Speaker 1:

Welcome to AACE Podcasts. Thanks for tuning in as we elevate clinical endocrinology by taking deep dives into trends and topics that can help us improve our patient care and global health. Find the latest episodes on aace.com/podcasts. And now let's meet the endocrine experts who will be talking with us today.

David C. Lieb, MD, FACE, FACP:

Hello and welcome to our AACE Podcast. I'm Dr. David Lieb, professor of medicine in the division of endocrinology at Eastern Virginia Medical School at Old Dominion University in Norfolk, Virginia. I also serve as our Endocrinology Fellowship Program Director. I was an author for the 2023 Protocol for the Development of AACE Clinical Practice Guidelines and Consensus Statements, and have been involved in work involving enhancing the trustworthiness of clinical practice guidelines. I was also co-chair for the AACE Empanelment Task Force for our 2025 AACE Clinical Practice Guideline on the pharmacologic management of adults with dyslipidemia. And that's our topic for today. Joining me today are Dr. Shailesh Patel, Chair of the Guideline and their Vice Chair, Dr. Kathleen Wyne. Thank you both for joining me today. Dr. Patel, can you please introduce yourself and tell us a bit about your areas of expertise and your role on the guideline?

Shailendra B. Patel, BM, ChB, DPhil:

Happy to David and I am the professor of medicine and endocrinology at the University of Cincinnati in Ohio here, enjoying our wonderful weather. And my expertise is that my research is really focused on lipid metabolism. I really am a endocrinologist who practices in management of neuroendocrine tumors, adrenal tumors, et cetera. I have been in practice for more than 30, 40 plus years and I was happy to have been mentored by Scott Grundy, who is considered one of the fathers of starting the lipid guidelines in the US. And I spent a lot of formative years with him, training with him, talking about lipids.

So my depth of lipid knowledge is really quite extensive, and independently my lab was the lab that discovered the genetic basis for sitosterolemia with the discovery of genes like ABCG5, ABCG8. And we work on rare diseases like Smith-Lemli-Opitz syndrome and cerebrotendinous xanthomatosis, et cetera. So my lipid knowledge is pretty extensive and I was happy when I was asked to be chair of this particular guideline, especially as we will get into it a little later, how it has changed how we are proposing the guidelines for practice.

David C. Lieb, MD, FACE, FACP:

Excellent. Yes, the changes I think are going to be so important to talk about. I tell our endocrine fellows, lipids are such an interesting part of what we do in practice and there's so many new medications and new indications, so I'm very excited. And Dr. Wyne, could you also introduce yourself and tell us about your areas of expertise and your role in the guideline?

Kathleen L. Wyne, MD:

Thank you. I'm an adult endocrinologist and professor of medicine at the Ohio State University. My clinical expertise is complex lipid disorders and type 1 diabetes. And my training actually starts as a graduate student at the University of Chicago where we studied the physiology of some of the apolipoproteins. And then I actually also did my fellowship at UT Southwestern in Dallas and so continued to train for working in the world of lipids. And then that also brought me into diabetes, which I have this combination of lipid disorders and type 1 diabetes as my clinical specialties.

David C. Lieb, MD, FACE, FACP:

Well, as a person living with type 1 diabetes for over 30 years, I appreciate your work in this area because I'm not getting any younger and I think the importance of lipid management are incredibly important for me personally and obviously for many of our patients.

Kathleen L. Wyne, MD:

So I know this is going to get edited out, but I just want to say we need to talk at the next annual meeting because there's a lot of focus on that now, finally in type 1 and I'd love to talk about it.

David C. Lieb, MD, FACE, FACP:

Oh, I would like that too very much. Today we're discussing the new AACE Dyslipidemia Guideline and this is an update to the guideline that came out in 2017. Dr. Patel, can you tell us what's new and what's different in the 2025 guideline?

Shailendra B. Patel, BM, ChB, DPhil:

Absolutely. So 2017 was the last time AACE had the lipid guidelines come out. So really in the past 8 years and really the past 6 to 7 years since this guideline starts at least a year or two before the final product is put forward, there have been a lot of changes. And even though in 2017 we had some novel medications that had come out, their use and their experience was just beginning to garner more and more trial data and the comfort as to how effective they were. So this particular guideline is really addressing the updates from 2017 to now in the interim. And that is the key thing. Remember that these guidelines are incremental. We've had guidelines before and all we are doing is building on that solid, solid base of science to make sure that the next things that happen update our healthcare providers to use the best science to treat and manage their patients.

