Canagliflozin - Another Top Longevity Drug

#1546

That’s a case where the AI has no understanding of the topic because it says:

Empagliflozin works by causing excess glucose to be excreted in urine. If your glucose levels are normal, there’s little to excrete—so the drug does almost nothing.

But then the following side effects mentioned all come from that very same glucose excretion that it just said does not exist:

Known side effects include:

  • Genital and urinary tract infections
  • Volume depletion and dehydration
  • Electrolyte imbalances
  • Rare risk of diabetic ketoacidosis (DKA), even in non-diabetics

BTW even non diabetic people get glucose spikes when they eat carbs and those spikes are reduced by the SGLT2i, which is considered useful.

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#1547

SGLT2 receptors are found in multiple organs/tissues, including the heart, blood vessels, brain, etc. Mechanisms for beneficial effects exist that have nothing to do with glucose excretion in the urine

Effects are also seen in isolated cells that don’t even express SGLT2. Splitting hairs here but SGLT2 is primarily a transporter, which is fundamentally different from a receptor.

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#1548

Re: Jardiance / Empa " India-based Alembic got the nod for a generic version in 2020 but with patent disputes pending, the generic likely won’t hit the market until 2029. In February 2025, the drug will lose exclusivity relating to labeling revisions regarding clinical studies." Key drugs losing patent protection in 2025 | Pharma Manufacturing

#1549

I built a table comparing from different perspectives the benefit/risk relations of the common “flozins” when used as a geroprotective by generally healthy, non-diabetic people 65 years and older. Empagliflozin was the best choice, perhaps at a dose of 5-10 mg/day. Is there a specific reason why canagliflozin is headlined?

#1550

I think it started as a thread about canagliflozin only (maybe in response to the positive ITP data), but then people starting posting data about other flozins and so its gradually become the de facto thread for discussing those as well.

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#1551

That’s interesting. I also take empagliflozin, recently bumped it up from 10mg to 25mg/day (I’m prediabetic). I have also looked at the various flozins, but didn’t build a table. For me it was a close choice between dapagliflozin and empagliflozin. Sometimes I think maybe dapa would’ve been a better choice, but empa seems to have very slightly fewer side effects, but overall very close call. What pushed you over to empa, and how does it compare to dapa for you, if you don’t mind? TIA!

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#1552

Thanks. I’m considering adding empagliflozin to my regimen, starting at 5 mg/day and increasing to 10 mg if all goes well. I’m taking 80 mg/day of telmisartan to bring high normal BP down to mid-to-low normal. My afternoon BP can now drop to as low as 108/65 and I would not want it to drop much lower so I thought I would monitor the empagliflozin for that effect. At low doses, other possible adverse effects are said to be rare.

#1553

It seems that we’re looking at the same things. Dapa came in a strong second and not much different. Empa might have a slightly stronger renal profile in older adults.

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#1554

The effects of sodium-glucose cotransporter-2 inhibitors in chemotherapy-induced cardiotoxicity and mortality in patients with cancer: a systematic review and meta-analysis 2025

Eleven studies were included with 88,096 patients with confirmed cancer (49% male). Among the total population, 20,538 received SGLT2 inhibitors (age 61.68 ± 10.71), while 67,558 did not receive SGLT2 inhibitors (age 68.24 ± 9.48). The meta-analysis found that the patients who received SGLT2 inhibitors had a significantly lower mortality rate than those who did not receive SGLT2 inhibitors (RR 0.46, 95% CI 0.34 to 0.63, p-value < 0.0001). Similarly, the cancer-associated mortality rate was also lower (RR 0.29, 95% CI 0.27 to 0.30, p-value < 0.0001). Further analysis found that the SGLT2 inhibitor group had a lower rate of HF hospitalization, compared to controls (RR 0.44, 95% CI 0.27 to 0.70, p-value = 0.0007). Moreover, patients receiving SGLT2 inhibitors had a statistically lower rate of arrhythmia (RR 0.38, 95% CI 0.26 to 0.56, p-value < 0.0001). Finally, patients in the SGLT2 inhibitors group had a lower rate of adverse events (RR 0.51, 95% CI 0.42 to 0.62, p-value < 0.0001).

