First report from Epiterna on the search for drugs that can extend human lifespan

[LukeMV]

Well I guess I might have to ask my doctor to switch me from 5mg Rosuvastatin to 10mg Atorvastatin now.

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@AnUser

Atorvastatin has already been proven to be superior to rosuvastatin in terms of side effects, lower diabetes risk and cataract surgery:

I didn’t know, so why do you take rosuvastatin then?

[AnUser]

I see no reason to switch right now to atorvastatin unless there is a large RCT that has showed benefit in all cause mortality like rosuvastatin.

[LukeMV]

Better question: If you were being prescribed statins for the first time and were given your choice of the two, which would you pick?

[AnUser]

I wrote more on rosuvastatin over atorvastatin here:

Rapamycin and risk of cardiovascular disease

I will do 10 mg rosuvastatin + 10 mg ezitimibe instead next. I chose rosuvastatin over atorvastatin: I already had success with rosuvastatin. It is not metabolized at CYP3A4 which mean I can try rapamycin later with GFJ, and also fewer drug interactions I guess. It being hydrophilic might give benefits. I can monitor diabetes risk anyway so it doesn’t matter that much that is has a higher causal risk compared to atorvastatin. Both Trump and Biden takes it. Peter Attia recommends it to start with.

Add in detected benefit for ACM for rosuvastatin. That’s much better. This is an association study. 10 mg atorvastatin had null effect in it.

I am thinking actually about skipping ezetimibe and going to high dose statins, because 20 mgs showed benefit in ACM in JUPITER.

[LukeMV]

Another thing I wonder.

I don’t see Tadalafil mentioned anywhere so I wonder if the mortality benefits were only seen with Sildenafil.

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@LukeMV

I don’t see Tadalafil mentioned anywhere so I wonder if the mortality benefits were only seen with Sildenafil.

It’s in the supplementary material: https://www.medrxiv.org/content/10.1101/2024.03.08.24303967v1.supplementary-material

The problem is that they didn’t do the disambiguation between generic names and brand names correctly, so for instance the dataset lists:

• FENBID and IBUPROFEN
• Tadalafil (HR 0.86 CI 0.75–0.99) and Cialis (HR 0.77 CI 0.60–0.99)
• IMIGRAN and Sumatriptan.

If done correctly, this might change the results.

Something else that I don’t understand: Telmisartan HR in males = 0.76 but HR for telmisartan 40 mg = 0.80 and HR for telmisartan 80 mg = 0.82. How can the HR for telmisartan be lower than the one for each telmisartan dose?! I would expect HR (A+B) < min(HR(A), HR(B)).

Also, in drugs, there is “FREESTYLE TESTING STRIPS”…

Not reassuring on the quality of the paper…

[LukeMV]

Yea this is extremely interesting but there still seems to be so many flaws here. I also can’t for the life of me understand how viagra could have more health benefits than cialis when it’s so much shorter acting.

[adssx]

I contacted the author (turns out we went to the same high school…): they’ll try to fix the various mistakes in the upcoming revision before final publication.

[Virilius]

Atorvastatin is the most commonly prescribed statin.

[vamin]

The statin data is really interesting. I think a lot of folks here have a preference for less lipophilic statins, on the theory that these will cross BBB the least and affect muscle the least. However, those statins also have the longest half lives, which could result in the statin building up in your system. I had a theory that it might actually be the more lipophilic, lower half life statins that are safer. Atorvastatin sits in the middle, moderately lipophilic, moderate half life. Maybe it’s a kind of sweet spot, though the half life doesn’t seem so much shorter than rosuvastatin.

I can’t find a good primary source right now, here are lipophilicity rankings from GPT-4:

1. Lovastatin - Highly lipophilic; easily crosses cell membranes and is metabolized by the liver.
2. Simvastatin - Similar to lovastatin in lipophilicity and is also a prodrug, activated in the liver.
3. Atorvastatin - Less lipophilic compared to lovastatin and simvastatin but still relatively lipophilic.
4. Fluvastatin - Intermediate; less lipophilic than the first three.
5. Pitavastatin - Has both lipophilic and hydrophilic properties.
6. Rosuvastatin - More hydrophilic than the previous statins, which may contribute to its lower rate of certain side effects.
7. Pravastatin - The most hydrophilic statin, which means it’s less likely to penetrate cell membranes and may have fewer side effects related to muscle tissue.

