Circulation August 27, 2019 Issue

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 cohosts. 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 from the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr Carolyn Lam:                In just a moment, we will be discussing further results from the CREDENCE trial. That's canagliflozin in patients with type 2 diabetes and chronic kidney disease, this time focusing on the cardiovascular outcomes as well as both primary and secondary prevention groups. Really exciting stuff, huh, Greg?

Dr Greg Hundley:             Absolutely, Carolyn. Got any papers you want to have a coffee chat about?

Dr Carolyn Lam:                Absolutely. So my first pick really tells us that allele-specific RNA silencing of human alleles may be effective in treating inherited cardiomyopathies. Want to hear more?

Dr Greg Hundley:             You bet.

Dr Carolyn Lam:                So, this is a study from Dr Ashley and colleagues from Stanford University School of Medicine who performed a selective allele-specific silencing of the human restrictive cardiomyopathy, a specific mutation of asparagine to lysine in the regulatory light chain, which is encoded by MYL2. So they did this in a humanized transgenic mouse model using an adeno-associated virus RNA interference approach. Using this approach, they showed that an interfering RNA treatment ameliorated disease phenotypes by specifically reducing the cardiac expression of the mutated allele, hypertrophic carb biomarkers and intramyocardial fibrosis. In fact, isolated cardiomyocytes from the treated animals showed normalization of contraction and relaxation dynamics with partial restoration of calcium re-uptake dynamics.

Dr Greg Hundley:             Boy, Carolyn, sounds like improvement in cardiovascular function, but were there any adverse effects?

Dr Carolyn Lam:                Great question. Well, they also performed cardiac genome-wide transcriptome profiling, which showed a reduction in the hypertrophic program without significant off-target effects, so that's important. So in summary, these results show the feasibility, efficacy, and safety of RNA interference therapeutics directed at human restrictive cardiomyopathy. A really promising step towards targeted therapy for a prevalent disease.

Dr Greg Hundley:             Very nice. Carolyn. So I'm going to start my discussion also with a basic science paper that's going to focus on ischemia reperfusion injury and looking at the mechanism by which mitochondrial dysfunction can be avoided. So, the paper emanates from Dr Yu-Lin Li from Beijing Anzhen Hospital at the Capital Medical University in Beijing. The study from Dr Li identifies an important mechanism of this myocardial ischemia-reperfusion injury in a mouse model and found, in human subjects, a biomarker that was predictive of adverse cardiovascular events after those individuals had sustained an MI.

Dr Carolyn Lam:                Oh, interesting. So tell us more, Greg.

Dr Greg Hundley:             Yeah, so the authors utilized a dynamic transcriptome analysis of mouse hearts exposed to various myocardial ischemia-reperfusion periods to identify a new inflammatory molecule that they termed S100A8/A9, and it was an early mediator. And then they measured this new inflammatory molecule level in patients, human subjects, after myocardial infarction, before and after they had undergone percutaneous intervention. So this S100A8/A9 was identified as the most significantly up-regulated gene during the early reperfusion stage and knockout of that molecule markedly decreased cardiomyocyte death and improved heart function, whereas hematopoietic overexpression of the molecule exacerbated myocardial ischemia-reperfusion injury.

                                                The authors then demonstrated that the levels in patients significantly increased day one post-PCI in anterior MI patients and elevated molecule levels were associated with the incidents of future MACE. So perhaps, in the future, targeting this molecule-initiated signaling may represent a novel therapeutic intervention for myocardial ischemia-reperfusion injury.

Dr Carolyn Lam:                Interesting and very nicely explained. Now my next paper, the title says it all. Three Public Health Interventions Could Save 94 Million Lives in 25 Years. So we know that preventable noncommunicable diseases, which are mostly cardiovascular diseases, are responsible for 38 million deaths annually. So, these authors who are Dr Danaei and colleagues from Harvard T.H. Chan School of Public Health in Boston, Massachusetts, quantified the global mortality impact of three high-impact and feasible interventions. One, scaling up treatment of high blood pressure to 70%, two, reducing sodium intake by 30% and, three, eliminating the intake of artificial trans fatty acids.

