Canagliflozin – Another Top Longevity Drug

Rapa+acarb+empa/cana in the ITP asap

Unfortunately only a few papers so far looked at how SGLT2i’s affect YAP/TAZ, and none of them in high-impact journals.

There’s another interesting drug (verteporfin) which acts as a direct YAP/TAZ inhibitor and now being used off-label by some hair transplant surgeons. It prevents the scarring response normally associated with wound healing, and even shows some capacity to regenerate secondary dermal structures like hair follicles.

Oh and there’s a number of papers linking YAP/TAZ to increased activity of the AP-1 family of transcription factors, which were recently shown to promote epigenetic aging across many different cell types. I haven’t got the chance to read over them yet but I’ll compile them in the AP-1 thread eventually. Also of note, various statins inhibit YAP/TAZ via their inhibition of the mevalonate pathway, although this appears unlikely with the doses used clinically.

I thought I would share my results after six weeks of using Empagliflozin and its impact on my hematocrit and hemoglobin levels. I started with 5 mg of Empa for the first two weeks, followed by a month at 10 mg. To achieve this, I split the 10 mg pill. Here are the key outcomes:

1. A1C Levels:

• My A1C went from 5.3 to 5.4, with no significant change in my diet. This slight increase is within normal variation, although disappointing because I was hoping for an improvement in A1C.

2. Hematocrit and Hemoglobin Changes:

• My hematocrit increased from 46 to 52.3.
• My hemoglobin increased from 16.3 to 17.9.

Given that hematocrit levels above 52 present a potential blood clotting risk, I am now titrating my dose back to 5 mg to see if I can reduce my hematocrit closer to 50. It is worth noting that I am on twice-daily 60 mg of Ticagrelor, 18 months post-heart attack, which provides some protection against clotting risks.

Why These Increases Are Expected

Mechanisms at Play:

• Diuretic Effect: Empagliflozin reduces plasma volume by promoting sodium and water excretion. This concentrates red blood cells, raising hematocrit and hemoglobin levels.
• Erythropoietin Stimulation: By improving kidney oxygenation, Empagliflozin stimulates the production of erythropoietin (EPO), which boosts red blood cell production.

Observed in Clinical Trials:

• The EMPA-REG OUTCOME study consistently observed increases in hematocrit (2–5%) and hemoglobin (0.5–1.5 g/dL) in most patients.
• These changes were associated with reduced risks of cardiovascular events, kidney decline, and all-cause mortality.

Beneficial Outcomes:

• Increased hematocrit and hemoglobin improve oxygen delivery, reduce kidney hypoxia, and enhance overall cardiovascular efficiency.

Based on this understanding, I’m titrating back to 5 mg of Empagliflozin per day to monitor whether my hematocrit and hemoglobin levels decrease while maintaining the therapeutic benefits of the medication.

Thanks for sharing.

Empagliflozin has NO diuretic effect. (already discussed here)

Does dapagliflozin have the same effect on hematocrit?

Unless I am misreading the literature, Empagliflozin does induce osmotic diuresis and natriuresis, which produce diuretic-like effects, even though it is not classified as a diuretic. These effects are part of the drug’s mechanism of action and contribute to its benefits in reducing blood pressure and protecting cardiovascular and kidney health. However, the magnitude of the diuretic effect is typically less than that of traditional diuretics. I would imagine that Dapagliflozin would have the same effect. https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.120.045691#:~:text=Empagliflozin%20causes%20significant%20natriuresis%2C%20particularly,neurohormonal%20activation%20were%20not%20observed.

Diuretic means that it would increase urine. But it does not: Rilmenidine vs Telmisartan or other BP meds for Longevity – #95 by adssx

Regardless of any diuretic effect, people on SGLT2i agents will urinate more because of increased fluid intake. Fluid intake is increased, because of decrease in the time urine spends in the bladder (overactive bladder). This effect is helpful, as you want glucose rich urine to spend as little time in the bladder as possible to decrease chances of microorganism overgrowth.

Changes in overactive bladder symptoms after sodium glucose cotransporter-2 inhibitor administration to patients with type 2 diabetes

https://wchh.onlinelibrary.wiley.com/doi/10.1002/pdi.2160

“SGLT2 inhibitor administration to patients with type 2 diabetes, but without overactive bladder, caused significant increases in daytime frequency but not in night-time frequency. However, in patients with overactive bladder prior to SGLT2 inhibitor administration, blood glucose control was possible without worsening overactive bladder.”

To prevent dehydration, you should increase fluid intake on SGLT2i regardless – you want to flush that glucose out as soon as possible, and not have it hang around your urinary tract leading to infections.

To be clear, it’s not that the SGLT2i increase the volume of urine, just the frequency of urination with roughly the same volume. But people will drink more to decrease the time glucose spends in the bladder.

In people with diabetes maybe, but is this effect significant in people without diabetes? I haven’t noticed anything.

What would be best if we had a lot of studies of pharmaceuticals in healthy people, but as you know, drugs are not foreseen often to be used by healthy people, so there are few studies. That’s why we try to guess effects by testing on people with different indications – so, since SGLT2i are indicated for diabetics, most studies are going to be in diabetics, and therefore if we want to get away from diabetics, we’ll get studies in f.ex. heart patients – you can try to draw some conclusions because they are not diabetic, though not healthy.

For example here is a study in heart patients. Fluid intake must be increased on SGLT2i agents, because of the effects of osmolality.

Effects of empagliflozin on renal sodium and glucose handling in patients with acute heart failure

“As more glucose is excreted as a result of sodium‐glucose co‐transporter 2 (SGLT2) inhibition, more water is drawn to the urine keeping osmolality constant. As a result of increased electrolyte free water excretion, plasma osmolality is moderately increased and total volume of plasma and interstitial fluid is decreased.”

To compensate for decreased plasma and insterstitial volume, you should increase fluid intake, which can result in more urination (if you drink more than the compensated amount).