In this episode of "Conversations with Dr. Coley," Dr. Payal Coley interviews Dr. John Osborne, co‑founder and CMO of Clear Cardio, about a citizen’s petition filed in April 2024 by a group of healthy women that urged the FDA to update fibrate labeling based on recent evidence. The FDA reviewed the petition, incorporated data from the PROMINENT trial and other studies, and revised fibrate labels to emphasize the lack of cardiovascular benefit and to add warnings for kidney injury, liver issues, and a two‑fold increase in venous thromboembolism. The FDA declined to issue a provider‑wide safety letter, prompting discussion of how best to disseminate this information. Dr. Osborne and Dr. Coley explain that the PROMINENT trial—10,500 high‑risk diabetic patients on statins—showed no reduction in heart attacks, strokes, revascularization, or cardiovascular death despite triglyceride lowering, and highlighted harms. They argue fibrates should be reserved only for patients with triglycerides >500 mg/dL to prevent pancreatitis, and should not be used for cardiovascular risk reduction in moderate‑risk patients. Alternative, evidence‑based therapies such as statins, icosapent ethyl, GLP‑1 receptor agonists, SGLT2 inhibitors, and aggressive blood‑pressure control are recommended. The conversation underscores the importance of clinician education, the power of grassroots advocacy to influence FDA policy, and a shift toward treating overall cardiorenal outcomes rather than merely correcting lipid numbers.
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Hello, and welcome to Conversations with Dr. Coley. I'm your host, Dr. Payal Coley, Associate Adjunct Professor in the Cardiology Divisions at Duke University and Johns Hopkins University, and founder and medical director of Cherry Creek Heart in Aurora, Colorado. And today, I'm so delighted to be joined by my colleague, Dr. John Osborne, who's the co-founder and chief medical and scientific officer of Clear Cardio in Dallas, Texas. You can learn more about Clear Cardio at www.clearcardio.com. Welcome, John. I'm so excited to talk to you today.
Oh, it's a pleasure. Thanks so much for having me back.
So, John, today I want to talk about a citizen's petition submitted by healthy women in April of 2024 to the FDA. And I thought this was really provocative because it really does represent the citizens making a change, making an appeal to the FDA and actually changing what the FDA does. So essentially what the Healthy Women put in the petition and asked the FDA to do was to really remedy what they called a widespread misimpression of the fact that fibrates have been believed, erroneously so, to improve cardiovascular outcomes. And what they wanted the FDA to do was to put in the newest data, including the PROMINENT data, And also to send out a letter to all healthcare providers telling them about this label change. Now, the FDA responded really positively. So I want you to summarize for me kind of what the key takeaways were from what the FDA actually did, and then what's your reaction to all this?
Yeah, so I have to give credit to the FDA. Our government is working in this particular situation. So I have to give credit because they really did a fantastic review of all of the prior trials that looked at the role of fibrates, either alone or with statins, with statins being the foundational drug for LDL lowering. Of course, we have lots of other drugs that treat LDL nowadays. But also included with that, a trial that came out just a couple years ago called the PROMINENT trial that trialed a novel fibrate. These are drugs we typically use to lower triglycerides and raise HDL. to see if that would lower cardiovascular events in a very high-risk population. These patients all had diabetes, they all had moderately elevated triglycerides, they all had lower HDLs, uh, and this is nearly 10,500 people, double-blinded randomized prospective trial over 3 years, uh, which showed absolutely no cardiac benefit. 96% of these patients were on background statin therapy, as, as is appropriate, Zero benefit. The, the event curves were completely superimposable, as we talk about it. No difference by adding—
What's interesting about that is what you pointed out, which is that the deck was stacked in the favor. Like, you had the highest risk patients, the ones that we thought would have benefited— low HDLs, high triglycerides— and there was no benefit despite the fact that it reduced triglycerides.
Right. If you were going to bet on this, the people in Vegas would say this trial's got to work, right?
I would've bet money on it.
I would've too. I'm glad I don't bet. But yeah, so I agree. It was a trial that was very well designed. I know the PIs behind it. They're great trialists. You would think with that population, that size of population, that follow-up, meeting all of those different criteria where we go, this is a high-risk population where efibrate would be perfect. They have high triglycerides. Let's knock 'em down. They're already on good statin therapy. The LDLs were well controlled. Complete bunkus. No benefit whatsoever. In fact, what they showed was no cardiovascular benefit, no benefit for heart attacks, strokes, revascularization, angina, cardiovascular mortality. But they did show harm. There was an increased risk of kidney issues. There was an increased risk of some liver issues. And also notably, and we had seen this in prior fibrate trials before, an increased risk of Venous thromboembolic disease, or VTE, or in other words, blood clots in the legs and lungs. So that those were increased by roughly twofold if you used defibrillate on top of statin in that high-risk population. So definitely words of caution, but no evidence of benefit for cardiovascular endpoints, for heart endpoints.
