← The Curbsiders Internal Medicine Podcast
The Curbsiders Internal Medicine Podcast
#526 DIGEST – game changers in pancreatic cancer, lipid guideline updates, and GLP-1/GIP endoscopy holds
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A
Hey, before we get to the show, I wanted to remind you to check out our patreon@patreon.com curbsiders. If you haven't signed up yet, sign up now to get ad free episodes, twice monthly, bonus episodes, and a whole bunch of other cool stuff@patreon.com curbsiders
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B
all
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A
right, I want to apologize in advance to the audience. Really scraping the bottom of the barrel for puns these days. But you know, Nora, I've learned something recently.
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B
What did you learn, Matt?
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A
You know, when you say, oh, this old thing, that's not an appropriate way to introduce your elderly relative. That's vaguely related to the episode tonight. All right, one more. Also vaguely related to the episode tonight. I want to start a new diet.
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B
What diet do you want to start, Matt?
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A
Well, I was going to start a new diet, but then I realized I have way too much on my plate right now.
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B
Bravo. That one's pret shameful.
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C
The Curbsiders podcast is for entertainment, education and information purposes only, and the topics discussed should not be used solely diagnosed to treat, cure or prevent any diseases or conditions. Furthermore, the views and statements expressed on this podcast are solely those of the hosts and should not be interpreted to reflect official policy or position of any entity aside from possibly cash, like moral hospital and affiliate outreach programs, if indeed there are any. In fact, there are none. Pretty much. We aren't responsible if you screw up. You should always do your own homework and let us know when we're working.
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A
Welcome back to the curbsiders. I'm Dr. Matthew Frank Waddo here America's primary care physician, Dr. Paul Nelson Williams. He is actually doing some primary care related duties tonight. But on tonight's episode, we are gonna discuss some recent articles from the Digest that piqued our interest. We have with us two fantastic guests, Doctors Nora Taranto and Doctors Laura Glick. Nora, Laura, how are you?
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B
So good. How are you on this fine May evening?
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A
Look, I live for the Digest. Lara, you've been on. Is this your fourth now? Third or fourth?
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D
Something like that. It's getting up there.
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A
Yeah. All right. You're now a regular.
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D
She's a regular. Yeah, she's a pro.
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A
You're now a regular on the show.
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D
I know exactly what I'm doing.
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A
Yes, I would agree. Before we get into the topics, I'll remind the audience that on the Curbsiders, we try to do expert interviews to bring you clinical pearls and practice changing knowledge. Tonight, our experts will be us three, and we'll do our best to fill that role, talking through these articles, talking about whether or not they'll be practice changing, and a reminder that this and most episodes will be available for CME credit for all health professionals through VCUhealthcurbsiders.vcuhealth.org and you can now get access to quarterly bundled CME through our patreon@patreon.com curbsiders and with that, let's get to our first article. Nora, did you have a chance to pour over the lipid guidelines? As a practicing oncologist, I'm sure it's very relevant to what you're doing on a day to day basis.
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B
I always make sure to read every single guideline, try to really dive into the strength of recommendation for, you know, recommendation 4. 3. 2.4 so that I'm up to date,
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D
you know, all the initial articles to make sure that you've gone back and double checked me too.
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A
There's a lot of sections and subsections. Lara, as a hospitalist, I'm sure you're looking at cholesterol once in a while, but probably not micromanaging the numbers like Paul and I usually do. But appreciate your commentary on this as well. So this is the 2026 ACCAH guideline on lipid management. We wanted to just highlight this. We do have a full episode on this plan, but we wanted to just give at least a peek into, you know, what, what's coming here. I thought it was interesting that the editorial that accompanied this by Blumenthal and Morris already talked about that there was this trial that came out after the guidelines were published or like as they were being published that they didn't have a chance to include. This was the Vesalius CV trial, which was of evolocumab in high risk people. And just kind of looking at like whether or not these were people at like high risk for MI, but without prior MI or stroke. And they basically found that they had a significant risk reduction by lowering their ldl. And the reason I'm mentioning this is because these guidelines have this weird like known ASCVD with you know, very at very high risk or not at very high risk. And this, the guideline authors are like, oh, next time we update it, we're just gonna have just one, like if someone has known ascvd, we're just gonna lump them into one group because this trial already has sort of debunked that. Nora, I thought that was an interesting thing. I don't know. The oncology guidelines have this living update as well, but that's a New thing.
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B
Yeah, it is kind of interesting. And I mean, I think it just supports the, like, general gestalt of the guidelines of just pushing. Pushing the numbers lower and lower and lower. And I think this trial kind of does that. But it is a kind of nuanced approach to these guidelines because we think of them as the document that exists until the next set of guidelines, but data comes out, like, two days after guidelines are published. And so how do you actually incorporate that and how do you actually share that kind of practice changing update with the world? It's an interesting kind of communications question as well.
