A group of 13 leading experts provides their perspectives on the top news in cardiovascular medicine from 2023, with responses ranging from novel approvals to new semaglutide data to gene therapy and more.
As the last meeting of the 3 flagship professional societies in cardiology, the American Heart Association Scientific Sessions serves as a yearly send-off for the community and, by extension, a celebration of the advances that defined the past year in medicine. This year’s meeting was no exception, with a wealth of breakthroughs showcased at AHA 2023.
With an interest in capturing the perspective of leading experts in the field as the cardiology community looks ahead to the close of 2023, the editorial team of HCPLive Cardiology asked 12 leading experts in cardiology what they will remember as the defining piece of news or advancement within the field from the past year.
Expert opinions spotlighted in this feature include those of Steve Nissen, MD, chief academic officer of the Heart Vascular and Thoracic Institute at Cleveland Clinic, Michelle Albert, MD, MPH, immediate-past president of the AHA and the Walter A. Haas-Lucie Stern Endowed Chair in Cardiology and Professor in Medicine at the University of California at San Francisco, Marc Bonaca, MD, MPH, director of Vascular Research at the University of Colorado Anschutz Medical Campus and executive director of CPC Clinical Research, Sadiya S. Khan, MD, assistant professor of cardiology and epidemiology at Northwestern University Feinberg School of Medicine and a Northwestern Medicine physician, James E. Ip, MD, an associate professor of clinical medicine at Weill Cornell Medicine at New York-Presbyterian Hospital, Rahul Aggarwal, MD, cardiology fellow at Brigham and Women’s Hospital, Viet T. Le, DMSc, PA-C, researcher and physician associate at the Intermountain Health, Ahmad Masri, MD, director of the Hypertrophic Cardiomyopathy Center at Oregon Health & Science University, Mandeep Mehra, MD, medical director of the Heart and Vascular Center at Brigham and Women’s Hospital, Christian T. Ruff, MD, MPH, director of general cardiology at Brigham and Women’s Hospital and senior investigator for the TIMI Group, Paul Ridker, MD, MPH, director of the Center for Cardiovascular Disease Prevention at Brigham and Women's Hospital, Deepak Bhatt, MD, MPH, director of Mount Sinai Heart and the Dr. Valentin Fuster Professor of Cardiovascular Medicine at the Icahn School of Medicine at Mount Sinai, and Ty Gluckman, MD, medical director of the Center for Cardiovascular Analytics, Research, and Data Science at the Providence Health.
Included below the responses of the aforementioned experts is a behind-the-scenes clip from the AHA 2023 episode of Don’t Miss a Beat, where hosts Muthiah Vaduganathan, MD, MPH, codirector of the Center for Implementation Science at Brigham and Women’s Hospital, and Steve Greene, MD, advanced heart failure specialist at the Duke Clinical Research Institute, discuss the same question.
Editor’s Note: These transcripts have been edited for grammar and clarity.
Nissen: I think that 2023 is the year that we began the pivot from what the old way of developing drugs, which was small molecules given with the hope that the favorable effects would exceed the unfavorable, to the directed therapies involving these short-interfering RNAs and antisense oligonucleotides. We're in that pivot. As you know inclisiran was approved, it was the first short-interfering RNA in the cardiovascular space and now, there are others for amyloidosis. It is an explosion of new approaches to drug development, and this is the year when that transition really began to accelerate.
Albert: Well, I think the trial that we saw about semaglutide, weight reduction, and perhaps this tie to cardiovascular risk reduction. Although, right now, we do not know that the weight reduction is what was tied to cardiovascular risk reductio—It could be the drug itself and how it's working on other mechanisms.
I think the other thing is the big news in the heart failure field. Whether you have heart failure with reduced ejection fraction or heart failure with preserved ejection fraction—whether you have diabetes or don't have diabetes— the SGLT2 inhibitors are extremely beneficial. I think those are the two big things I think about so far.
I would also add, as it relates to the last year, when we think about late breaking science, we a lot of times do not include social factors and social determinants of health. I think the growing recognition among all scientists and clinicians of the importance of social determinants of health is an advance, honestly. I would say 5 years ago, it was tougher to bring clinicians and researchers over that hump.
Bonaca: That's a great question. I haven't had a lot of time to think through this, but off the top of my head, I would say the focus on cardiometabolic disease. I think at ESC, STEP-HFpEF reminded us that you do not need a big trial to have a big impact. There has been a notion of "healthy obesity," and I believe it dispels, at least in part, the idea that treating individuals who are obese with a GLP-1 receptor agonist might benefit those with heart failure with preserved ejection fraction.