                                                So, they used global data on mean blood pressure levels and sodium and trans-fat intake by country, age and sex from a pooled analysis of population health surveys and regional estimates of current coverage of antihypertensive medications as well as cause-specific mortality rates in each country, along with projections from 2015 to 2040. They used the most recent meta-analysis of epidemiologic studies to derive the relative risk reductions for each intervention.

                                                And, in summary, they found that the combined effect of the three interventions delayed 94.3 million deaths during 25 years. Increasing the coverage of antihypertensive medications to 70% alone would delay 39.4 million deaths, whereas reducing sodium intake by 30% would delay another 40 million deaths and eliminating trans-fat would delay an additional 14.8 million deaths.

Dr Greg Hundley:             Aha. So controlling blood pressure, cutting salt, eliminating trans fats, but are there any regional differences around the world, Carolyn, your part of the world versus United States?

Dr Carolyn Lam:                Good question as always. So the authors also estimated the impact in different parts of the world and found that the estimated impact of trans fat elimination was largest in South Asia. Sub-Saharan Africa had the largest proportion of premature delayed deaths out of all delayed deaths. National and international efforts therefore need to scale up these interventions and this should be a focus of cardiovascular disease prevention programs.

Dr Greg Hundley:             Oh, my. Really interesting. Well, I'll tell you what, Carolyn, my next article is going to take us to space, the unified efforts of all these countries in the world trying to examine the effects of prolonged space flight. So this article, it's headed up by Dr Ben Levine at University of Texas Southwestern Medical Center, but it has a very large group of coauthors and examines the impact of prolonged space flight on orthostatic tolerance as those astronauts return to earth.

                                                So, as we know, astronauts returning to earth usually demonstrate reduced orthostatic tolerance, especially when you assess them on a tilt table. But no studies to date have evaluated sort of the post-flight return to earth effects of orthostatic on activities of daily living, and those are most clinically relevant. So in this study, ambulatory blood pressure variability, that's already been known to be associated with orthostatic intolerance in other patient populations and can capture clinically significant orthostatic hypertension during activities of daily living. So, in the study, ambulatory beat-to-beat blood pressure was recorded using a portable device for multiple 24-hour time periods before, during, and after six months of space flight in 12 astronauts, four women, age averaged 48 plus or minus five years.

Dr Carolyn Lam:                Fascinating. What a clever study. So what did happen to the astronauts when they returned to earth?

Dr Greg Hundley:             So, in contrast to previous studies which employed the tilt tables or the stand test, no astronaut experienced orthostatic intolerance or hypertension during activities of daily living before or after space flight. 24-hour systolic blood pressure decreased in space as we might expect, but it returned to normal upon landing and diastolic blood pressure was unchanged during and following space flight. Systolic and diastolic blood pressure variability remained the same before, during, and after space flight. Given the current countermeasures that include exercise, training in flight, volume resuscitation on return, no astronauts experienced orthostatic hypertension or intolerance during routine, for landing day, activities in the initial 24 hours after landing, following six months in space. And prolonged exposure to space fight, therefore, had little impact on systolic blood pressure variability and its distribution. Though the latter showed just a transient change in space and that might be expected. It returned, however, to preflight values when we got back to earth. Very nice work.

Dr Carolyn Lam:                Yes, indeed. Very clever. But let's carry on with our feature discussion, shall we?

Dr Greg Hundley:             You bet. Welcome everyone to our featured article discussion, and we're going to learn more about primary and secondary cardiovascular-related events from the CREDENCE trial and we have with us, Dr Ken Mahaffey from Stanford Medical Center in California and our associate editor, Professor Naveed Sattar from Glasgow in the United Kingdom. Welcome to you both and we feel very honored to be able to discuss this paper today with you, Ken.

                                                Can you just refresh our memories a little bit about the CREDENCE trial? What were its primary results? I understand they had patients with diabetes and chronic kidney disease. Maybe tell us a little bit about how that was defined and then transition to what were the hypotheses in your study that you were going to test?

