Canagliflozin - Another Top Longevity Drug

[desertshores]

But there is virtually no suppression of SGLT-1 by empagliflozin.

[Neo]

Yes that is my point: Why do you prefer that one if it doesn’t have hardly any SGLT1i / how do you weigh that factor?
(Since there are ones like Cana that was used and is continuing to be used in NIH ITP, etc).

No need to spend more time on this - just trying to clarify what I want originally was asking.

[desertshores]

[quote=“Neo, post:619, topic:91”]
I’m just asking why you feel that less SGLT1 is good
Never said that. Case closed.

[adssx]

@Neo

I’ve actually agreed the whole time that the clinical trials have a lot of merit and that should be weighted in the equation and that in many ways those data sets favor Emp and Dap.

Yes I know, my question isn’t “who’s best” but I was trying to steelman the case for SGLT1i and was still blocked on that point.

Let’s imagine the extreme case: SGLT2 is great for some diseases (HF, T2D, CKD, etc.) but in itself isn’t pro longevity (like metformin) whereas SGLT1 is prolongevity. So the positive outcome of the canagliflozin ITP trial is 100% due to SGLT1. Then what could explain sotagliflozin and canagliflozin’s relative underperformance?

1. As you said, maybe a less favorable safety profile resulting in a lower treatment adherence so lower SGLT2 inhibition and therefore uncontrolled disease (as these trials and longitudinal studies are not done on healthy people),
2. Maybe sotagliflozin and canagliflozin are not as good SGLT2 inhibitors as dapagliflozin and empagliflozin (in the same way that, for example, losartan isn’t as good as telmisartan) so they cure these patients less and this is not compensated by their SGLT1 longevity properties. For instance, maybe SGLT1 increases lifespan by x% and SGLT2 increases lifespan of people with these diseases by y% but sotagliflozin and canagliflozin do it by y/2% so if x+y/2<y (so x<y/2) we wouldn’t see any positive effect of sotagliflozin and canagliflozin,
3. As most trials are short and small, their pro longevity effects cannot be seen,
4. The above objection dose not apply to large longitudinal studies, but I saw where canagliflozin under performed were mostly related to psychoneurological conditions like dementia and depression. Maybe mice don’t suffer from that? Or maybe it doesn’t affect their lifespan much? And the ITP doesn’t measure the cognition of mice?
5. SGLT1i pro longevity effects might weaken in sick people? In the same way that SGLT2i do not lower your blood sugar once you have CKD and a very lower eGFR. Maybe for whatever reason if you have high Hb A1c it’s harder for SGLT1 to exert its pro longevity effects (whatever they are).

This is all I can think of.

[Rmun]

This is an interesting discussion.

I have been prescribed empagligozin since November 2019 for heart failure. For me it has been a life saver. The diastolic dysfunction has improved, I have no longer been rehospitalized, and even my kidney function is better. So the question of longevity linked to SLGT1 is of course an interesting one, but it has to be seen in the context of off-label administration in people with no pathologies.

[Neo]

A lot of good questions. I really don’t have good answers.

@adssx

canagliflozin under performed were mostly related to psychoneurological conditions like dementia and depression. Maybe mice don’t suffer from that?

Cana did seems to have positive neuro effects, here from Richard Miller, et al:

Neuroprotective effects of Canagliflozin: Lessons from aged genetically diverse UM-HET3 mice

Hashan S M Jayarathne et al. Aging Cell. 2022 Jul.

Neuroprotective effects of Canagliflozin: Lessons from aged genetically...

[Neo]

Fill paper here:

https://onlinelibrary.wiley.com/doi/10.1111/acel.13653

[Neo]

@Neo

recruitment process and you are invited to participate in an exclusive 2-week study that examines the efficacy and tolerability of Canagliflozin on glucose biomarkers. We are offering 20 interested patients access to 1-week of Canagliflozin Rx, Urine Test Kits, and a Continuous Glucose Monitor, and will provide you with your urine glucose and average glucose biomarker results.

I just had my screening call for this (very quick and simple) and think I’m going to do it.

Seems like a great way to help the movement forward. If AgelessRx (a) publishes on SGLTi’s use in healthy individuals, even if very short study, (b) they demonstrate that half / eod dosing is works re the glucose modulation part, and especially (c) they as a leading, mainstream longevity medicine provider start offering Cana (or other flozin) as part of their services/products it could help generate much more interest for SGLTi as a gerotherapy…. (and may lead to HealthSpan and other competitors following suit and that driving even more interest as they both do social media marketing, etc)

… anyone else interested?

you would do everything from home, they send you the things home and everything iscovered by them/not cost to you.

Everyone does both a treatment week and a control week - so you are granted to test Cana, not risk that you are only in some control arm.

The main exclusion criteria is to not be taking another glucose lowering med (Acar, Metformin, GLP-1a).

If interested they said to email: research@agelessrx.com

(I have no affiliation, just think this is important for our mission and the longevity field).

