#142

Is there any evidence that an equal distribution is required?
Or to put it another way: Is there any evidence that an unequal distribution would be less effective? We have evidence that drugs such as rapamycin are effective in unequal distributions.

#143

That’s a fair question.
So side effects of any medication tend to be worse with higher dosing. Efficacy is worse with lower dosing (unless you believe in homeopathy then the reverse is true).

With doing 20 mg every 4 days, day 1 20 mg goes down to 10 mg effectively by 18 hours, then by 36 hours we are at 5 mg active, then at 54 hours down to 2.5 mg… etc.

So you will be getting a huge variation in side effects at the beginning (if any) but then efficacy loss later on.

There is obviously no outcome data, but we know different doses have different efficacy and side effects.

I tend to run all my long term medications in a way to keep a fairly
smooth level - but that is just me and how I was trained.

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#144

I don’t know if there is a proven association, but ED is often seen in patients with DM, CAD, PAD all of which I could see be a risk for dementia.
In association studies your comparing those on the drug for ED with those not on the drug because they don’t need it. So you may be comparing unhealthy with healthy. My guess is the unhealthy will have greater chance of dementia.

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#145

Before we only save our Cialis for “special occasions”, let’s not forget it appears to have good cardiovascular benefits

(Mouse study)
Tadalafil Prevents Acute Heart Failure with Reduced Ejection Fraction in Mice - PMC.

And for BPH
A review of the use of tadalafil in the treatment of benign prostatic hyperplasia in men with and without erectile dysfunction - PMC.

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#146

ED is not an independent risk factor for dementia as far as I know. Even if it was, it doesn’t matter for association studies looking at people with ED only.

Regarding other risk factors such as DM, these are adjusted. From a 2024 paper:

Adjusted estimate represents the results from propensity score-derived stabilized inverse probability of treatment weights: covariates included are age, calendar year, heart failure, chronic obstructive airways disease, dyslipidemia, diabetes, arrhythmias, ischemic/coronary heart disease, cerebrovascular disease, peripheral vascular diseases, renal disease, hypertension, schizophrenia and psychosis, bipolar disorder, depression, anxiety, liver disease, benign prostate hyperplasia, hypothyroidism, head injury/trauma, Townsend deprivation quintile, mean systolic and diastolic blood pressure, body mass index, smoking status, alcohol status, antidepressants, noninsulin diabetes treatments, insulins, antipsychotics, antihypertensives, antiplatelets, anticoagulants, anticholinergic drugs with an anticholinergic burden ≥3, lipid-lowering therapies, and thyroid replacement therapies.

No:

  1. Some studies compare BPH patients on PDE5i vs other drugs (alpha blockers or finasteride)
  2. For studies on ED: “The comparison group was men also newly diagnosed with ED and no prescription for PDE5I (nonusers/nonexposed).” (same paper as above) And among PDE5i users they look at the frequency of usage.
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#147

From what I understand for BPH, as monotherapy tadalafil is inferior to alternatives such as terazosin. See: Terazosin / doxazosin / alfuzosin may protect against dementia with Lewy bodies

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#148

Also the UK Biobank’s study had very convincing evidence that the PDE5i meds helped lower death rates in humans. Enough to even convince Matt K to start taking one. https://www.youtube.com/watch?v=Ju1p_L-2Bq4

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#149

Indeed, still great drugs, but I’ve felt there was reasonable indications of neurocognitive benefits specifically. I’m doubting this now - but for longevity/vascular - are a yes.

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#150

Really disappointing from Matt K. That specific study is a preprint. With many mistakes. See there for instance: First report from Epiterna on the search for drugs that can extend human lifespan - #26 by adssx

Also at low dose and high dose neither sildenafil nor tadalafil were associated with increased lifespan. Only the “medium” dose was. And they did not take into account the potential confounders.

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#151

Here’s the paper: The association of tadalafil exposure with lower rates of major adverse cardiovascular events and mortality in a general population of men with erectile dysfunction 2024

Overall mortality rate was 44% lower in men exposed to tadalafil (HR = 0.56; CI = 0.43−0.74; p < .001).
Men in the highest quartile of tadalafil exposure had the lowest rates of MACE (HR: 0.40; 95% CI: 0.28−0.58; p < .001) compared to lowest exposure quartile.

