#1305

Absolutely brilliant post. The only way in which it could be better is if the first paper wasn’t Chinese. But. There are many other good papers here and very intriguing reasoning following the breadcrumbs of multiple organ fibrosis, with known effects. Excellent all around, and worth a deep dive - I’m rolling up my sleeves and tucking in. Thank you, jnorm!

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#1306

Rapa+acarb+empa/cana in the ITP asap :pray:

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.

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#1307

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.
  1. 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.

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#1308

Thanks for sharing.

Empagliflozin has NO diuretic effect. (already discussed here)

Does dapagliflozin have the same effect on hematocrit?

#1309

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.

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#1310

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

#1311

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.

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#1312

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

#1313

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).

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#1314

Incidentally, because I am vigilant about the osmolality effects of empagliflozin, I have increased my intake of taurine to 3-4g/day. Taurine works at the cellular level.

Taurine Homeostasis and Volume Control

“Taurine content is high (mM) in mammalian brain. By its major role as an osmolyte, taurine contributes to the cell volume control, which is particularly critical in the brain. Taurine participates in osmotic adjustments required to maintain the organization and size of intracellular compartments. It counteracts volume fluctuations in unbalanced transmembrane fluxes of ions and neurotransmitters, preserving the functional synaptic contacts. Taurine has a key role in the long-term adaptation to chronic hyponatremia as well as in other pathologies leading to brain edema. Together with other osmolytes, taurine corrects cell shrinkage, preventing mysfunction of organelles and apoptosis. Swelling corrective taurine efflux occurs through a leak pathway, likely formed by LCRR8 protein isoforms. Shrinkage-activated influx comes largely by the increased activity of the Na+/Cl–dependent transporter. The brain taurine pool results from the equilibrium between (i) dietary intake and active transport into the cell, (ii) synthesis in the brain itself or import of that synthesized elsewhere, and (iii) leak and posterior excretion. The interplay between these elements preserves brain taurine homeostasis in physiological conditions and permits the proper adjustments upon deviations of normal in the internal/external environment.”

But this is true of other cells in the body, not just the brain. In any case, in my opinion, if you take SGLT2i, supplementing with taurine is helpful to offset possible osmolality side effects from those agents.

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#1315

Every single drug is tested on healthy people in phase 1. So the effect we’re talking about, if significant, would have been reported I think.

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#1316

Hi, Just my experience (with Canagliflozin 150 mg) and I saw this pattern twice. Using Canagliflozin for 3+ months then taking a break. Values seem to quickly drop after stopping Canagliflozin.

Hematocrit and Hemoglobin Changes:

  • My hematocrit increased from 40 to 48.
  • My hemoglobin increased from 14 to 17

So not insignificant but not too bad.

I also just recently got a DEXA with the new year (first DEXA so nothing to contrast it with) and it showed my bone density was in the lower 15% of men my age (Almost 50). I squat, deadlift, walk a lot and such so this was a surprise. I know Canagliflozin has been shown to reduce density. I’m currently taking a break from Canagliflozin to see if bone mass density (BMD) increases with the next DEXA.

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#1317

Is offering sglt2s now. Let me inquire on which one it is and their rationale. +1 for another data point, but have to take it with a grain of salt because I’d imagine they’d balance safety and profit over efficacy.

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#1318

I’ve been taking Empagliflozin 25mg for ~5 months now along with Mounjaro 5mg. Some results:

A1c: 5.1 → 5.1
Fasting Glucose: 97 → 83
CGM data (before numbers are rough estimates):
Average Glucose: 95 → 87
Glucose Variability: 11 → 8
Glucose Peak: 160 → 120
Time in range of 70-110: 95% → 99%
Glucose in urine/day: 40g (based on 2g/dL measurement and ~2L urine per day)

It’s interesting that my A1c is unchanged, despite all other markers improving. My numbers were pretty good before, and they’ve gotten even better with the addition of these 2 medications. No other changes in this time period that would be likely to move these numbers as significantly.

Also, we learned that some testing providers will call your Doctor on seeing that much glucose in urine.

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"Pre-Diabetes": (?) How aggressively to treat?
#1319

Great post, but this particular part is actually not true, and I will be jumping for joy if this myth can finally die one of these years. The TRT world has proven that these increases are not harmful at all. It’s only a concern if you have high platelets or test positive for the genetic clotting factors you can get blood tests for (like Factor V and JAK2).

There is not one single study that exists showing a hematocrit of 50+ in isolation by itself presents any risks of cardiovascular events. In fact, people living at very high altitudes can see hematocrits over 60, and they are not dropping dead of thrombotic events.

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#1320

Any body weight, lean mass, fat % before-and-after measurements?