Now, everybody asking the question, "Is it the weight loss or the heart failure?". And the answer is yes, because these things are linked, right? They're not independent. Then SELECT is going to be presented at AHA. So, I think this story of cardiometabolic disease and weight loss is really what I think is the story of 2023. Where the field is moving, I think brings big challenges, though. Patients cannot access these drugs. They are super expensive, and you can't come off. So, I think that the future is going to play out as: How we use these agents? Are there better agents? How do we sustain the benefits without lifelong treatment with it being a very expensive therapy?
There's a big, what I would say is a corollary story, is the first digital therapeutic for treating diabetes was approved by the FDA. This approach utilizes cognitive behavioral therapy and nutritional cognitive behavioral therapy to genuinely educate individuals on lifestyle modification. To me, it prompts the question of how we conceptualize cardiometabolic disease. Should we consider these potent new drugs, such as semaglutide and others in the pipeline, as inducers for rapid weight loss? Then, can we view digital cognitive behavioral therapy and other strategies as maintenance tools that could potentially facilitate individuals coming off these interventions? I think this is a big part of 2023.
Khan: I think it is going to be the GLP-1 receptor agonists for 2023. I think in 2022 it was the SGLT2 inhibitors. Now, 2023 is the GLP-1 receptor agonists. I would say, from a trial perspective, that's true. But I would caution by saying, I actually don't want to say that's the story of 2023.
I think they are amazing therapies and it's wonderful that we are at this point, but I think the story should be: How do we get the right therapies to the right patients? So, maybe that's 2024, because it's wonderful that there are wonderful drugs that are very helpful and effective, but we need to make sure that the right patients are getting them at the right time.
Ip: As an electrophysiologist, I am very excited about several advancements within my field. I'm involved in various aspects of EP, but the one that I was most excited about, especially this week because it's so fresh in my mind, is dual chamber leadless pacing. We now have technology that involves two separately implanted devices, one placed in the right atrium and one in the right ventricle, that can communicate wirelessly with each other on a beat-to-beat basis. This has opened up the world of leadless pacing for patients who need pacemaker therapy — in cases of sinus node dysfunction or atrioventricular block – that requires a dedicated atrial device. Before this week, we only had the option of implanting a single leadless pacemaker in the ventricle. The dual chamber leadless pacemaker was FDA-approved earlier this year and we did our first commercial implants this week. So, that that was certainly a highlight of my year and my week. But I would also would like to call attention to the results of the ReVeRa trial, presented at the AHA, that evaluated a novel, intranasally delivered calcium channel blocker called etripamil. The NODE studies showed the safety and efficacy of using this drug for treatment of paroxysmal supraventricular tachycardia, and ReVeRa now shows how etripamil can be potentially used to control atrial fibrillation with rapid ventricular rates. There are many other technologies being explored for arrhythmia management, but those are the ones that come to my mind.
Aggarwal: I think this year the major kind of changes, there's a lot of emphasis not just on what therapies work, but on ensuring that patients get the therapy, and the therapy is prescribed. So, for me, I think what's going to really stand out is that we're really focusing on how can we initiate therapy early? How can we get patients on therapy who may not reach their follow up or who may not see their follow up provider very quickly? So, I think the emphasis is shifting a little bit from just finding therapies that work to also how do we get the therapies to reach our patients. I think that's been a major shift in focus within a lot of the population health-based studies this year.
Le: It's a little unfair to pick one, because there are 3 things that I think about that have kind of come the confluence of things that have happened in 2023.
First of all, I think as we look back to 2023, what we'll recognize is the power of nucleic acid therapies. So, these are the antisense oligonucleotides and the siRNA. We're seeing it across lipids. We're seeing it not just in LDL-C, but we’re seeing it in Lp(a) now. Also in the hypertension space, where it's one injection for three or six months of therapeutic benefit, at least in terms of reduction of blood pressure. We'll see if that translates otherwise.
Here, the American Heart Association just presented what we all kind had been dancing around, which is CKM or cardiovascular-kidney-metabolic. This confluence of we need to work together upstream. These are the patients that we see in our cardiovascular clinics, but we need to be working on all of the organs and certainly the constellation of what diseases do to lead to cardiovascular outcomes and morbidities.
Lastly, this is the year obesity has really come to the forefront with this idea that it is not just an inability to choose lifestyle or right things. We're recognizing this is much deeper than that. It is social determinants, and it is deeper in our biology, in terms of obesity. We have therapies that touch upon and can help really relieve the burden as well as stigma that a lot of our patients face when they go to their provider and are told, "You probably are just eating too much or not exercising enough". My heart is just sick when I get referrals for patients and that is what they've heard. So, this is the year that we have awakened the reality to obesity management and that it is a disease—not just willful ignorance or choice to feel poorly. I think those are the main 3 takeaways from to 2023.
