Do Viagra and Cialis Help You Live Longer? What This Study Actually Found

Chapters:
00:00 - Introduction & AMA Catch-up 
00:28 - Does Fibromyalgia Affect Heart Health? 
01:43 - Advanced Markers for Inflammation (hsCRP, oxLDL) 
03:04 - Upcoming LIVE AMA Details 
03:48 - Is it Safe to Stop Lipitor for High Cholesterol? 
05:23 - The "700 Point Drop" in CAC Score: What is Plaque-X? 
07:51 - Testosterone & The FDA Black Box Warning Update 
08:33 - Deep Dive: Do Viagra and Cialis Impact Mortality? 
09:54 - Study Funding and Conflicts of Interest 
10:51 - How PDE5 Inhibitors Actually Work 
12:53 - Observational Studies vs. Clinical Trials 
14:41 - Understanding the Dataset (TriNetX) 
16:41 - How Patient Cohorts are Defined 
19:54 - Comparing Cialis vs. Viagra for Heart Benefits 
21:26 - Why Prostate Health Matters in This Research 
24:21 - Breaking Down the Five Key Outcomes 
26:30 - Statistical Matching: Making the Groups Fair 
30:03 - The Results: Mortality, Stroke, and Dementia Risk
33:57 - Absolute vs. Relative Risk Reduction 
37:29 - Tadalafil’s Half-Life Advantage 
39:18 - Crossing the Blood-Brain Barrier 
41:04 - Study Limitations: What We Might Have Missed 
42:24 - The "Partnership" Factor in Longevity Data 43:32 - Final Thoughts: Is it Time for a Label Change?

In this session, I'm diving into your questions from our last AMA and taking a deep look at a fascinating new study on PDE5 inhibitors like Cialis (tadalafil) and Viagra (sildenafil). We explore whether these medications could have a role in longevity, heart health, and even dementia prevention. I also address questions on fibromyalgia, stopping statins, and the latest on testosterone and cardiovascular risk.

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___________________________
🧬 About Dr. Lily Johnston
  
Dr. Johnston is a double board-certified vascular and general surgeon in San Diego, specializing in metabolic and cardiovascular prevention. She’s the founder of CorSight Health and a passionate advocate for reimagining how medicine approaches chronic disease.
  
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Transcript

SPEAKER_00 0:00

You guys showed up like a maze balls for our last Ask Me Anything, but there were some comments I didn't quite get to and some questions. We are gonna get after it here today. Stick around for the end for a deep dive into Cialis and its impact on mortality. If you're new here, I am Dr. Lily Johnston. I am a board-certified vascular surgeon and I specialize in cardiometabolic prevention. So hopefully you will never need me as a surgeon. Men's feet for women. I'm probably gonna need a little more information about that name, but says uh I have a tough one for you. If you have fibromyalgia, will it affect your cardiovascular health in the future? Any comment is appreciated. Thank you so much. Fibromyalgia, which of yes, of course, is a real disease, falls in the category of inflammation more broadly. And it's hard for me to know how much inflammation you're gonna have in the body with that. And sometimes even our measures like high sensitivity C reactive protein, which is the one I follow in your lab work, to measure your cardiac risk, because that is the particular one that has been very well documented in the scientific literature. Your HSCRP could be normal with fibromyalgia or it might be elevated. If it's normal, it doesn't mean you don't have inflammation, but it means that it's not detectable through that particular lab test. What we don't know is whether inflammation that's not reflected on a C-reactive protein is still relevant. I personally believe it probably is, but it just hasn't been very well tested unless it's interleukin 6 or some of the other more esoteric inflammatory measures that we don't check very often. You could also check things like oxidized LDL, LPPLA2, myeloperoxidase. There are a few other more advanced markers that could be checked that might or might not be elevated. Short answer, we don't really know. But the other thing I'll say is that patients who have chronic diseases of any kind, and fibromyalgia is certainly one, and chronic pain have in general increased chronic stress in the body. And we also know that people who have chronic stress for whatever reason, be that chronic disease, shift work, history of adverse childhood experiences or trauma, all have a higher risk for cardiovascular disease. That doesn't mean that you should freak out about it. It means we have to figure out how to help manage chronic stress. All of us have chronic stress in our environment and in our daily lives. We need to be able to adapt to that and find ways to increase our capacity to manage and deal with that stress, whether that is a mindfulness practice, exercise, time in the sunshine and in nature, all of these things are helpful and how you choose to incorporate it will impact your mental health and your physical health. So is there a direct link that's been well documented? No. Do I think it's relevant? Absolutely. Great question. Thanks for asking. Next up is uh KW8310. Damn, I missed it. When is the next session? All right, we are gonna do this monthly. So I'm trying to work on the end of the month. Our next one will be July 25th. Same time, same bat