#1246

From RapAdmin’s article:

" Canagliflozin vs other SGLT2i?

  • While all drugs in this class have affinity for SGLT2, they have different selectivities for SGLT1 vs SGLT2. Canagliflozin has a selectivity ratio of ~ 160–410 for SGLT2 over SGLT1. In comparison, dapagliflozin’s ratio is 1,200 and empagliflozin 2,600. Due to canagliflozin’s lesser SGLT2 to SGLT1 selectivity, it is known to have effects on not only renal glucose reabsorption, but intestinal glucose absorption and metabolism as well. Thus, canagliflozin may work as a local and low-potency SGLT1 inhibitor as well as an SGLT2 inhibitor and it is possible that its effect on SGLT1 is important for senolytic function."

RapAdmin, if you don’t mind sharing, but what were the side effects you experienced on Canagliflozin (versus Empagliflozin)? I wonder if such side effects may lessen/become more tolerable with time.

2 Likes
#1247

The side effect I seemed to have was extreme fatigue. It may have resolved with longer use, or more pulsed dosing, hard to say. Here is my writeup of my experience: Canagliflozin for Anti-aging (part 2)

3 Likes
#1248

I also had fatigue w/canagliflozin, but switched to full dose Jardiance (empagliflozin) for the past couple of years and have had no such issues.

5 Likes
#1249

Here is a paper comparing SGLT2 inhibitors. They like Empagliflozin

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#1250

Thanks all, this is helpful.
Quite a few members that take an SGLT2 inhibitor, take Empagliflozin it seems. Yet I thought Canagliflozin is still the only SGLT2i-drug tested in the ITP of which we know it demonstrated lifespan effects, also in combination with Rapa. (Albeit only in male rodents). Canagliflozin has also been proven to have senolytic effects. (Albeit it seems only in rodents thus far?)
And, as that article Rapadmin posted also points out, Canagliflozin “may work as a local and low-potency SGLT1 inhibitor as well as an SGLT2 inhibitor and it is possible that its effect on SGLT1 is important for senolytic function.” Whereas the other SGLT2i’s demonstrate a very high degree of selectivity for SGLT2 compared to SGLT1.

Albeit Empagliflozin has demonstrated better effects on cardiovascular outcomes (as World Traveler’s paper also suggests), I’m still wondering whether members that use Empagliflozin are not worried they may ‘miss out on’ potential effects on lifespan of Canagliflozin.

That is, if the rodent studies may translate to humans in the first place. (Some suggestions of Perplexity.ai with that regard:
"The research on the senolytic effects of SGLT2 inhibitors like canagliflozin shows promising results in animal models, but its translation to humans remains uncertain for several reasons:

  1. Mechanisms in Animal Models: Studies have demonstrated that canagliflozin enhances the clearance of senescent cells in mice through mechanisms such as AMPK activation and PD-L1 downregulation, which boost immune-mediated senescent cell removal 1
    2
    5
    . These findings suggest potential therapeutic effects on aging-related conditions, such as metabolic dysfunction, cardiovascular disease, and atherosclerosis 3
    4
    .
  2. Lack of Direct Senolytic Effect in Human Cells: In vitro studies on human cells have not shown a direct senolytic effect of canagliflozin, even at high concentrations 1
    .This indicates that the observed effects in animal models may rely on systemic or immune-mediated mechanisms rather than direct action on senescent cells.
  3. Species Differences: The immune systems and metabolic pathways of mice and humans differ significantly. For example, the role of T cells and AMPK signaling in senescence clearance might not translate directly to human physiology 5
    .
  4. Clinical Evidence Gap: While SGLT2 inhibitors like canagliflozin are already used clinically for diabetes and cardiovascular conditions, there is no direct evidence yet from human clinical trials showing their efficacy as senolytic agents or anti-aging drugs 4
    6
    .

In conclusion, while the preclinical data is encouraging, further research, including well-designed human trials, is necessary to determine whether these findings can be effectively translated to humans.")

5 Likes
#1251

Canagliflozin treatment prevents follicular exhaustion and attenuates hallmarks of ovarian aging in genetically heterogenous mice

Ovarian aging is characterized by declines in follicular reserve and the emergence of mitochondrial dysfunction, reactive oxygen species production, inflammation, and fibrosis, which eventually results in menopause. Menopause is associated with increased systemic aging and the development of numerous comorbidities; therefore, the attenuation of ovarian aging could also delay systemic aging processes in women. Recent work has established that the anti-diabetic drug Canagliflozin (Cana), a sodium-glucose transporter 2 inhibitor, elicits benefits on aging-related outcomes, likely through the modulation of nutrient-sensing pathways and metabolic homeostasis. Given that nutrient-sensing pathways play a critical role in controlling primordial follicle activation, we sought to determine if chronic Cana administration would delay ovarian aging and curtail the emergence of pathological hallmarks associated with reproductive senescence. We found that mice receiving Cana maintained their ovarian reserve through 12 months of age, which was associated with declines in primordial follicles FoxO3a phosphorylation, a marker of activation, when compared to the age-matched controls. Furthermore, Cana treatment led to decreased collagen, lipofuscin, and T cell accumulation at 12 months of age. Whole ovary transcriptomic and proteomic analyses revealed subtle improvements, predominantly in mitochondrial function and the regulation of cellular proliferation. Pathway analyses of the transcriptomic data revealed a downregulation in cell proliferation and mitochondrial dysfunction signatures, with an upregulation of oxidative phosphorylation. Pathway analyses of the proteomic data revealed declines in signatures associated with PI3K/AKT activity and lymphocyte accumulation. Collectively, we demonstrate that Cana treatment can delay ovarian aging in mice and could potentially have efficacy for delaying ovarian aging in women.