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A
And guidelines are like guardrails for us. They're not, like, you don't have to 100% follow them. They're suggestions. And to some extent, they protect us and also just help make it so we don't have to read hundreds of articles and, like, be an expert on every single thing. But to define ASCVD just because it'll. We'll mention it. Basically, atherosclerotic cardiovascular disease in the guidelines is defined as, like, acute coronary syndrome, MI angina, arterial revascularization, stroke, TIA, or peripheral arterial disease. So basically, you know, like, they've had, like, clinical. They have clinical, like, atherosclerosis. And I think when you look at the guidelines, like, most patients, if they have atherosclerotic cardiovascular disease, these new guidelines are really pushing for. Most people are gonna have enough risk factors of one kind or another to push their LDL down to less than 55. And this new concept that we talked about back in December on our lipid episode is this non. It's not a new concept, but it's an older concept that we're now, like, kind of giving more upfront play to the non HDL cholesterol, which is your total cholesterol minus HDL. So basically, whatever your LDL goal is, your non HDL goal is, like, 30 points higher. So for anyone with established cardiovascular disease, you could push their LDL to 55 or less and their total cholesterol to 85 or less. Laura, what do you think about those targets based on, you know, the conversation about cost and feasibility? I know you had some comments.
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D
Yeah, I mean, I think that these guidelines are a huge shift in preventive cardiology. I think we're focusing on earlier and also more individualized and really more aggressive prevention. It is. It's interesting because I do worry about how realistic some of the recommendations are going to be for patients and providers, especially when it comes to cost and access. So there Is, you know, the new guidelines place an increasing emphasis on things like coronary artery calcium scoring as a tool. But these scans are often not fully covered by insurance. And I think the same goes for tests like apolipoprotein B and lipoprotein A and some of these medications. Is that my hope is that the insurance coverage and access will improve as the tests become more routine. But I do worry about the feasibility of implementing some of these guideline recommendations.
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B
And the guidelines kind of recommend pretty broad, they make pretty broad statements about patients should have this test at least once in life or at least once after age 19 or things like that. And kind of how that's actually going to play out especially, I mean our electronic medical records are becoming more and more shared. But is that actually going to be borne out as a single test or is this going to be something that kind of patients just end up getting their cholesterol checked every year like happens in a lot of primary care.
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A
Yeah, patients do like to, I mean cholesterol can be a little bit volatile, but for a lot of people, like if it's been the same five years in a row, unless there's been a major change in their health or lifestyle, it's probably going to be the same that 6 year. I think these new targets of like less than 55 for LDL and less than 85 for non HDL are hard to hit even on a max like high dose statin. So it's really you're talking about like statin plus ezetimibe or statin plus PCSK9 inhibitor. And then the guidelines mention adding bempedoic acid or inclisiran as other agents if they can't tolerate statins or if you can't get them there with just what we Talked with the PCSK9 alone or a statin alone. So definitely there's a little bit of obstacles. I think in the US it's much more realistic but also still depends on your practice setting.
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D
But it also is interesting because you're adding pill burden right when you keep adding all these medications. And I think it's a risk benefit analysis. But what you don't want is to add so many pills that patients aren't taking them.
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A
Yeah. So we talked about this with our guest and he's part of writing the guidelines, our guest back in December. And this CPR framework basically talking about you calculate a 10 year risk with the prevent score. You then personalize it kind of looking at people's family history and any other blood biomarkers. You have their LP apob? Do they have a prior calcium score? Sometimes a calcium score can reclassify somebody from a lower risk into intermediate or high risk. That's still a little controversial. You'll see articles written that it's not as good at reclassifying as we think, but it's out there. And a lot of people are coming in requesting them now or just getting them on their own because the cost is between, I would say, $75 and $300 out of pocket. So a lot of people can just afford that and they will just get them. I am seeing a lot of them come across my desk as a primary care doctor. And what's even more alarming is people are. It's coming across my desk and it was like two years ago they got it and it was over. Their calcium score was over 100, which is in the moderately high category. And which would. That should prompt you to be like, being more aggressive about lipid management. And these people, no one's even mentioned it to them. And they are not on therapy. So I do think, like, if you're going to get it, at least use the test. And you mentioned apob lp. I will tell the audience in my practice, I am ordering those already. I haven't had too much issue with cost. And if you just put elevated LP as the reason for ordering it, it's usually covered by most insurances. And for apob, I've just been ordering that along with a lipid panel. And some of the labs have it just kind of lumped in with the regular lipid panel now. So it's. It's not too bad.
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D
What about with coronary artery calcium scans?