place, 2 p.m. Pacific, 5 p.m. Eastern. And P.S. Can I ask a question in advance? Time difference might make it difficult. Absolutely. There is always a link to the anonymous question form that we will have available. Look out for that in our shorts and in the community post prior to the session. And that will be the place for you to ask questions in advance. Thank you. And I look forward to seeing you there. All right. Next question. At Vito says, Is it safe to quit taking Lipitor for high cholesterol? I feel it does more harm than good. This is in the general bucket of medical advice, so I'm not giving medical advice. I need you to talk to your doctor about it. But there's a difference between I have high cholesterol a little bit, or I have really high cholesterol because I have a genetic problem and it's been with me since childhood. And I have high cholesterol and I have plaque. Those are three pretty different scenarios. And the question is what is the harm and what is the what is the possible benefit? So in primary prevention, meaning you don't have heart attack, stroke, or in my opinion, any plaque, then we can talk about whether the risks of lipid lowering therapy are really worth it to you. And could there be alternatives? And how high is your risk? Are we going to follow you for plaque? At that point, I think it's a reasonable conversation to have with your doctor. Calculate your 10 and 30, your risks, go image for plaque, get a CIMT or a CCTA or a coronary calcium score, whatever is available and makes the most sense to you and your clinical team, by all means, go get that checked out and then reassess. I don't disagree that there are side effects, and for some people, there is absolutely harm associated with these things. And there can be protection in very high-risk individuals or individuals who have plaques. So I can't answer that for you without knowing more, but I think it's always a decent question to ask your clinician. At Joghog asks, what treatment did the person say dropped their CAC score? 700 points. 52X treatment is what I heard. So this was something uh called plaque X, so like atherosclerotic plaque dash X. And I looked this up because I hadn't heard of it. It is an IV-based therapy, and it is phospholipids, but I don't know which ones, and they are derived from soy. So I don't know which fatty acids are involved in that. What I gathered from open evidence, because that is the tool that I use when I'm looking things up, is that there are interesting preclinical data, which means rodent or animal models or laboratory studies that haven't been used in patients. It is not a FDA-approved therapy. There are no patient, good patient studies that I could find. I didn't look very hard, to be clear, but um, again, because it's not an FDA-approved study or uh excuse me, treatment. So, and again, I'd be curious to see those test results. Um, a 700-point drop makes me curious, was the word that I used during the ask me anything. That is not common, and I typically tell people if they see any reduction in a coronary calcium score, I think it's probably measurement error within the test. 700 points is too high to be a measurement error, but it could, I don't know. Um, that is just not something that we see clinically ever happen. So either this is some brand new thing that is gonna take the world by storm or not. And um, but I don't know, right? I'm I'm open-minded enough to ask and be willing to take a look at all that data. I uh am not sure that that's something I would sign up for IV therapies, especially lipids, right? Is are they do they have omega-6s? Are they gonna be oxidized? Where did they come from? How long have they been there? How have they been stored? Are they sterile? I don't know. All of these are very interesting questions when you're talking about a non-FDA approved IV therapy. So I think caution is warranted. I didn't see anything that would make me want to talk about it or recommend it at any length, but that's what it was. And uh I saw it advertised in a number of different like medispas and IV therapy centers. So if you um want to check it out, that's where you will have to go to learn more about it. All right. And Jag Hog has a part two. Um, they're gonna go get their CIMT. That's awesome. Great job. And they say, I believe the FDA removed the cardiovascular black box warning from testosterone uh after the traverse trial. Yes, that is correct. The black box for cardiovascular risk was taken away after the traverse randomized control trial. There are still other warnings on testosterone therapy for risk of blood clots and risk for high red blood cell counts or something called erythrocytosis, too many red blood cells. So there are still several warnings on testosterone, but the black box for cardiovascular events was indeed taken away after the traverse trial. Thank you for uh reminding us of that. Okay, our last question is gonna be a little bit of a deep dive because we're gonna make that a thing, I guess. Um, and it is from Jan Humerick, who says you may have to look at that study benefits of tidalophil and sildenophil on mortality, cardiovascular disease, and dementia. This was in response to a question somebody had about the use of cialis or