Canagliflozin - Another Top Longevity Drug

#1768

Comparative effectiveness and prescribing patterns of dapagliflozin vs empagliflozin in type 2 diabetes patients: a target trial emulation 2025

Dapagliflozin and empagliflozin showed similar cardiorenal and safety outcomes.
However, analysis among patients without stable prior ACEI/ARB exposure revealed a higher risk of all-cause mortality with empagliflozin. Dapagliflozin was more often prescribed by cardiologists, while endocrinologists and nephrologists favored empagliflozin.

Sodium-glucose cotransporter 2 inhibition restores testicular microvascular perfusion via endothelial signaling in a large animal model of metabolic syndrome and heart failure 2025

Canagliflozin enhances testicular microvascular perfusion in a swine model of metabolic syndrome and ischemic cardiomyopathy.
Treatment increases phosphorylated endothelial nitric oxide synthase, extracellular signal-regulated kinase, and focal adhesion kinase expression – regulators of vascular tone, endothelial function, and cell survival.
SGLT2 inhibition reduces expression of BCL2-associated agonist of cell death, enhancing cellular survival.

Evaluation of Key Safety Outcomes of SGLT2 Inhibitors in the Real World: A Target Trial Emulation Study 2025

After propensity score via overlap weights and in the ITT analysis, the SGLT2i group showed significantly lower incidence (per person-year) compared to the DPP4i group for several safety outcomes: UTI (20·67‰ vs. 25·57‰, hazard ratio [HR]: 0·81, 95% confident interval [CI]: 0·79–0·83), fracture or falls (16·59‰ vs. 18·06‰, HR: 0·92, 95% CI: 0·90–0·94), AKI (0·94‰ vs. 2·04‰, HR: 0·46, 95% CI: 0·41–0·50), bullous pemphigoid (0·05‰ vs. 0·10‰, HR: 0·50, 95% CI: 0·33–0·76), and all-cause mortality (13·64‰ vs. 23·73‰, HR: 0·57, 95% CI: 0·56–0·59). Conversely, the risk of genital infection was significantly higher in the SGLT2i group (2·50‰ vs. 1·54‰, HR: 1·62, 95% CI: 1·52–1·73). These findings remained consistent in the PP analysis and across most subgroups.

SGLT2 inhibitor therapy and lower incidence of iron deficiency anaemia in patients with type 2 diabetes: A retrospective cohort study from Germany 2025

SGLT2i therapy was associated with a lower incidence of IDA in T2DM patients compared to DPP-4i therapy. These findings suggest a potential hematologic benefit of SGLT2 inhibitors, warranting further investigation in randomised controlled trials.

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#1769

Gut microbiota–tryptophan metabolism–GLP-1 axis participates in β-cell regeneration induced by dapagliflozin2024

In summary, treatment with dapagliflozin in type 2 diabetic mice promotes β-cell regeneration by upregulating GLP-1 production, which is mediated via gut microbiota and tryptophan metabolism.

In that case, shouldn’t all patients using certain statins be immediately put on an SGLT2i (dapagliflozin)? Because [CAUTION: Chinese!]:

Statins aggravate insulin resistance through reduced blood glucagon-like peptide-1 levels in a microbiota-dependent manner

https://www.sciencedirect.com/science/article/pii/S1550413123005053

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#1770

12 posts were merged into an existing topic: Cardiovascular Health

#1771

Very true, except it can be higher than the 52-54 range as long as there are no genetic risk factors like Factor V (which a blood test can check for) and elevated platelets (also hypertension, high fibrinogen, high WBC).

From Vera AI: The average adult male living at the world’s highest permanent settlements** (Andean highlanders, La Rinconada) typically has Hb ~19–21 g/dL and Hct ~58–65%

Those people do not have any more thrombosis than the sea level population (unless they have high platelets or genetic clotting risks).

But yes, SGLT2’s do indeed raise hematocrit and hemoglobin.

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#1772

Right, but the key difference is that adaptations to high altitude are different than what occurs with elevated hematocrit from testosterone (and/or SGLTIs). The adaptations from high altitude implement a coordinated physiologic response that reduces the risk of thrombosis, whereas such adaptations do not occur with testosterone therapy. This explains it pretty well:

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#1773

Oh I know they’re different. I’m just pointing out I don’t think there is a big concern with elevated hematocrit and hemoglobin regardless without the other aforementioned risk factors. There certainly isn’t with SGLT2’s. In fact, I would imagine the risk would be greatly reduced on an SGLT2.

#1774

I really do wish that were the case, but it seems there is a big concern:

“Recent multi-institutional cohort studies have demonstrated that elevated hematocrit (≥52%) in men on testosterone therapy is independently associated with a higher risk of major adverse cardiovascular events and venous thromboembolism, even in the absence of other risk factors. For example, men who developed polycythemia while on testosterone had a significantly higher incidence of MACE/VTE compared to those who maintained normal hematocrit, with an odds ratio of 1.35 (95% CI 1.13–1.61) in the first year of therapy.[3] This risk appears to be independent of baseline thrombophilia or other traditional risk factors.”

