Canagliflozin - Another Top Longevity Drug

[DeStrider]

My wife has had several UTIs. Drinking cranberry juice was recommended by the doctor to help clear it up. It appears to help a lot.

[adssx]

Yes, it’s been confirmed by this recent Cochrane review: Cranberries for preventing urinary tract infections

These data support the use of cranberry products to reduce the risk of symptomatic, culture‐verified UTIs in women with recurrent UTIs, in children, and in people susceptible to UTIs following interventions.

[Joseph_Lavelle]

The old tricks are the best tricks. Cranberry juice has been my go UTI solution for 40 years.

[adssx]

Dapagliflozin ameliorates diabetes-induced spermatogenic dysfunction by modulating the adenosine metabolism along the gut microbiota-testis axis 2024

We found that dapagliflozin treatment significantly alleviated the diabetes-induced spermatogenic dysfunction by improving sperm quality, including the sperm concentration and sperm motility. […] Our findings support the potential use of dapagliflozin to prevent the diabetes-induced impaired sperm quality and to treat diabetic male infertility.

[Neo]

Extremely helpful. Thanks a bunch.

[szalzala]

I keep reading mixed things about the generic availability of Invokana. One day, it seems like its just right around the corner, the next day I read that it might not be until 2027.

Here is the basis of the trial:
Some of the SGLT2i meds seem to have a decent half life or activity on the SGLT2 receptor.
If taking for longevity, a person might not need to take it every day
We obtained tablets from all 5 approved SGLT2i meds. Only canagliflozin was amenable to breaking in half. The other tabs were oddly shaped (likely on purpose if I were a cynic) and could not be easily broken.

We have preliminary data that taking half tab of 300mg canaglizflozin (150mg) every other day seems to provide a decent amount of glucosuria every day (not just the day taken).

Our next step is to scale this up to include a few dozen participants and use CGM sensors and urinalyses to validate if 150mg every other day will show adequate results.
Since the 100 and 300mg tabs are the same cost for Invokana, taking 1/2 tab QOD effectively drops the price by 1/4. Still expensive, but might be reasonable for some enthusiasts.

I think we will enroll from our internal patient base. but you care reach out to research at agelessrx dot com to express interest in our trial

[Rapasailor]

I’ve never noticed an affect on CGM data when on an SGLT2 (tried Cana and Emp). Have others seen this?

[RapAdmin]

I’ve found it very effective at flattening post prandial (meal) blood glucose curves. See my posts here: Canagliflozin for Anti-aging (part 2)

[SNK]

@szalzala

The other tabs were oddly shaped (likely on purpose if I were a cynic) and could not be easily broken.

I hear you, but I bought a pill cutter/divider on amazon a while back, and I have yet to find a pill that will not be cut in 1/2 almost 100% of the time. And, when i want 1/4th of a pill, I cut the half again and that gives me the correct dose. Cutting pills in more than four parts it’s probably harder (or never tried it)

[Jay]

SNK, Can you provide a link to this pill cutter?

[SNK]

I bought this one, but there is many options.

Amazon.com: Ezy Dose Pill Cutter and Splitter with Dispenser, Cuts Pills, Vitamins, Tablets, Stainless Steel Blade, Travel Sized, Colors May Vary : Health & Household

[adssx]

Diabetes, antidiabetic medications and risk of dementia: A systematic umbrella review and meta-analysis 2023

Metformin, thiazolidinediones, pioglitazone, GLP1RAs and SGLT2is were associated with significant reduction in risk of dementia. When studies examining metformin were divided by country, the only significant effect was for the United States. Moreover, the effect of metformin was significant in Western but not Eastern populations. No significant effect was observed for dipeptidyl peptidase-4 inhibitors, α-glucosidase inhibitors, or insulin, while meglitinides and sulphonylureas were associated with increased risk.
Metformin, which remains the first-line medication for the management of type 2 diabetes, did show benefits for dementia risk in our meta-analysis, yet newer treatments may confer greater risk reduction for dementia; this finding is of importance, given the extensive use of GLP1RAs and SGLT2is in clinical practice at present.
The meta-analyses showed an overall protective effect of:
metformin [RR 0.83 (0.71-0.96)],
thiazolidinediones [RR 0.770 (0.593-0.999)],
pioglitazone [RR 0.74 (0.55-0.98)],
GLP1RAs [RR 0.35 (0.16-0.78)] and
SGLT2is [RR 0.39 (0.20-0.76)] on risk of dementia.
DPP-4is, α-glucosidase inhibitors and insulin had a neutral effect on risk of dementia, while meglitinides and sulphonylureas were associated with increased risk.

Yet another study that found that for dementia prevention, acarbose is useless (“neutral”), while GLP1RAs and SGLT2is seem magical. Metformin is “meh”, especially useless for Asians.

[DeStrider]

You’ve convinced me. The next Med I’ll add is empagliflozin or canagliflozin.

[scta123]

Your are really driving my interest in SLG2i.
Have you found anything negative? Because I know a lot of doctors and they seem not as convinced as you… but I have a box of Jardiance (Empaglifozin) sitting in my cupboard for a while now. Maybe I should give it a try.
My main concern or maybe is just my obsessiveness is trying to figure out how many calories are you loosing via glucose excretion. I am currently doing CR(ON) of 10% and this keeps my weigh stable and adding Empaglifozin would effect this balance?
I also was wondering if I could take it intermittently (EOD) and if I could do it half of 25mg pill.