tadalophil for longevity and whether or not there are any signs that this is something we should be thinking about in a wellness and longevity space. So let's hop over to the paper and we will take a look. So this is the clinical research study published in the American Journal of Medicine. And I have skimmed this a little bit, but we're really gonna go through it and dive into it together because I haven't gone through it all. So I'm per usual, I'm going to skip the abstract here. Let's just look at the funding while we're on the first page and conflicts of interest, since that is always a hot topic. This research was supported by the Institute for Translational Sciences at the University of Texas Medical Branch, and by an award from the NIH. So I don't see any um industry funding here. The authors declare they have no known competing financial interests or personal relationships that would have influenced the work reported in this paper. Okay, great. So minimal conflicts, that's wonderful. And let's get right into it. So rather than read the whole introduction, I think I'll just start with this um clinical significance part here, since you can read that and it will sum it up for us. Tadalophil and Sildenophil, so that is Cialis and Viagra are the brand names. They are increasingly being prescribed for erectile dysfunction and lower urinary tract symptoms. So these are generally men who are experiencing frequent urination at night due to an enlarged prostate. They'll define that a little bit further in the paper, but that's what they mean. These drugs are associated with lower all-cause mortality, myocardial infarction or heart attack, cerebrovascular accidents or stroke, venous thromboemedy, deep vein blood clots, and dementia. And tadalophil is associated with significantly more cardiovascular benefits compared to sildenophyll and erectile dysfunction patients. Okay, so I was hoping that that was going to be all the introduction. Those last two bullet points are actually the findings of this study. Um, so let us actually go through and talk about what these drugs do and how they work, and then what they actually looked at in this paper and why I think it's an interesting finding, but perhaps not ready for total practice changing prime time just yet. So here in the second paragraph of the introduction, they say phospodiesterase 5 inhibitors such as tidalophyll and suldenophil have emerged as possible therapeutic agents for cardiovascular disease due to their ability to inhibit the degradation of cyclic GMP in smooth muscle, which leads to relaxation and improved blood flow. Essentially, what this does is prevent the breakdown of nitric oxide, which is that molecule that allows all of the relaxation. So you still have to produce enough of it, but at least we're stopping the body from breaking it down faster. These medications are FDA proof for treating erectile dysfunction, idiopathic pulmonary hypertension, so that is increased pressure in the pulmonary arteries, not what you measure at home with a blood pressure cuff, but actually the arteries between the heart and the lungs, and lower urinary tract symptoms associated with prostatic hyperplasia or an enlarged prostate gland. Research has explored the cardiovascular benefits with several smaller studies indicating that these medications may reduce cardiovascular complications and mortality in patients with erectile dysfunction. However, many of these studies focused on specific populations, such as those with type 2 diabetes. And they're going to go on and say evidence from animal models and retrospective studies hinted a cognitive benefit, but large-scale clinical trials are lacking. And in fact, there have not been any clinical trials for any of the endpoints or outcomes that we're talking about today. So heart attack, stroke, dementia, there's been no randomized controlled clinical trials, and that's important for reasons that we'll get into. All of the work that's been done has been observational, meaning these men are prescribed this for their own clinical reasons, and then we look retrospectively. But what you have to keep in mind with observational studies like this is that there can be very pronounced differences between people who are prescribed a drug and people who are not. And those differences could actually be the explanation for the difference in outcomes rather than the drug itself. We'll come back to that toward the end. So this longitudinal study aims to evaluate the effects of tidalophil and codenophyll on all cause mortality, the development of heart attack, stroke, deep vein blood clots, and dementia over a three-year follow-up period. Good, that's a nice medium-sized time window using a real-world large database. Database is always a little bit of a flag. It's a great tool, but it has some limitations. So we're gonna go through that. Okay, method section. Data collection and analysis was performed using the TriNetX database, a global health research network that is both HIPAA and GDPR compliant. I looked this up because I have seen more and more studies coming out of the TriNetX data set. It's a very interesting database because it has, like the company who runs it or the group that runs it has aggregated