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#1775

You would think they would be adequately powered: “23 RCTs with 155,443 participants included in the meta-analysis”. But:

According to the results, compared with placebo, no significantly altered dementia risks were observed in patients receiving DPP-4i (RR = 1.19, 95%CI, 0.61 to 2.32), SGLT-2i (RR = 0.45, 95%CI, 0.67 to 3.12), GLP-1RA (RR = 1.08, 95%CI, 0.57 to 2.05), TZD (RR = 0.73, 95%CI, 0.09 to 32.74), or sulfonylurea (RR = 1.75, 95%CI, 0.66 to 4.63). With respect to the risks of Alzheimer’s disease, vascular dementia, and dementia with Lewy bodies, no significant associations were observed when intercomparing all anti-diabetic agents and placebo as well. …

since the included RCTs were mostly designed for other evaluation outcomes, the reported dementia events were with unclear event disclosure and in lack of adjudication by professionals. The meta-analyses results generated by data from RCTs may not adequately reflect the actual association between anti-diabetic agents and dementia event risks.
Anti-diabetic agents and the risks of dementia in patients with type 2 diabetes: a systematic review and network meta-analysis of observational studies and randomized controlled trials | Alzheimer's Research & Therapy | Full Text

#1776

Why are these figures different from those in Table S6 and S7?

Then, those are short RCTs for diabetes so it’s not surprising not to find anything statistically significant. Still, SGLT2 are on the “good side of null” and combined with MR and longitudinal studies, that’s enough for me: Canagliflozin - Another Top Longevity Drug - #1742 by adssx

A small RCT of dapagliflozin in AD also found cognitive improvement (posted here previously).

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#1777

New mechanism of action? Dapagliflozin sustains heart function in type 3 cardiorenal syndrome by restoring DUSP1-dependent mitochondrial quality control 2025

Defective MQC critically contributes to CRS-3-related myocardial dysfunction. The study proposes that DAPA therapy may normalize DUSP1-dependent MQC and consequently alleviate the cardiac depression associated with CRS-3.

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#1778

Second study says:
Results: A total of 5,842 men who received TT and developed polycythemia were matched and compared to 5,842 men who did not develop polycythemia. Men with polycythemia had a higher risk of MACE/VTE (number of outcomes: 301, 5.15%) than men who had normal hematocrit (226, 3.87%) while on TT (OR 1.35, 95% CI 1.13-1.61, p <0.001).

While I suppose you’re right, that’s still a pretty small risk and 5.15% compared to 3.87% doesn’t seem like much, given the large number of people.

Nattokinase I believe is the best safe insurance policy we could take to mitigate any increased risk. I have a high hematocrit so I take plenty of that (8000FU + a bag of fermented natto daily), just in case.

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#1779

It’s a 33% increased relative risk, bringing it up to more than 1 in 20, so with my cardio history (calcium score and high Lpa), I need to be careful. I’m anxious to see what my hematocrit is today after stopping empagliflozin, changing TRT to daily microdose, increasing cardio, increasing to max dose irbesartan and staying well-hydrated :crossed_fingers:

I also take nattokinase every night (10,000 FU). I’m not convinced it’s helpful because the research quality is shaky at best, but risk of harm seems low and it’s cheap.

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#1780

SGLT2 Inhibitors Increase Hemoglobin and Hematocrit Levels in Patients With Chronic Kidney Disease: A Systematic Review and Meta-Analysis 2025

in three studies evaluating Hct levels, SGLT2 inhibitors significantly increased Hct levels compared with controls (SE = −0.453; 95% CI −0.829–0.077).

Same in T2D: https://onlinelibrary.wiley.com/doi/full/10.1111/jcmm.17115

Potentiall MoA:

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#1781

Odd. I don’t think I have kidney damage, as none of my other numbers say so. T2DM, same, A1c 5.7, FBG 98. Maybe I was slightly dehydrated for the test (approx. 18 hours with no liquids).

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#1782

If you only tried it for one day, that’s just not a good test: it could have been some other, random thing. Try five days at a low dose, five days off, and five days on again.

You and @Pender could also try canagliflozin, which is a dual SGLT1/2 inhibitor, so you absorb less glucose in the GI rather than only losing it out the urine.

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#1783

In what way can a CGM not work for you? You have no glucose in your interstitial fluid?

#1784

They don’t work for me because I have essentially zero fat over top of my triceps muscle, so the needle goes into my muscle, hurts like hell the entire time the CGM is on, and gives sketchy readings.

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#1785

Excellent summary w/references of the MOA of increased hematocrit from SGLT2 inhibitors. It does NOT require chronic kidney disease to see this effect:

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#1786

The CGM I tried was the recent Abbott OTC one. I tried it twice, so have a roughly 4 week experience. I followed all instructions carefully.

It was perfectly useless. It gave wild and bizarre readings. At night (and sometimes during the day) it would always show my glucose reading below the parameters which they measure (itself a shit design - why won’t it measure below x or above y?), so there’d be a multihour gap in data, when according to the CGM, I guess I’m comatose, glucose so low it’s undetectable by this shit detector.

For no discernable reason it would show randomly readings go up or down by 30+ points within a minute or two, and I’m not doing anything, just sitting (not eating, not drinking, not cold/hot, excited, etc.).

But fundamentally, it had zero accuracy. I would regularly (several times a day) check against my fingerprick glucose monitor, and the readings comparison would be all over the place, often by 30-40 points (and yes, I accounted for time shift between interstitial vs serum readings).

Finally, I performed a three way validation test. At UCLA, I had my blood drawn, within seconds I did a fingerprick reading on my glucose monitor, and read out the CGM over the next few minutes multiple times (to account for the time shift). The venipuncture serum by a phlebotomist at a teaching hospital UCLA, the gold standard, my glucose monitor was 7 points lower (i.e. within the expected margin of error for that unit), and the CGM was off by 30+ points.

A device that is so erratic and with such huge swings and wildly off readings (and not even by a consistent amount off, just random) is the definition of useless.

I tried two sensors in case one was faulty. Garbage.

Clearly it works for many (most?), but for me, it was throw it against the wall and stomp it useless. YMMV.

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#1787

My readings are accurate even going directly into the tricep muscle. +1 on pain/annoyance though.

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