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- [00:00]
A
Hello, I'm Aaron Lohr and this is the Endocrine News Podcast. Today we're talking about acromegaly. We're going to cover a lot prevalence, diagnosis, traditional treatment, new therapies and current gaps in understanding. And joining me is the wonderful Dr. Maria Flecheirou. Dr. Flecheirou is professor of Medicine and professor of Neurological Surgery at Oregon Health and Science University and she's also director of the Pituitary center that's also at the Oregon Health and Science University. She's authored hundreds of articles, including guidelines and consensus papers. She's a frequent plenary guest speaker at meetings and she's past president of the Pituitary Society. She also currently serves on the Board of Directors for the Endocrine Society. I could not be happier that she's our guest here on the podcast once more. Welcome, Dr. Flasher, you.
- [01:05]
B
Thank you so much. It's always a pleasure to be here and to talk about rare diseases. And today is going to be acromegaly.
- [01:13]
A
We should just jump in. So what is acromegaly and what do we know about its prevalence?
- [01:20]
B
Acromegaly is a disease most of the time. And when I'm saying most, it's 98% coming from a pituitary tumor secreting growth hormone. Now, the exact prevalence, it's a good question. Do we know it yet? No. And there are no studies in us showing either the incidence or the prevalence. We're doing now a large prospective registry for pituitary adenomas called Nuspar. That would be the first one in us and we hope that we're going to find out. However, if we're looking at studies mostly coming from registries in Europe, the prevalence is somewhere in between 2.83 to even 13.8. That would be almost 14. A meta analysis looking over the last 60 years showed a pooled prevalence of about 6 per 100,000 persons. I'm sure this is under diagnosed because now when we do an IGF one, for example, and we'll talk later about diagnosis, but just to show why it's hard to find sometimes these cases, when we do an IGF one in anyone that has a pituitary adenoma diagnosed on imaging, we find more and more cases with no significant signs and symptoms yet. So it's a rare disease, very important to increase awareness and to think about it. And the reason it's so important is that the delay in diagnosis is still significant. So we're doing better than before. But there are studies again, most of them coming from Europe that show that while getting better every decade, it's still a diagnosis delay of about five years now. And something that I'm really frustrated is that the diagnosis delay in women versus men is also significantly higher in women. So in women maybe a little bit because of premenopause and estrogen that's slightly decreasing the IGF one. But in women we have to make a concerted effort because the studies show that they are going to the doctors, they see more physicians. And still these physicians don't think about pituitary disorders. And they think that some of these symptoms are PCOS or something else before the classical signs and symptoms. Where it's acromegaly coming from? Because you started with acromegaly. Yeah, it's gross hormonic stress. But the names comes from Greeks, from enlargement of extremities. This is very, very late. So that's why the delayed diagnosis before was 11 years. Because we're talking about the latest of the diagnosis when you see facial changes, when you have increased shoe size, sometimes with several numbers, increase ring size. But we shouldn't wait for that. There are several symptoms that are much, much earlier. These patients have diabetes, hypertension, sweating. Women have irregular periods. So if it's a corollary of some of these signs and symptoms, the physicians should think earlier about possible pituitary disorders and acromegaly should be on the list. Earlier is not as easy to diagnose. But if we're making a concerted effort, we should get better to that. And then reason I mentioned the studies from Europe rather than us is also related. There were some studies showing that maybe it's population. Some small areas, especially in Europe have more mutations like AIP mutation. Where some studies in Italy saying that highly polluted areas have more acromedaly, we really don't know. So I just bringing it up for more research. But that's why we need better data, especially in US both for incidence and prevalence.
- [05:09]
A
We mentioned diagnosis a few times already and I appreciate you sharing the importance for early diagnosis because it's so important. So how is diagnosis typically done? And maybe talk a little bit about the challenges maybe involved with early diagnosis.