clinical data, and that's an important distinction because some of our big database studies are using billing data, and that, of course, is not quite as good as the clinical data. Um so these study organizers, the people that run TriNet, have looked at the back ends of all of the electronic medical records and various hospitals and medical systems around the world, or at least in the United States. Says it's global. Yeah, global. And brought in all of these patient records. And so they're attributable to individual patients. They're protected, though, so they're de-identified, meaning no patient information is part of this. But um it's it's got a lot of potential, but I don't have a deep sense for how granular the data are. Meaning, it says it's a clinical data set, but if I wanted to know the average blood pressure of these patients, that's a clinical data point. That is not a billing data point to like billing data point is a diagnosis of hypertension, right? You write that down on the chart and you put a code there, and that's how you have that record. Clinical data says I have blood pressure measurements from every time this patient or this, these million patients came to the office, and the average blood pressure in the group was 118 over 74, right? That would be a super healthy group of people, but that's what you'd like to know. I'm not sure based on how they are defining these cohorts, it's gonna, it sort of feels like it's more of a billing data set, but they say that it's there are clinical data. So I don't really know. All that to say, the granularity of the data, how specific we can be, and how reliable and um how much we trust these labels is really important as we think about this. The really nice thing about this data set is that it's enormous. We are gonna see how many patients they have in this study, but it's a lot, and that comes with some real power. So that's great. All right, and we're coming up to the next column here. And institution specialty physician services, community hospitals to provide de-identified electronic medical record data. So, what do they have in there? Diagnoses, procedures, medications, and lab values. So they don't have the blood pressures necessarily, but they say they have the laboratory values for over 50 million male patients within the United States. Cohort definition: who did they study? How did they break out the groups? How did they slice and dice these 50 million men to figure out who to study? The cohorts were developed based on ICD 10 codes. So these codes are the diagnosis codes that are assigned, and this is again sort of getting back to a billing data issue. Um, I can see a patient, for example, in my clinic who has a diagnosis of peripheral artery disease. And if I am being complete, I should document that that patient also has whatever other risk factors they may have, like a history of smoking and high blood pressure and inflammation and coronary artery disease, whatever else they may have, I should be assigning all of those diagnoses when I write my note. But if you have a really busy clinic day, you might not check all those boxes or take the time to put all of those things in. Now, maybe that patient has another doctor in the system and that doctor has, you know, done that due diligence and put all those things in. What I'm getting at is there's nothing that mandates that every little thing about a patient is written down at any given time, right? And patients know this because when you come to the doctor's office and I ask you, like, well, what medications are you on? Well, it's in my chart. And what medical history do you have? Well, it should all be in my chart. Maybe, maybe it's in there somewhere, um, but maybe it's not that easy for me to find. Maybe somebody wrote it down in a note but didn't actually click the box. I'm getting off track. This is just a uh, it's an important point about how you interpret these big database studies. And I say this as somebody who's done that research, and I was really excited to like have all of this data and all of this stuff. But, you know, the bigger the data set, the messier the data get. All right, let's keep moving. Primary analysis was conducted of men at least 40 years old with erectile dysfunction, without a history of cardiovascular disease, who were given any dose of tadalophil without any other similar drugs within six months, on or after the diagnosis, compared to a similar group who were not given any inhibitors. So this is men who were diagnosed with erectile dysfunction over the age of 40. Some got the drug, some did not. Study period was from 2004 to 2021. They are listing all of the different drugs that are available. Cardiovascular disease was defined as patients with a diagnosis of acute myocardial infarction, heart failure, cerebral infarction, which would be stroke, or unstable angina, which is chest pain. Interestingly, they don't list a diagnosis of coronary artery disease here or peripheral artery disease here. I consider all of that also cardiovascular disease, but these are much more acute type of presentations. So that's interesting. The same cohorts were compared for patients who received five milligrams of tadalophil within six months on or after the