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#1555

SGLT-2 Inhibitors in Cancer Treatment—Mechanisms of Action and Emerging New Perspectives

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#1556

Another possibility they don’t mention is that SGLT2i is modulating fibrosis/ECM architecture, as ECM architecture can predict survival in at least some types of cancer. See for example a 2023 paper in Cell Reports Medicine: Desmoplastic stromal signatures predict patient outcomes in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second leading cause of cancer-related death. Hallmarks include desmoplasia with variable extracellular matrix (ECM) architecture and a complex microenvironment with spatially defined tumor, stromal, and immune populations. Nevertheless, the role of desmoplastic spatial organization in patient/tumor variability remains underexplored, which we elucidate using two technologies. First, we quantify ECM patterning in 437 patients, revealing architectures associated with disease-free and overall survival. Second, we spatially profile the cellular milieu of 78 specimens using codetection by indexing, identifying an axis of pro-inflammatory cell interactions predictive of poorer outcomes. We discover that clinical characteristics, including neoadjuvant chemotherapy status, tumor stage, and ECM architecture, correlate with differential stromal-immune organization, including fibroblast subtypes with distinct niches. Lastly, we define unified signatures that predict survival with areas under the receiver operating characteristic curve (AUCs) of 0.872–0.903, differentiating survivorship by 655 days. Overall, our findings establish matrix ultrastructural and cellular organizations of fibrosis linked to poorer outcomes.

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#1557

An exceptionally informative lecture by Dr. Ralph DeFronzo on SGLT2i mechanism of action in the kidney. It shows by the example of 10mg/day of dapagliflozin that urine excretion starts at roughly 40mg/dL glucose levels, whereas in healthy people not on SGLT2i it’s about 180mg/dL, and depending on severity (how high the A1c), it’s 200 and above. The paradox is that in T2DM, the glucose excretion threshold keeps going up as does glucose reabsorption in concert with rising A1c leading to uncontrolled rises in BG. Tons of interesting info - the yt video is almost a decade old(!).

Mercodia Webinar Dr. Ralph DeFronzo Glucagon Release with SGLT2 Inhibition

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#1558

God I so badly want a SGLT2 inhibitor that doesn’t cause glucose excretion, wouldn’t that be a great longevity drug?

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#1559

That is kind of an SGLT1 inhibitor

(And may be partially (or largely) why Cana has the great ITP longevity results)

#1560

It might lead to lower kidney benefits on eGFR though, and possibly none at all without glucose excretion (proxy for SGLT2 inhibition)

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#1561

As the yt video I posted above explains: without any SGLT1/2 inhibitors, in a person with normal glucose control, the SGLT2 transporter is responsible for 80-90% of glucose reabsorption, while the SGLT1 transporter for the remaining 10-20%. If you now however implement an inhibitor of SGLT2, you don’t get 80-90% glucose excretion, because the SGLT1 transporter takes over and increases absorption dramatically, so that instead of excreting 80-90% of glucose, you might excrete as little as 40-60%. In other words, when the SGLT2 is blocked, SGLT1 is revved up in the kidney.

DeFronzo therefore said, that likely if you want to increase glucose excretion you should combine the SGLT2 inhibitor with a SGLT1 inhibitor. However, there is a problem. While you can block almost 100% of the SGLT2 transporter, you can’t do so with the SGLT1 transporter. The reason is that while SGLT2 transporters are substantially found in the kidney, the SGLT1 transporters are prevalent elsewhere, especially in the gut where they facilitate the uptake of glucose from the gut. If you now cut off that completely, you suddenly have no glucose coming in from food. That’s obviously not sustainable. So the trick is inhibiting SGLT2 and only inhibiting SGLT1 partially.

This is where the variability among the flozins enters. This is expressed by how selective the given flozin is - is it mostly SGLT2 with minimal SGLT1 or what the proportions are along a spectrum (of course there are other distinctions, like clearance, how long it is effective within 24 hours etc.).

There are tables that show the selectivity of the various flozins for SGLT2. For example, empagliflozin is more SGLT2 selective than dapagliflozin, while dapagliflozin is more selective than canagliflozin etc.

However, we also have to note differing side effects and risk levels. So it’s more complicated than just selecting the right ratio between SGLT2 and SGLT1 inhibition.

Furthermore these transporters (especially SGLT1) are found across various tissues in the body, so the long term effects of the size and duration of inhibition have to be evaluated.

Still, SGLT2/1i are very exciting drugs and are already good longevity drugs, especially wrt. healthspan.

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#1562

Why would this be a good thing?

#1563

Many of the beneficial effects are not related to lowering blood glucose, and glycosuria can have negative effects. So if you could capture the non-kidney specific effects in another way that might be a great drug.

#1564

Exceedingly rare negative effects, especially in males who aren’t immunosuppressed.

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#1565

More rare and less severe than the documented negative effects of many statins. SGLT2i are overwhelmingly safer with fewer side effects than statins. Statins can not be tolerated at all for a percentage of people (genetic differences), some statins can cause new onset diabetes in a fairly high proportion of people, and more rarely muscle problems. I still take pitavastatin enthusiastically and think that statins are fantastic drugs (if you can tolerate them).

That said, SGLT2i are exceptionally safe, way safer than statins, though of course there are some risks, especially for subgrouos of patients. And kidney health is a huge part of the benefit. Glycosuria risks are negligible for the vast majority of people.

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