[adssx]

@Neo

Cana did seems to have positive neuro effects, here from Richard Miller, et al:

Thanks. His paper refers to canagliflozin as an SGLT2 inhibitor. But adds at the end:

Among commonly used SGLT2i, Cana has the least specificity and can potentially inhibit both SGLT1 and SGLT2 transporters (Ohgaki et al., 2016). SGLT1 and SGLT2 have been detected in many areas of the brain (Głuchowska et al., 2021). Brain expression of SGLT2 is lower than SGLT1 but was detected in the microvessels of the blood–brain barrier, hippocampus pyramidal and granular cells, and astrocytes in the ventromedial hypothalamus (Poppe et al., 1997; Enerson & Drewes 2006; Fan et al., 2015; Tahara et al., 2016; Koepsell 2020; Nguyen et al., 2020). Thus, while Cana’s effects on CNS can be indirect, secondary to peripheral changes, or mediated via the activity of autonomic inputs to the hypothalamus (Spallone & Valensi 2021), it is plausible that Cana can attenuate hypothalamic gliosis directly via binding to the SGLT1 or SGLT2. Additional studies will be required to address this question.

It’s also entirely possible for me that the positive effects of these drugs are not related to SGLTi but other unknown targets (USP30 is one of them).

[Joseph_Lavelle]

I have to say a big thank you to you guys (@adssx @Neo ) who are chasing down these details on sglt2 inhibitors. I should have known that the rabbit hole goes deep. There are no easy answers. And wrong guesses can have negative consequences for health.

I don’t recall which aging researcher said it but the effort to guess at benefit by imagining mechanisms is fraught with peril. Studies on mice have many challenges when translating to people but it’s better than hand waving at mechanisms that we (or maybe just I) really don’t have any way to understand.

Fortunately there are lots of human studies on sglt2 inhibitors. The sglt1 inhibition benefits vs risks seems more unknown than known at this point. I don’t plan to take any leaps of faith here just yet.

Thanks again.

[Joseph_Lavelle]

Has this old post or related study come up with this thread? It’s seems to be about an interesting study about Cana…other beneficial effects.

Nicotine, Cognition and Neuroprotection

There is growing evidence that apart from direct mechanisms of SGLT2 inhibitors in the central nervous system, they also exert a beneficial pleiotropic effect. In silico studies indicate that flozins have the molecular ability to inhibit acetylcholinesterase. Canagliflozin was even called a ‘dual inhibitor of SGLT2 and AChE’ as its estimated inhibition constant K i (i.e., the concentration required to produce half-maximum inhibition) against AChE was 0.12859 µM [58]. It is clinically relevant as patients taking canagliflozin reach a serum drug concentration of 10µM, and the brain/serum ratio of canagliflozin is 0.3. Therefore, the amount of canagliflozin penetrating the brain (3 µM) is enough to inhibit AChE [17,59]. As for other SGLT2i, the K i for inhibiting AChE is 0.177 µM for empagliflozin and 25.02 µM for dapagliflozin, and brain concentrations are 0.5 µM and 0.3 µM, respectively, so out of those two, only in the case of empagliflozin, brain concentration is enough to inhibit AC…

[Neo]

I don’t think so. @adssx any thoughts?

[AlexKChen]

ardpharma

300 Mg Canagliflozin Tablets

does this look legit at all?

[RapAdmin]

Sure, probably - 1450 Rupees equals about $17 US (83 rupees to the US$), for what I assume is a box of 30 (3 “stripes” of 10 pills each) for a price per tablet of about $0.58.

Thats about typical pricing I think. Check out the price comparison spreadsheet: Rapamycin etc., Purchase Price Comparison Spreadsheet, and Issues Discussion

[adssx]

Thanks @约瑟夫_拉维尔. Table 1 is interesting and suggests canagliflozin and empagliflozin might be best for neuroprotection, with more data on empagliflozin regarding BNDF. However it’s not a great journal and it doesn’t come out of great research institutions either.

According to this more recent (and better?) paper: https://journals.sagepub.com/doi/full/10.1177/20406223221086996

Among the 19 studies, 5 were bioinformatic studies investigating the docking of SGLT2i with molecules involved in the pathophysiology of AD, such as AChE. For example, Shaikh et al.22 found that the docking energy between dapagliflozin and SGLT2, and between dapagliflozin and the CAS domain of AChE, were similar, which suggested that dapagliflozin may be a dual inhibitor of SGLT2 and AChE. Similarly, canagliflozin was found to have significant interactions with the S203 and H447 amino acid moieties of AChE.23 Overall, all SGLT2 inhibitors formed stable complexes with AChE in these five docking studies. Alafnan24 expanded upon these findings by revealing strong bonds between SGLT2i and other molecular targets implicated in the amyloidogenic and phosphorylation pathways of AD.

[Joseph_Lavelle]

@adssx Thanks. I’m convinced that sglt2 inhibitors are a good thing. I’m glad I’m taking one (Farxiga / dapagliflozen). I started on it to get weight loss and lower blood sugar; I didn’t get either. But maybe I’m getting these other benefits.

[Neo]

@Joseph_Lavelle

lower blood sugar

You might be getting lower spikes and less variation in your blood sugar. And hence less AGEs and also less insulin. Do you have data on your insulin on and pre SGLTi?

Might also be lowering your IGF-1 - Do you have data on that on vs pre SGLTi?

[Joseph_Lavelle]

No data from before sglt2. My insulin and HOMA-IR are normal post sglt2 so what you say is possible. My HbA1c did not improve significantly until Akkermansia.

[Neo]

@Joseph_Lavelle

My HbA1c did not improve significantly

In the successful ITP longevity studies that was actually the case for the mice too (even if in clinical studies humans do have an HbA1c lowering).

[adssx]

I’m even not sure that non diabetic humans see an HbA1c lowering.