- [05:25]
B
So the diagnosis of acromegaly is made on IGF1. IGF1, it's insulin growth factor one made in the liver, not in the pituitary. But the excess growth hormone from the pituitary tumor goes to the liver and makes IGF one. And it's important to know that both of them have direct and indirect effects everywhere in the body. Both on soft tissue, that's why you see swelling, but also on heart bones and enlargement of other organs. And we'll review more when we talk about complications because I definitely want to bring that up because it's important to diagnose and treat in the same time. So how we make the diagnosis if we think that somebody has acromegaly, we need to check an IGF one. The IGF one is the best diagnosis for acromegaly. The recent consensus guidelines changed the role of the oral glucose tolerance test. And I'm very happy talking about earlier diagnosis because before the guidelines all mention that you need both and I have been in this camp because you don't want to make over diagnosis. So you need abnormal IGF one with some caveats that we'll talk later. But then you also need to make sure that the gross hormone is not suppressed into glucose. So this was the ogtt, the regular OGTT that we do for diabetes, but done to suppress the gross hormone. And if was considered that if the growth hormone suppressed patients don't have acromegaly. But again, this was for late diseases. US and others have found that up to 30% of patients can have early acromegaly and have still normal glucose tolerance test growth hormone suppression. So that's why if the patient has sign and symptoms of growth hormone excess and high IGF1 with a caveat, that has to be a good assay. There are some interfering medications, especially estrogen, that's falsely decreasing the IGF one, hyperthyroidism and but mostly should be a good lab with a good assay, then you don't need the odt. We do it sometimes because we do it to make sure that the patient doesn't have diabetes and to know how to follow the patient. But we have treated several patients just this year that ended up having surgery, documented acromegaly and still had normal ogtt. And I have to tell you because I presented the middle professor of acromegaly at the ENDO in Boston this year and after I presented one of these cases, I got texts and emails from several of my colleagues really worrying how many cases potentially they were waiting on and maybe they were missed. So I think we need to to change this paradigm. So this would be one of the challenges. The other challenge is the variability of IGF1 and the lack of good assays in many, many local centers. So that's when we do research. It's fine because we send all in one place. And I have to say that's actually in Europe for IGF1, but in US, if a patient comes to me as a second opinion with another IDF1, sometimes the variability with our lab could be 40%, the normal variability is 20%. So there are some issues there that I would consider part of the challenge. And the next one should be at least for anybody that has a small P2 teradenoma. Even if they have prolactinomas, they could be mixed tumor. Check on IGF1 before starting treatment because these would be the earlier cases that we can diagnose much earlier and then less complications and smaller tumors. So then cure with surgery.
- [09:04]
A
Now let's say that the diagnosis has been made in its time for treatment. How is acromegaly traditionally treated?
- [09:12]
B
So the reason I brought earlier the tumor size is that a treatment has different chances of remission based on adenoma size. That's very important. If we have an earlier diagnosis, then the tumor of the adenoma would be smaller. And then with surgery, the cure rates in a specialized center has to be a pigmentary tumor center of excellence to get better outcomes would be 80 to 90%. So that patient has a higher chance remission, cure. That depends how you define. They rarely come back, but still sometimes they do. So I like to use the word remission. However, because of the late diagnosis, half of these patients will have a tumor that's extending in the cavernous sinus, which even with new methods now where they can do medial wall resections, still the chances of cure are significantly lower. So because of that, these patients will need to go on medications. These medications are working a different type of site, so they are pituitary directed drugs. And then we have a growth hormone receptor antagonist. Now keep in mind that we are trying to push towards individualized therapy. Sometimes insurances don't agree with us, but that's what we're doing for many, many years. And it's a study, a very recent one like few weeks ago from Spain, showing at national level that with individualized treatment you can get to normal IGF one in half of the time. So it's very important to look at the patient as a whole, to look at the tumor size, to look at pathology markers, which we have done and published now 15 years ago, but we do it all the time because if for example, it's a sparsely granulated tumor after surgery, you see that some, you can have an indication even before surgery on mri, but it's not as good as pathology. And then on top of that we also do somatosetin receptors, type 2. So if you have the sparsely granulated and NO receptors. The likelihood of responding