Jan 23, 2023
Please join author Subodh Verma and Guest Editor Christopher Granger as they discuss the article "Empagliflozin and Left Ventricular Remodeling in People Without Diabetes: Primary Results of the EMPA-HEART 2 CardioLink-7 Randomized Clinical Trial."
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-host. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Dr. Peder Myhre:
And I'm Dr. Peder Myhre, social media editor and doctor at Akershus University Hospital at University of Oslo in Norway.
Dr. Carolyn Lam:
Peder, I am so excited to be discussing this issue. So many great articles and a feature discussion coming up on the SGLT2 inhibitor, empagliflozin. And do you think it's got effects on left ventricular remodeling in people without diabetes? Very interesting question.
Dr. Peder Myhre:
That is so interesting, Carolyn. I can't wait to hear this discussion.
Dr. Carolyn Lam:
Yep, I agree, but we got to wait till we discuss the other papers in today's issue. I want to go first. So we know that non-vitamin K oral anticoagulants, or NOACs, they've become the standard therapy for preventing stroke and ischemic thromboembolism in most patients with atrial fibrillation. But, what is the effectiveness and safety of NOACs in patients on dialysis? That is hemodialysis. The AXADIA-AFNET 8 study sought to test the hypothesis that apixaban would be non-inferior to vitamin K antagonists in these very patients undergoing hemodialysis.
Dr. Peder Myhre:
Oh wow. This is really a gap of knowledge that we've been waiting to hear more about. NOACs in patients with hemodialysis. Tell us about this trial, Carolyn.
Dr. Carolyn Lam:
Sure. So this is from corresponding author, Dr. Reinecke, and colleagues, from University of Munster in Germany. And it's an investigator initiated prospective randomized open-blinded outcome assessment of 97 patients with atrial fibrillation on chronic hemodialysis randomized to either apixaban 2.5 mg BID, or a vitamin K antagonist, aiming for an INR between 2 and 3. Over a median follow-up time of 429 days for apixaban, and 506 days for the vitamin K antagonist, the composite primary safety outcome of first, major bleeding, clinically relevant, non-major bleeding, or all cause death, occurred in 46% of patients on apixaban, and 51% of patients on the vitamin K antagonist. That would be a hazard ratio of 0.91, with a p for non-inferiority being 0.157.
How about the primary efficacy outcome? While this was a composite of ischemic stroke, all cause death, myocardial infarction, or deep vein thrombosis, and/or pulmonary embolism, and that occurred in 21% of patients on apixaban and 31% of patients on the vitamin K antagonists. Again, no difference when there was testing. So, in summary, Peder, there were no differences in the safety or efficacy observed between apixaban and vitamin K antagonists in patients with atrial fibrillation on chronic hemodialysis.
Of note, however, even receiving oral anticoagulations, these patients remain at very high risk of cardiovascular events. So these data really support the consideration of apixaban for prevention of cardiovascular complications in patients with atrial fibrillation on chronic hemodialysis, but larger studies are definitely needed.
Dr. Peder Myhre:
Oh wow, Carolyn, that is so clinically relevant. And the next paper is also a clinically relevant paper. And it comes to us from the SPRINT authors. And to remind you, the SPRINT study was a study of intensive systolic blood pressure lowering compared to standard blood pressure lowering. And the results demonstrated that there was a robust reduction in both heart failure endpoints and all cause mortality. And in this sub-study that comes to us from corresponding author Jarett Berry from University of Texas Tyler School of Medicine, these authors look at the mechanisms through which intensive blood pressure lowering reduces the risk of these endpoints. And given the important role of cardiac injury and neurohormonal activation in the pathways leading from hypertension to heart failure, and strong association that has been observed between hypertension and levels of cardiac troponin and NT-proBNP, the authors hypothesized that intensive systolic blood pressure lowering would decrease levels of high sensitivity cardiac troponin T and NT-proBNP.
Dr. Carolyn Lam:
Cool. That's interesting. So how did they do this, and what did they find?