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A
That is just. I just tell patients to plan for out of pocket. And I have. I think it's probably going to be covered by insurance eventually. Now that, like, because it's not that expensive and it is in guidelines now, but I mostly just been telling people you're going to pay out of pocket. And then it just. There's no. If it does get covered, it's like a pleasant surprise. So that's kind of what I've been doing. We could discuss this forever. There's just so many. There's so many nooks and crannies to this, which is why we want to have a full episode on this, and I promise we will. The only other thing that I wanted to mention, and we'll put this in the show notes because we've talked about the keto CTA study a couple times. This is where you have These, it's a very niche thing, but it's out there. And I think it's being misinterpreted by like most of our population with high cholesterol is also metabolically unhealthy or they just have like they were born with high cholesterol. And we know people born with really high cholesterol that maintain that over the long term are at high risk for, you know, premature cardiovascular disease. But there are some people who basically are born with normal cholesterol or not super elevated cholesterol and then they adopt a like high fat ketogenic diet for maybe because of food allergies or because of the way, you know, they're however they want to look, whatever they want their body fat to be. And these people have LDLs that go through the roof and total cholesterol through the roof. And now there's some evidence this guy Nick Norowitz writes about it and recently published an article about it. How he, for seven years his total cholesterol has been above 700, his LDL has been above 500. I think his APOB has been in the three hundreds. All that is astronomically high. And he had a coronary CTA with the AI overreading and he had zero plaque volume. So basically he was someone who started with a relatively normal cholesterol panel, went on a high fat diet because of inflammatory bowel disease and had these astronomical levels maintained for seven years very publicly and now has, has proven that he did not develop coronary disease. So I think that means there's something there. He explains in his post, basically his body is just, it's so high because his body is using fat as fuel. And he talks about how he like if he eats Oreo cookies, he proves that his LDL comes back down because then it's, you know, it doesn't need such high fat around because he's now got carbohydrate for fuel. So it's interesting. But if your patient tells you they think they're Nick Norowitz and can get away with a LDL of like 300 and no consequences, I would be highly skeptical that they have that same very specific background. So I'm just mentioning it. It's kind of niche, but it's out there on the Internet and TikTok and whatnot. And I think people. It's prime for misunderstanding.
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B
It probably does. That's a good point. The kind of balance of fat, high fat, high cholesterol diet and probably comes, comes at a loss of the high carb which we also know, kind of causes all sorts of problems. So there, there is probably something to that. And yeah, people, people ask about this stuff all the time. And it's, it's a good thing to be kind of thoughtful about how you're thinking about the specifics of the patient in front of you.
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A
I think most people cannot maintain that discipline. And it's the worst of both worlds. They're eating like a terrible high carb, high refined carbohydrate and refined sugar and high fat diet. And they think like, oh, fat is fine. Because I heard this guy, Nick Norowitz say fat is good for you. And the way he's using it as his primary fuel source, it seems to be safe. But he's like very strict. And this is like, I just know people are not going to be able to sustain that. So I'm just fascinated by that.
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E
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A
Nora, we should move on to another topic. Not really Related. Hard to find out how this is related. This is maybe the first time we've had like a press release as a lead, as, like a lead hot take on a digest episode. But why are we covering a press release?
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B
Yeah, I think we're covering it because it is already in the news. It's been in the New York Times and a number of other media coverage sites over the last month. And people are excited about it and I think intrigued. But we have to keep in mind that we don't have all the data yet. And this is in my space in the oncology space, and focuses on pancreatic cancer and specifically metastatic or advanced pancreatic cancer. So this press release focused on a drug from Revolution Medicine, which is a drug development company in oncology, among other things. And press release focused on this drug, duraxonrecib, rolls off the tongue there in metastatic pancreatic cancer. This drug is a KRAS inhibitor. It covers multiple different mutations in kras. And KRAS is a pathway that is mutated in the majority of pancreatic cancers. It's also mutated in other cancers as well. And there are a number of different mutations that are present in pancreatic cancer. There have been other KRAS inhibitors in the past, but they've targeted very specific mutations, like one specific one in particular. So those drugs you may or may not have heard of, Sotorasib, Atagrasib, kind of the Rasib, is the KRAS inhibitor. And this drug actually covers them all and also inhibits the wild type, the unmutated KRAs. And so it blocks the KRAS pathway, which is activated in pancreatic cancers in a number of different ways. It's an oral drug. It's a pill that patients take once a day. And this press release got a lot of traction in the press and is going to be covered and discussed in detail the results of it at asco, the big clinical oncology conference, in a couple weeks, because they reported a significant improvement, almost a doubling in overall survival with this drug, Diraxon Recip, compared to standard of care physician's choice chemotherapy for patients who had already had at least one line of therapy for metastatic pancreatic cancer. So this is not first line. This is after the study, which is called Rasalute 302. It's a phase 3 clinical trial, studied this drug, Diraxon Recib, in patients with metastatic pancreatic cancer who had already had at least one line of therapy. It appears to be a positive study. And not only was this an improvement in survival and progression free survival and overall survival, which is what we look for in these trials. But it was a significant improvement. It was around a doubling in overall survival, which in oncology is pretty rare to find agents that do that. Especially in pancreatic cancer, which is a really hard to treat type of cancer, where overall survival is. Is quite guarded for patients like around a year for most patients who are diagnosed with metastatic pancreatic cancer.
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A
Can I make a comment?
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B
Yeah.
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A
They use the term RAS addicted. And the first time they used it, I thought it was like a typo or something or just like. And then I. Then they used it like three times in there. Is that what they were saying? That because ras is like an on switch, that these cancers get almost like addicted to, just like multiplying through that pathway. And then if you shut it off, that's how it works. But that's a term I've never heard that before.
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B
I mean, the kind of thinking behind that is exactly what you just said, which is that the pathway is the driving force of the cancer. Growing, replicating, developing resistance. Even these pathways have so many different components to them. Upstream, downstream, in the middle. And so if, if you can imagine for pancreatic cancer, which is particularly RAS addicted, if we're using that phrase, you can block one thing, but when the cancer evolves, it may develop resistance downstream. And even just blocking one thing, there are going to be other isoforms of the proteins of interest. And so blocking one specific piece of it doesn't tend to be quite as effective as these new types of drugs. This drug, Dereck Sonrisit is it targets multiple forms of the proteins, both mutant forms and wild types. So it kind of hits all of these different frames of the protein. And it also hits the active state, which has been something that has been really challenging to target historically. And so often these drugs, these KRAS inhibitors, would historically target the off state, but as soon as you get one on protein, you kind of can't shut it off with these drugs.