Masri: It's been a very, very busy year for us in 2023. So, I honestly cannot take a single item to talk about as the biggest one,but I'll allude to some advancements in the cardiomyopathy space. The first one is that we presented data from aficamten and nonobstructive HCM from the REDWOOD-HCM cohort 4 study, which allowed us to progress to a large phase three trial in this space.
The second one is related to amyloidosis. We received the first chunk of data from a phase 1 trial for anti-ATTR antibody. That was published in the New England Journal of Medicine and showed that there is a strong rationale behind this and some more data is coming out. From the National Amyloidosis Centre in the UK, we also saw the autoantibodies that naturally develop in amyloidosis. That was also important.
The first patient with MYBPC3 hypertrophic cardiomyopathy was dosed in the Tenaya gene therapy program. This is the first patient ever to be loaded with gene therapy specifically for MYBPC3 hypertrophic cardiomyopathy. We're also seeing a lot of the data coming out from the phase one gene editing in transthyretin amyloidosis. We know that the FDA also just gave the go-ahead to proceed with the phase 3 global trial for CRISPR-Cas9 in ATTR cardiomyopathy. Last but not least, we have also seen proof of concept for gene editing in preclinical hypertrophic cardiomyopathy—there are two Nature papers on this. So, it's been really, really busy, but a lot of good things are happening in our space. We're very excited to see how these progress over time.
Mehra: The big story of 2023 is that we now have great medications to undo the problems of our own personal lifestyles, but, with this, we have created an opportunity that will expose healthcare disparities in a much more magnified way. I think that's terrible and I think we're going to have to all attend to that, you know, as a community.
Ruff: I think it really has to be, and we have seen it even in the lay press, the role of the GLP-1 receptor agonists broadly in health, but particularly in cardiovascular health the impact could be just enormous. Obviously, these drugs were initially developed to lower blood glucose and people with diabetes and then, many years ago, we learned they have cardiovascular benefit in diabetes and then they have cardiovascular benefit in non-diabetics.
The fact that they cause tremendous amounts of weight loss, will, even in patients with no known heart disease, reduce their risk of heart disease. There may be no other drug in clinical practice that has such an enormous effect on health across such a broad population of patients who have diabetes or preexisting cardiovascular disease as well as the effects on the epidemic of obesity. I think that's really going to be one of the landmark findings of this year that will have a lasting impact on the way we treat patients in cardiology and really in all medicine.
Ridker: It has been a remarkable year for cardiovascular advances. For my interest, I put them in three categories. The first is the remarkable ability of the SGLT2is to actually change outcomes in our patients who have heart failure and to see this data extend out into other settings, like chronic kidney disease has been quite remarkable. The second has to obviously be the success of the GLP-1 receptor agonist. We're seeing multiple different drugs coming on market very fast, with multiple different ways of addressing these issues. We're seeing not just weight loss, but event reduction in patients with diabetes. As we're all looking forward to the data from the AHA on event reduction in patients who don't have diabetes and realizing that this is going to change how medicine is practiced. The challenges for us will be to figure out how, where, and why, but that'll be interesting.
Third is my own arena. I think it's been exciting to see the US FDA, pretty much on its own, decide that it was time to label a drug, low-dose colchicine, for anti-inflammatory therapy. That's a big issue for the vascular biology world to say, "Yes, the regulators, as well as the vascular biologists, now believe that the data are rock solid that we should be targeting inflammation, as well as hyperlipidemia".
I think a fourth area is the novel therapeutics we're seeing. Without going into specifics, we're seeing new types of drugs where maybe we can actually change the underlying biology of cells in the liver on a lifetime basis, to alter Lp(a) or to alter ApoB production or to alter various different proteins. To watch many different scientists working with industry to figure out a whole new way of addressing whether we can modify disease on a lifelong basis. Particularly for extremely high risk—I think of a patient with homozygous FH or maybe very severe heterozygous FH—is there a way to change their underlying hepatic biology?
We don't know whether it's completely safe yet, but the preliminary data look like it might be. I recognize we have to wait 10 to 15 years perhaps to know about safety, but it's a very exciting direction to think about: Can we actually alter the biology, rather than just simply giving drugs on a chronic basis? So, all those things to me are very exciting and, again, it's a real reminder of how science moves forward and how we as clinicians have new options for our patients.