Figure 1 seems to show that the more exposure, the better. And the survival curves look very good:

image
image1200×1719 137 KB

It’s quite convincing. Of course, there’s still the issue of potential confounders (the authors note it: "Weaknesses include the retrospective nature of the study, the possibility of unknown confounding variables and the unknown issue of whether the drug conferred direct benefit or whether sexual activity promoted by the drug led to a benefit. "). It would be good to have the same study with sildenafil. Anyway, for men with ED, tadalafil seems to be a no-brainer. For men without ED I don’t know. (and ED is probably underdiagnosed).

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#152

Here is a new one

Over a median follow-up period of 4.3 years, this pooled analysis of 16 studies demonstrated that the risk of major adverse cardiovascular events and all-cause mortality was reduced by 22% and 30%, respectively, in patients exposed to PDEi compared to controls.

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#153

Limitation here is they might have lumped all PDE5 studies together as far as I know so we still don’t know if the benefits are more specific to viagra

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#154

Sildenafil, good or bad for the brain?
It might be both, and it might depend on the dosing. To much nitirc oxide in the brain might be detrimental and a cause for harmful oxidation just as to little NO might be a cause for hypoperfusion

Functions and dysfunctions of nitric oxide in brain - ScienceDirect

“Nitric oxide (NO) works as a retrograde neurotransmitter in synapses, allows the brain blood flow and also has important roles in intracellular signaling in neurons from the regulation of the neuronal metabolic status to the dendritic spine growth. Moreover NO is able to perform post-translational modifications in proteins by the S-nitrosylation of the thiol amino acids, which is a physiological mechanism to regulate protein function. On the other hand, during aging and pathological processes the behavior of NO can turn harmful when reacts with superoxide anion to form peroxynitrite.”

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#155

I thought Matt K. said they did try to adjust for confounding issues? I know that is extremely difficult to with these types of studies.

I’ll admit I didn’t read through the preprint; I just trusted Matt’s judgement.

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#156

Tadalafil caused severe muscle cramps waking me up at night. After quitting, the cramps gradually receeded over a few months. Debating whether to try sildenafil.

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#157

PDE5’s can increase risk of eye problems by 85%. Probably why they give me bloodshot eyes and force me to use Lumify eye drops, which I’d rather not do every day.

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#158

There’s no reason not to. It’s dirt cheap, at least from India.
It’s the one the study used.
There is no reason to think tadalafil is superior. At least there is no proof that it is.
Due to its long half-life, dosing is more problematic.
Maybe the shorter half-life of sildenafil will cause you less problems.

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#159

Indeed. Good that you wrote this - a reminder for me to get on board for sildenafil. Muscle cramps are less reported on sildenafil (quite uncommon) than with tadalafil and if they do show up I will know now to quit at once.

#161

How concerned should we be with the risk of viagra causing eye problems? I’m not talking about going blind, although going blind is no fun, but may there also be more subtle damage to the eye? The danger of damage being irreversible is giving me pause.

#162

Here is a fair summary on this topic:
Visual changes associated with Viagra (sildenafil) and Cialis (tadalafil) are generally reversible and temporary. These medications, which are phosphodiesterase type 5 (PDE5) inhibitors, can cause mild and transient visual symptoms due to their effect on phosphodiesterase type 6 (PDE6) in the retina. Common visual side effects include changes in color vision, light perception disturbances, blurred vision, and photophobia. These symptoms occur in approximately 3-11% of users and are usually non-permanent, resolving after discontinuation of the drug 12.

For sildenafil, visual effects typically last 3-5 hours, aligning with the drug’s half-life. In the case of tadalafil, effects may last longer due to its extended half-life of 17.5 hours. However, these effects are generally reversible once the drug is metabolized and eliminated from the body 23.

While serious vision-threatening complications such as nonarteritic anterior ischemic optic neuropathy (NAION) are rarely reported, there is a lack of conclusive evidence linking PDE5 inhibitors directly to these severe ocular events. The incidence of such complications in users does not appear to exceed that in the general population 36.

In summary, while sildenafil and tadalafil can cause visual changes, these effects are typically reversible. Patients experiencing visual disturbances should consult their healthcare provider for appropriate evaluation and management, which may include discontinuation of the drug if necessary.

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