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A
Laura, what did you think about this?
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D
Yeah, I mean, I think it's really exciting. I mean, I think there's. We may be starting to see the first major breakthrough in metastatic pancreatic cancer in a long time. I'm joining NOR in the oncology world as oncology hospitalists. And so I've talked to a few colleagues about this. And I think the reaction to Derek's onrazib has been kind of a mix of genuine excitement and also a little bit of cautious optimism. I think the Data are incredible. You know, it's amazing that the reported median overall survival nearly doubled in this group in patients with previously treated metastatic pancreatic cancer, because as Nora said, it's a disease where. But really incremental gains are much more typical. I think my initial thoughts are that this may represent the latest paradigm shift from the non specific chemotherapy toward precision oncology in the pancreatic cancer world, paralleling some of the earlier revolutions in cancer treatment like the EGFR inhibitors in lung cancer and BRAF inhibitors in melanoma. I'm interested to hear your thoughts, Nora. I don't think diraxonazib will be the endpoint. I think it's more likely and I'm hopeful that it will be kind of the beginning of a completely new era in pancreatic cancer treatment and trying to figure out where it fits in the algorithm. But I'm interested to hear what you think.
- [25:17]
B
Yeah, I think that that's likely the case. And there are a lot of other clinical trials ongoing through many different drug companies that are making many different KRAS inhibitors that target different forms, different, and then also other targets in pancreatic cancer and in other cancers. And there are a lot of open questions right now. Does this drug work better in patients who have mutated disease or does it really work across all comers? Most of the patients in this trial, I believe had mutated pathways in their KRAS pathways. And we don't know how that kind of split out between the wild type patients and the KRAS mutated patients. We also don't know where in the order of treatments this is going to land. The study was in the second line here, or at least previously treated. And there are ongoing studies right now looking at this drug in the first line setting. So that's before patients have had chemo and then also in combination with chemo. We don't know whether it will be better with or without chemo. I like the idea of sequentially using these drugs, but we're going to have to under. We're going to have to test that does it actually work better by itself or does it work better in combination? And I will say the one thing in terms of thinking about combination therapy here, in addition to needing to ask the question about whether combination therapy is better than single agent, just this drug is. The toxicities are worth noting here with the drug that skin toxicities are probably the most notable. They are on target toxic effects. So this is like a known side effect from KRAS inhibition and they may correlate with response to therapy. Anecdotally, I will say a lot of oncologists say actually my patients who get the worst skin rashes tend to remain on these drugs for longer, often at lower doses because they need to have dose modifications. But we're learning a lot about how to manage those side effects. And this makes the idea of combining it with standard chemotherapy, which is what we use right now for standard of care, pancreatic cancer, that's with taxanes and with full fear Knox, those sorts of drugs. The idea of combining chemo with this drug that also has toxicities that may be a lot for patients to handle. So it's going to be a toxicity and efficacy question.
- [28:10]
D
Yeah, I think the big question is looking at the data set. Right. Like that's, that's going to be really exciting because I think, you know, before we move forward and you know, obviously this is really exciting news, but I think that the key is going to be in the data and it'll be very interesting to see what that has to say.
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A
To channel Rahul, we need to see like the CONSORT diagram how many patients, you know, how highly selected was this, how was the blinding? And I would, what were the baseline characteristics? Was it like super sick group that got like their standard chemo and then this super.
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D
The comparison group will be interesting.
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A
But the other thing I just want to point out, doubling survival is great. It's six months difference. Right. Six and a half months difference, which is not nothing if you're at the, if it's like you'll be dead in six months or you'll live an extra six and a half months, you know, that's, that's not, that is a big deal. But it was not like this is not a cure. This is like an, like an incremental benefit, but a very significant one. It's not.
- [29:06]
D
Yeah, but I think compared to some of the other, I mean I certainly, certainly important to consider that too. But I think in the grand scheme of where, you know, the small increments that we have in something like metastatic pancreatic cancer, this is actually quite significant and I think it brings a lot of hope too. But it is true that it's not a cure.
- [29:24]
B
Yeah. And I will say the one other thing that I think is I mentioned earlier but is worth just thinking about here is it's not a chemotherapy. And so I think patient, this is really appealing to patients to have an option, whether it's after chemotherapy or before chemotherapy that doesn't have them hooked up to a pump. And in the infusion center every however many days. And so I will say just like, from, like from a physical and kind of mental perspective, that is like, a huge difference for patients just to be able to bear, like, they're living their normal lives kind of with these sorts of agents.
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A
That's great. That's a great point. Okay, let's go on to GLP1 agonists, which are, I guess, becoming one of the favorite pills in the country.
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D
But what's an episode without talking about GLP1s?