So the new things in this particular guideline are that we're going to be discussing the appropriate use of all of the newest medications that are FDA approved and what are the pros and cons of using them? What's the science base that allows us to look at that? And more importantly, when we did the 2017 guidelines, they were done in the same contextual framework as when all of the major societies were doing their guidelines. And what is different is that we are going to be using the GRADE approach to actually propose the newer changes and updating hopefully the previous ones using the GRADE methodology.

David C. Lieb, MD, FACE, FACP:

I was going to ask Dr. Wyne, given that this is the first AACE guideline using GRADE methodology, how did the GRADE framework impact the development of the guideline? I know you've been involved in AACE guidelines in the past too, so you can compare how things used to be with how things are now.

Kathleen L. Wyne, MD:

That's exactly what I wanted to do, is really to give my personal experience, how I see it different. What I felt in using the GRADE is I really felt confident that we had called all the possible clinical trials, we had applied a standardized approach to looking at them to determine if we should use the data to assess the quality of the data. And I truly felt with this guideline, confident that we had looked at everything we possibly could. I think it's important though, I'm not saying that we did not do a good job in 2017 because I thought we did an amazing job in 2017.

But remember, we worked with the data that we had available to us and I just remember how hard it was to pull, to find the data that we needed for the questions we were asking, how hard it was to make sure that we were assessing them properly. And so that's really where I felt this made a difference, that we had a standardized approach, that we really applied it to a much larger body of data. And I really feel confident that we've looked at all the possible data here and can give a good assessment that the clinical endocrinologist in daily practice can drop on it and not worry they might be missing something.

Shailendra B. Patel, BM, ChB, DPhil:

David, let me interject here and also add, because many of our listeners will not be familiar with GRADE, GRADE is something that is a new approach to thinking about how we assess the totality of the science behind all this. So for those of you that are listening, GRADE, G-R-A-D-E stands for the Grading of Recommendations, Assessment, Development and Evaluation, hence the terminology. And what it does is that it takes not just the science base, but it actually looks at the applicability, it looks at the populations that we are studying. It actually grades the level of evidence so that instead of just saying, "Oh, here's a randomized clinical trial and here's how it is," it's taking into account those things and then it's into account the applicability at the level of the person to say that is this suitable and how cost-effective is it? And also takes into account the patient's perspective as well. So this is really a more encompassing effort to try and make sure that these guidelines actually take care of a lot more than just looking at a particular clinical trial, looking at the conclusions and saying, "Here's our recommendations."

David C. Lieb, MD, FACE, FACP:

And I know for this guideline there was a patient group that was also involved, correct?

Shailendra B. Patel, BM, ChB, DPhil:

Correct. Very much so. And the way that that works is that the professionals on this panel would come together, they would ask certain key questions and then use the GRADE methodology to address them. So when you read the guidelines when they come out, we've spelt out these questions up front, then you use the GRADE methodology to draw in all of the data, put it together, meet, grade the whole stuff, put the conclusions together, and then that information is then shared with the second group of people who will then read it, assess it, appreciate, and provide feedback for us.

Kathleen L. Wyne, MD:

I think one piece to add into that also is not just did the draft go to patients and ask them for feedback. We also had primary care input during the process. And I can remember in the meetings where we'd say something and our primary care doctor would say, "Wait a minute. In reality, my patients can't drive two hours to the city to do this." And so it really helped us think of, okay, here's what I do day-to-day as a clinical endocrinologist but how does this apply to everybody across the country? And that's also the perspective the patients were able to bring to us.

David C. Lieb, MD, FACE, FACP:

Yeah, the practical aspect, which is exactly what we need out of the guideline. In addition to the science and the evidence, it's got to be practical so that we can use it in the clinic. Dr. Wyne, were there any surprises with respect to the evidence assessments and overall recommendations?

Kathleen L. Wyne, MD:

Were there any surprises? I would say there were actually quite a few. I was impressed at the volume of data that's available but the fact that the majority of it is really not of adequate quality to be able to assess therapeutics and make recommendations for clinical practice. And that really surprised me that how very little data was actually available for us to work with, quality data. I think that's the first thing.