to either of Trotad and Laotide is very low. So if we're looking at this, why to start these medications when we can move directly to another somatosetin receptor ligand, pasirotide that in these type of patients can improve control in another 20 to 25% of patients. Not everybody. I have a lot of patients that if they have these parameters, I start them directly on combination therapy, either octotide and lilotide with pegvisaman for example, which is the gross hormone receptor blocker I was mentioning earlier, and these combinations. There are now several studies that you can use the monthly injection, for example, and then adding Peg visoment once or twice a week. And then we can control in some studies up to 95% of patients. So virtually a lot of patients, the treatment persistent and adherence are an issue. We look recently at large databases and keep in mind this is a monthly injection for Octobertide and larotide for now that the patients have to go to a center to have it. There are some data and we have published a meta analysis looking at extended release, for example, for lariotide, six weeks can work in some patients. And again, we have to think about that too, because this saves some injections for patients the pecvizomed. The patients can inject themselves, but some patients do not like injections. For the last few years in U.S. oral Octootide has been approved and we presented some data at Endo where we looked at the pool analysis of all this data from all the clinical trials and the patients that were on injections and then switched to oral octreotide, for example, maintained control where they started up to 1.3 in about 80%. So not everybody will respond, but the large majority will. And the symptoms also improved in the large majority of patients. So an injection once a month versus capsule twice a day, it's improving symptoms because probably the variability of these drugs. However, not everybody wants to take a medication twice a day because these patients are taking already more than three medications. Again, we looked in a claims database because we don't have prospective studies yet. And the patients with acromegaly compared with matched controls had more than 80% several comorbidities and also taking more than three medications. So this is very important when we are thinking about one medication versus the other. And I would definitely like to cover soon all the new data from this Endo 2024 in Boston.
- [14:14]
A
Absolutely. When you think about the challenges associated with treating acromegaly it sounds like adherence is certainly one. Is that the biggest? Are there others?
- [14:23]
B
So I think the main one, it's actually the long term treatment. So it's both persistent and adherence. If the patients won't have radiation that we use a third line where yes, at some point you can achieve rehition of acromegaly. But also hypopydoitrys means these patients will need to take in half of them at five years with the radiation we have right now. So it's possible we'll get better over time. So don't quote me that in 10 years. But now we fix the acromegaly. They don't need medications for acromegaly, but if they are pan hypopic they will need to take replacement for steroids, replacement for thyroid, replacement for gonadotrop. So it's just you're changing something. Some patients will need to. Because if the tumor is growing or it's aggressive, then we recommend radiation on top of that. So the main challenge is actually the multimodal therapy because these patients will need surgery, will need medications. We didn't even talk about that. In very large tumors where the patients have significant comorbidities, we used medical therapy even before surgery to try. We had some patients where we had to use medical therapy to be able to have anesthesia because of the all the swelling that was present. The data on improving cardiovascular disease, we want it to be good, but doesn't seem like, also doesn't seem like it's improving biochemical remission post surgery. But overall I have some patients every year that we have to treat preoperatively to improve their comorbidity so they can go to surgery. Then if they have a large tumor and we go back again to late diagnosis, then we they have to go back on meds and then they have to be on these monthly injections. Now luckily in us, but it's not available all over the world. They don't have other medications. They have to go to a doctor every month to have the injection. And then sometimes they need combination also. I'm convinced that if we're using the personalized treatment and we get to the control earlier and the patients will feel better because the quality of life it also very important. It's decreasing acromegaly and with treatment it's not always improving. There are some like joint pains that persist and even get worse and a lot of other symptoms that decrease concentration and memory and cognitive function. So they don't go back to normal immediately. The patients start properly to think, why am I taking the treatment? And we notice even with injections the week before injections, it's much worse. So that's why the oral medication that's approved and we have several studies that show that it's better just because it has a different bioavailability of the drug. So adherence, persistence, cost. Also