Dr Kenneth Mahaffey:   So, the CREDENCE trial was a trial of an SGLT2 inhibitor, canagliflozin, in patients with diabetes who had chronic kidney disease with albuminuria. And it was the first of any of the SGLT2 inhibitor trials that was done in a dedicated renal population with a primary outcome that was a composite of renal outcomes along with cardiovascular death, and the trial was stopped early by the data safety monitoring board on an interim analysis when they found overwhelming efficacy. And, at the end of the day, the final results showed that canagliflozin compared with placebo showed a 30% reduction in the composite renal outcome as well as important reductions in cardiovascular outcomes without any evidence of increase in amputations.

                                                Now, the study that we're talking about today is a pre-specified, pre-planned subgroup analysis from CREDENCE where we wanted to look at how canagliflozin worked in people or participants who had known cardiovascular or cerebrovascular or peripheral vascular disease and those who did not. And one of the reasons this was an important analysis was that in previous studies of SGLT2 inhibitors, there has not been a consistency in the message about whether the drug worked in both primary and secondary-prevention populations.

                                                And what we found here in this analysis was that in the primary-prevention participants, which actually was 50% of the overall trial recruitment, had very similar reductions in renal outcomes and cardiovascular outcomes compared with those who were a secondary-prevention cohort. So a very different results and a very important result in this patient population.

Dr Greg Hundley:             Really interesting. So in terms of the patients that you evaluated in this sub study, were they any different than the whole cohort and, in terms of participants and compliance with the therapy, was there any difference with the placebo versus the study drug that you noticed and can you infer from that any particular groups of patients that may benefit more or be able to take the therapy more? Just more about compliance.

Dr Kenneth Mahaffey:   First of all, you asked how the primary and secondary-prevention groups in the study were different and they were, as one would expect. Those participants who did not have prior atherosclerotic cardiovascular disease tended to be younger. They were more often women. They had shorter durations of diabetes and they were less often treated with cardiovascular preventive medications, in terms of staph and antiplatelet therapies. All the patients were on an ACE or an ARB.

                                                In terms of overall compliance with canagliflozin, it was very good. Now, the SGLT2 inhibitors, as a class, have a number of important side effects including genital mycotic infections in both men and women. They do cause some hypovolemia and volume depletion, but we found overall in the CREDENCE trial that fewer participants stopped the study drug prematurely in the canagliflozin arm than in placebo arm. So we feel that we had a very, very good comparison of the two therapies in the overall trial and in the primary and secondary-prevention analyses.

Dr Greg Hundley:             And so just general thoughts of how do you think this might impact the results of your study, or treatment, when we see patients with diabetes and chronic kidney disease?

Dr Kenneth Mahaffey:   I think there's potentially a big impact moving forward. Now, the SGLT2 inhibitor classes were approved based on the early cardiovascular outcome trials, did not enroll participants with lower EGFRs. So once these data are reviewed by the FDA and if they accept these findings and change the label, then the proportion of patients with diabetes who also have EGFRs down to 30 would be potential candidates for this therapeutic intervention. And it's important to point out that the CREDENCE trial that showed this reduction in renal events in patients with type 2 diabetes and chronic kidney disease, this is the first positive trial in 20 years of an intervention and 20 years ago we had both ACEs and ARBs based on large outcome trials, but we've had nothing since then that could be a therapeutic intervention to improve outcomes in this very important patient population.

Dr Greg Hundley:             Thank you so much, Ken. And, Naveed, I would like to just turn to you and ask you a couple things. One, can you put this study on the SGLT2 inhibitors with all the other information that's coming out related to potential benefits, not only in controlling blood sugar, but impacting cardiovascular disease-related events? How does this fit in to all of the other studies that we're learning about in such rapid fashion?

Dr Naveed Sattar:            This comes on the back of the three major trials and extends the evidence based so that, yes, I think we now show clear evidence that these drugs work in people with impaired renal function down to a level of 30 which I think is very important, so that will extend the guidelines. Yes, they seem to work in primary prevention. Of course. I think Dr Mahaffey would accept that these are probably high-risk primary prevention individuals because you also have evidence for chronic kidney disease and I suspect a lot would probably have subclinical cardiovascular disease if we went to look for it.