Dr. Peder Myhre:
So, as expected, Carolyn, the authors found that increases in troponin and NT-proBNP from baseline to 1 year were associated with a higher risk of heart failure and death. And there were really no significant interaction by treatment assignment. But let's look at the changes in troponin. And these results showed that randomization to intensive blood pressure lowering versus standard blood pressure lowering resulted in a significant 3% increase in cardiac troponin T level over 1 year follow up, and a higher proportion of participants with more than 50% increase, and that's with an odds ratio of 1.47. And Carolyn, in contrast, NT-proBNP decreased by 10% in intensive blood pressure arm. And these patients had substantially lower probability of increasing more than 50% in NT-proBNP, with an odds ratio of 0.57 compared to the standard arm.
And now, to the most interesting part of this analysis, Carolyn, the association of randomized treatment assignment on changes in troponin was completely attenuated after accounting for changes in eGFR during the follow up, whereas the association of treatment with NT-proBNP changes were completely attenuated after adjusting for changes in systolic blood pressure. So Carolyn, the authors highlight in their discussion the importance of non-cardiac factors influencing variation in cardiac biomarkers, and raise questions about the potential role of cardiac troponin T as a surrogate marker for heart failure or death in blood pressure lowering studies.
Dr. Carolyn Lam:
Wow, very interesting. Thanks, Peder. Can I tell you now about a preclinical study? Very interesting, because it shows that cardiac inflammation and hypertrophy are regulated by a heart-brain interaction.
Dr. Peder Myhre:
Wow, Carolyn, a heart-brain interaction. I'm excited to hear more about this. Please explain.
Dr. Carolyn Lam:
I'd love to, but first some background. Interleukin-1 beta, now that is a pro-inflammatory cytokine that causes cardiac hypertrophy and heart failure. I need to familiarize you with this, the nucleotide-binding domain leucine-rich containing family, pyrin domain-containing-3, NLRP3 for short, which is an inflammasome, which is a cytosolic multiprotein complex that mediates active interleukin-1 beta production. Okay? So you know these terms, and now I want to tell you about the study.
This is an elegant series of experiments performed by co-corresponding authors, Dr. Higashikuni, from University of Tokyo, and Dr. Sata, from Tokushima University Graduate School of Medicine, and their colleagues. They first showed that genetic disruption of the NLRP3 inflammasome resulted in significant loss of interleukin-1 beta production, cardiac hypertrophy, and contractile function during pressure overload. Next, a bone marrow transplantation experiment revealed an essential role of NLRP3 inflammasome in cardiac non-immune cells in myocardial interleukin-1 beta production and the cardiac phenotype. It was extracellular ATP released from sympathetic nerve terminals that induced the hypertrophic changes of cardiac cells in an NLRP3 and interleukin-1 beta dependent manner in vitro. And finally, depletion of ATP release from sympathetic efferent nerves, or ablation of cardiac afferent nerves, or a lipophilic beta-blocker, all reduced cardiac extracellular ATP, and inhibited the NLRP3 inflammasome activation, the interleukin-1 beta production, and the adaptive cardiac hypertrophy during pressure overload.
So all of this suggests that controlling the neuronal brain signals might have therapeutic potential for the treatment of hypertensive heart disease. Neat, huh?
Dr. Peder Myhre:
Oh, that is so interesting. The heart and brain interaction. And, Carolyn, we're going to stay in the field of preclinical science. And now we're going to talk about another field that is really interesting, and that is regeneration of cardiomyocytes. Because, Carolyn, developmental cardiac tissue holds remarkable capacity to regenerate after injury, and consists of regenerative mononuclear and deployed cardiomyocytes. Whether reprogramming metabolism promotes persistence of these regenerative mononuclear and deployed cardiomyocytes that enhance cardiac function in repair after injury is unknown. Therefore, these researcher, led by corresponding author, Mohsin Khan, from Temple University School of Medicine, investigated whether the RNA binding protein, LIN28a, which is a master regulator of cellular metabolism, plays a role in cardiac repair following injury.
Dr. Carolyn Lam:
Wow. That is always, always interesting, regeneration and repair following injury. So what did the authors find?