diagnosis. Okay. I'm gonna scroll through this here. I'm getting lost in the weeds. Subgroup analysis was performed comparing any dose of tadalophil without any other PDE5 versus any dose of cyldenophil. So they're just trying to distinguish is there any difference between Cialis and Viagra? They're gonna look at that as part of this study. Secondary analysis with lower urinary tract symptoms. So again, I mentioned that an enlarged prostate causes men to have to urinate multiple times, and the drugs are actually indicated to help with that. Why is that an important secondary endpoint? We have talked about the fact that erectile dysfunction can be a real canary in the coal mine for a diagnosis of artery disease, right? The plaque that builds up in the arteries can show itself, especially in men, as sexual dysfunction. And because blood flow is impeded getting to the groin, then you don't have the erection that you want. And therefore, that's a sign it could be a problem with your vascular supply, which could be a problem relating to plaque buildup. It's not always, but it's an important question to ask. However, an enlarged prostate has nothing to do with plaque in the arteries or any issues like that. So you could imagine that patients who are prescribed these medications for lower urinary tract symptoms and a big prostate, which is sometimes just a normal part of aging for men, might have very different risk factors and a very different clinical trajectory over time than men who have erectile dysfunction who get these medications, who may have more likely have plaque in their arteries. Okay, so they're gonna do that secondary analysis. Here is the flow sheet that they have. Again, they are starting with over 3 million, 3.7 million male patients with either erectile dysfunction or lower urinary tract symptoms. And they exclude a bunch. That's about half a million patients with erectile dysfunction. And it is about a million patients with lower urinary tract symptoms, most of whom do not get these medications, but um 30. 47,000 give or take are getting Cialis for that. And we have um about 180,000 patients getting Viagra, 80,000 patients getting Cialis, and 240 or so getting no drug for their erectile dysfunction. Okay, so you get a sense for how big this data set is, and there is a lot of power in big numbers. There's also a lot of power in big numbers, and what does that mean? It means sometimes it's really easy to detect stuff that isn't quite real or that is clinically not significant, uh, even though it's statistically significant. So we'll take a look and see what they find and whether we we agree that that's important or not. Okay, I'm gonna skim through here the rest of this method section. Same cohorts were compared. They're gonna list again all of these different codes to help us understand how they defined these cohorts. That is important. If anybody ever wanted to reproduce this finding, they would be able to go back and define the groups in the same way that the authors did. Uh, post hoc analysis was done to evaluate the impact of socioeconomic status and potential confounders relating to affordability and accessibility for the prescriptions. Uh, these are not terribly expensive medications, but you can imagine, again, patients with more means may be more likely to get these drugs than patients who are struggling to afford even the most basic of their daily needs and medications. So that's a worthwhile thing for the authors to look at. This was done exactly just to ensure that prescriptions for todalophil did not just represent higher socioeconomic status, which we also know is associated with improvements in mortality and morbidity. Outcomes. We examined five outcomes in the study: all cause mortality, heart attack or myocardial infarction, stroke, venous thromboembolism, so DVT, deep vein clots, or PE pulmonary embolisms, and dementia. Again, they don't specify what kind of dementia. I think they're gonna lump everything in there. So everything from vascular dementia, frontotemporal dementia, Alzheimer's dementia, all of those things. All right. Outcomes were measured from the day of the index event to three years after the index event. Okay, statistical analysis. So, as I mentioned, when you do these cohort studies, you are assuming that there is actually inherently something that is different about people who are prescribed the drug versus people who are not. Most of the statistical analysis uh work in these trials is trying to do your very best to make the patients look like they were randomized, which means, for example, let's say that the patients who get the medications are on average 10 years younger than patients who don't get the medications, right? They all have erectile dysfunction, but the group who's getting Cialis is on average 45. And the men who are not getting Cialis are on average 55. It's not fair to compare those two groups. The men who are younger are gonna do better than the men who are older in terms of heart attacks and strokes, right? That makes total sense. Part of the statistical work in these trials is rearranging these groups a little bit so that you make them look as much the same at baseline as possible. So they're gonna cherry pick men who