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A
I've just been talking about them all the time because I get asked about them all the time, and it's an area where there's a lot of movement. So semaglutide, which is, you know, you can use it for diabetes, you can use it for weight management, it comes in pills. Now, we covered that recently. Now, There is a 7.2mg dose that's FDA approved. So normally the pens only went up to 2.4 milligrams. We knew there had been trials going up to 7.2 milligrams. I'm not sure if they didn't approve that dose because the side effects get so high when you get to that dose. But they saw about an extra 3% weight loss in people that were on 2.4 milligrams versus 7.2 milligrams. So you can go, you know, you jump right from the 2.4 milligram pen to the 7.2 milligram pen is what was done in trials. And you might get an extra 3% weight loss or if someone's responding, but not quite as much as you want. It's a reasonable thing to do. We mentioned this before. Dysesthesia. I've seen it once clinically. I thought it was just like a idiosyncratic thing that happened to this patient on semaglutide, but at the highest doses, so the 25 milligrams and up of the oral semaglutide, or the 2.4 and up of the injectable, you do see dysesthesia. And at this 7.2 milligram dose, almost one in five patients reported dysesthesia. And I was trying to look up. I put some resources in the show notes, but there was a dermatology letter to the editor writing about. They're cataloging some of these and they're seeing alopecia. The dysesthesia is definitely more common than alopecia. But then there's also been some reports of Some more nasty stuff like pemphigoid and things. So we'll see how much of that pans out. It's an association, not a causation, but look out for that. Any comments, questions? We have more GLP1 stuff to cover but Nora or Laura, any comments or questions about that?
- [32:33]
B
I'm always just very grateful to hear how you all are using these drugs and the updates in what's approved and available. Just because I do feel like even in my oncology clinic these are coming up all the time, patients are asking constantly whether they can be on them at the same time as their chemotherapy and or targeted therapy. And so I do think knowing what side effects are common with these drugs and especially at the different doses is actually really helpful for me me Is
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D
your one of those medications?
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A
Can I ask your response to that before we go to Laura? Are you? I'm sure it's very nuanced, but it's not like a hard no, I imagine,
- [33:15]
B
but no and I will say so. I work primarily in the breast cancer space and a lot of the drugs that we use in breast cancer actually have side effects like have effects on the metabolic profile of our patients. And so we are learning more by the day, by the month about how GLP agonists work in these patients. But oftentimes we will have patients who some of their most bothersome side effects are slowed metabolism, kind of various other effects like that. And so I actually think these can be really helpful for patients in those cases, obviously chemo where kind of weight changes are going to be dramatically shifting, nausea like side effects that are overlapping. I tend to discourage patients from using them in those moments. But otherwise, especially in the kind of survivorship and surveillance space, totally
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A
Laura in the hospital we're going to talk about the perioperative GLP1 use. But what have you seen done perioperatively for patients on these?
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D
It's interesting. I've seen so many different preferences and I feel like the preferences are very dependent on the specific procedure, the specific anesthesiologist and you know, the duration of how long these medications are held very widely. And so it'll be interesting to, you know, talk about, talk about this upcoming study. But I do feel like this is a conversation that has led to lots of unplanned canceled procedures. And I think the question is, is, you know, what's safe? And I'm looking forward to talking a little bit more about it because I have seen such variation.
- [35:01]
A
So the 2025 multi society perioperative guidance on GLP1 receptor agonists. They have what they say is if someone's on a GLP1 receptor agonist and they don't have any, like, significant GI symptoms, then you can continue it without interruption. This is before this study. I'm just kind of laying the landscape. And then basically they're saying you should fast From Solids for 24 hours before your procedure, and clear liquids are okay. And then there's a little bit more nuance in there for, like, how long? Up until the procedure, you can have clear liquids, like four to eight hours. But then if they have significant GI symptoms, then it says delay surgery and refer to prescribing physician for diet and medication modification, which is, I guess, where I would come in as the prescribing clinician. So kind of that's where we're at before this. And this is a study from JAMA Internal Medicine. It appeared May 2026 by Ahmed et al. And they looked at whether or not continuing GLP1 agonists and GIP agonists before upper endoscopy is going to cause this primary composite outcome or not. And this was the Oculus randomized clinical trial, which is, I'm sure the acronym there would make Paul angry. So this study was a randomized trial of 60 adults taking a stable dose of GLP1 or GLP1 Gipsy. They had to be on it for at least one month. And it was done at two different sites of Cleveland Clinic. And they were undergoing elective endoscopy, plus or minus colonoscopy. And essentially what they found is they actually stopped this early, after there was supposed to be 120 patients enrolled, but they stopped after they enrolled 60 patients because they found that the residual gastric volume was high in a significant number of patients in the group who continued their agent compared to people who had stopped the agent, basically skipping one dose and having seven to 13 days since their last dose when they went in there. So the primary outcome, and then I'll take your questions, was they were looking for either significant residual gastric volume, which meant the gastric contents were so much that they precluded endoscopic examination, or required premature termination of the procedure. And then the rest of the composite outcome was like, did the patient require intubation? Did they have an aspiration event? Or did they need to be, like, admitted to the hospital?
- [37:53]
E
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- [39:19]
A
So Lara, what did you think about this and the findings?