4 Likes
#1252

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Citing:

  • Beyond ketosis: the search for the mechanism underlying SGLT2-inhibitor benefit continues 2024: “Moving forward, the field clearly must also consider SGLT2-independent mechanisms of action for SGLT2i. Recent and conclusive genetic evidence has demonstrated that SGLT2i can act independently of SGLT2 to ameliorate HF in mice, since SGLT2i produce beneficial cardiac effects in HFrEF and ischemia models even in germline SGLT2-knockout mice (20, 21, 24). Off-target cardiac candidates include NHE1, a cardiac sodium-hydrogen transporter and a target of cariporide drug trials in the early 2000s (25, 26), PANK1, a rate-limiting enzyme in replenishing CoA pools (27), and other glucose transporters. Inhibition of NHE1 or activation of PANK1, which are expressed in heart, could elicit direct cardiac effects on ionotropic or metabolic signaling that might explain the cardiac benefits of SGLT2i. Thus, the search of the mechanism continues, and will likely require a “Yes, and” understanding of the pleiotropic effects of this drug class.”
  • SGLT2 inhibition alters substrate utilization and mitochondrial redox in healthy and failing rat hearts 2024

@Pat25: on canagliflozin vs others: note that there’s also one Chinese rodent study that found life extension with empagliflozin (not ITP). In C. Elegans, none of the SGLT2i increased lifespan, though.

7 Likes
#1253

Could be relevant , but also likely not as they don’t have kidneys

Animals are most relevant when the thing you are stying is conserved from us to that species across evolution

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#1254

Unless the longevity effects of SGLT2i are unrelated to kidneys.

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#1255

I am revisiting this topic after some time away, and found the prospect of reading 1250 posts daunting.
I
used Google Gemini 1.5 Pro to summary this post, and you can read the summary here:

I actually think it’s pretty good.

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#1256

This is amazing. @RapAdmin we really need to add this feature! :slight_smile:

4 Likes
#1257

I don’t think many will use that function (because it’s probably subpar compared to this now, you need to feed the entire thread into a large context window like the Gemini models provide…), and if you do decisions based on summaries from large language models… that’s not good either way.

I have yet to see IMO someone make a good case for off-label use of SGLT2 inhbitors. I’d like to see it based on outcomes in RCT’s, that can be extrapolated with MR and applied for early use, like that can be done for statins.

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#1258

This is not a good case for you? => “Kidney function starts declining at age 30. SGLT2i slow down eGFR decline across the board. So if your eGFR is below 90 then SGLT2i makes sense.”?

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#1259

Discourse AI Summarize can use whatever model you want: Discourse AI - Summarize - Site Management - Discourse Meta

1 Like
#1260

I haven’t seen anyone make the argument persuasively, combined with MR for that. You’d want to see if it’s compounding (exponential) with time as well. I would be as big of a proponent if it is like it is for statins.

#1261

If you want an MR (for male longevity only): Canagliflozin - Another Top Longevity Drug - #1067 by adssx

And there are dozens of RCTs (cited in this thread) + association studies (for instance here: Optimal Blood Pressure we Should Target? Systolic Under 110 or 100? - #392 by adssx ) for low eGFR and all-cause mortality. There’s also this MR: Kidney Function Measures and Mortality: A Mendelian Randomization Study 2024: “MR analysis suggested that a genetically predicted lower eGFRcyst was linearly associated with a higher rate of cardiovascular mortality (HR, 1.43; 95% CI, 1.18-1.75) across the entire measurement range (every 10-mL/min/1.73m2 decrement). Nonetheless, no causal associations between eGFRcyst and all-cause mortality (HR, 1.07; 95% CI, 0.98-1.17) or any types of noncardiovascular mortality were detected.” (all-cause mortality borderline significant, I’ll take it!).

And life extension in male mice for canagliflozin (ITP) and empagliflozin (non-ITP).

So the case in men with an eGFR below 90 seems strong to me (even below 100?). In females: I don’t know. In people with eGFR > 100 and perfect glycemia: I don’t know.

4 Likes
#1262

I meant MR for eGFR and SGLT2 or SLGT1 inhibition, bringing up all-cause mortality or longevity is not important at this stage.

That’s why statins and other similar drugs is so persuasive.

They lead with reducing cardiovascular events, that is compounding over time with massive decrease. This is just so much different information you brought up, and mice studies are not persuasive. That’s why I am not using these. No good, organized, arguments.

#1263

Of course SGLT2i protects eGFR. We don’t need MR for that we have hundreds of RCTs. But here is an MR: SGLT2 inhibition, high-density lipoprotein, and kidney function: a mendelian randomization study | Lipids in Health and Disease

The case seems easy to me:

  • For eGFR the higher the better (RCTs + association studies + MR)
  • eGFR declines from age 30
  • Once eGFR goes below 15 you die
  • SGLT2 prevent eGFR decline across the board (RCTs + MR + association studies)
  • Cherry on the cake: SGLT2i increases longevity in males (MR + mice studies)

What else do you need? The case seems stronger than for statins to me.

5 Likes
#1264

@adssx From the many papers you have seen about the SGLT2i’s over the years: was there any difference in outcome between females and males, that you know of - besides the ITP? And what is your thought about the root of the differences in outcome between genders in the ITP, if you don’t mind me asking?
Years down the line, I’m still wondering what may have been the reason Cana has been sown to extend lifespan in male, but not in female rodents.

#1265

Beta 0.05 = 5% increase in eGFR for every 1 SD increase in SGLT2 inhibition… lifetime… not clinically relevant?