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The Curbsiders Internal Medicine Podcast
#517 DIGEST: Weight regain after weight loss medications, GLP1/GIP comparisons, valacyclovir for Alzheimer’s, and nudges to encourage deprescribing
01:05:41
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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. You know, Paul, I once had a dream I was floating in an ocean of orange soda.
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B
Tell me more. I can get there. I know I can. But we only have so much time. Actually, it was a fantasy.
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A
It was a fantasy. Yes, Paul, yes.
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B
All right, now I'm ready for the show.
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A
You're so good at guessing these.
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C
The Curbsiders podcast is for entertainment, education
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and information purposes only.
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And the topics discussed should not be
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used solely to diagnose, treat, cure or prevent any diseases or conditions.
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Furthermore, the views and statements expressed on this podcast are solely those of those and should not be interpreted to reflect official policy or position of any entity aside from possibly cash, like moral anaphyll outreach programs, if indeed there are any.
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B
In fact, there are none.
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C
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 Watto, here with my great friend and America's primary care physician, pun expert, Dr. Paul Nelson Williams. Hey, Paul.
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B
Hey, Nat. How are you?
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A
Good. You've guessed a couple lately. That's really. I got to get more clever with these or the Internet has to get more clever when it serves me these puns is what I should say. Paul, we are doing a digest episode tonight where we're going to run down some recent articles, news stories that we thought were important for the audience to know about. And we have two people with us who are, I'll say, smarter than me. Paul, you can judge if they're smarter than you. But Paul, I'm happy to have them here before we introduce them. What is that we do on Curbsiders?
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B
Sure, Matt. So typically we are the internal. Well, we're always the internal medicine podcast, but we usually use expert interviews between clinical roles and practice changing knowledge. This is one of our episodes that's a little bit different. So we do have experts with us, but those experts are not us, Matt. But we're actually talking about articles that were featured in the Curbsiders Digest, which is we'll talk about in the outro is the monthly newsletter, Dr. Toronto Indeed. That will update us on things that have been happening in literature, exciting news updates. They have appetizers, main courses, all kinds of ways to sort of learn about what's happening in research and in the literature. It's just another way to keep current. So, Matt, I'll let you introduce our two co hosts for the episode, and we can roll right into this.
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A
Sure. So we have with us, of course, Dr. Nora Taranto, who's our editor in chief of the Digest and has been for. I don't know, Nora, has it been going on four years now? Maybe. Maybe five years. I don't even remember.
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D
It has. Yeah. It's been longer than I thought about, actually. It's been a bit.
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A
Yeah.
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D
About half my time with you guys.
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A
Crazy enough time for you to go through fellowship and become an attending physician.
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D
Wild.
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A
Yeah. All right. And then also with us from the Digest is Alex Chatoff. Alex. Did I say your last name right? I can't remember if it's Chatoff. Chaitoff. Something else, I guess. Wrong. Most of the time, I would even
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C
answer to hey, you. But yes, Chatoff was perfect.
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A
Okay. All right.
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B
Well, the main reason I pointed to you, by the way,
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A
Alex, you do some great work for the Digest. I really enjoy your critical appraisal, and I'm glad that you're going to get to showcase that tonight. First up, this is a little bit of a combination. We're going to talk about an article, but we're also going to just kind of do a quick rundown of the GLP1s. We talked about them, actually, on Hotcakes last month. But the landscape is. Is just growing so much here, Paul. And are you keeping up with all the latest and greatest with, like, what's coming out with?
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B
Oh, absolutely, yeah.
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A
In the GLP1.
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B
Yeah. I'm just waiting with bated breath for more drugs that will be denied for my patients. I'm excited to hear about new opportunities.
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D
Yeah.
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A
So maybe I'll actually start with this. So right now, I think most people know that what most people are getting prescribed is semaglutide, which is available either injection or tablets.
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D
And.
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A
And then tirzepatide, which is available by injection. But there are a number of drugs in the pipeline, so. Orfor. Paul, this one. Can you say this one? Orforglipron? You think I said that right?
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B
I think it's perfect. Yeah. No notes.
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A
That is a small molecule, GLP1. It's a tablet and it's in phase three trials. They're looking at it for type 2 diabetes and obesity. It might be approved in 2026 for type 2 diabetes at least, but as of right now, I don't think it's available in the US or it is not available yet in the US the other one which has made waves in the peptide industry. Have you ever heard of retatrutide?
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B
You did this to yourself, buddy. No, I've not. I've not heard of this.
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A
Nora or Alex, have you heard of this?
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D
No. What is the peptide industry?
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A
Okay, so the peptide industry, like GLP1s are peptides, right? But there are all these peptides that are out there in these kind of boutique wellness clinics. They're basically research use only chemicals that have shown promise in these small, mostly animal studies or just there's some basic science mechanism that's really sexy that gets people real excited. BPC157 is one of the most popular ones. And it's like, I think they cut the Achilles tendons of rats and then they injected BPC157 into their stomachs and apparently their tendons reattach, hatched and we're healed. So people are taking that as like a recovery agent. And so they ship over these research, use only chemicals. A compounding pharmacy blesses them somehow and then they're safe to give to people. And there's just like all these different peptides and they cost hundreds of dollars a month. Then you get them from hopefully a pharmacy that is doing things safely and then you take them. But retatrutide is actually, it's in that industry already and it's being used, but it is also being officially studied and should be, I believe, will be officially approved. There's been phase three trials, the triumph trials. And this has not only GLP1, not only GIP, it also has glucagon in it. So it's like a triple agonist.
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B
We're just gonna be eating pancreases by the end of this.