are younger in the non-treated group and men who are older in the treated group, and they're gonna try to match them so that on average, at the baseline, the treated group and the untreated group are the same age. And the same goes for all of the other things that would matter at baseline, like diagnosis of hypertension, diagnosis of dyslipidemia, diagnosis of diabetes, all of those things. You're gonna make sure or do your best to make sure that the groups look as even as possible before you start assessing for what happens later. Okay. So that is what they're doing here in terms of this propensity matching and all of this stuff. Um, it is not really the same as completely randomizing people because there are things that you don't measure that may matter, and you can't adjust for what isn't measured. All right, let's just go through the results. We talked about how many patients they had, and um, this is just them saying how they broke that all out. Tadalophil versus no drug in erectile dysfunction. Okay. Patients with erectile dysfunction who received tadalophil showed reduced all-cause mortality, improved cardiovascular outcomes, and lower rates of dementia compared to those who did not. Uh, that is going to be shown in table two. I wish they would give the numbers here. It's a little weird in a results section not to actually give the numbers, but we'll go look at the tables together. Sildenophil, Viagra versus no PDE5 inhibitors. Sildenophil was associated with reductions in all-cause mortality, cardiovascular events, and dementia. Results were significant before and after propensity matching. And Cialis versus Viagra. Tadalophil was associated with significantly lower rates of all-cause mortality, heart attack, and stroke compared to Viagra. Rates of VTE or venous thromboembolism and dementia were similar between the two. Okay. And lower urinary tract symptoms. Tadalophil use in lower urinary tract symptoms was linked to lower all-cause mortality. This trend was consistent. Um, things like linked to and trend suggest that maybe it wasn't statistically significant. Let's go look in table two and figure out. But those are a little bit of um hedgy words that make me wonder about that. And then their post hoc analysis of socioeconomic status. Patients prescribed Cialis were less likely to be unemployed or face housing and economic issues compared to those not prescribed, showing relative risks that only varied by one to four percent. So indeed, patients who get this medication are a little bit better off socioeconomically than those who don't, but they're saying that this factor had minimal impact on the results. Maybe, at least the best that they can adjust statistically. Before we get to the discussion, let's go and look at their table here and um see what's going on. So table one is the propensity matching. This is where I tell you that they are adjusting these things. Um, again, I picked age out of the out of my head, but um, you can see here that the um ages were adjusted as part of this. So 58 versus 60. Now they're after propensity matching, 58 and 58. Great. So they'll go through all of these things and adjust for that. You can see what they've adjusted for age, um, ethnicity, diabetes, kidney failure, and chronic kidney disease, overweight and obesity, a history of cardiac arrest, uh ischemic heart diseases. So again, coronary artery disease, lung cancer, COPD, and hypertension. Um I don't see a history of smoking in here or active smoke tobacco use. That would be something potentially to adjust for, but okay. Um, and I don't see any mention of some of the other cardiovascular risk factors, dyslipidemia uh in particular. All right, here is table two. This is the outcomes table. All right, sorry for the back and forth here. So let's go through this. Ah, sorry. Okay, 2A, erectile dysfunction cohort. Um tidallophil all, no PDE5. So mortality was about 2% in the tidalophil group versus 3.2% without. So that's a 40% risk reduction, um, relative risk reduction before propensity matching. And it's gonna be a 1.3% absolute risk reduction. So we can calculate number needed to treat later, but let's actually see what it is after the matching. It's closer to 1% absolute risk reduction. So again, deceased is this top line here. It may be hard for you to see. It is 1.95% in the tadalfil group, 2.94% in the untreated group, and a 44% risk reduction, relative risk reduction, but a 1.1% absolute risk reduction. So that will get the number needed to treat. Let's look at heart attack 0.91% versus 1.25%, heart attack um stroke, 0.8 versus 1.2, VTE 1.26 versus 1.6, dementia 0.42% versus 0.6%. So um that is statistically significant, but it's a very small absolute risk reduction. That is a 0.2% absolute risk reduction compared to the you know, over 30% relative risk reduction. And that is again where we the devil's in the details here. So um it could be real, but it's pretty small in terms of total impact. And this is where when you have millions of patients, this stuff becomes statistically significant, but may or may not be clinically relevant. All right, and then they have these different breakout groups. So the five milligrams of tadalophil, we can look at the mortality here again, 1.8% versus 