[adssx]

Haha, actually, I’m not trying to convince anyone other than myself… For context, I’ve had issues with my glucose levels, especially reactive hypoglycemia. Acarbose improved the situation, but not enough. I suggested a GLP1RA to the doctor (based on this paper + their overall positive effects) to which he answered: “GLP1 will increase your insulin, you have reactive hypo, you don’t want more insulin” and prescribed an SGLT2i. Before starting it, I did my research and the more I looked, the more impressed I was. So I started dapagliflozin (5 mg, then 10 mg per day). I’ve been taking it for exactly 1 month now, and, I don’t want to jinx it, but I feel way better…

Here are all the “negative” things I’ve found:

• UTIs and fungal infection: we discussed it a lot. The risk seems limited among non-diabetic people with good hygiene and can be limited even further with cranberry products. I started taking cranberry pills, I hope they’re as effective as cranberry juice,
• DKA: risk seems non-existent in non-diabetic people, but those on a keto diet should look further at this,
• It’s recommended to stop them 3 days before surgery because of DKA risk after fasting for surgery (Figure 1 is nice btw): I’m OK with that,
• Lipid profile: SGLT2-inhibition increases total, LDL, and HDL cholesterol and lowers triglycerides: Meta-analyses of 60 randomized trials, overall and by dose, ethnicity, and drug type 2023 but “Overall, changes were modest and not likely to be of clinical relevance.” (according to DrLipid, it’s “not an issue”)
• It’s unclear which one is “best” between cana, dapa, empa, and others. My understanding so far that is they’re overall identical but there might be subtle differences for some applications (for instance, dapa might be potent to prevent depression: The potential antidepressant effect of antidiabetic agents: New insights from a pharmacovigilance study based on data from the reporting system databases FAERS and VigiBase 2023, while cana and empa might be better for PD: Repurposing the inhibitors of MMP-9 and SGLT-2 against ubiquitin specific protease 30 in Parkinson’s disease: computational modelling studies. 2023)
• Some early studies (2014, so 1y after their approval) reported an increase in PTH and bone fractures: SGLT2-inhibitors Trigger Downstream Mechanisms That May Exert Adverse Effects Upon Bone 2014. However, two serious meta-analyses (one Italian and one Chinese) from last year concluded that there was no elevated risk: Effect of SGLT2 inhibitors on fractures, BMD, and bone metabolism markers in patients with type 2 diabetes mellitus: a systematic review and meta-analysis 2023 and Adverse effects of sodium-glucose cotransporter-2 inhibitors in patients with heart failure: a systematic review and meta-analysis 2023
• Increased urinary frequency during the day, but not at night (I noticed this as well, which I think is not so bad because I was not drinking enough water before, now I drink more): Changes in overactive bladder symptoms after sodium glucose cotransporter-2 inhibitor administration to patients with type 2 diabetes 2018
• SGLT2is inhibit mTOR, so should you cycle them? What’s the optimal dose? Are lower doses better? (the ITP is now testing a lower dose of cana) However, I don’t know how their mTOR inhibition potency compares to rapamycin. Daily SGLT2i is maybe like microdosing rapa, I don’t know.

[Neo]

@adssx

It’s unclear which one is “best” between cana, dapa, empa, and others. My understanding so far that is they’re overall identical but there might be subtle differences for some applications

One difference — that I don’t know how meaningful — is that Cana is also SGLT1i not only SGLT2i, while the other main ones are just SGLT2i I believe.

(And we don’t know how much the SGLT1i was behind the ITP results)

Not sure how much to weigh that, but it is nudging me towards Cana until more data on that comes out.

@adssx do you have a sense for what direction it takes for mTORC2? See this decedent discussion:

Is there a way to selectively upregulate Mtor2 while on Rapamycin?

Has anyone explored the idea of getting an “insurance policy” against overdosing of Rapamycin; by upregulating Mtor2 through medication or supplements?

[adssx]

I have the opposite reasoning Because empagliflozin and dapagliflozin are highly selective for SGLT2, I feel like they’re safer (and they seem to be, based on trials and longitudinal data). But there’s really not enough evidence around this.

I know nothing about mTORC2, but this 2023 paper concludes: mTORC1 and SGLT2 Inhibitors-A Therapeutic Perspective for Diabetic Cardiomyopathy - PubMed

Further studies are warranted to establish the underlying cardioprotective mechanisms of SGLT2is under diabetic conditions, with selective inhibition of cardiac mTORC1 but the concomitant activation of mTORC2 (mTOR complex 2) signaling.

[AnUser]

@adssx

Because empagliflozin and dapagliflozin I very selective for SGLT2, I feel like they’re safer (and they seem to be based on trials and longitudinal data)

I haven’t payed much attention to these drugs yet but I will soon since they look so promising.

But do you mean because that the mechanism of action is more clean? (It’s less of a dirty drug). And as you say based on trials and longitudinal data as well.

[adssx]

Canagliflozin binds to SGLT2 and a bit SGLT1. Sotagliflozin binds to both well. All others (including dapa and empa) bind to SGLT2 only. I think I posted a few papers previously showing that empa and/or dapa had better positive effects and fewer adverse events than cana. But nothing super convincing yet.

[desertshores]

Canagliflozin would have to be shown to be much better than the others for me to take it again. I put up with an uncomfortable lower digestive system with canagliflozin for months before I stopped taking it.