Dr. Peder Myhre:
Well, Carolyn, through a number of elegant experiments, the authors made the following key findings. For the first time, they documented a role for RNA binding protein LIN28A in regulating cardiomyocyte turnover in the postnatal and adult heart. And LIN28a overexpression promotes cardiomyocyte cell cycle activity during postnatal development and extends cardiac regenerative ability of the mammalian heart to postnatal day 7. And in the adult heart, the authors could demonstrate that LIN28a drives new myocyte formation, augmenting cardiac structure and function after myocardial injury. And Carolyn, I'm sure you're going to ask the clinical implications of this study.
Dr. Carolyn Lam:
Indeed.
Dr. Peder Myhre:
And that is that these results may suggest a novel translational role for LIN28a based strategy to replenish cardiomyocytes in the adult heart after injury.
Dr. Carolyn Lam:
Very nice, Peder. Thank you. Also in the issue is a Research Letter by Dr. Bick on interleukin-6 receptor polymorphism attenuates clonal hematopoiesis mediated coronary artery disease risk among many individuals in the UK Biobank. There's also Cardiology News by Tracy Hampton, where she highlights few really interesting things, like aging cardiomyocytes accumulate new genetic mutations that was published in Nature Aging, cytokines promote tissue repair after a heart attack in mice, and that was published in Science, and scientists identifying molecular alterations in a failing heart at a single cell resolution, which was published in Nature.
Dr. Peder Myhre:
And there are a couple of other papers also in this issue, Carolyn. And there's first, an exchange of letters by Drs. Halushka, Lu, and Mayr, regarding the article "Circulating MicroRNA-122-5p is Associated with a Lack of Improvement in Left Ventricular Function after TAVR and Regulates Viability of Cardiomyocytes Through Extracellular Vesicles."
And finally, we have an "On My Mind" piece by doctors Monda and Limongelli entitled "An Integrated Sudden Cardiac Risk Prediction Model for Patients with Hypertrophic Cardiomyopathy."
Dr. Carolyn Lam:
Oh, nice. Nice full issue. Thank you, Peder. Let's go to our feature discussion now. Shall we?
Dr. Peder Myhre:
Let's go.
Dr. Greg Hundley:
Welcome listeners to this feature discussion on January 24th. And we have with us Dr. Subodh Verma, from St. Michael's University in Toronto, Canada. And a guest editor, Dr. Christopher Granger, from Duke University in Durham, North Carolina. Welcome gentlemen. Well, Subodh, we will start with you. Can you describe for us some of the background information that went into the preparation of your study, and what was the hypothesis that you wanted to address?
Dr. Subodh Verma:
First, my great pleasure to be here, and thank you very much for the opportunity to discuss this paper with your viewers. As you know, SGLT2 inhibitors have been truly transformative therapies. From a heart failure perspective, we know that they prevent incident heart failure in people with diabetes who have vascular disease or risk factors. They also have been shown to treat prevalent heart failure in people with heart failure and either a reduced, mildly reduced, or preserved ejection fraction independent of glycemic status. And really, these have been the basis of very strong recommendations to use these agents in the prevention of heart failure in people with diabetes, and also in the treatment of prevalent heart failure in people with and without diabetes.
Now, the fact that these drugs have such broad effects in people with heart failure has led to a theory that maybe these drugs could be introduced earlier on in the natural history of heart failure in people who neither have diabetes nor have significant heart failure, the so-called sort of stage A or stage B patient. But there really have been no clinical trials evaluating this question. There've been a lot of translational randomized trials that have provided some mechanistic insights about LV remodeling in people with diabetes or in people with prevalent heart failure. And we hypothesized that maybe the first step to evaluate whether SGLT2 inhibitors may have favorable effects on cardiac remodeling in people without diabetes or without heart failure would be to conduct a randomized double-blind control trial looking at indices of left ventricular remodeling in a population that I've just described.
Dr. Greg Hundley:
Very nice, Subodh. So you've started us into your study design. Maybe describe that a little more fully, and then who was included in your study population?
Dr. Subodh Verma:
So EMPA-HEART 2 CardioLink was a multi-center double-blind placebo control randomized trial in which we studied the effects of empagliflozin, an SGLT2 inhibitor, at a dose of 10 mg per day versus placebo in people who did not have type 2 diabetes or significant heart failure. We included people who were adults between the age of 40 and 80 who met 1 of 2 entry criteria. Either they had to have one major criteria, which was an increase in left ventricular mass index by specific echo criteria or MRI criteria, or they could have increased LVH as identified by ECG or by intraventricular septal or posterior wall thickness. They could also get in if they had resistant hypertension, hypertension despite being on 3 antihypertensive agents, or the second strata was entry through 2 minor criteria, which included a history of myocardial infarction, a GFR between 30 or 60, or evidence of overweight or obesity.