would be important to look at the patient as a whole and find out the right treatment based on tuber characteristics. What patient preference? Some patients, I might think that it's easier to take an oral. Some patients want injections. How much do I know that the patient would be controlled? I have patients that I tell them is probably going to be with this medication 50% do you want to try? And they say yes, even if it's 50. I don't want to have radiation, for example. Or patient preference should move up in the personalized treatment. And also comorbidities. They are medications like pesterotide that are worsening diabetes. Combination of octoatide or lariotide with Peglisament, it might even improve the diabetes or at least it's neutral. So we need to think about all these overall. And then I think that what also it's very frustrating for the patient is the corollary of screening and complications treatment that we need to do in the same time, which once you are past that this is improving how patients are feeling. But otherwise we see them. I'm trying not to do it in the first visit and do it in the second. But then we tell them you need screening for colonic polyps. So they leave our office with an echo, a sleep study, a colonoscopy, a dexa X rays to rule out vertebral fracture and then work up for diabetes possible if they have some hyperglycemia and lipids. And some of these patients didn't even know they had anything. They just weren't feeling good. Or some had a pituitary adenoma found on CT because they fell skiing. So it's a huge change overall and has to be approached and it's very important. And these patients have patient support group and they like discussing one with each other because I think especially at initially we as providers are overwhelming with what we request of these patients. And again, I'm trying not to do it the first visit when we talk more about surgery and medications and all that, but has to be serial. And I have to say that telemedicine, it's advancing this significantly because then patients don't have to travel back and we can do it in another visit and then another visit to discuss questions and alleviate their questions and hopefully giving them good answers.
- [19:35]
A
So we've talked about personalized treatment a couple of times and you gave some things that we should really look at, including that the patient's perspective. But for those who are listening, who want to learn more about how they should adapt their approach to make sure they're providing that personalized approach, do you have any encouragements to give them? Like, here's some things that you really want to consider as you dive more into a personalized approach to treatment?
- [19:57]
B
That's a very good question. And I think we need more data to recommend broadly a lot of other markers. But for now, what I can strongly recommend is the tumor size, the age of the patient. And cavernous sinus invasions are very good proven predictors. For example, for response to surgery. And we tell patients in advance because again, as I said earlier, it's easier for them if they know from the beginning surgery is not going to fix all the issues. You need a tumor out, but you will need medications after that so they have time to be prepared. So for surgery would be this. For the somatosetin receptor ligands, especially octreotide andreotide, sparsely granulated tumor most likely won't respond. If it's an absence of SSC2A receptors, they are not going to respond. The dose of the medication is very important because we see patients that are not properly up titrated and then the adverse events also varies in between patients. If I see that the patient has adverse events immediately, then I know I can get to a very high dose and then I'm thinking about combination much faster. So for all these patients that I said earlier that I know they won't respond, I switch either to pesiratide, that's also a somatostatin receptor ligand. But I tell patients from the beginning the likelihood of developing diabetes could be half even for that. We have a perspective now and we looked in several clinical trials. If the patients are younger, the likelihood of developing diabetes is much less. If they already have hypertension, diabetes and dyslipidemia, for example, we know they're going to develop diabetes. So then I start metformin or other medications earlier, even if they have pre diabetes. Thinking of that for combination I usually use, I told you either Octobertide and lirotide to once a month and then adding peglisamine twice a week cost effect. It seems that even once a week might be a good option. However, you can see more lipodystrophy with the injections. They're subcutaneous, patients can do it. And I have to say it's the combination, it's not FDA approved, we're using it off label. There are of course some biochemical markers, there are some tumors, specific biomarkers that are in research and some show that work, some show that it's really not as important. So it's more, more research to come in that direction.
- [22:28]
A
Also we talked a little bit about traditional treatment earlier, but I kind of want to shift more to some more novel therapies. So when you think about what are some of those more novel therapies for acromegaly that we should be thinking about, what comes to mind.
