0:23 EPISODE INTRODUCTION by moderator Archie: My name is Archie Franklin. I'll be your moderator for today's discussion about the latest news surrounding the use of incretin hormones like GLP-1 receptor agonists, metabolic disease, and management of psoriasis and psoriatic arthritis. Joining me is the leading dermatologist and the Vice Chair of the NPF Medical Board, Dr. Ronald Prussick, who is the Medical Director of Washington Dermatology Center in Rockville and Frederick, Maryland. Dr. Prussick is also a clinical associate professor in dermatology at George Washington University in Washington, D.C. Also here is Dr. Brittany Weber, cardio-immunologist who is the director of the Cardio-Rheumatology Cardio-Dermatology Program at the University of Texas Southwestern, where she is also a member of the Division of Cardiology, a clinical investigator, and imaging specialist.
Welcome Dr. Prussick and Dr. Weber. It's a pleasure having you here to discuss the latest research around incretin hormones like GLP-1 receptor agonists, and metabolic disease in relation to psoriasis and psoriatic arthritis. Dr. Prussick, let's start with a broad discussion about incretin hormones like GLP-1 receptor agonists. There seems to be more of this type of medication released every year. In fact, orforglipron was just approved by the FDA on April 1st. And we really like to know what are incretin hormones and what does GLP-1 receptor agonists or GIP RA stand for? And how do they work in the body to regulate appetite and initiate weight loss?
2:06 Dr. Prussick: Well, thank you very much for having me. And what incretin hormones are, they're produced by specialized cells in the small bowel after nutrient ingestion. So they work by lowering blood sugar, by stimulating insulin production, and they inhibit glucagon. And what this does is it slows the stomach from emptying so the stomach feels fuller. And that's why you don't have as much need or feeling that you need to eat because your stomach feels full. It also affects the receptors on the brain to also make you feel fuller quicker after you eat. So what GLP-1 stands for, it’s called glucagon-like peptide-1 receptor agonists, and GIP stands for glucose-dependent insulinotropic polypeptide agonists. So basically, these are just the two most important incretin hormones that are produced by the small bowel from specialized cells from the gut. And these drugs are approved, they were approved initially for treating diabetes, and then at higher doses, they're treated for weight management. And they are available through subcutaneous injections, and now there are two oral versions.
3:29 Archie: That's great that there's options for patients. I think it's very important to have options like we do in both oral and injection. You know, just amazing how this hormone in the gut can have such an impact. Why are incretin hormones like GLP-1 receptor agonists of interest in the management of psoriasis and psoriatic arthritis?
3:50 Dr. Prussick: Well, we know that obesity drives the psoriasis. We know that patients who are already overweight or obese have a higher risk of developing psoriasis and psoriatic arthritis if they have the genetic susceptibility. So by tackling the obesity, that will reduce the inflammation in the body. So if you think about fat cells, the fat cells that are in the stomach area, the center part of the body are different from the fat cells in the arms and legs. They're metabolically active and they produce a lot of the inflammatory cytokines that trigger psoriasis and psoriatic arthritis. So that's why the obesity is so important and that's why people who have obesity are at a higher risk of developing psoriasis and psoriatic arthritis. And we know that patients with obesity have more of these inflammatory cytokines because they have more of these specialized fat cells that are in the center of the body. So that's why we're really focusing on reducing the obesity, reducing the fat cells, reducing the source of inflammation, because psoriasis isn't just a skin and joint disease. It becomes a systemic inflammatory disease with a lot of comorbidities and a lot of health risks, including the risk to the heart and the liver, et cetera. So we're trying to prevent all that by reducing the obesity.
5:23 Archie: Certainly, we've been talking about comorbidities for years, and this is wonderful news that we have some products that actually help that systemically -- which brings us to Dr. Weber. Hearing this connection between GLP-1, psoriasis, psoriatic arthritis, what's the connection with metabolic and cardiovascular disease and the immune cascade associated with psoriatic disease?