2.9%. That's a 1.1% absolute risk reduction, almost a 40% relative risk reduction. Sildenophil mortality for was 2.4% versus 3.2%, so less than 1% absolute risk reduction here, which is why they're saying that the Cialis was more effective uh than the um Viagra. Okay. We are gonna finish this out here, and here is their comparison for that. Lower urinary tract symptom cohort. So this is what I was saying they said was suggestive, but I wasn't sure because the language sounded a little bit hedgy. However, I'm looking at this last column here where they have their confidence intervals, and these are all still highly statistically significant. So um let's again go through mortality here. In the Cialis group, the mortality was 2.5% versus 5.8% in the untreated group. Dementia, just as another, was 0.6% in the treated group versus 1.4% in the untreated group. When we're looking at um the tidalophil 5 milligrams, similar mortality, 2.5% in the treated group versus 6.3% in the untreated group. And we have modest reductions in heart attack, stroke, and blood clots. Dementia was 0.7% in the treated group versus 1.3% in the untreated group. So across the board, we absolutely see an impact of these PDE5 inhibitors, Cialis and Viagra, uh, for mortality, heart attack, stroke, blood clots, and dementia. And what I will say about, let's go through their discussion and then we'll see what they have to say, and then we'll see what I have to say. Too fast. Too fast. Okay, so they're gonna summarize their results. We showed a reduction in all of these things in these men with both Cialis and Viagra. Their secondary analysis for lower urinary tract symptoms results showed that the Cialis results in significant reductions in all-cause mortality. We showed all of that. These results align with previous reviews, which noted an independent association between tadalophil and major adverse cardiac events, showing benefits in all-cause mortality and venous thromboembolism risk. Tadalophil's recommended dosages range from 5 milligrams to 20 milligrams daily, and clinical practice often involves titration to balance efficacy and side effects. A recent cohort study with 50,000 men with erectile dysfunction and high cardiovascular risk noted a dose-dependent reduction in overall mortality and major adverse cardiac events. And that's an important thing when you're thinking about association versus causation. For many of these things without a randomized controlled trial, we are gonna use the Hill criteria to think about all of the different ways in which an association provides evidence to be compelling for possible causation. One of those is a dose dependency, meaning if you give something at a low dose and it has a small effect, then at a higher dose you would expect a higher effect, if in fact that thing is causally related to the outcome that you're talking about. So the fact that another study showed dose dependency is very helpful. They didn't break out anything other than five milligrams here versus other doses, and I'm not sure why, because they had the numbers to do that, but they didn't. It's an interesting point. All right. Tadalophil may be more effective than sildenophil due to its longer half-life. Uh, 17 hours in healthy men, up to 21 hours in elderly men, compared to Viagra's four hours. This extended therapeutic window and daily dosing could explain why tadalophil is favored in this study. This corresponds to a therapeutic window of approximately 36 hours. In addition, it is often prescribed as a daily dose both for erectile dysfunction and for lower urinary tract symptoms. Okay. Just skip through the table. The continuous mechanism over time may be a reason why the data in this study favor tidalophil over codenaphyl. Tadalophil may also serve as an adjunct for treatment-resistant hypertension in men with a diagnosis of erectile dysfunction. This is a synergistic effect with other medications. And anecdotally, I have absolutely seen this in patients. I have patients who come to me and have been on this medication. They were started for possible erectile dysfunction or prostate issues, and they were left on it because their blood pressure control got just a little bit better and their primary was happy with it. These drugs, as you might know, were actually originally investigated for the use in blood pressure control. Um and the side effect of causing erections was how they became designed or labeled for that purpose. And they have also been explored for managing angina, heart failure, stroke, and LUTS, previous studies. Okay, we talked about that. These medications have anti-aggregatory effects, an increase in CGMP, which may ameliorate small vessel dysfunction. Again, this is talking about the prolonging, prolonging the effects of nitric oxide, which we talked about. Um these have additional uses outside of the cardiovascular space. They reduce pulmonary hypertension, which could aid in high altitude illnesses, kidney protective role potentially in some animal models. Sildenophil and tadalophil are noteworthy in that they cross the blood-brain barrier. Okay, this is cool. And these enzymes are expressed in brain neurons as well as subcortical white matter cells. Given this, these drugs may