- [22:41]
B
There are several drugs in development and I'm going to focus on what was presented at the end of 2024. This is as brand new as it can be. And one of the medications is this is a non peptide SST2 receptor agonist. Keep in mind octlotide and laureotide also act more at the receptor type 2. The piltuzatine advantage is that it's once a day and it's an oral medication. And there were several clinical trials presented at Endo with different designs. So I'm just going to give you the summary overall. So the long term phase two study was presented that showed for the patients that responded continuous IGF1 control and symptom control because that's what's important. These were patients changed from injections. Then it was one large phase 3 clinical trial that was multicenter international double randomized placebo. All of the patients were on injection before and then switch either to baltuzatine or to placebo. And then for these patients, large majority of patients had a rapid and persistent control on the drug. And of course not so much on placebo. But as I said, even for the oral octariotype the difference was that the patient saw improvement in symptoms. And the second large trial that was presented also at Endo with this drug was a different design. So these were patients either completely naive to therapy and this is very important because we did not have this before with new medication in long time that patients were not treated or washed out completely from therapy for many years. So the advantage to this is we would see with an oral medication how these patients can be controlled. And overall in both groups was over 50% response rate. But what was interesting was that for patients completely naive, not just wash out was more than 40%. And this is higher compared with other retrospective studies for oxreotide or lariotide for example. But it's hard to say because you're comparing a prospective study with something retrospective or a different design. So we can't really put them head to head. But it's encouraging because we have no oral medical therapy for naive patients immediately after surgery approved yet. So the studies were good, but let's look and see if they will be approved by the fda. The other major advantage for patients potentially if it gets approved by the FDA were novel subcutaneous depo octootide that's in a pre filled syringe sub Q once a month so the patients can inject themselves. It's like the insulin needle, they don't have to go to the physician. So again that would be a major change for patients if it gets approved. And there were two studies again with different designs. The patients noticed a significant decrease in IGF1 and the large majority of patients that were normal on injections were normal on this sub Q injection. Also that's octreotide. Furthermore, because the bioavailability of this octreotide is five times higher than the regular octreotide, we were able to see in the studies that the symptoms improvement was also significant compared with the patients before. These were patients for all the studies I'm describing you entering control. So when you are asking me what's the challenge these patients still had symptoms while they were biochemically controlled. So normal IGF1. So with all these new medications, starting with the oral octotide studies we have observed over time that control doesn't mean just numbers. The symptoms are important. And of course in clinic we don't have the luxury that we have in respective clinical trials to look serially all the time and with symptom diary with treatment satisfaction questionnaire that of course patients prefer medications that they can take at home and self administered versus to go into an office and see their doctors. This is not approved yet. So if it will get approved would be also an advancement for patients both preference also not needing to go to a physician's office. And then it was another study that was just in healthy volunteer when with some previous studies in rats and healthy beagle dogs that it's a small receptor peptide that's antagonizing the growth hormone receptor. So that would be again an advancement if all the studies will work out because it's longer acting compared with the pigvisament that it's approved now as a daily medication. And I told you before that we are using it twice a week as sub Q in combination. But if it's not in combination you need it probably every Day. So again that would be if the studies the data enhance you volunteer also in combination with some other receptor ligand look good. But again we have to see more data. But for the other two drugs that I mentioned, there are two phase three for each of them. All of them with with promising results. There are studies now with better surgeries getting into the medial wall of the cavernous sinus. Hopefully more improvement. The new methods of radiations are getting better and better. So I think the future looks good, especially if the patients will have smaller tumors. So I'm going back to where we started earlier. We have to to make an effort to diagnose this disease earlier.
- [28:34]
A
It's certainly encouraging to hear that the current research out there is as promising as you describe. And throughout our conversation it sounds like there's still a lot of things that we may not have answers for. So where might we still need more research in both understanding and treating acromegaly.