5:46 Dr. Weber: Yeah, thank you so much for this question. And what an excellent topic that we're getting to discuss today. So first, I will say that psoriatic disease exists within a complex network of systemic inflammation. It's really where it’s the confluence of the condition -- skin inflammation, metabolic dysfunction, and cardiovascular disease. We now know these are interconnected through shared inflammatory pathways rather than just simply co-occurring together. We know that the chronic inflammation in psoriasis involves many of the same pro-inflammatory cytokines. These include things like TNF-alpha, IL-6, IL-17, that also drive insulin resistance and atherosclerosis and cytokines that we think about from the cardiology angle itself. And so what does this create? It creates what I describe to the patients as suspicious cycle, where inflammation really is promoting the metabolic dysfunction, and that's perpetuating more inflammation in this kind of ongoing feedback loop. We also know, as just mentioned earlier, that metabolic syndrome is really common in our patients with psoriatic disease. This has been substantiated in large data sets where the prevalence is much higher compared with the controls, with increasing proportions to how severe the psoriasis itself is. And so we know the adipose tissue itself plays a central role. It's a kind of an active immune organ that I'd like to describe to my patients. It secretes its own inflammatory adipokines. It creates this abnormal profile. And this shared inflammatory biology really explains why targeting these pathways, whether it's through the traditional biologics or emerging therapies like the GLP-1 receptor agonist, can potentially address both the skin and the cardiometabolic complications together.
7:19 Archie: Again, great news for patients like me, and we're always looking forward to new and better treatments. One of the most frequent conversations I have with my fellow psoriasis patients is this comorbidity issue. And you mentioned some of the larger studies. Research from Dr. Joel Gelfand and Dr. Nehal Mehta has shown people with psoriatic disease are at a higher risk for cardiovascular disease. Is it possible reducing inflammation through the use of systemic treatments and GLP-1 receptor agonists will impact cardiovascular risk?
7:53 Dr. Weber: This is such a great question and also a big one. So first, I will say that we know that the cardiovascular impact on our psoriasis patients is substantial. The statistics can be alarming to patients. Severe psoriasis can carry upwards of a 70% increased risk of having a heart attack, 56% risk of having a stroke, and overall 39% increased cardiac mortality, even after accounting for those traditional risk factors. So it's very important that we don't negate the importance of treating the traditional risk factors, but psoriasis itself is inherently high risk. And why is that important? Well, it's important because our guidelines you know that we use in cardiology, recognize the limitations by which our risk calculators assess risk. And so psoriasis is labeled in the guidelines, including the most recent updated guidelines that came out within the last month, the PREVENT Guidelines and the new dyslipidemia guidelines of psoriasis as a cardiovascular risk enhancer. So going to your question, it's clear, as I just mentioned earlier, that reducing inflammation through treatments like GLP-1 receptor agonists appears to reduce cardiac risk. And then we can talk about biologics. Certainly when we talk about some of the studies you were mentioning, the evidence is stronger for some therapies than others. However, what we're learning is that their complementary mechanisms, biologic targeting disease-specific inflammation and GLP-1 receptor agonists through both the metabolic improvement and some direct inflammatory effects. And so if you just look at these studies a little more in depth, there's really been multiple observational studies demonstrating that biologics reduce cardiovascular events compared to topical therapy and methotrexate and psoriasis points. There's also been population-based studies that have shown similar effects. I will say I don't think we have the granularity to say whether one specific biologic -- an IL-23 compared to an IL-17 is more beneficial in this question, although I do feel confident when I tell my patients that treating their psoriasis with appropriate biological therapy will reduce their risk. And then speaking along to the GLP-1 receptor agonist, the cardiovascular evidence is really robust. If you just look at meta-analysis, which there's been many in cardiology, we can observe that these agents reduce major cardiovascular events by 12 to 14%, cardiovascular death by 12 to 13%, stroke and heart failure hospitalizations among people with diabetes. And then we have the landmark trial in patients without diabetes. So that's why when we're discussing these topics for our patients with psoriasis, I would say that how I think about approaching GLP-1s in a patient with psoriatic disease, having psoriasis and obesity, it's not that you automatically mandate these therapies for reducing their psoriasis therapy, but it certainly creates a compelling rationale for consideration.