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A
Like that's gonna be maybe, maybe Paul. But it is in the trials. And the timeline for this being approved is unclear as of my research. But it's boasting nearly 30% weight loss. And some people I saw even had like 35% weight loss. And it looks like they might even be going for like back and knee pain approval and things. I don't know how that works other than just the weight loss. But you know, they're really, they're kind of potentially going for all of it. Like mace make, you know, masled everything. Paul. All the organ, all the organs. So that's one to watch. And then the other, the only other one that I wanted to mention, that people may or may not have heard of. And this has been published. Cogrillentide mixed with semaglutide. Paul, so this is an amylin analog. Remember there was pramlintide, that's like an amylin analog that they use for diabetes. So this is another drug in that class, I guess. And they're mixing it with semaglutide. It has some weight loss. Amylin itself can act on the brain and it can help with satiety as well. So that drug is also being studied. It's in phase three trials. It might be approved for either weight loss and, or diabetes in 2026. So that's another one that I'm, I'm watching Cagrolinatide and semaglutide and I apologize to the audience for not probably pronouncing those correctly. Paul, will you be prescribing these?
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B
Oh yeah, absolutely. Try and stop me. They all sound very promising and good,
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A
but there are at least eight other compounds that I'm not mentioning that are in the pipeline as well. And they're just basically all mixes of these various peptides and mechanisms. So we'll see what happens there. But something that we're covering that I think will happen much sooner is tirzepatide in the SURPASS CVOT. So the SURPASS cardiovascular outcomes trial appeared in December 2025 New England Journal and the top line result here is that they looked at tirzepatide versus dulaglutide in patients with type 2 diabetes and known cardiovascular disease and they proved that it was non inferior. So I think we're going to be getting an approval for tirzepatide for patients with type 2 diabetes and known cardiovascular disease to reduce major adverse cardiac events. Paul, what do you think about all these various indications that they're going for for this? Do you think this is just a class effect? Does it matter? Should we be, you know, using all this money to study these things?
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B
You're stacking questions, wado? Yeah, no, I think we talked a little bit before we started recording. I do think this is probably largely class effect. I'm sure there's hand wavy pleiotropic stuff at play too. But it does seem in the study that I'll be talking about a lot of the benefit was proportionate to the weight loss that came with these things. So I think the more options we have, the better the various indication shuffle. It just feels more important to the FDA and insurance companies and things than it does in terms of how I actually Prescribe. Fundamentally how I prescribe these medications is based on what I can actually get covered by the patient's insurance. And the indications seem to be a soft target at best. Like you never quite know how it's going to shake out and you have to trial and error and fight the fight and whatever I can get approved is what I end up prescribing because they all seem to have benefit to some extent or another.
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A
Alex or Nora, any comments, questions about this topic or this trial?
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C
I think the similarly certainly do prescribe will continue to prescribe these to patients. The one thing that it just tells you because I'm a nitpicker, right, If I can find those curves, they converge too early in the survival curve analysis or too much loss follow up, I'm happy to comment on it. One thing that is, I think that the evidence both from the real world and these trials is really compelling, especially this one. But it is interesting that in these trials the dropout rates are substantially lower than what we see in real life as far as people continuing these meds. So in this trial it looks like the discontinuation rate with a median follow up of four years was in the 20% range. And we know that 12 month discontinuation rate in real life is closer to 50%. And so it's not to say the drugs don't work. I'm convinced they do. But if there's a no do gap, if we know they work and we can't implement it, whether that's because of insurance or that's because in real life we don't get as good a side effect control because the clinicians delivering it don't have the same time a trial might to troubleshoot and keep people on meds. We're not going to see the population health benefits that we might otherwise. And so I would love to see a move from just proving that they work really well to proving how do we get the folks that really need them to be able to stay on them. And some of that's obviously cost, but there's probably other things as well.
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A
Yeah, that's a great point. That is a really great point. I think you just mentioned a lot of reasons. Sometimes it's just they lost access to the medication, sometimes it's side effects. A lot of the times I talk to patients and they weren't, there was no counseling, they were just prescribed the medication. No one told them that they might get nauseous or constipated or various other things that could happen. And that's why? So with the appropriate counseling, I think you'll probably get better than a 50%, you know, or still taking them after a year. But Nora, how about you? Anything?
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D
I was pleasantly kind of reassured by the fact that a lot of these patients obviously having diabetes are on a bunch of different agents. And it seemed like while there were some differences between the two arms in terms of like how much insulin patients were on in each. In each arm, the there, there didn't seem to be signals towards like increased toxicity with either of the agents with SGLT2 inhibitors or insulin kind of in particular. So just kind of as these are a little bit newer, I think it's somewhat reassuring that you can combine them with. With other agents that are kind of goal directed for cardiac and diabetes conditions. Yeah, that honestly that was my main
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A
other note as far as getting these covered, Paul, which you kind of brought up. The one thing that I will say, I think the hardest indication to get them covered for is just straight up obesity. Like tirzepatide has an approval for a moderate to severe sleep apnea, so you could potentially get it covered for that. And semaglutide has this cardiovascular risk reduction indication, so you could try to get it covered for that. Like that usually gives you a little bit more of a bargaining chip than just obesity. So kind of playing up the comorbidities on your applications is what seems to get it covered. Diabetes is the easiest.
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B
If I seem especially nihilistic, it's because of the January formulary shift and then having to try to get prior authorizations through for sleep apnea. And then the questions for the prior authorization include, you know, are they followed by a sleep specialist? Yeah, of course, if they're still sleepy. Have they tried like stimulant therapy, like modafinil? It gets to a very great like it makes like you truly. It needs to be filled up by a pulmonologist if you want to fill that completely. And because we're all type A maniacs, like I think a lot of us are not willing to just kind of like fudge it just to get the medication approved. So it's. There are structural barriers that are obviously very intentionally being thrown up. So while I'm excited with this class of medications, all potential benefits they offer, I think there's systemic barriers nevertheless is, I guess the larger point, I'll say without getting myself in too much trouble.
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A
Yeah.
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D
One fun thing I did note in the adverse effects, the adverse effects table, they did list as one of the adverse effects of note at serious atrial fibrillation, which I don't know if any of you noticed that, but I was. I didn't know what to make of that.
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A
I kind of glossed over it because there weren't. There weren't a lot of events, were there? How many?
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D
No, no, there were like six. Six percent of. Yeah, so it was not a high, high rate event, but I was just like, huh, that's an interesting.