- [39:23]
D
Yeah, I mean, I think it's a super interesting article. I think my biggest question is does this increased residual gastric volume actually translate into a clinically meaningful outcome? It certainly found that continuing these GLP1 and GIP agonists before the upper endoscopy significantly increased the residual gastric contents. But despite the retained gastric contents, the increase in retained gastric contents, there was no cases of unplanned aspiration events, intubations or hospitalizations. So it does make me wonder, are we sort of treating a surrogate, a surrogate endpoint or are we actually preventing something that causes real harm?
- [40:02]
A
Yeah. Yeah. I mean, Nora, what did you think about this?
- [40:09]
B
I totally agree with what Laura was just saying that I do kind of wonder about the composite endpoint here that obviously noting that procedures and procedural delays do affect length of hospitalization do have kind of financial toxicity to patients and a number of other potential toxicities. So canceling a procedure, delaying a procedure is not nothing but, but clinically I agree that there weren't really any any differences in clinical events between the two groups. I was also really interested in the the clear liquid diet component. That was fascinating the the study and how that seemed to kind of abrogate the differences between the two groups. So if patients were getting an endoscopy with a colonoscopy and they therefore had to do a clear liquid diet for the Day before, there did not seem to be any differences in this clinical, in the, in the surrogate endpoint between the two groups. And so it does make me wonder whether that is a useful piece of information to know. And for patients who maybe it's going to be really hard for some reason to, to skip a dose or kind of hard to coordinate, maybe that's, that's a useful tool though, yet again, that's, that's a hard diet to stand by for patients as well. So, so there are kind of benefits and drawbacks to all.
- [41:43]
D
But I think it is interesting to consider because, you know, there are real concerns related to this and including the cancellation of procedures and also just worsening glycemic control. And I think the other thing that's interesting is there's some like, you know, it's, I think there's probably some confusion that it leads to for patients and clinicians about, you know, when to hold, how long to hold. And these medications do have a long half life. So it's not like we're holding one to two days if we're doing it. And I think kind of on top of that, another question is really, how long do patients need to hold the medications for? Does it need to be a full 7 to 12, 13 days? Can we do a few days? And so I think that would be an interesting aspect to look at too, because holding these medications for some people for 12, 13 days will make a difference.
- [42:31]
B
And will they go back on to them? Is I suppose, a kind of follow up question.
- [42:35]
A
Yeah, I think to tell the audience about just the significance of this, I mean, the residual gastric volume in patients who skipped a dose, there was about 3% of patients overall had some residual gastric volume versus 25% in those who continued therapy. So it's like a 22% absolute difference between the two groups. And then as Nora was saying, if you just look at the group that had an EGD only, which is really like these are people who could have been on clear liquids up to just a couple hours before the procedure. The difference was 5% in the group that discontinued, that skipped a dose versus 46.7%. So a 41% difference, absolute difference in this occurring in the group that just went for egd. And as Nora said, if someone for colonoscopy, the standard instruction is like clear liquids the day before your colonoscopy. So when people were getting both procedures, as you said, I think where this is going to, I think we're just going to have to tell People going for upper endoscopy, if they're on these clear liquids for 24 hours before, that's what I would do.
- [43:55]
B
I feel like that's where we're going with it. Right.
- [43:57]
A
If you don't want your procedure canceled, you know, and that's kind of what the algorithm in that guideline. Regardless of symptoms. That's what that guideline said. It said you should hold for 24 hours, they should be on clear liquids. And then you just have to decide how close to surgery do you stop clear liquids. But usually people say two hours, but it looks like they said the 2025 multi society guidelines said four to eight hours before surgery you should stop clear liquids. So you know, I think that's probably for now a safe way to go and we'll probably get more data on this. And it is. Even though, even though it's not showing that people are being hospitalized or having aspiration events. I think the fact that like if you get a procedure canceled, it's like such a painful experience. I think, you know, you take a day off work, whatever to get a procedure and then it's canceled. I think it's just better for everyone if you're just safe about this. So I give this like a 3 out of 5 on a scale of 5 being the best. But I think it's interesting. Definitely we'll be practice changing the way I have this discussion with people.
- [45:14]
B
Can I ask you guys one question about this? I don't know the answer to this. So I noticed that in the two arms there were slightly different proportions of tirzepatide and like the different agents, the GLP one versus glp. Do we know if there are any physiologic differences in gastric emptying across the agents? Do you guys?
- [45:38]
A
I do not know offhand someone might know that answer. I will say that as far as GI symptoms go, it does seem like there's less symptoms with the like tirzepatide then semaglutide, which are the two that I'm primarily prescribing right now. Okay, so something about the dual peptide seems to be better tolerated by people. But that's more anecdotal I would say. I don't know that it actually amounts to like if you were to do gastric emptying testing, that'd be different.
- [46:12]
D
I also heard there's kind of new medications in the pipeline that are called Triple GS that also include glucagon. So that'll also change the landscape. It'll be interesting to See what?
- [46:23]
A
Yeah, Retta. I, I heard, I heard a cool person call it retta. It's apparently like that, like in the Internet community, they, they, because ratatrutide is hard to say. They say they call it retta. But yeah, it's a, it's a triple agonist and it's like 25 to 33% like weight loss, you know.
- [46:45]
B
Wow.