I think the second thing I would say is the quality of the data, although statins are the foundation of all our therapy, the quality of the data there isn't as good as I had really thought it was. And especially not with respect to the intensive therapy. When it comes to triglycerides, I wasn't surprised at the lack of quality data because I knew that we didn't really have it, but I was disappointed that we didn't find something I didn't know about that could really give us good strong recommendations.

David C. Lieb, MD, FACE, FACP:

But it gives us hope for studies that need to be done in the future. I think a lot of times a guideline will help to create a pathway for what needs to be done next. Dr. Patel, any surprises?

Shailendra B. Patel, BM, ChB, DPhil:

Not for me. I thought that overall I figured that what we were going to see is what we pretty much expected. And I think that in the guidelines when people read them, and for the readers when the actual guideline comes out, the key table is going to be table three, which is a really wonderful summary that summarizes everything very quickly for someone to quickly look over. No major surprises except for the fact that it highlights that when clinical trials are designed, many of them, while they are clearly designed to sell a specific pharmacological agent, the idea that they are going to be testing hypotheses or mechanistic pathways is always missing. And the thing that always misses is that while we are talking about triglycerides and cholesterol, and I've told this to our panel and I tell it to our fellows, it's about the mechanisms because if you understand them, you do a better job of actually treating your patient.

And the mechanisms where lipids are concerned is really to do with lipoprotein metabolism. It isn't about the cholesterol, the triglycerides, but it's about the particles that they are contained in. And I think that when clinical trials don't address the particle metabolism, so they measure these surrogates like cholesterol or triglycerides, that's where some of the weaknesses come in. And the surprise was that really none of the studies that we had looked at previously and of course the newest ones addressed that particular concern. But overall, I think that these updated guidelines are not only building on a very solid basis as Kitty alluded to, but they are now extending it with the newer agents that will then allow people to use them in a more judicious way.

David C. Lieb, MD, FACE, FACP:

And what should clinicians know about implementing the new recommendations in practice? I like that you already mentioned, "This is the table. This is one of the big things you're probably going to be flipping to, looking at, printing out and putting up on your wall in the clinic." Any other thoughts with respect to the practical use of the guidelines?

Shailendra B. Patel, BM, ChB, DPhil:

Yes. I mean, I think before people go into the depth of looking at all of the guidelines, I think that because this is great methodology, I think it's also very important to educate our readers and listeners because when we do GRADE, it is a different way of giving recommendations. Unlike the past recommendations, we would say this panel strongly recommends the use of this agent, yada yada yada. And then here's the level of evidence. I think that the language is going to change a little. So GRADE has an ability to talk to you about the size of the effect. So there are three factors, size of the effect, the certainty of the evidence, and then clearly the level of statement, how does it get phrased?

So you actually have the level of evidence which is going to actually talk about how strongly does the evidence support the guideline recommendation, the certainty of the evidence, and then clearly the recommendation. We don't use words like strongly or maybe, but they get a little bit different. So for example, the certainty is going to be is or probable or maybe. And I think that as more and more guidelines around the country are going to be using GRADE, we need to make sure that that language becomes a little bit better and more comfortable as people evaluate GRADE. I think this is going to be very important.

David C. Lieb, MD, FACE, FACP:

Absolutely.

Kathleen L. Wyne, MD:

I think there's another piece to that, and as Dr. Patel said, table three is the most important one. I think some people are going to be disappointed because they're going to look for their favorite little thing and find out that we don't have a recommendation because we don't have data. And so I think that that's one of the things we're going to hear is people are going to say, "Well, why didn't you do this? Why didn't you do this?" But we're really limited by the questions that have been asked and the data that's available to assess them.

David C. Lieb, MD, FACE, FACP:

And that leads very nicely into my next question, Dr. Wyne, which is what do you hope to see in the next set of guidelines? Where are the gaps in the literature? You've already mentioned some. What studies need to be done before more guidelines can come out?

Kathleen L. Wyne, MD:

So you've actually picked one of my favorite topics there, and that's why I say it was a challenge to see what the data did and didn't support. One of the big topics, and I know we've been talking about it for a long time, I'm starting to see some of the waves change on this, is diversity in clinical trials. And we've been asking for this for a long time. Some of the trials have slowly improved diversity. I'm seeing more of an effort in the last couple of years, and that's something that at Ohio State we really focus on. And that's our goal, is to get people who don't have English as a first language, people of different backgrounds involved in these trials.