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A
Yeah. Well, these people had known cardiovascular disease, so. And you know, they're. The BMI was elevated. You know, like people. There are people that I. It's not shocking that they. They had afib events, I guess.
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B
Mr. Smith, I'm afraid you have atrial fibrillation. Doc, how bad is it? I'm afraid it's serious atrial fibrillation. The worst kind.
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A
Is that a New Yorker cartoon, Paul?
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B
Yeah, it could be.
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A
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- [18:59]
B
Oh, masterful segue. So that leads us into our second article. This was covered by, I believe by Alyssa Mancini in the Digest. This is west et al and BMJ looking at weight regain after cessation of medication for weight management. It was a systemic review and meta analysis. So basically, guys, the background, obesity is a widespread relapsing disease. It's a chronic disease. There have been lots of enthusiasm for weight loss medications, hence the many episodes and hotcake topics about those things. And the authors mentioned that the cardiometabolic benefits are largely proportional to the degree of weight loss that you see. But as Alex mentioned, real world observational studies showed about half of patients stopped GLP1 agents, at least within 12 months of them being prescribed to them. So the authors thought, well, we should probably figure out what happens to these patients after they stop these medications. So it's a systemic review, meta analysis. They included studies that looked at basically any medication that has or has ever been approved for weight loss. So the list is kind of funny. So there's Tirzepatide and semaglutide, but Orlistat made it in Phentermine, topiramates, lorcaserin, naltrexone, bupropion, some of the older stimulant medications. And their primary analysis was weight regain after discontinuation. And they also did pre specified subgroup analysis, looking at between the various classes.
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D
And.
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B
And there was also a secondary analysis that looked at the cardiometabolic changes. So things like changes in A1C blood pressure, total cholesterol after these medications were discontinued. So it included 37 studies that amounted to over 9,000 patients. 35 of them were randomized controlled trials. And most of the studies, the support that was given to the patients after these medications were discontinued was identical. So they also did pay some attention to what non medication support was offered to patients within these studies. So the top line stuff I will just say lined up with what we kind of knew already and that patients start gaining weight after they stop these medications. So on average about 4kg per month after cessation of any of them, but even more so with the newer incredent memetics.
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A
So things like 0.4, right? 0.4 kilograms per.
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B
Did I say 4 kilograms? Yeah, because that would be impressive. Yeah. 0.4 kilograms. Yeah, they ballooned up instantly. No. So thank you, Matt.
- [21:08]
A
Yeah, so 0.4 in the chocolate factory if you eat the wrong candy.
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B
Veruca solved it out of there. I think that was her. Yeah. So 0.4 kilograms per month. Thank you for clarifying of any of the medications. But even more so. So up to 0.8 kg for semaglutide tirzepatides of the world. And what they projected is that patients would return to their baseline weight about 1.7 years after discontinuation of these medications and even a little bit faster for the incretin mimetic specifically. So patients who stopped semaglutide or tirzepatide were actually achieved a return to their baseline body weight in a little shorter period of time. And the cardiometabolic parameters followed along with that. So patients had increases in their systolic and diastolic blood pressure, their A1C started to go back up, their cholesterol went back up as well. And that did not seem to be impacted by the behavioral support that was given while these patients were on the medications. So I'll pause there and just ask if this surprises anyone or if this is even consistent with what you've all seen in actual practice.
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A
Yeah, it is, Paul, and I would love to hear how you talk to people when they ask about this because this is One of those things where recently I've just had patients, when I start blood pressure meds or statins or weight loss drugs, they ask me when can I stop this medication? And usually with blood pressure meds, that's not really a thing. People just know just from seeing family members that you're gonna be on them for years and maybe if some major health thing happens, you stop them at some point. But how do you counsel people through that? Because this is a unique question to these drugs, I feel.
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B
Yeah, no, I agree with you and I think it' sthere are a couple questions there. I'm happy to answer. But I was looking this up because I was curious. In the accompanying editorials and even the discussion of the article, people mentioned that this 50% of patients stopping these medications within a year means that these might not be ideal for long term weight management. And I'm not quite sure I understand how you get to that point. Because if you look it up, about a half of patients stop their antihypertensives. And to your point, Matt, no one's saying, well, I guess that means we shouldn't prescribe high blood pressure medications. Long term. The framing is different and I don't quite understand why if we're framing obesity and its comorbid conditions as chronic conditions. So I think when I talk to patients, truly for me, my non expert opinion is this is an entire clinic visit unto itself, talking about the side effects, the contraindications. And I start by telling patients these are chronic medications. When you stop them, you regain the body weight. So this is not something where you lose ten pounds and you get to come off of them and you're done with it. They don't work that way. So if you're interested, you're going to be taking these for years and years unless they're real issues or you're okay with kind of regaining the weight. And many patients will kind of reverse course. There's a lot of understandable enthusiasm for these. I think lots and lots of people are interested in weight loss and appropriately so. But I don't think it's fully explained or discussed that these medications only work while you're taking them. So I think once you frame it that way, if patients still show interest, you might see much better adherence and sort of more consistency with weight loss. But that's just again, not an expert opinion and kind of theoretical at this point.
- [24:07]
A
Yeah, I tell patients, look, this is a chronic issue that you've dealt with. Most people that I'm putting on medications, especially if it's for weight loss. They've been dealing with a weight problem for multiple decades in many cases. And it's like you've tried lots of different things. This is already a chronic problem. So we're starting what is a chronic solution to this problem and you should plan to be taking this in the long term. Nora?
- [24:33]
D
Oh, I was, yeah, I was just thinking about how it was interesting the kind of comparisons they tried to make to the behavioral weight management programs. And yeah, I mean, I think the trends over time are slower in terms of the kind of weight regain in that population. Obviously they were doing it in a little bit of a. I think they called it an indirect way where they weren't using arms run like in the same trial per se. They were really using the historical data from prior analyses. But it did strike me that kind of to what you're saying, Matt, to get sustained weight loss in a behavioral program, I imagine that the behaviors are there and actually they looked at the, the behavior plus medication arms and they did not see that there was additional benefit to the behavior addition to medication management. And so that just goes to show like how difficult this can be and how the behaviors to succeed in this take a long time often if they actually happen. And therefore when you just stop a medication without actually using any of those, additionally, it's not going to have as long term of success.