Well, and I think it's really nice that the FDA has now actually incorporated the increased risk of venous thromboembolism into the label change. And they've also said again and reemphasized that the fibrates are not associated with any proven cardiovascular benefit. I thought it was interesting that they actually turned down the idea of sending a letter to healthcare providers to inform them of this, because we know that when they had done a label change in the past, the message didn't really get out. So why do you think these types of conversations that we're having today are so important, and these citizens' petition to the FDA, and why do you think this message needs to get out?
Yeah, I think if this were a baseball game, I think this is a strong triple, right?
Okay.
I wish they would have gotten the message out. I wish they would have sent out the letter to the docs, really not just to make the changes in the labels. And by the way, this is across all fibrates— Gemfibrozil, which has been approved for a long, long time, the Tricor and FidoFibrates. All of the fibrates will have this in their label. I wish they had—
I do too.
Done that, that letter to the doc, as they do, because we do know literally millions of people in the US are on fibrates and statins for no benefit but documented harm. So I wish they had done that. That really would have made me feel much better. I— but unfortunately, still millions of people are, and we'll just have to keep getting the message out like we're doing today.
Yes, I love that. And, you know, I don't know much about baseball, but I always do listen to my coach. So if I was a baseball player, I'm a healthcare provider, you know, what should I do different? I know I still use fibrates for patients with triglycerides over 500, but what should I be doing different for those patients in that moderate risk range where the trigs are less than 500, but obviously they have cardiovascular risk? Should I be using the fibrates?
The data says no, we have not a shred of evidence that shows benefit. We do have evidence of harm, and as I always think of my patients as I'm their advocate, I'm always thinking what's the potential benefit? What's the potential harm? And here we have a situation where the harm is evident; the benefit is not. So in in cardiology, we have these different classifications of therapy, right? Class one A means it's standard of care. Everybody should be doing it unless there's a really really good reason not to. Class two maybe possibly. Class three is there is harm.
Yeah.
So this is a class three indication. So you want to remember the ones because that's standard care. You want to remember that the threes do not go there. The twos, you know, there's some shuffle room there. But this is an important. I would you know number three category. Do not use these drugs. No evidence of benefit. But and and not just no harm, but evidence of harm. No evidence benefit. So stay away there. And and I think clinically in this patient. population. We do, though, have very good data about other adjunctive lipid-modifying tools, drugs we can use. And really, that's icosapent ethyl. Icosapent ethyl has been tested in a population very similar to PROMINENT, but somewhat smaller, but did show another 25% reduction in major adverse cardiac events in patients on statins at high risk, either patients with diabetes or known cardiovascular disease, Basically everybody was on statins, well-controlled LDL, modestly elevated triglycerides. There we saw a home run, a grand slam if you will. We got 4 runs off that. The batter brought everybody home and huge, huge win there. And this data's been around for a number of years now, published back in 2019, early 2019, endorsed by every cardiovascular and metabolic and diabetes organization out there that issues guidelines, even including the KDOKS, and included— and also included in guidelines, recommended in over 60 international guidelines throughout the world across diabetes and cardiovascular disease. So lots of great data for something that does work, unless we still have millions of people on fibrates for an indication that we have great data showing it doesn't work. So—
Well, I'll say a couple of things. First, we're really getting deep into those sports analogies here. So I have to try to keep up. Sports is not my forte. But secondly, most importantly, I want to emphasize something you said, which is that we all took an oath as healthcare providers, the Hippocratic Oath, which is first do no harm. And the fact that despite years and years of data, and despite the FDA already having changed the label not once but twice, we continue to do something that doesn't provide benefit and potentially harms our patients. So I know that if I was a patient, and I had moderately elevated triglycerides, this is not the drug I would reach for fibrates. I would wanna reach for risk-reducing drugs, like you said, statins, icosapent ethyl. We even talk now about going upstream and treating the diabetes and treating, you know, the obesity with agents like GLP-1 receptor agonists. So, so many tools in our toolbox that actually work. So what should be my takeaway if I was a patient? And what does this really mean for me in terms of my treatment choices? And how should I think about it if I'm already taking a fibrate for cardiovascular disease? What should I do?