Bhatt: The year 2023 was a really good year for cardiology, cardiometabolic disease, and cardiorenal disease. There are a lot of advances, there were a ton of stuff that just came out of the AHA, at the ESC before that, and at the ACC before that. So, it has been a good year. There have been a lot of important practice-changing trials. If you force me to just pick one thing, I think what Verve Therapeutics announced here, in terms of data that they've produced in a relatively small number of patients, was amazing—the first use of human gene-editing to lower cholesterol levels.
They were targeting PCSK9 and, at the higher doses, saw about a 50% percent reduction in LDL cholesterol that was durable out to 6 months of data. To me, that concept of editing genes in humans in a way that will hopefully be safe and durable—we will need more patients followed for longer—so far looks like a really promising approach and opens the door for that approach for a variety of cardiovascular disease conditions and risk factors, including things like Lp(a). So, to me, that's really exciting for that particular approach and could be an opening-the-door strategy to a variety of approaches in the future.
To me, genetics and AI are really two exciting areas that have been hyped for years, at least with respect to cardiovascular applications, where there really was not anything, but now we have FDA-approved AI algorithms for ECGs for echocardiograms, among other things, and now we have gene editing in humans that actually seems to be really effective. It's a whole new world out there. Again, to me, those are some really exciting developments.
I was also excited to announce to the American Heart Association from the podium the TRANSFORM trial. This is going to be a randomized clinical trial of about 7500 patients or so followed for a while in the primary prevention universe.
So, we are taking primary prevention patients and then getting a CT scan on them, which will use an AI-enabled algorithm to determine the staging of the coronary plaque. Stage 0, for example, means you don't have any plaques, or you probably don't need to be on a bunch of meds. Then the successive stages 1, 2, and 3—sort of like staging cancer—with staging plaque based on plaque volume, plaque burden across all the different coronary arteries, and plaque composition. So, incorporating all that in a pretty sophisticated AI-enabled algorithm to take the risk of that individual patient, based on their stage of plaque, and then, using that information, to counsel the patient on lifestyle, but also to titrate, very intensive medical therapy beyond what the guidelines currently recommend, including things like colchicine, SGLT1/2 inhibitors, or bempedoic acid, where all these agents have outcome data in different sorts of settings. We want to see, can you use plaque to add agents, these and others, to really refine how we treat patients with respect to cardiovascular risk reduction. Patients will be randomized to that approach or a guideline-based approach following current guidelines where they also get a CT at baseline and also at 2 years. That arm will be blinded until the end of the trial, but we will know the answers in the investigation arm.
So, this will give us 3 different opportunities within TRANSFORM. TRANSFORM-Classify will see if this approach is better than conventional risk scores. TRANSFORM-Plaque will look at CT at baseline and a repeat CT at 2 years to see if there is plaque progression and whether we can impact that with intense medical therapy versus standard guideline-directed therapy as it currently stands as well as whether those changes in plaque that may occur from baseline and 2 years do or don't predict subsequent cardiovascular events. Then, in TRANSFORM-Outcomes, we are actually going to look at major adverse cardiovascular events to see if the strategy using AI-enabled imaging and then incorporating that information to intensify medical therapy is better than just doing what the guidelines would tell us to do. So, that's the cardiovascular outcome part of the trial.
This is something that will take a few years to reach the end, but when it's done, whatever it shows, I think it will be informative about whether imaging should be part of how we stratify patients in terms of their risk in the primary prevention world and whether we can or should not use that information to them titrate their medical therapies.
Gluckman: I would say 2023 has been a year and maybe several years leading up to it that has really reinforced the importance of targeted therapies for cardiovascular, metabolic, and kidney disease. Maybe that's all ensconced in the fact that a therapy that can help facilitate weight reduction as a GLP-1 receptor agonist and that translates into blood pressure improvement, cholesterol improvement, anti-inflammatory properties improvement, and glycemic control can improve cardiovascular outcomes at-risk individuals, but I think the intersection of high cholesterol, diabetes, high blood pressure, obesity, chronic kidney disease, nonalcoholic fatty liver disease really reinforces the importance from a public health standpoint, from a cardiovascular prevention standpoint, when close to 70-plus percent of the US population is overweight or obese. When we have rising rates of diabetes and unacceptably, high rates of lack of control for high blood pressure and high cholesterol. We need to do better. So, I hope that this is a furthering of acceleration in terms of therapeutic approaches that can wind that back.
Click here for the full AHA 2023 episode of Don’t Miss a Beat, which focuses on SELECT results and DAPA-MI.