- [26:02]
A
Yeah, I think there's all sorts of physiology working against people too. Just, you know, if you believe in like the set point where just like the body thinks it's starving and tries to slow the metabolism, make them feel hungry so that they get back to the other weight. But yeah, so we can tell people this. What was useful about this is we can say like, yeah, it looks like if you look at across studies, it looks like within two years you'll have gained back all the weight if you stop this. And a big part of that is going to come back in the first year once you stop the medication. Alex, any comments or any other thoughts on this?
- [26:40]
C
I really love the framing around the antihypertensives. We accept 50% discontinuation rates in other diseases, meaning we don't say that the medicines therefore are not good. We say we need to figure out better ways to improve adherence. And when these drugs are generic, you know, you can put this in your prediction book for, you know, five or ten years from now. We'll be saying the same thing here. It won't be, oh, they're not good meds. We'll be saying, we just have to increase adherence is my guess. Two things or one other thing that did jump out is I do wonder, I know now we've just seen a study, we've seen the studies of when you start them, then you see the studies. Now what happens when you stop them? I am curious. So like, are they just as effective for the person going on it the second time? Because while patients may stop it, I have no reason to believe they wouldn't be. But I'm not a physiologist in this area. But if a patient says I'm going to use this, I'm going to lose weight for a year and a half, for six months or a year, I gain that weight back, I really want to come off it. But then they go back on it again and say, okay, unfortunately that didn't work. I guess I'll just go back on it and it still works. Well, I think that's also another potential to me that's reasonable for patients is one year of risk of interruption for 10 years of use. If getting to come off of it and try keeps you on it, then going back on it long term, that may be something else to look at. So I don't know that we have that data yet. But to me, even if patients come off of the med and want to try coming off of it and say, listen, I don't want to use this forever, to me that's not a reason not to say, okay, we can try it. Let me let you know that you'd be in the minority if you can keep that weight off. But my hunch is that you can always go back on it if, if needed in the future.
- [28:24]
D
Yeah, I think I, I was thinking much the same with just the like trajectories and some of the figures of weight loss and kind of cardiometabolic biomarkers improving. And then you know that there was shorter follow up overall in these, in the, this kind of, this review and meta analysis. And so you don't actually see the numbers meeting where the started in a majority of them for the biomarkers. It's kind of predicted based on the trend. But so I do kind of wonder that presumably that time below the baseline or improved from the baseline is still getting a patient something.
- [29:03]
A
Yeah, anecdotally I have seen patients who came to me and had been on them and lost weight and want to go back on them. And a lot of the times they've, they've been off them for like three to six months because they lost access to it. And then we're Restarting it. And it seems like they are able to lose weight. Sometimes I'm switching them from like semaglutide to cerzepatide or something like that, but I don't have a reason to believe that it wouldn't work if you started a second time. I am curious to see what happens when people are on these for like 10 years or more. Are they going to become ineffective? Kind of the way that, like a, you know, gastric bypass, sometimes people will regain all the weight or a lot of the weight. So I don't know. I think that's to be determined. Paul, any final thoughts on this one?
- [29:54]
B
No, I'm glad the study was done. I think it's nice to have sort of concrete numbers to share with patients as we're having this informed discussion about the medication that they may or may not be starting, because I think it felt sort of vague before. So the fact that I can actually cite some actual real world data and some projections is very helpful to me. But nice article, strong work by the authors, et cetera, et cetera.
- [30:14]
A
Yeah. And I just want to say to people out there, just keep an open mind about these. I feel like there's so much moralizing about this and some people are embarrassed that they're on it or people are like the way that someone loses weight. If someone's had trouble losing weight for decades and then they're finally able to have success, I think we should be happy for them and they should be happy for themselves. And that is just a weird thing that I just see playing out where some people. People just feel a certain way about it and some people are open to it and some people aren't and they. Anyway, I don't have much more to say than that, Paul, but it's just. It's something that I've been noticing and people say things to me about it.
- [30:57]
B
I know. I agree with everything that you're saying. I think it's. The framing around these conversations is odd sometimes. I think that's very well said, Matt.
- [31:04]
A
Yeah. Back to the blood pressure thing. It's not like we would be like, oh, you cheated. Your blood pressure's only good because you took a medication that you needed. Like, you know, we should be happy that their blood pressure is controlled now.
- [31:17]
D
Yes.
- [31:18]
B
Yeah, absolutely.
- [31:19]
D
I mean, I do think. Yeah, I do think there's a lot of kind of probably background and like the history of stigmatization of. Of weight and all of that that goes into this and, and it being like a moral failing of some sort which it absolutely is not. If you can't. Can't do this yourself. You know, that's kind of the.
- [31:38]
A
It is no one's business how you lost the weight. If you don't want to tell, you
- [31:41]
D
don't have to disclose.
- [31:42]
A
It's just that you took. You don't have to disclose that your blood pressure is normal because you're taking a medication. Unless you're talking to your doctor, then you should tell them what medications you're taking. Well, that's enough on GLP1s for this episode. But, Nora, let's change gears completely. And are you going to be telling us about a trial called Velad? How are we pronouncing this in? Maybe we should have Paul rate this one.
- [32:09]
D
Yeah. So I was wondering how one pronounced this. I've been calling it valid in my head.
- [32:16]
A
Oh, that's good.
- [32:20]
D
Which is funny because we'll get to the top line results. So. But yeah, Paul, what do you think of that acronym for a trial name?
- [32:28]
B
It doesn't mean anything. Like it's. Again, it feels very low efficacy.
- [32:32]
D
It's Valacyclovir for Alzheimer.
- [32:35]
B
And tell me, what does the word VAL AD mean?