And half lives, also from GPT-4:

1. Simvastatin - Approximately 2 to 3 hours.
2. Lovastatin - Around 3 hours.
3. Fluvastatin - Approximately 3 hours.
4. Atorvastatin - About 14 hours.
5. Pitavastatin - Roughly 11 to 12 hours.
6. Pravastatin - Around 19 hours.
7. Rosuvastatin - Approximately 19 to 20 hours.

[RapAdmin]

Source: https://x.com/j_n_justice/status/1767620724515094654?s=20

[DeStrider]

This provides another reason to add a flozin like empagliflozin to my stack. Thanks for this!

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@Virilius

Atorvastatin is the most commonly prescribed statin.

Not in the UK:

The 3 most prescribed drugs in the dataset were amoxicillin (N=73371), simvastatin (N=45776), and omeprazole (N=44100).

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There are weird findings in the paper, for instance, for sartans:

The results are only statistically significant for candesartan (and in a bad way…), but what could explain the positive trend for telmisartan and the neutral one for losartan?

Many people consider (and I think they’re wrong) that candesartan is as good as telmisartan. Candesartan failed the ITP and the ITP is now testing telmisartan.

Same for what they found regarding statins (atorvastatin better than simvastatin): simvastatin failed the ITP and atorvastatin is now tested (combined with telmisartan).

So either this paper is crap (it’s possible, most papers are crap, and there are many mistakes in this one), or they really found something interesting…

[LukeMV]

I jumped on the Empagliflozin train a couple years ago.

Also, this doesn’t get enough attention but it’s the only drug class to show potential benefits for diastolic heart failure. No other drug has succeeded in doing so.

Empagliflozin for Heart Failure With Preserved Left Ventricular Ejection Fraction With and Without Diabetes

Conclusions:

In patients with heart failure and a preserved ejection fraction enrolled in the EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction), empagliflozin significantly reduced the risk of heart failure outcomes irrespective of diabetes status at baseline.

https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.122.059785

[AnUser]

@AnUser

But has atorvastatin reduced all-cause mortality, which rosuvastatin has?

Yeah pretty much in two clinical trials for primary prevention (one in hypertension, one in diabetes):

Rosuvastatin versus atorvastatin treatment in adults with coronary artery disease: secondary analysis of the randomised LODESTAR trial (2023)

[image] colhoun2004-1.pdf (198.9 KB) P=0.059 so technically not statistically significant, but I am pretty much convinced that atorvastatin reduce all-cause mortality in primary prevention for heart disease. [image] I did try 20 mg atorvastatin for a few days but I switched back to rosuvastatin. I will try again since the drug pretty much reduces all-cause mortality, all statins cross the BBB, and more importantly it has a lower causal risk of diabetes compared with rosuvastatin. If it wasn’t for the latter I wouldn’t try and switch. The STAREE trial and STAREE-MIND trial chose 40 mg atorvastatin as well for its research, reading a bit in the supplementary information, they cite research which suggest lipophilic (meaning drugs that can pass the BBB), might be superior for dementia and as many of us know APOB causes Alzheimer’s according to MR studies. [image] [image] [image] bmjopen-2023-April-13-4–inline-supplementary-material-3.pdf (2.9 MB) [image] [image] [image] bmjo…

[RapAdmin]

Lifespan IO write up on this paper

Existing Drugs May Lengthen People's Lives | Lifespan.io

[LukeMV]

I am still thinking about that Naproxen result. I am wondering if the people took it daily or only as needed. I’ve always tried to only use it if sick but I have to say, the feeling of having minor joint pains go away on it is very appealing if it’s also going to extend lifespan.

[desertshores]

Interesting paper.

It has been discussed in other threads whether or not tadalafil would be as effective as sildenafil because it would perhaps be more convenient to take tadalafil because of its longer half-life.

The possible confounders regarding dosing are not discussed.

[dicarlo2]

I’m curious about the confounders here as well. Tadalafil is typically prescribed at a once daily dose of 5mg (for BPH and maintenance treatment for ED), whereas 10mg and 20mg are typically only prescribed to be taken prior to sexual activity. This could indicate that 10mg/daily is not the same as the dose used by participants in the database (possibly 10mg/sexual activity). Personally, I’m giving 10mg/day a try to see if I notice anything subjectively different (eg more muscle pump in gym). I can’t say I’ve really noticed anything from 5mg though.