10:30 Archie: Certainly so. And as someone who's, psoriasis for over 40 years, I'm feeling somewhat guilty that I haven't seen a cardiologist since my disease, but I will be, yes.
10:39 Dr. Weber: Oh no, well, we have to change that. And I certainly will say that we're really excited as a plug that I'm down here at UT Southwestern just recently moving from Brigham and Women's. And it's an exciting time because we've established the very first cardio-dermatology program. And so I'm really hoping that we can, advocate for more programs like this across the United States.
10:59 Archie: Well, thank you so much, Dr. Weber. Dr. Prussick, back to you. What treatment challenges do you typically see in people with psoriatic disease who are overweight or obese? And when would you consider prescribing a GLP-1 in combination with diet and exercise?
11:15 Dr. Prussick: Well, this is an important question because obesity will significantly affect treatment response. What we know is that patients who have obesity have about a 30% reduced chance of achieving a PASI 90 response. So the treatment response won't be as good. And therefore, we often have to try something, then it doesn't work, then we have to switch to something else, then switch to something else. So I think that we see more switching and poorer response due to high BMI’s because there's more systemic inflammation, there's more comorbidities, there's increased depression and there's increased cardiometabolic disease. There's also been some studies that show when you look at the UK General Practice database over a 16-year period, when psoriasis patients gained weight -- so they went from a BMI, from let's say 25 to 30, there was a 13% increased chance of eventually developing psoriatic arthritis. And the opposite happens when they lost weight, when they went from a BMI of 30 to 25, they had a 13% reduced chance of developing psoriatic arthritis. So obesity will increase the risk of developing psoriatic arthritis as well.
12:37 Archie: I can remember when I was in one of the clinical studies for a biologic, they had two different doses and I had to take the higher doses because I was heavier. So very interesting that that's been around, I guess, and we understand that.
12:47 Dr. Prussick: Yeah. Yeah. It's good you brought that up because over the years, we've had a couple of drugs that are actually weight-based dosing, one called infliximab, the other was ustekinumab. But unfortunately, most of the other drugs are not weight-based dose. So if you think about it, you're giving the exact same dose for someone who weighs 150 pounds and someone who weighs 300 pounds. And so, of course, you're relatively underdosing the people who are heavier.
13:21 Archie: And could that cause why sometimes many of my fellow psoriasis patients had to switch biologics?
13:29 Dr. Prussick: Yeah, because they're getting a lower dose relatively, and also the fact that they have more systemic inflammation. Because when we talked about that belly fat, you're getting higher levels of systemic inflammatory cytokines, so it's harder to bring them down when you have more.
13:45 Archie: Very interesting. And certainly I really appreciate and thank you for addressing the impact associated with systemic inflammation and the use of GLP-1s or GIP medications. Such issues and more recently addressed in the NPF position statement “GLP-1 Receptor Agonist in Psoriasis, a primer from the National Psoriasis Foundation Medical Board” of which you are both authors. Can you please each speak to the key points around the use of GLP-1 receptor agonists when managing psoriasis and psoriatic arthritis, as well as the new field of cardio-dermatology? So we can start with you, Dr. Prussick.
14:27 Dr. Prussick: Well, from my point of view, the main point is that psoriasis and psoriatic arthritis shares similar inflammatory pathways to obesity. And so I think that it makes sense to reduce the obesity by any means you can, including using GLP-1 receptor agonist. So you have to realize that the GLP-1 drugs improved many of the comorbidities associated with psoriasis as well by patients losing weight.