- [28:52]
B
Erin, the list is so long but I don't think you want to stay with me until tomorrow. But let me briefly cover. We have to have better idea of one assay so I think that's a big challenge that we need to understand why we have an issue. So it's more logistically than science, but it's really impacting the care of these patients. And then physiologically we also have a science question why 30% of patients have discordant GH with IGF1. So I think this is very important. There are some studies showing talking about the OGTT and response we didn't even cover earlier that have paradoxical response to glucose. So instead of decreasing, they actually increase. And it's possible to be new different type of receptors like GIP which have an impact to that and it's possible that that will predict we're not there yet, but that will predict the worst prognosis. So these patients have to be put much faster on treatment and maybe the tumors will grow. So that's something we should look into for diagnosis overall then what we also need and I mentioned briefly earlier, but I think that's where the research should come in the tumor itself. Do we have any genetic markers? We didn't cover about genetics. It's possible that yes, some patients can have me N1 and we know about the AP mutations and in kids there are few other mutations that are known but these tumors run and acromegaly in general could run in families and the IP mutation is negative. We just did it in few patients and they have family history. So what else is going on So I think that would be important to find out the genetic and also the biomarkers. So if you have. We know now that if you don't have receptors type 2, you don't respond well, but if you have, you still don't respond in 20% of cases. And what's the role of the type 5 and what's happening with the other receptors? And is this, that if you have different bioavailability that you get a drug much faster in that's the response related to that or what is actually happened post translocation at receptor level. So I think we have to think more about that. Why some patients have no symptoms at the same degree of IGF1 and why some patients have significant symptoms. We had patients with cardiomyopathy that had the disease not for long term, but because they were young. It improved immediately once we treated, which is again very positive. And I like to check it to make sure though it's not improving in everybody. We know now that the patients with acromegaly have more vertebral fractures, though the bone density is normal. We used to think, and I remember telling even fellows 20 years ago that at least if you have growth hormone. Growth hormone is building bones, but it's building bones, but we didn't know it's building bad bones. So these patients have more fractures if you check for it. Exactly. The mechanism and also talking about personalized treatment, it's not a lot of data. So that's why I didn't bring it into the personalized. But in the future we have shown that somatosetic receptor ligands like pesirotide for example, works better for the bone than the peglisament. So blocking the receptors, These patients seem to have more fractures longer term even after they are controlled than with passionuratide. This was a small study, multicenter that we ran. Now do we know the exact mechanism? No. So we still have to find that and then how to measure the patient reported outcomes because now we have accurate quality of life. We have treatment satisfaction questionnaires, we have several other measurements, but we need a unified one to actually find out which symptoms is more prominent for that patient and how to actually improve it. And then the cost effectiveness of all this treatment that I've shown you, even the one that I told you that the personalized it's faster and cuts in half. Is this cost effective? We don't know. Probably for complications, if you're asking me. Makes sense, but we have to prove that. So we have a long list and I hope in several years. I'm coming back and I will just report to you that check, check, check to all these so we can actually improve the outcomes in these patients with rare disorders and acromegaly especially.
- [33:23]
A
Well, I certainly look forward to getting all those boxes checked off. And I can't wait to have you back on and say that that's indeed what happened. We covered a lot of ground today, but we are out of time. So I want to thank my guest, Dr. Maria Flasheri. Thank you so much for sharing your time with us.
- [33:39]
B
Thank you so much. It was a pleasure.
- [33:42]
A
And that's all for this episode. I hope you enjoyed hearing from Dr. Flasheriu. Is there a topic in endocrinology that you'd like to hear us talk about on the podcast? Let me know by sending your recommendation to podcastendocrine.org that's podcast endocrine.org I'd love to hear from you. We'll be back soon with another fascinating dive into the world of endocrinology. Until then, thanks for listening. Endocrine News Podcasts are a free service of the Endocrine Society. To learn more or to become a member, visit the society's website at www.endocrine.org.