Right. As always, talk to your doctor, right? However, I would say, if you fall in that scenario where you're taking a fibrate, it's not because your triglycerides are super high, it's because it's given to you for cardiovascular lowering. We have no evidence behind that. Please, please, please talk to your doctor whether that is right for you.
And I love that. And I've actually been de-escalating a lot of my patients, 'cause we know they've been taking fenofibrate for the last 20 years. And 20 years ago, maybe it was the right medication to start, But now at this point, it's not the right medicine to start unless your triglycerides are over 500. And in those select cases when you do use it in combination with a statin, not just to, you know, treat cardiovascular risk, but to treat the number because the trigs are elevated, you're trying to get them down to reduce risk of pancreatitis. You want to make sure you look for drug-drug interactions, keep a close eye on those liver function tests, keep a really close eye on the renal function, as well as the risk of myopathy and other side effects.
Right.
So really using it in this kind of moderate-risk population shouldn't happen anymore. I would even go so far as to say it's medical malpractice because it's been made clear that it causes harm. But I think there's still more work that needs to be done. And I think, of course, part of that, as we've discussed today, is education. But what else do you feel are the residual gaps in this space when it comes to how we're maximally reducing and managing our patients' cardiovascular risk?
Yeah, I so heartily agree with you. We have so many proven effective tools. Let's really advance all of those because those clearly do work. They add clear benefit. All of them play nicely together in the same sandbox. And let's really advance those. And that includes, obviously, all the wonderful LDL-lowering drugs we have. We've got some new stuff that'll be here soon. The ones we have are remarkable. The stuff in the pipeline is amazing. Incredible drugs for weight loss, cardiovascular reduction, et cetera, as you know, with the GLP-1s and of course the SGLT2s in our patients with diabetes or chronic kidney disease or heart failure. So we have so many highly effective and proven therapies that we can use and use together and layer all those benefits on top of one another to further ratchet the risk of cardiovascular events, strokes, heart attacks, kidney damage, kidney failure. And also too, I gotta say, since we now have the new hypertension guidelines from August also emphasizing Lowering blood pressure, not related to triglycerides, but lowering blood pressure, huge benefit, not just heart disease and heart failure and stroke, but also dementia too. So that's kind of new news out there as well, not in the lipid space. But again, we have so many proven effective tools. Let's really advance those. And it's time for us to give up some of the blankies, the binkies, if you will, like phenofibrates that we thought were— in fact, if you look at the data you mentioned, you know, 20 years, there is no data published in the 21st century where 25 years into it that shows fibrates work for cardiovascular risk reduction, but have proven harm.
You know, I think you made such an important point there, John, which is that we really need to talk about treating the risk, not treating the number, because PROMINENT and other trials have showed us that even if you treat that number, you treat those triglycerides, you don't end up reducing their risk. And I really sort of now start to focus on what I call cardiorenal outcomes, thinking about cardiovascular kidney metabolic syndrome, which we know 90% of America already has stage 1, CK-M, stage 0 being no risk factors at all, stage 1 being already at risk for it. So I think we just need to take a step back and say we're not so fixated on numbers, even though numbers help us on a day-to-day basis with blood pressure, with A1C, with LDL lowering to get to where we need to. But really, at the end of the day, we want to think about the bigger picture, keeping them alive longer, reducing MIs, reducing strokes, reducing heart failure. And to that end, as you said, we have so much to offer. So Thank you, John. This has been a scintillating conversation. I—
Always a pleasure.
Yes, I'm really, really excited that the citizens' petition has actually prompted a tangible change with the FDA. I think that portends really well for people saying, hey, let's make a difference. If you see something, say something, and perhaps the FDA will listen. And I really do hope that this message gets out to everybody out there and they start to change their clinical practice, not just hear the message, but actually implement changes. Because as you pointed out, it's been 25 years coming. And so I know I'm gonna be making sure that I get this message out to my APPs and other practice providers as well. Any last words before I—
No, I think it's fantastic. And again, kudos to the grassroots for making the effort and really making the FDA review the data and really come out very unequivocally, I think. I wish they'd sent out the letter to the docs, but very unequivocally, Really, just don't go there for the vast majority of people, and don't go there for cardiovascular risk reduction.
Those are perfect words. Just don't go there. I love it. All right. Don't go there. Well, thank you again, John, for your time.
Always a pleasure.
It's been a great conversation. And thank you all for tuning in to Conversations with Dr. Coley. We hope you found this episode interesting, enjoyable, and practice-changing. Until next time.