There are several other topics that I think are important that we just didn't have enough data for, and one is really just refining the use of the risk factors. We asked the question, we looked at coronary artery calcium, [inaudible 00:18:03], and I was actually surprised to find that I'm involved in a recommendation that is consistent with what the USPSTF recommends, which I've always thought is very conservative. But now I have a better understanding of what they do because we couldn't recommend regular use of these markers. And so I think that those are things that really need to be refined more so that we could figure out how to use them.

The other big ones I see, and I've already alluded to the triglyceride issue, and triglycerides have always been a problem. And if you look at all the guidelines, they don't actually give you a target. They just say normal is below 150. And now there's a guideline that says non-fasting is below 175. But that's a huge one, and we just don't have a clear picture of who to treat. And the people we think we have a clear picture like our severe hypertriglyceridemia, pancreatitis patients, we don't have data for that.

And then the other couple ones that I've thought about, and one again we've highlighted for a while and things are starting to happen is the patient with peripheral artery disease. There's been so much focus on the heart and the brain, we've forgotten about the legs. And so that's where we really need dedicated clinical trials to address that population. Their risk factors are a little bit different. We have no interventional trials with them.

What else do we need? Age. We highlighted this in the document that there's not good data in age over age 65, and that's something that has been an interest for NIH for many years and still has not really come through.

And the last one that I wanted to mention is just the type 1 diabetes. And Shailesh can tell you, we tried. We tried to include it, we asked the question, and we just discovered that there's almost no data on cardiovascular intervention or prevention in type 1 diabetes. So it's not in this guideline.

David C. Lieb, MD, FACE, FACP:

Dr. Patel, any gaps? I know you mentioned some already.

Shailendra B. Patel, BM, ChB, DPhil:

No, no. I think Kitty's covered most of the big gaps. And clearly there are areas that will still need to be improved upon. So for example, with our normal therapeutics, so we've got the PCSK9 inhibitors, both antibody-based as well as the small interfering RNA ones like inclisiran, we've got the bempedoic acid. And clearly the clinical trial data don't address all of their uses that some of our providers are using them for. There's not enough evidence to support their extensive use. So I think our guidelines is going to clarify when it is appropriate to use these novel therapeutics, which are very, very powerful of course. But they also need to look into the cost-effectiveness and efficacy of those agents. And so I think this guideline is certainly going to help address that.

And the one thing I think our guideline also does is it finally, hopefully puts to bed agents that I think we should not be using as much as we used to in the past. And the three agents to really call out here are going to be the fish oils, whether it's eicosapentaenoic acid alone or eicosapentaenoic acid plus docosahexaenoic acid and niacin. EPA is a little unusual in that there's one trial data that clearly shows some benefit, but overall, when you look at the fish oils together, the evidence is really very weak. And our recommendation for niacin is that we really don't see a very good role for it to be part of most major therapeutic interventions using that particular agent. So I think those are some of the good things that have come out of this new updated guideline. And as we move forward, hopefully we've highlighted the areas that need greater research and better design studies, and that will hopefully plug in the areas. And as Kitty says, type 1 diabetes and cardiovascular intervention is clearly one, but so is peripheral vascular disease. So hopefully future trials will be aimed at that.

And I certainly think that from a science base, again, hopefully they will pay attention to the fact that we want to study the lipoproteins and not these individual components. Because again, the reason why we are confused about triglycerides is that the triglycerides are contained in the lipoprotein particles. And with triglycerides, the particles that matter are actually the remnant particles. So chylomicrons and VLDL are the richest source of triglycerides, and course any of their metabolites into the smaller particles that come into remnants is where the triglycerides at. So hopefully addressing that concern and addressing that aspect will give us some high quality science in the future for the therapeutic parts.

David C. Lieb, MD, FACE, FACP:

I want to thank you both again for joining me today. This guideline is an essential tool for practicing clinicians. It really translates the latest research and evidence into practical advice, which I think is key, helping us to make informed treatment decisions, and ultimately to improve the quality of care that we all provide to our patients. To read the full guideline and to view our podcast on the methodology used to develop this guideline, visit pro.aace.com/clinical-guidance. Thank you.

Speaker 1:

Thanks for listening to another great AACE podcast. Join us for another episode at aace.com/podcasts and help us in our mission to elevate clinical endocrinology. Together we are AACE.