I won’t be throwing my Tadalafil away anytime soon
AI analysis from Vera: Systematic review and meta-analysis of cohort studies including 1,257,759 men with erectile dysfunction (with or without coronary artery disease). PDE5 inhibitor use was associated with a 22% reduction in major adverse cardiovascular events (RR 0.78, 95% C| 0.69-0.89) and a 30% reduction in all-cause mortality (RR 0.70, 95% C| 0.56-0.87) over a median follow-up of 4.3 years.
From 2025
https://www.amjmed.com/article/S0002-9343(24)00705-8/fulltext?utm_source=chatgpt.com
The final cohort included 509,788 men with erectile dysfunction and 1,075,908 with lower urinary tract symptoms. Tadalafil and sildenafil were associated with significantly reduced risks of all-cause mortality (RR 0.66/0.76), myocardial infarction (0.73/0.83), stroke (0.66/0.78), venous thromboembolism (0.79/0.80), and dementia (0.68/0.75) in erectile dysfunction patients, with tadalafil showing more significant benefits. In lower urinary tract symptom patients, tadalafil was similarly associated with reduced mortality, cardiovascular disease, and dementia.
The confounders are massive in those studies. What’s the comparison? Someone taking sildenafil or tadalafil has a partner (= emotional support), an active sex life (= happiness), and is proactive towards their health (= probably similarly proactive in other areas). Massive healthy user bias. That’s why those longitudinal studies should just be hypothesis-generating. Then if not confirmed by MR and clinical trials: most likely trash/confounding.
I agree, the only trouble is the current MR trials are trash too:
PDE5 inhibitors are weak systemic antihypertensives. So Brennan and Tinworth (2025) used systemic blood pressure as a mathematical proxy for a drug that doesn’t actually lower systemic blood pressure very much in real life, their study likely captured the neurological risks of lifelong lower blood pressure, rather than the real-world effects of taking a PDE5 inhibitor.
Re Lewy Body Dementia: clinical consensus points to an optimum blood pressure target that is notably higher and more flexible than standard guidelines—specifically aiming for a systolic target around 130 to 140 mmHg. Basically hyperperfusion due to low blood pressure is thought to be a risk factor for the brain stem, causing LBD.
Summary : ignore the current MR studies - they’re useless because they don’t identify pde5 inhibition genes.
I copied your message in ChatGPT 5.5 Thinking Extended and asked its opinion. Conclusion:
I would not ignore Brennan & Tinworth, but I would downgrade it heavily for real-world decision-making.
Best interpretation:
For occasional sildenafil/tadalafil use: this MR paper should probably change your risk estimate only slightly, if at all.
For chronic daily tadalafil as a “brain health” intervention: it is a real caution flag. The evidence is too conflicted to assume benefit, and the LBD signal in particular may partly reflect BP/autonomic/hypoperfusion biology rather than direct PDE5 inhibition.
For PDE5 inhibitors as dementia-prevention drugs: current evidence is not convincing. Clinical trials and better pharmacoepidemiology matter more than this MR signal alone.
I disagree with this completely. When certain patterns are strong and results speak for themselves then to me that is the best study one can have/hope for. Finding confounders is like making excuses to deny reality. There are no coincidences and/or confounders when results are overwhelming. A
s an example you say having a partner =emotional support, it is the opposite for a lot of people, you get better emotional support from an animal/pet. For me and I know for many of my friends’ long-term relationships tend to add a bit of stress and not the opposite. We are not made well to deal with the BS that woman go through and throw at us LOL, so IMO that confounder is null at best, or the opposite at worst.
I’d also read a study (as an example) that people in high altitudes had much lower incidences of CVD and then toward the end of the study the mentioned that it may be the case that people are more active, to me that is total BS to undermine something that is very real and obvious.
The data is pretty clear for men that marriage is a huge longevity intervention. Has been known for 50+ years.
So what you or your friends might interpret as stress maybe is good stress.
The data is pretty close to irrefutable despite lots of confounders. Certainly mental illness is bad for longevity and the more severe tend to be single.
There is a huge healthy user bias and probably a marriage bias in PDE5 studies. Doesn’t completely negate it in my opinion but I don’t deny the bias is there.
But that’s the whole point: the evidence in favor of sildenafil/tadalafil is NOT strong. Many papers found nothing and Mendelian randomization is negative. The few studies that found benefits often do not find a dose-response relationship and are poorly controlled for confounders.
Well, I thought our friend @LukeMV posted few studies showing pretty convincing benefits. So, I don’t know maybe now it’s become mine is better than yours (studies) lol. To be fair, I do get somewhat of a less clear vision when using either (Cialis a bit more so) and that definitely is a turn off, but the benefits are also HUGE (as in performing better than in your 20’s) if nothing else the EGO man, holly molly big boost LOL. Maybe I’ll use them more sparingly or as needed but there are definitely benefits to be had knowing that you’ll be more of a man than you’ve ever been. Nothing more depressing for a man than a limp limb😂
You didn’t get my point: There are papers that found benefits. There are papers that found no benefits. And there are papers that found risks. And when you look at papers that found benefits they’re often low-ish quality (especially poor control for confounders + no dose-response). So overall the case for those drugs is not strong. It does not mean those drugs are bad. But it’s not like statins, SGLT2i or GLP-1RAs for instance.
BTW, GLP-1RAs are evil. I’ve cursed the person that invented them for seven generations LOL
I might just do a microdose of 1mg weekly for a bit of appetite suppression but NEVER again at doses suggested to lose weight. Using them made me experience what it is like to be 110 years old at only 55 LOL.
A great sign of having at least an average iq is the understanding that your own experiences are not necessarily universal.
I think the argument for both sides are valid. While the drug classes you list are much better, I still think it’s a net positive and will continue to take Tadalafil because I think the nitric oxide boosting effects are unique to PDE5s and probably part of the reason they would reduce mortality. That being said, I reserve the right to change my mind as more data comes out.
So true. Really, from a quality-of-life aspect these drugs are absolutely amazing.
But I do agree with @adssx that the purported benefits are not as exciting as I think we’d initially hoped. I think he’s correct that any sort of observational study has a huge amount of confounders at play, and that’s definitely made me re-evaluate whether to keep using these medications.
There’s strong evidence that GLP-1RAs increase depression risk. This might be what @Kelman felt?
Yes, my criticism is that I feel they’re overhyped vs the current evidence. It would be better to say “if you’re a man, those are great drugs for your quality of life, and, cherry on the cake, they might have some long-term health benefits”.
No, I wasn’t depressed, but it was weakness to the point of not wanting to get out of bed. P{lus had big GI issues especially heartburn and indigestion. Might have also affected sleep negatively though my poor sleep I think was mainly due from Cialis.
‘Viagra has many benefits, but it does not seem like the drug that will extend lifespans.’
From the writeup:
My verdict, if I had to guess, is that {Viagra or Cialis} is good for cardiovascular health quite broadly and mildly, and if you’re at high risk of bad cardiovascular outcomes, then it will probably help you to live longer and to live healthier. Moreover, it’s good to take anyway for the treatment and prevention of ED if you’re a man.
Ah just seeing your post now, anyway I posted it there: Crémieux: Viagra for Life Extension Does it work? I'm doubtful
The good part is that it includes another MR for AD that we missed (or at least I did) and it does not seem harmful.