#6

This a complex one, and I’ll wimp out and go with AI on this one. However, Canagliflozin has unique activity the others don’t. I guess if you are going to be on an SGLT2i, possibly consider this. However, in my writeup on these, it appeared to be less impressive and inferior to the other agents in class for dementia reduction. Article on this

Current evidence does not clearly indicate that canagliflozin is superior to other SGLT2 inhibitors in reducing death, malignancy, or cancer risk. All SGLT2 inhibitors, including canagliflozin, have demonstrated benefits in reducing cardiovascular death and all-cause mortality in patients with type 2 diabetes and high cardiovascular risk. However, no specific SGLT2 inhibitor, including canagliflozin, has been shown to be superior in these outcomes. The CANVAS program reported a 13% reduction in cardiovascular death risk with canagliflozin, but similar benefits have been observed with other SGLT2 inhibitors like empagliflozin and dapagliflozin 1.

Regarding malignancy and cancer, the evidence is limited and inconclusive. A meta-analysis found no significant increase in overall cancer risk with SGLT2 inhibitors, and the CANVAS program reported no significant difference in cancer rates between canagliflozin and placebo groups. Concerns about specific cancer types, such as bladder and breast cancer, have not been substantiated in long-term studies, and no significant association has been found between SGLT2 inhibitors and these cancers 2.

In summary, while canagliflozin is effective in reducing cardiovascular mortality, it does not appear to be superior to other SGLT2 inhibitors in decreasing death, malignancy, or cancer risk. More comprehensive studies are needed to establish any potential differences among SGLT2 inhibitors in these outcomes.

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#7

The AI is not incorporating anything about senescence or longevity here though

Will take a look at your blog, thanks for sharing.

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#8

One protocol could be to switch to Cana for a few weeks a few times a year and hedge in case Empa is not driving clearance of senescent cells.

I’m thinking of going between Cana and no Cana a few times per year. (And then calibrating as more data comes out)

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#9

Do you have a link to the paper?

I think a lot of senescent cells are stem cells that have failed to differentiate and are best helped to differentiate.

#10

Sure:

It’s the paper that the thread was started with, see above

#11

As a reminder, empagliflozin extends lifespan as well in mice (at a dose way too high, TBD if a lower dose would increase more): Empagliflozin rescues lifespan and liver senescence in naturally aged mice 2024 (“Further exploration discovered that empagliflozin increased the concentration of SCFAs, decreased the levels of the inflammatory factors TNF-α, IL-6, and CXCL9, and regulated the PI3K/AKT/P21 and AMPK/SIRT1/NF-κB pathways, which may represent the underlying mechanisms involved in these beneficial hepatic effects.”)

AMPK is also activated by dapagliflozin: Dapagliflozin restores autophagy and attenuates apoptosis via the AMPK/mTOR pathway in diabetic nephropathy rats and high glucose-induced HK-2 cells 2024

In C. elegans, no SGLT2 increased lifespan: Million Molecule Challenge Results and Leaderboard – Ora Biomedical, Inc. (But I think the dose was too high and I sponsored another experiment at 5 µM, my bet is on dapagliflozin)

So the case for canagliflozin over empagliflozin and dapagliflozin seems very weak to me. Even more so considering that dapagliflozin and empagliflozin have a better safety profile than canagliflozin and are linked to better outcomes in RCTs and association studies (including on dementia).

For cancer, this 2017 blog post (I have no idea how reliable it is) concludes:

Based on the above you could argue that we should chose between e.g. Dapagliflozin and Canagliflozin depending on the tumor size and glucose status in the body.
Therefore, Dapagliflozin may be more relevant for the very large tumors, while Canagliflozin may be more relevant for smaller tumors in people with high blood glucose levels (e.g. who do not follow a low-sugar diet and do not use other glucose lowering medication).

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Everolimus instead of Sirolimus / Rapamycin? Anyone else trying?
#12

@adssx Have we seen any Mendelian Ranomization for SGLT2i yet?

That we have that for SGLT1i (together with multi ITP studies on Cana vs the single somewhat weird one-off study on Empa) does still hold some weight in the direction of Cana if one’s goal is lifespan extension and longevity, and not just health improvement.

