                                                And that's just the beginning. I mean, I think it's fair to say that, as Gabriel mentioned, a huge amount of work went into putting this together, right? And we're actually not only expanding things from a standpoint of outcomes. We're also expanding things from a standpoint of countries that will be participating in CVD-REAL consortium.

                                                So we're actually planning to add at least two or three more countries from Europe, Middle East, and Asia in the coming months, and more so in the future. And of course, once you have a resource like this, there are additional questions that can be addressed, actually, both with SGLT2 inhibitors as a class, but also with other classes of type 2 diabetes medication. So that's, I think, as much of a sneak peek as I can give you right now. Just definitely promise you that there is a lot more coming.

                                                In addition to ADA, we're going to have abstracts being presented at ESC in August, and also the European Association for the Study of Diabetes meeting in Lisbon, in September, and there's going to be a lot more afterwards as well. So just stay tuned, I would say. This is definitely just the beginning. There's going to be a lot more coming.

Dr. Carolyn Lam:               You took the words right out of my mouth. Listeners, stay tuned, and don't forget to tune in next week as well.