- [32:40]
D
That's a great question.
- [32:42]
B
And listen, and I'm especially disappointed because the ID doctors usually knock it out of the park like I think they usually do. Really?
- [32:47]
A
Portmanteau of valacy cyclovir and the acronym for Alzheimer's disease.
- [32:52]
B
Portmanteau is a word, Watto. Valad is not a word.
- [32:55]
A
I know. Well, maybe we're making a new word. Croissant wasn't a word before we combined croissant and donut.
- [33:04]
B
Paul, I. Nora, tell us more.
- [33:07]
D
This is the future. Yeah. So, to this trial with a fun name. This was just published by Devanand et Al in JAMA and covered by Dr. Beth Gasperlin in Digest 74. And this was a small randomized placebo controlled trial of patients with early Alzheimer's disease or mild cognitive impairment with positive Alzheimer's biomarkers. Looking at at valacyclovir versus placebo and the background for this. Why would we use this drug in Alzheimer's disease, you might wonder. Well, there has been a decent amount of observational data and studies that have been published over the last couple years looking at associations and finding associations between viral infections and an increased risk of Alzheimer's disease. This is both with herpes simplex virus or HSV, and varicella zoster or VZV or the virus that causes shingles. There have been a Couple different studies over the last few years that have shown varying levels of association with increased risk of Alzheimer's disease development in patients who have positive markers for prior viral infections. And there's been a decent amount of animal models cell in vitro that have also looked at actually the mechanism of HSV infection. It's a neurotropic virus, it infects nerves and then it can actually get into the brain through the nerves through retrograde transport I think is what the term is. If I am going back to neurobiology. There have been associations looking at specimens both in animal models and in autopsy studies of patients with Alzheimer's disease that have found CO located HSV particles and the pathogenic proteins that are associated with Alzheimer's. So amyloid and phosphorylated tau. And so those kind of biologic plausibility studies led to some animal studies looking at antiviral medications that seem to show some differences in accumulation of amyloid and the with phosphorylated tau in animals that received antiviral medications. And so now we came to the Velad study, valid study, however we want to say it, that was a small study looking at whether or not valacyclovir, which is an antiviral, could improve cognitive outcomes in patients with early Alzheimer's. Before I get to the study design more in depth, I'll just say this was a negative study. And so patients were randomized to either valacyclovir or placebo, and the patients randomized to valacyclovir actually had greater cognitive worsening than those assigned to placebo. Now, it was a small study and so before I get into the details, I'm curious whether anything jumped out to any of you about the top line results or kind of questions you would have about how one would design a study like this.
- [36:42]
A
Well, I just wanted Alex to comment on the rationale for even doing this study. And what are your thoughts in general about that?
- [36:52]
C
Yeah, I think on one hand I really like the, like this is the way it should be where we have an introduction that essentially says here's the basic science of why we think this could work. And then you move on to the epidemiology saying, look, and the epidemiology supports what we're seeing here. The one kind of like pause that would have made me think, well, maybe this actually wasn't going to be as likely to be positive. Even before we ran this trial was looking at the study they cite that shows starting this medication is associated with reduced likelihood of developing dementia. And essentially they looked at the study conducted in Taiwan of about 8,000 people and they looked at medication, they mentioned how they looked at medication for HSV infection was associated with decreased risk of dementia. And the hazard ratio they report is 0.09. And I went to the original study to make sure I wasn't just imagining it. But that would be a 90% reduction in the hazard of developing dementia if you start this medication. And when you see an estimate like that, you can essentially say this is probably biased in some way. And then they go on to cite several additional studies across multiple European countries that did not necessarily see an effect. And so I think that while there was great bio plausibility in the basic science and I love how they laid that out, I think I already began questioning the likelihood this was going to work when you looked at the epidemiology behind it, which wasn't necessarily there.
- [38:20]
A
Can I just make a follow up point to some of what we were talking about? I was mentioning peptide industry and that sort of thing. What happens online so much is you have a great basic science theory, people just fall in love with it and then they just jump oftentimes over any kind of actual trial to just like, let's just do this, let's just start. And then it just. Sometimes these things take hold and they're almost impossible to talk people out of most of the time. It's not dangerous stuff that they're doing necessarily. It's just kind of waste of money or distracting from other things that could be better for them.
- [39:00]
D
Yeah, I do, I feel like the question in the oncology space, I've heard just anecdotally like coming up more and more of like, how do you not know this will work? And I think that kind of relates to a lot of what you're referring to. It's like, how do you not know that giving me this despite no trial data will not help me? And I mean there's obviously a lot of, a lot of basis to that. Like there we are moving towards more of a personalized medicine approach. But, but yeah, I do, I do think there's.
- [39:35]
A
And my honest answer to people is I don't know. And I'm not going to claim that I know, but the influencer online who is very certain that they know what they're talking about, they just, they're overconfident like in, they're overconfident in the information, the way that they're giving you this information because they shouldn't be that confident if they understood how science actually works. That's kind of my answer to people.
- [40:00]
B
But I love the Air Bud proposal. There's nothing in the rule book that says a dog can't play basketball.
- [40:08]
C
Ain't no rule.
- [40:13]
B
Perfect logic.
- [40:14]
C
I completely agree. And I will say the one where it begins to I think when there's risk of harm, chemotherapy or an unregulated peptide that isn't necessarily being checked for purity or what have you, when it's something that is like the versus, what are you going to do? If somebody came and said, we have some evidence that the US Pointer trial came out and showed maybe some reduction in incidence, I mean, maybe small effects, but some reduction in incidence of dementia if you live a healthy lifestyle, get your blood pressure under control, keep your lipids under control, have social, meaningful social interactions. Because if somebody said I'm going to not care about my blood pressure, not care about diabetes, not try to live a healthy lifestyle, but I'll take Valcyclovir, then I would be like, hey, we have to worry oftentimes if the medicine is less harmful and there's not an either or, it's like, well, I'm just going to do it. In addition to things, I mean, I'm a little less hesitant to come down strongly, although it sounds like nor in this trial. Maybe the answer wasn't. Maybe it's not so benign.