- [46:46]
A
So it's like, it's like a step up, you know, each of these generations is getting better. It seems like it still has the same GI side effects, but I think it's, we're probably going to start getting like the phase three trials done later this year. Like they're ongoing and I think people are already buying that from peptide websites as a research use only chemical and just kind of diying the dosing. I tell patients not to do that, as you might imagine.
- [47:18]
D
Interesting.
- [47:19]
A
Wow. Yeah.
- [47:21]
B
Wild world.
- [47:22]
A
It's a wild world. Okay, well, speaking of something a little more tame, you know, this is not the wild world. This is levothyroxine deprescribing. We love deprescribing on this show. We actually, we even have a geriatric focused series like within the show now, which, and you know, the geriatricians love deprescribing. Lara, tell us about this study you reviewed.
- [47:48]
D
Yeah, for sure. So the next study we're going to discuss, very exciting study about levothyroxine, which is one of the most commonly prescribed medications. I know that. I'm sure all of us have had patients that have been on levothyroxine and it's one of those medications that we see all the time. And usually once patients start it, they sort of continue it indefinitely. But many patients are started on levothyroxine based on mild or subtle clinical thyroid abnormalities that are often transient. And at the same time, we know that too much thyroid hormone, especially in these older adults, can have real consequences. This study was recently published in jama and it's thought to answer the question, can levothyroxine be safely discontinued in adults age 60 years or older? It was an open label prospective study conducted in The Netherlands included 370 adults, all age 60 or older, and all patients who were taking a stable dose of levothyroxine dose less than 150 micrograms per day for at least one year and had a thyroid stimulating hormone or TSH level less than 10. And so these participants underwent a structured stepwise dose reduction protocol with close monitoring of thyroid functions. Researchers actually found that over one quarter of the participants were able to stop levothyroxine at one year while maintaining a TSH less than 10 and a free T4 within reference range without any worsening quality of life. And these success rates were substantially higher in patients taking lower doses of levothyroxine. And actually, over 63% of patients that were taking 50 micrograms or less successfully discontinued the medication at the year mark. So I would love to stop there and hear what your thoughts are on the study and what your takeaways were.
- [49:40]
A
Well, they. They excluded people. I just want to make sure they excluded people that had, like, a total thyroidectomy. Right. Because that, like, there's certain conditions where, like, it's like, a permanent. You would not expect recovery of thyroid function. So I think they did a good job of that. Yeah.
- [49:55]
D
They excluded people that were taking high dose of levothyroxine to above 150 micrograms, had a history of any thyroidectomy, or like a radioactive iodine treatment, congenital hypothyroidism, all kind of what you would think would make sense to be excluded on that front. And also separately from the thyroid patients with dementia, life expectancy under six months. So there was significant exclusion criteria.
- [50:21]
A
Nora, did you have any major thoughts on this? I definitely have some thoughts, but I will defer to you.
- [50:28]
B
No, I thought it was an interesting, interesting study about a medication that I, as an oncologist, have really no idea what to do with and rarely, rarely want to touch. So it actually was very useful to see that some patients can successfully come off of this medication that I think of as, like, a lifelong replacement medication for most patients. But it seems that that is not the case for all patients. Yet again, noting that these are, like, selected patients and that this will not apply to all patients, and that even among the patients who wanted to do this, not all of them actually were able to. So I think that's actually an important kind of flip side to the fact that, like, around a quarter of patients were able to, is that three quarters of them weren't. A lot of them came down on their dose, which was very nice to see. And I do think, like, not that I'm going to be titrating this medication for my patients, but it did provide a kind of nice framework for how one might actually try to get patients off of kind of even higher doses, not just the lowest of the low. So I think it was a nice study that kind of provides proof of principle for some patients, but I just don't know how widely applicable it is.
- [51:52]
A
This I can say being in primary care, you see a bunch of people and you're like, why are you on thyroid hormone? They're like, well, a couple of years ago, you know, someone. Someone just told me I should take it. And then you look back and they had one TSH that was 5.5 and someone started them on like 25 or 50 micrograms or. And they're on a low dose. And you just really wonder like, does that person really need it? You know, So I think obviously the person who's had their thyroid removed or destroyed, they're gonna need replacement. But there are these people out there. And one of the things that I just wanted to highlight and there I highlighted an article from it's circs in 2007. I put the link in the show notes. There's some tables in there and like, as you go up in age, the percentage of people with a TSH that's above 4.5 goes up. And it. And they also have a graph that shows like, basically the normal distribution of TSH by age. And as your age goes up, that normal distribution, like shifts to the right. Meaning, like the average TSH is higher as the age goes up and there's more people at these like higher TSH values. So you might. I think what's happening is a lot of people between, with a TSH between 5 and 10 are getting thrown on like low dose levothyroxine because they're like, oh, I'm a little constipated and I feel a little fatigued. And someone's like, oh, let's check your thyroid. Oh, it's 5.5. I guess we'll just put you on it and see what happens. But it is not like the safest thing. It's not good for your bones, it's not good for the heart, can increase your risk for arrhythmias. So I think we really have to have a high threshold to start it in that person, like that older adult that has like these very like just vague symptoms and like a slightly high tsh. So I think that's probably who they were finding. They were kind of like working backwards and taking those people off. And so like 25% of people in this study were probably that person I just described. So that's my take on it is like we shouldn't have to be deprescribing if people were appropriately prescribing.