                                                Nevertheless, I think it will extend the guidelines in the sense that physicians are not only going to be potentially using these drugs in people with existing cardiovascular disease but also patients like those in CREDENCE with chronic kidney disease or a very high risk of cardiovascular disease without having had an event. So I think that's also very reassuring as well and exciting. And I think also the benefits of kidney outcomes is, as we said beautifully, that this is a game changer. Over the last few decades we've not really had any major trials to excite the renal community. But now we have. This trial extends the promise that we saw in the three previous trials and takes it a bit further, that these drugs have substantial and meaningful benefits in prevention of important kidney outcomes in our patients with diabetes. It looks like those benefits appear across the spectrum of diabetes. Whether they've existing disease, chronic kidney disease, or even a primary prevention when previous colleagues looked at it in a meta-analysis.

                                                So, I think that's exceptionally exciting and I think, therefore, given the profile of these drugs and as we're improving our safety in the sense we're able to use these drugs better in groups and also advise how to reduce side effects. I think really they're changing the paradigm of how we care for many of our patients with diabetes and I'd be interested to see what Dr Mahaffey thinks about those comments. My sense is this is really exciting.

Dr Greg Hundley:             Ken, any thoughts?

Dr Kenneth Mahaffey:   I think it was nicely articulated, some of the important observations here. I do agree that the patient population here that has chronic kidney disease but no known atherosclerotic disease and therefore primary prevention, it had higher risk. The event rates in CREDENCE were much higher than event rates in the CANVAS trial where the mean eGFR was much higher and so I agree that these patients may have some subclinical atherosclerotic disease, but they are clearly at higher risk of developing it.

Dr Naveed Sattar:            Again, this would be interesting to take Ken's take. But if people have chronic kidney disease, they are, in a sense, revealing themselves to have evidence of end organ damage or be at the level of the kidney but not necessarily the heart. So my sense is there's still people with evidence of disease and it's just that we're seeing it in a different way. I don't know what Ken thinks about that as a kind of interpretation.

Dr Kenneth Mahaffey:   Again, I think they're at high risk and we know that people who have kidney disease often are at higher risk of having cardiovascular disease during their lifetime and where we are in the spectrum of those new disease processes. We don't necessarily have the data in CREDENCE to understand that at a very granular level, but I think it's an important area that we need to evaluate sooner and it raises that issue of treatment for primary prevention should occur earlier and what we're seeing now is that when people develop type 2 diabetes and we notice that they have chronic kidney disease with microalbuminuria, that is the time to intervene, intervene soon. We now have a single therapy that's safe and effective and reduces the metabolic derangements with improved glucose control, improved blood pressure control, improved weight. It also has an important impact on the renal outcomes and important impact on cardiovascular outcome. So it's really a trifecta from a single therapy that can be prescribed easily.

Dr Naveed Sattar:            I agree. And all those means of treatments were very, very favorable as well across the board, which I think is also important.

Dr Greg Hundley:             So, Ken, what are some key clinical aspects related to your study that you feel we need to address?

Dr Kenneth Mahaffey:   What we need to think about carefully is we now have a new therapy. These types of patients are actually seen by a whole host of clinicians in our healthcare systems, at least in the United States. They're seen by diabetologists, cardiologists, nephrologists, and primary care. And we need to think of ways that we can educate all four of those groups of clinicians about these important data and provide learning and other mechanisms to integrate these therapies into clinical care. It's a message I've been trying to get out.

Dr Greg Hundley:             Well, listeners, what a great discussion between Ken and Naveed on this very important topic, the emergence of SGLT2 inhibitors and the results of these primary and secondary cardiovascular prevention group analyses from CREDENCE.

                                                We want to thank each of you for listening with us this week. Carolyn and I look forward to talking with you next week. Take care now.

Dr Carolyn Lam:                This program is copyright American Heart Association 2019.