- [41:17]
A
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- [44:15]
D
just to get into the details a little bit of this study. So the study enrolled 120 patients who were at three different memory clinics within the US and they had to have a clinical diagnosis of probable Alzheimer's or a diagnosis of mild cognitive impairment. With these positive positive biomarkers for Alzheimer's, they also had to have a positive HSV1 or 2 serum antibody test and the majority of those patients had IGG antibodies, so suggestive of prior infection as opposed to like very recent infection. And then a MMSE score of 18 to 28. And patients were randomized to either 4 grams per day of valacyclovir or placebo and then followed for I think over 78 weeks for outcomes and patients were 71 on average, majority female. Most patients actually did complete the trial and the primary outcome was looking at this least squares mean Change in the 11 item Alzheimer's disease Assessment Scale cognitive subscale score or the. I think it's ADAS Cognitive subscale.
- [45:29]
A
It's the 0 to 70 score.
- [45:31]
D
Yes, exactly. Higher scores indicate greater impairment and the change over that period of time was 10.9 in the valacyclovir group compared to 6.9 in the placebo group. A between group difference of just under 4. This suggested actually worse cognitive worsening in the valacyclovir group. They did note, and this was useful for me, that a difference of three points on this scale is considered a clinically meaningful difference, which was not something I you to this point.
- [46:04]
A
So they were meaningfully worse is what you're saying?
- [46:06]
D
They were meaningfully worse, not just statistically worse.
- [46:11]
A
Yeah, yeah.
- [46:12]
D
And they, they do posit. And this is kind of useful to know like that Valacyclovir, the dosing kind of for initial infection is usually 3 grams per day. And then I think in recurrent infection you can use 4 grams per day. But. But it is a higher dose over a longer period of time in El patients who are presumably on other medications and might be at increased risk of side effects. And you can have neurotoxicity with the medication. So I do wonder whether that is a component of what we're seeing kind of long term use of this medication that can, can cause, cause neurocognitive decline, is causing or may be causing neurocognitive decline.
- [46:59]
A
But I'm glad, I'm glad they looked at this because this could have been one of those things that's out there, you know, like patients, patients are like hoarding Valacyclovir and giving it to their parents with dementia or something like that. I think that's something.
- [47:14]
D
Yeah. I feel like there have been enough observational studies over the last several years that have come out and I think gotten a decent amount of press at least they seem like they've been covered by various media sources that I do wonder whether this is coming up. I don't know whether any of you have actually had people ask about it, but not yet.
- [47:37]
A
We should ask some of the geriatrics folks on our team because maybe they would have heard about this. But. No, but I think that this is, it's good to point to, I think. And the varicella zoster vaccine. Right. The zoster vaccine, reducing the risk of dementia. You know, maybe that's just reducing like another hit of neuroinflammation by preventing shingles. I think that's the proposed mechanism. So that seems a little more. Because, Alex, you were mentioning the IGM thing here, right? Like, the patients weren't actively having an infection. So you're just kind of throwing the Valacyclovir in there, hoping it's gonna kill latent virus.
- [48:23]
C
Yeah, it's. You know, I think bio, first of all, I should say, because I feel like I've said only negative things about why this was not going to be positive. But I actually think this is the kind of trial we should probably do more. And if you ask patients, my guess is if you polled patients said, what trial would you like to see? This is the kind of trial they'd say, I would love to see this. And so important disease a lot of people consider important. A medication that's generic would be affordable. Like, you know, I think so. Very thankful. Think this is a great study overall. But to your point, it's a medication that doesn't clear latent virus being given for people who mostly have latent virus. So I think that's another reason to kind of wonder and I also think another reason to wonder if this was the right population, because this was done by a. And maybe this explains the trial name run by memory. It looks like focused mostly in neurology and memory centers. If you look at the MMSE average in this trial, it's about 21. If you look at clarity AD, or you look at the Trailblaser trials for Donanemab and Lecumab, the new Alzheimer's antibodies, it's closer to 25 plus. And there's some signal in those trials that actually if you're close to mild cognitive impairment, those medications have more effect. So if we think that taking away the hits, the neuroinflammation, the plaques, whatever, something, but essentially intervening early is going to maybe have better effect. And once you've got the plaques, once the inflammation is there, trying to then act. That's another reason that this trial may have kind of been coming at it from behind the eight ball a little bit. They took, you could argue, a sicker population than the latest kind of Alzheimer drug trials. And so you wonder, is it a population choice? Maybe they repeat the trial in patients with better scores on the mmse. And look, and maybe there's something there. So. So I think great trial, but a lot of reasons to kind of maybe have thought it was going to be an uphill battle of showing, in effect,
- [50:22]
A
Noor, what about your bottom line for this one?
- [50:27]
D
I similarly really like this trial. I think it answered a question that I had been kind of thinking about. Not this specific study design, but I think, wondering kind of when this sort of study was going to be done. And so I do think it actually answers a very practical and important question that would be surprised if people aren't already getting some in some clinic settings just because dementia is such a tough, tough disease for families, kind of people are looking for, for anything and everything. And so I can imagine this will come up.
- [51:04]
A
Okay, well, with dementia, there's a lot of drugs. There's. I'm trying to. I'm trying to craft a brilliant transition here.
- [51:14]
B
I felt it.
- [51:17]
A
Look, Paul, if someone has dementia, there's a lot of drugs you don't want to be giving them. Let's say benzos, gabapentin, things like that. So, Alex, what should we do in that situation if people have a bloated medication list filled with things that might not be serving the patient anymore?