play a role in the modulation of vasodilatory responses in the central nervous system, which is why you might think they would have a role in dementia or Alzheimer's disease. And animal models have demonstrated an improvement in memory deficits after 10 weeks of treatment, as well as decreased Tau phosphorylation. So tau is that one of those proteins that we're measuring now to help us understand people's risk for developing Alzheimer's disease. All right. Results of the study show promise, a study in the UK. Okay, great. Future research should explore the effects of less commonly prescribed PDE5 inhibitors, strengths, and limitations. Large sample size, practical implications of inexpensive. The follow-up for mortality is excellent in this database as 94% of sites are linked to death registries in the United States. Okay, great. Follow-up for other outcomes could be missing if an individual sought subsequent health care outside of the HCOs. What does this mean? So I mentioned that this data set is linked to these certain participating heart or excuse me, hospitals and health systems. What this means is if you are a patient, let's say you're a patient at hospital A and you see doctors at hospital system A, but one night you're at home and you get chest pain, you call the ambulance, the ambulance takes you to hospital B. Hospital B may not participate in this registry and your records may not reflect the fact that you had a heart attack and were treated at hospital B. The hope is that when you come back to your doctor who's in system A, hospital A, they would put it down in your chart and then it gets populated into this database. But if it happened right at the very end of their three-year study window, it might not, right? You can imagine that somebody might be treated at another hospital right at the end of the study period, and that doesn't get put back into their primary care doctor's records until later. So it's very possible that there are outcomes like dementia, heart attack, stroke that we missed because patients were treated either at a specialty center elsewhere or a different facility. But the mortality data, because that's linked to a national registry or at least statewide registries, we feel much more confident that the mortality data are pretty good. And again, we can establish correlation, but not causality. While propensity matching accounted for diabetes, kidney failure, obesity, heart conditions, cancer, COPD and hypertension, other diseases and socioeconomic factors may not have been fully controlled. Um, I think this is where I'm gonna put in my my two cents about this. So if you are bothered by your erectile dysfunction, that tells me that you are sexually active with a partner. And it that's an assumption, but it's not a bad one. Having a partner is associated with improved long-term mortality, right? Married, and at least for men, um, married men live longer than unmarried men. Um, it's not true for women, by the way, but the idea, right, that you have social support, that you have somebody in your life that you care about, that you're in a relationship with that's strong enough for you to want physical intimacy, all of these things matter. And there may be men who have erectile dysfunction who don't know it or don't want to talk about it with their physician because it's not impacting their everyday life. Maybe because they're not in a relationship right now and they don't feel compelled to talk about physical intimacy with their physician. That is a signal for mortality risk in general. So I just wonder about whether there is a piece of this that's related to having partnership in life. Now, that if that were true, then we wouldn't see the signal with lower urinary tract symptoms. The fact that we see it there too is suggestive that there is indeed perhaps some underlying biological mechanism that is very helpful. And in general, I think these are very interesting and useful drugs. And I'm curious about their potential for improving cardiovascular risk. There's no label for that, there's no indication for that. In general, I am not prescribing them outside of a labeled indication, but I'm curious and interested in how this is going to play out in the next few years. So, you know, again, is it something to do with partnership? Is it socioeconomic status? Is it people who are comfortable bringing this up with their physician versus those who are not? There are all kinds of things that we cannot account for when we are looking retrospective big observational cohorts. And that's just a limitation. But having a million men in your study, that is a pretty big strength. So, overall, very interesting signal. I am fascinated to take a look at some of the other papers that have been done, especially in higher risk groups. If you are interested in that, let me know. We can do a really deep dive into all of the studies that have been done and what I think those look like. Please drop that down in the comments below if you want to see more about this class of medications and how they work, what their cardiovascular risk reduction might be, and whether we should be more aggressive in prescribing this when there's an indication. Until next time, guys, take really good care.