Dr. Greg Hundley:
And how many subjects did you randomize?
Dr. Subodh Verma:
So we randomized, of the 318 that we screened, 169 were randomized to receive empagliflozin 10 mg or a placebo. Patients had a baseline cardiac MRI done, and then the exposure was 6 months. They had a follow-up MRI at the end of 6 months. And the primary outcome measure was a 6-month change in left ventricular mass index from baseline to 6 months between the two groups.
Dr. Greg Hundley:
Very nice. And so , Subodh, can you describe for us now, what did you find? What were your study results?
Dr. Subodh Verma:
So, first and foremost, what we found in terms of baseline characteristics was that we enrolled a population of people with a mean age of around 60 with a BMI of around 30 kg/m2, predominantly men, about 80% or so were men. These were patients who did not have significant heart failure. The NT-proBNP at baseline was around 50 pg/mL. The eGFR was around 80 mL/minute, and the vast majority of these patients actually had a history of hypertension. Of course, none of them had diabetes by definition. The hemoglobin A1C was around 5.8%.
Now what we found was, despite the fact that we went after patients who we thought would be enriched for a baseline increase in LV mass indices, the baseline LV mass index was mildly elevated, was around 63 g/m2. And over the course of 6 months, we did not find any significant difference in terms of LV mass regression between the placebo and empagliflozin groups. In fact, the adjusted treatment effect was minus 0.30 g/m2, which was not statistically significant. No other differences were found in terms of other indices of a remodeling, including left ventricular and diastolic or end systolic volume indices or in terms of left ventricular ejection fraction. There was a 2% increase in ejection fraction, and the p-value for that was 0.07, but really was not statistically significant.
Dr. Greg Hundley:
And very nice. And realizing that women may have smaller LV masses, any stratified analysis that evaluated effects on men versus women? And then what about, perhaps in the higher quartile versus lower quartile, of age?
Dr. Subodh Verma:
Right. So, Greg, we actually did look at various subgroups and covariates, including gender, including age. And age or gender did not really influence the overall result that we obtained. There was really a neutral result in empagliflozin, irrespective of these 2 covariates. We also looked at baseline blood pressure, baseline NT-proBNP, LV mass indices, the presence or absence of heart failure, chronic kidney disease. So for the covariates that we have evaluated over a short term of 6 months in this relatively low risk population, we did not find any heterogeneity the result, per se.
Dr. Greg Hundley:
Very good. Well, Subodh, thank you so much for that beautiful presentation. And listeners, now we're going to turn to our guest editor, Dr. Chris Granger. And Chris is an expert in the field of heart failure. Also, a lot of familiarity with HFpEF, which sounds a little bit, we're looking at precursors. We don't have HFpEF yet, but maybe trying to inhibit this from happening using empagliflozin. How do you put these results in the context with other studies that have emphasized utilizing SGLT2 inhibitors in patients with sort of a preserved ejection fraction and absence of diabetes?
Dr. Christopher Granger:
Yeah. Well thanks, Greg. And again, congratulations, Subodh, to your study. And I think you framed some of the context here as these drugs, the SGLT2 inhibitors, as being transformative, which I think is exactly right. And it's such a fascinating story. Right? These drugs, which we thought originally, with their cause of glucose spilling in the urine, and a modest decrease in blood glucose, might have a role for modestly improving glucose control in diabetes. And low and behold, they've turned out to be one of the great stories I think in recent, across all of medicine, in terms of their consistent and substantial improving clinical outcomes for patients with heart failure, with diabetes and cardiovascular disease, and now even kidney protection, and much broader implications. And their well tolerated, and they don't have dose titration. So there's some practical appeal to this class of drugs in terms of their benefits, in terms of clinical outcomes.