- [51:36]
C
Yeah, I appreciate this opportunity because while you guys are talking about getting all these patients on more medications, I'm just excited to get to present the other side of the coin here, getting people on less medication. And it's important to think about 129 million people in the United States have at least one chronic disease. By some estimates, treating chronic disease is about 90% of our health expenditures. Older adults are on increasingly more medications. Polypharmacy rates are rising quite quickly, about 3% per year in older adults. And this wouldn't be a problem if medicines were all good and no bad. But we know that there are millions of healthcare visits a year due to adverse medication events, whether that is just a side effect that needs to be checked in on, or somebody becoming lightheaded and falling, for example, and having a hip fracture. So there's been this growing movement, if you will, to start deprescribing. And there's several definitions in the literature about what exactly deprescribing is, but at its core, it is proactively removing a potentially harmful medication from generally an older adult's medication list before it has time to do harm, when the risk benefit profile of that medication no longer favors benefit. And that is where this randomized trial comes in and is trying to weigh in. And what Laufenberger et al wanted to look at is could they develop, using behavioral science, a nudge in the electronic health record to get clinicians to deprescribe High risk medications. And high risk medications in this case, and in many cases refer to benzodiazepines, highly anticholinergic medications, Z medications. And the way that they did this is they decided to run a cluster randomized trial. And so they first recruited physicians who had in the past prescribed some of these high risk medications to older adults. And they were randomizing them to one of three arms. Two of these are behavioral science informed arms. So the first one is a pre commitment arm. So these folks are going to see an electronic medical alert when they see a patient on benzodiazepines, for example. And it's going to say, hey, you should consider in the future deprescribing this medication for them. And we'll keep you updated. The next time they come in, we'll send you another alert. Make sure we try to get that medication off. So that's one pre commitment saying like, hey, you commit in the future that you're going to deprescribe this. The other one is boostering, essentially keeping the idea of deprescribing top of mind. And so if physicians randomized to this arm got an alert in the electronic medical record at the point of care saying, hey, you should deprescribe this. And if you choose not to deprescribe this benzo that this patient is on, we can definitely remind you next time, let's keep this top of mind. We can send you an inbox reminder to think about this in the future because we want it sitting there at the forefront or the third arm. Usual care did not get these alerts. And these physicians saw these alerts when they saw a patient who was on one of those high risk medication classes. So it wasn't for every patient being told, hey, don't take the patient off a benzo who's not on a benzo. It was only when they saw that patient with a benzo coming into their clinic prospectively. There were 201 physicians that were put into these three clusters and there were about 1,100 patients that these physicians saw over about 290 days on average. These folks were followed. What they found was that in the pre commitment and the boostering groups respectively, There was a 40% and a 26% increase in the likelihood of experiencing a deprescribing event compared with usual care. That means those people getting the boostering or the pre commitment. Excuse me, the pre commitment or the boostering, they were more likely to essentially not be on the medicine that they had previously been on that benzodiazepine or that antihistamine cholinergic medication if they saw the alert. And that's measured through the electronic medical record. So it's not necessarily that there was some button that was clicked that said discontinue the medicine, but it was either the medicine was just fell off and was not renewed, or that the clinician actually went in and said, taper this or stop this medicine. And so this is considered top line, certainly a positive study. That's a huge risk reduction. You can imagine a number needed to treat around 10 to 14, 10 to 14 of these alerts. And you're going to get one person off of one of these medicines, something of that nature. From that standpoint, I think it really shows the power of using behavioral science nudges, which is one takeaway that I had here, that we can get patients off of these high risk medications. I think the question this trial, and frankly much of the deprescribing literature at this point leaves still up to question is what is the actual benefit patients get from coming off of these meds? And this study is another one in a long line of deep prescribing trials from shedmeds to Optica to the Empower trial back in the early 2000 teens that show we can get patients off of these high risk medicines, but unfortunately have not clearly demonstrated that getting them offset medicines reduces their hospitalization risk or improves their quality of life by reducing pill burn.
- [56:49]
D
Yeah, I was, I. Did they have any kind of clinically positive outcomes in the study that of the ones they assessed as secondary endpoints? Because it seemed like there were none that were kind of significantly improved in either of the arms. And in fact they seemed like they had more pills prescribed in the actual nudge arms, or at least the boostering one.
- [57:18]
C
Yeah, that is exactly right. Essentially they looked at, for example, lorazepam milligram equivalents and there wasn't necessarily a difference between arms. But there may have been more pills prescribed potentially in the boostering arm compared with the usual care arm of just potentially inappropriate medications in general. Which does make you wonder, okay, if you say don't be on a benzo, but then you replace it with. With some other potentially inappropriate medication that has sedating effects, did you really get a win? Which is certainly something I think is reasonable to question, but do you think
- [57:52]
A
they should have made a. What would you like to see as a researcher? What would you like to see? Some sort of composite of falls, dizziness, fractures, things that could plausibly be related to these inappropriate drugs that Cause somnolence, dizziness, sedation or cognitive scores improving. Do you think that those. Do those trials exist or should they exist?
- [58:22]
C
They definitely should. I can never blame the researchers in this case because the fact is a drug trial is paid for by a drug maker who can power it to certain endpoints. It's going to be much harder to power these trials about taking medicines away using NIH funding or what have you, that is much smaller to get those clinical outcomes. So not a comment on, oh, they should have picked a different outcome. I think this is what we can do in this moment. And then there's kind of a leap to saying, and if they come off the medicines, maybe that's something good. I think two things, unfortunately. Most patients, we know this, we've looked and we know that most patients with a deprescribing opportunity also have a prescribing opportunity. They have high blood pressure, they have an elevated BMI and could qualify for a GLP1, they are depressed and may benefit from an antidepressant, et cetera. And so it's not, you know, it may not be as clear as if they have a deprescribing opportunity. That's what you should focus on. And I do think that that nuance is important to kind of consider. I think you'd want to see some sort of clinical outcome to put into the context of if I deprescribe versus using my visit to talk about antihypertensives, which is going to be better in this case. So in that sense I do think it is necessary to get those clinical outcomes. But I would settle for anything. I would settle for these studies, including surveys and just proving that coming off of a med actually improves quality of life. That pill burden matters because I would argue that a lot of these folks are on a lot of medicines and going from 7 meds to 6. Especially when one of those meds is not to treat chronic disease, but it's to treat symptoms of something. I could imagine a world where actually it's not necessarily helping folks or they miss that medicine in the end or they turn to something else to kind of replace what the benzo was for them. Maybe especially in states where cannabis is legal. I would love to see like did you use more non prescribed medicines to kind of replace the medicine that we deprescribed? I have no evidence of that. I'm not suggesting that's the case. But I think these are all really important things where we should all certainly if a medicine is futile and harmful, deprescribe it, no questions at all. But before we kind of prioritize deprescribing in the average patient who is otherwise coming in and has other things to address as well, I would love to see more evidence just to, to strengthen the reasoning for choosing to spend that entire visit on deprescribing unless it's patient driven and they say I want off medicines. Let's talk about it.