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#13

You’re right; the SLGT1 MR study gives one point to canagliflozin.

For SGLT2, we have this one: Canagliflozin - Another Top Longevity Drug - #1067 by adssx “Our study supported that SGLT2 inhibition increases father’s attained age, cognitive function and intelligence, which was mediated through brain images of different brain regions.” (males only again!)

And for SGLT2 and CVD & MI, we have these:

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#14

RCT’s and MR is the only way.

(and maybe mice longevity studies)

#15

How would you see if cycling on and off works via MR?

Seems like we perhaps can use MR + mechanistic understanding of MR points to general benefit (which it does for SGLT1)

#16

How is SGLT1 different now that we have an MR for SGLT2 and male longevity as well? SGLT2 Inhibitor Canagliflozin eliminates senescent cells and alleviates pathological aging (in mice) - #13 by adssx

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#17

I’m not an expert, I only have surface level understanding of MR. I’m not personally interested in any mouse, human, yeast, or cell mechanistic papers with buzzwords like “senescence”, “inflammation”, “metabolic dysfunction”, “mitochondrial function”, “neurogenesis”, “BDNF”, and other ones.

#18

Not sure that it is different. Did not say it is different in my post you are referring to. But I have not yet read the SGLT2i paper and the abstract of the paper felt weird/i’m not understanding it yet so don’t want to tell people in a post that we have (good) MR analysis of SGLT2i before I have studied it and know if I believe that we have or not.

SGLT2 inhibition was associated with longer father’s attained age (years of life increase per SD (6.75 mmol/mol) reduction in HbA1c levels = 6.21, 95%CI 1.95 to 11.15)

Is that relevant for people in a normal range - or it just saying that people with massively higher HbA1c live shorter than those with massively lower HbA1c?

As mentioned, I have not yet been able to read the paper, so I just don’t know what it means yet

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#19

Come on man - don’t spin things. You totally know how that MR is a lifelong average exposure type of thing and hence cannot distinguish between a constant vs cyclical dosing.

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#20

I’m not knowledgeable enough to conclude on this. They note at the end:

Fifth, using a genetic variant in SLC5A2 to proxy the pharmacological SGLT2 inhibition, a recent study reported the cardioprotective effects of SGLT2 inhibition ([62](javascript:;)). However, the effects may not be attributed to lower plasma glucose since only a minimal mediation proportion was found. As our instruments were selected based on the HbA1c-lowering effect of SGLT2 inhibition, we should view our results with caution.

But they also write:

SGLT2 inhibition was associated with changes in the right supraorbital sulcus area (beta = 1.84, 95% CI 0.40-3.28, P = .01) and thickness of the paracentral area in the left hemisphere (beta = 1.52, 95% CI 0.08-2.96, P = .04), both of which led to an increase in father’s attained age (beta = .014, 95% CI 0.001-0.028, P = .04; beta = .023, 95% CI 0.004-0.042, P = .02). (Fig. 3 and Supplementary Table S4) (36). An indirect effect via these 2 IDPs accounted for 9.8% and 12.8% of the total effect between SGLT2 inhibition and father’s attained age (Supplementary Table S5) (36).

image

So I understand that ~80% of the increased lifespan (of the father!) is due to HbA1c lowering (“direct effect”) and 20% to indirect effects.

Is there a better way to do an MR study on lifespan?

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#21

I don’t know if I’m not an expert… I can think of situations where there can be cyclical effects from gene variants. There’s no spin, just a response to your question.

If you can’t find MR or RCT’s then maybe you don’t have enough evidence unless you think the expected benefit outweighs the risks. I’m not going to look or investigate all of those +EV bets if they are small as that’s too much cognitive load… Pascal’s Mugging Spam. And why I tune out from anyone or any studies using a bunch of buzzwords.

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#22

But the MR could not capture that at that level

#23

Thx @adssx . Well try and read the paper when things slow down a bit for me.

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#24

Can turn it on so you can accept DM messages, tried to send you one but it did not go through because not accepted

#26

@AnUser

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