But we're left with having this amazing evidence-based generated without really understanding why are these drugs so effective? And what are they doing? And you've provided, I think, an important piece to the puzzle. We did have the data from patients with diabetes and heart failure, with diabetes and left ventricular hypertrophy, that there is a modest reduce in LV mass with SGLT2 inhibitors. And what you've shown is that for patients that with mild LVH, with risk for LVH, that we simply don't see a substantial reduction in LV mass with the use of these drugs. So I think that provides this evidence that that's not a major cause of benefit, at least in this earlier phase of development of heart failure.
And I think it really underscores the fact that there's a lot of work to do still to understand. We know that the renal effects are obvious place that these drugs have such an important benefit. And then the linkage of renal disease and cardiac performance is one of the areas, I think, that's a very exciting aspect of a probable contribution of the mechanism of these drugs. But I think in the end, we're left with still not really understanding why these drugs are so beneficial. But understanding that, I think, will be important, both for opening new avenues of targeting pathways, as well as being able to tell the clinical community, okay, you have these important benefits, but people do want to also know why are we seeing these benefits.
Dr. Greg Hundley:
Very nice. Well, listeners, we're going to turn back to Dr. Verma here. Subodh, what do you see is the next study to be performed in this sphere of research?
Dr. Subodh Verma:
Well, first, my thanks to Professor Granger, Chris, for handling this paper and for his very thoughtful comments. And he's absolutely right. We have such wonderful clinical data, and these results, of course, should not in any way take away from the importance of using empagliflozin or other SGLT2 inhibitors in the prevention of heart failure in people with diabetes, or in the treatment of HFpEF or HFrEF. But we're struggling with trying to understand what is the dominant mechanism of action here. And, in the previous precursor to EMPA-HEART 2, we did EMPA-HEART 1 in people with diabetes, and we saw a modest effect that was statistically significant of reduction in LV mass index. And we did not see this, of course, in a lower risk population without diabetes. And that tells me that remodeling may be occurring to a modest effect, it may require a longer time to actually show its benefits, but that this is unlikely a dominant sort of mechanism through which these drugs are working.
And I do share Chris's thoughts that one of the key mechanisms of benefit that needs to be further explored is looking at the renal cardiac axes. We know that these drugs are profoundly renal protective, and that the benefits may actually be secondary to improvements in renal hemodynamics, improvements in renal function. And I think that is a population that needs to be, that's a mechanism that needs to be studied further.
So I think the next generation of translational mechanistic studies need to really tease out the renal cardiac axes, maybe tease out populations that are at risk but have more significant left ventricular hypertrophy, maybe evaluate patients for a longer duration of treatment, or select people who truly have significant hypertension at baseline. I think those are groups and questions that need further exploration. And, of course, the translational science needs to be also studied in the context of larger completed clinical trials, where biomarkers are currently available and they can be linked, of course, to the outcomes in those trials. So those are some of my thoughts as to where the field could move towards.
Dr. Greg Hundley:
Very nice. And Chris, do you have anything to add?
Dr. Christopher Granger:
Subodh, I think that was a great summary. And I might just make a comment on the other end of the spectrum. That is, we have these drugs and the evidence of their benefit, and yet they're grossly underused in the populations that have proven to have benefit. Now it takes some time to educate, to get people familiar with, and get them to integrate these treatments into practice, but there's an enormous opportunity, and I think there is a linkage here. I think when people understand the mechanism, and when they're thoughtful about how these drugs may be working, that that really helps to make the case that the drug should be used, and that people are on board with using them. So I think there's this linkage here, there's the need to both better understand mechanism, and there's the need to have systems of care where these treatments are integrated to provide the benefit that's been so clearly shown in the randomized trials.
Dr. Greg Hundley:
Very nice. Well, listeners, we want to thank Dr. Subodh Verma, from St. Michael's University in Toronto, and our guest editor, Dr. Chris Granger, from Duke University in Durham, North Carolina, for bringing this paper highlighting that among people with neither diabetes nor significant heart failure but with risk factors for adverse cardiac remodeling, that SGLT2 inhibition with empagliflozin did not, did not, result in a meaningful reduction in LV mass index after 6 months.
Well, on behalf of Carolyn, Peder, and myself, we want to wish you a great week, and we will catch you next week on the run. This program is copyright of the American Heart Association 2023. 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.