- [60:41]
A
Paul, are you against deprescribing?
- [60:44]
B
No, I am pro deprescribing. I think patients should be taken off of dangerous medications. I will say if I got an inbox message sent to me four weeks after I saw a patient saying hey, don't forget about that benzo, you would be talking me off a ledge or I would set myself on fire. Our attention is at such a premium. I get so many pop up messages, so many EHR alerts, many support messages. Every time I prescribe naloxone for a patient who's on an opioid, I get a warning saying those things don't work together. Which thanks. And that's kind of the point. And my point being is I don't. So this was done with EPIC and probably what I'm assuming is a fairly well supported system. I'm not sure that that approach is uniformly useful. I also think there is known literature that shows that frequent EHR pop ups and alerts create fatigue, foster burnout. And I just, I worry like Harrison. You know, there's Kurt Vonnegut wrote this story called Harrison Bergeron. Have you guys heard of it or read it?
- [61:37]
A
I don't know that one. No, I know.
- [61:39]
B
So it's set in this dystopian future and in order to make sure that there is equality all the way around, people with really great vision have wear glasses smeared with Vaseline and people with good hearing wear things over their ears and people are very strong wear weights and people who are smart get these headphones that just blast random things in their ears so that they can't complete a thought or actually finish a sentence. And I worry about. So I think about that all the time in medicine where I'm just getting these ER JR notifications and text messages and emails about application that I've never used in my entire life fighting for my attention. And I worry it's going to make me miss something else. So sure, maybe getting harassed with operant conditioning and punishment to deprescribe a medication might actually facilitate that outcome. But I do worry at what cost too. And I'm being serious. Mental health. And then the Other things that I'm also trying to take care of in the span of a visit. So. So I hate that this was an effective study because I do worry. It actually forwards this idea that EHR alerts are these really useful tools when in fact they make me want to not do primary care. So that's my only hesitation. I think we should deprescribe left and right. I love it as a concept. It's just how he got there that makes me a little bit queasy. So sorry for the rant.
- [62:45]
A
That's great. I feel like we need some special music to introduce that segment.
- [62:51]
B
I wouldn't.
- [62:55]
D
No, Paul, I had very much the same initial instinct with this like a visceral reaction to the nudges and just envisioning the pop ups that I get the reminder message, absolutely useless. They are.
- [63:11]
A
Paul, we need to end on a positive note. What's a positive? Give me something positive just in life. Yeah. I don't know, Paul. Come on, Paul, give us a pick of the week. Let's end on a spontaneous pick of the week. You weren't preparing anything.
- [63:28]
B
No, I will say I posted this on Blue sky and it's true. And I was actually referring to you specifically, Watto, in case people couldn't figure it out. But I never thought when I was in my wasted youth that my middle aged friendships would involve me texting pictures of sourdough bread to my friends and they would be replying, nice loaf, man. Like in all sincerity. So I made a really good sourdough. It is chili crisp with cheddar and scallions in a sourdough loaf that I didn't make grilled cheeses out of. That turned out really well. So that was my positive thing from the past weekend. So there you go. So go do that people. Make some sourdough.
- [63:59]
A
Make some sourdough bread. Yeah. All right, Paul, let's get to. Let's get to an outro
- [64:09]
D
Foreign
- [64:13]
B
this has been what an episode of the Curbsiders bringing you a little knowledge food for your brain hole.
- [64:20]
D
Yummy.
- [64:21]
B
Thank you. Still hungry for more? Join our Patreon and get all of our episodes ad free plus twice monthly bonus episodes at patreon.com curbsiders. You can find our show notes at the curbsiders.com and sign up for mailing list to get our weekly shownotes in your inbox. This includes our Curbsiders Digest represented so Wells night which recaps leaders, fact changing articles, guidelines and news and internal medicine
- [64:39]
A
and we're committed to high value, practice, changing knowledge and we want your feedback. So email us@askcurbsidersgmail.com a reminder that this and most episodes are available for CME credit for all health professionals through VCU health@curbsiders. VCU health.org A special thanks to our writers and producers for this episode, Dr. Alex Chatoff, Dr. Nora Toronto, Dr. Paul Williams, and to our whole Curbsiders team. Our technical production is done by the team at podpace, Elizabeth Proto does our social media, Jen Watto runs our Patreon, Chris the Chu Manchu moderates our Discord, and Stuart Brigham composed our theme music. And with all that, until next time, I've been Dr. Matthew Frank Waddo, I've
- [65:19]
D
been Dr. Nora Taranto, I've been Dr.
- [65:22]
B
Alex Chadoff and as always, remain Dr. Paul Nelson Williams. Thank you and goodbye.
- [65:43]
A
Day or night, VRBoCare is here 24? 7 to help make every part of your stay seamless. If anything comes up or you simply need a little guidance, support is ready
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C
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A
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- [65:59]
C
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A
We're here to help things run smoothly because a great trip starts with the right support. And hey, a good playlist doesn't hurt either. At Energy Trust of Oregon, we know it isn't easy the tremendous weight of today's operating costs working in cold, drafty spaces with inefficient heating systems or under
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C
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- [66:27]
A
But we also know how to help you upgrade those systems, lower those costs and meet the demands of your business
- [66:33]
C
with smart, energy efficient solutions. Find cash incentives@energytrust.org Energy Trust of Oregon
- [66:40]
A
More power to you.