- [54:02]
B
Are there in guidelines for hypothyroidism, like the recheck that we often do in. You know, I'M thinking of heme, heme rechecks for like APLs, things like that. But are.
- [54:16]
D
Yeah.
- [54:17]
B
Is there kind of that like second test in any guideline that we know of? I don't, I don't know off the top of my head. I'm just curious.
- [54:25]
D
Well, I think some of the, some of the trouble with, and maybe resistance with deprescribing is that there aren't really good clinical guidelines related to how, when, who to deprescribe levothyroxine. And so I think that that is also contribute some of this prescription inertia or prescribing inertia where once they're on it, they don't have any side effects. There's kind of some, you know, it's just easy to keep, keep them on the medication. And there really aren't good guidelines in terms of recheck. I actually don't know about that, but I know that there aren't great guidelines in terms of deprescribing.
- [55:01]
A
So for the audience, I would just say this was like an open label, relatively small study. I don't think you should just start trying to pull every single person on your panel off their levothyroxine. But you should, I would say consider if someone has a really weird story about why they're on it and you know, they're on a very low dose and you never, you can't find any like biomarker that really suggests they strongly need it, that might be the person to try this in. But you would really need to closely follow how they're feeling and follow their, their leave, you know, their TSH every six to eight weeks, something like that. That's what I would do if I was trying to deprescribe for somebody.
- [55:46]
D
So, yeah, I think that's kind of the big takeaway. It'll be interesting to see how practice changing this is. I think what you're saying that we may see patients on low dose levothyroxine increasingly undergo some type of deprescribing trials. And at the same time, I do wonder if providers will be a little bit more reluctant to discontinue levothyroxine, especially without clear guidelines and if patients are on a stable dose and patients get attached to their medication. So I think there's a lot of this good data, especially in people on lower doses and older. And there's real consequences and side effects to having too much hormone replacement. But it'll be interesting to see how often we actually see this in practice.
- [56:29]
A
Mobeen is working on another. On a thyroid episode. So maybe this will be one of our cases, like the deprescribing or the inappropriate prescription in subclinical hypothyroidism.
- [56:41]
B
I feel like it could happen. It so easily happens. And, you know. Yeah, it just. I'm sure it's like a significant proportion of patients on thyroid replacement.
- [56:55]
D
Yeah. I mean, I think the fact that over 60, like, 63 point something percent on 50 micrograms or less, like, that's a huge proportion of people that were off of it at one year.
- [57:05]
B
Yeah.
- [57:05]
A
Yeah. Well, look, you know, in primary care, one of the great joys we have is trying to figure out why someone's on this wacky medication regimen and then trying to decide if we can stop something or not. Laura, that's kind of in the inpatient side. That also is, like, there's a lot of wacky regimens you come up against, and you're trying to figure out why they're on it and decide if you should rock the boat or not. So you probably feel my pain a little bit.
- [57:29]
D
I feel on both sides, and I definitely feel that. Continue and talk to your PCP about that. Maybe consider. I had somebody that was on, like, 35 micrograms, and. And I was like, you know, maybe talk to your PCP about whether you need levothyroxine, but I'll keep you on it for now.
- [57:47]
A
Well, if anyone's taking care of my patients, you can message me, call me, and I'd be happy to talk it out with you. All right. Well, I think this has been a great show, but at some point, it has to end, so we should get to an outro. And, Nora, would you read Paul's part? Sure.
- [58:13]
B
I can't replace him, but I'll. I'll try my best to read this. This has been another episode of the Curbsiders, bringing you a little knowledge food for your brain hole.
- [58:26]
A
Laura, you gonna say it? No.
- [58:30]
D
Long. Yummy, yummy. I just. I told you, you guys have to tell me when to say yummy.
- [58:34]
B
Perfect. Oh, so good.
- [58:38]
D
Yummy, yummy, yummy.
- [58:41]
B
Still hungry for more? Join our Patreon and get all episodes ad free, plus twice monthly bonus episodes at patreon.com curbsiders you can find show notes@thecurbsiders.com and sign up for our mailing list to get our weekly show notes in your inbox, including, including our Curbsiders Digest, recapping the latest practice, changing articles, guidelines, and news in internal medicine.
- [59:05]
A
And we're committed to high value, practice, changing knowledge and we want your feedback so you can email us@askcurbsidersgmail.com reminder that this and most episodes are available for CME credit for all health professionals through VCU healthurbsiders.vcuhealth.org you can also get quarterly CME through VCU Health by signing up at@patreon.com curbsiders Special thanks to our writers and producers for this episode, Doctors Nora Toronto and Lara Glick, and to our whole Curbsiders team. Our technical production is done by Podpaste. Elizabeth Proto does our social media, Jen Watto runs our Patreon, Krista Chumanchu moderates our Discord. Stuart Brigham composed our theme music and with all that, until next time, I've been Dr. Matthew Frank Waddle I've been Dr. Nora Toronto.
- [59:51]
D
I've been Dr. Laura Glick.
- [59:53]
A
Thank you and good night.
- [60:08]
F
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