#1321

I’ve been tracking with frequent dexa scans and I’ve lost ~7lbs of fat mass. I’ll hold off on reporting lean mass/body comp until after I’m weight stable and back to maintenance (or even slight surplus) calories because it’s quite variable for me with food intake between additional water weight/glycogen storage/food in GI. In other words, just by going on a hypocaloric diet it looks like I lose 5-10lbs of lean mass.

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#1322

Healthspan response as of 1/19/25

we prescribe bexagliflozin as part of our metabolic protocol to support improved metabolic health and longevity. Bexagliflozin is in the same class as Canagliflozin and works by reducing glucose reabsorption in the kidneys, allowing excess glucose to be excreted through urine. While SGLT-2 inhibitors offer significant metabolic and healthspan benefits, they are generally not recommended alongside low-carbohydrate or ketogenic diets. The combination can elevate the risk of euglycemic diabetic ketoacidosis (euDKA), a condition characterized by dangerously high ketone levels despite normal or low blood sugar levels. Low-carb diets naturally increase ketone production as the body shifts to fat metabolism, and SGLT-2 inhibitors further enhance ketogenesis by promoting free fatty acid mobilization. This synergistic effect can inadvertently push ketone levels into a hazardous range. There is also an increased risk of dehydration and electrolyte imbalances as well. If you are eating higher carb meals occasionally it would be recommend to continue with Acarbose for those meals.

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#1323

Serum phosphate levels were significantly increased compared with placebo for dapagliflozin 5 mg (WMD 0.04 mmol/l [95% CI 0.01, 0.06]) and 10 mg (WMD 0.05 mmol/l [95% CI 0.02, 0.09]) (Table 1 and ESM Fig. 3).

Is this a bad thing from the perspective of dapagliflozin? Isn’t phosphate linked to Klotho? The study doesn’t mention that other SGLT2 inhibitors significantly raise phosphate levels. Or is the entire study nonsense? Or could it be that in the case of SGLT2 inhibitors, Klotho increases even though phosphate levels also rise?

1 Like
#1324

More recent papers:

  • Effects of Dapagliflozin on Circulating Markers of Phosphate Homeostasis 2019: “Patients were randomized to dapagliflozin 10 mg/d or placebo during consecutive 6-week study periods, separated by a 6-week wash-out. […] Thirty-one patients (age 62 years; 23% female) were analyzed. Compared with placebo, dapagliflozin increased serum phosphate by 9% (95% confidence interval, 4% to 15%; P=0.002), PTH increased by 16% (3% to 30%; P=0.01), FGF23 increased by 19% (0.3% to 42%; P=0.05), and serum 1,25(OH)2D decreased by −12% (−25% to 4%; P=0.12). Calcium and 25(OH)D were unaffected. We found no correlation between changes in markers of phosphate homeostasis and changes in eGFR or 24-hour albumin excretion during dapagliflozin treatment.”
  • Effects of empagliflozin on markers of calcium and phosphate homeostasis in patients with type 2 diabetes – Data from a randomized, placebo-controlled study 2022: “After 3 days of treatment empagliflozin significantly increased serum levels of phosphate (baseline: 1.10 ± 0.21 mmol/L; day 3: 1.25 ± 0.23 mmol/L; p = 0.036), parathyroid hormone (PTH) (baseline: 57.40 ± 30.49 pg/mL; day 3: 70.23 ± 39.25 pg/mL; p = 0.025), fibroblast growth factor 23 (FGF23) (baseline: 77.92 ± 24.31 pg/mL; day 3: 109.18 ± 58.20 pg/mL; p = 0.001) and decreased 1,25-dihydroxyvitamin D (baseline: 35.01 ± 14.01 ng/L; day 3: 22.09 ± 10.02 mg/L; p < 0.001), while no difference of these parameters was recorded after 3 months of treatment. Empagliflozin had no significant effects on serum calcium and markers of bone resorption (collagen type 1 β-carboxy-telopeptide = β-CTX) or formation (osteocalcin) after 3 days and 3 months of treatment.”
  • Effects on calcium phosphate homeostasis after sodium-glucose cotransporter 2 inhibitor in patients with advanced chronic kidney disease and type 2 diabetes mellitus 2024: “We analyzed 1,450 SGLT2i users and 4,350 control subjects. At the 12th month, SGLT2i users had a slower increase in phosphate levels (absolute change: −0.01 ± 0.28 vs + 0.14 ± 0.34 mmol/L; percentage change: −0.74 % ± 25.56 vs + 10.88 ± 28.15 %, P for both < 0.001). The proportion of patients with high phosphate was lower with SGLT2i (8.2 % vs 24.6 % increase). In the generalized estimating equation, SGLT2i was linked to a longitudinal reduction in phosphate (B −0.039, P<0.001).”

How to make sense of all of that? Short-term increase followed by a return to baseline and eventually a lower increase than controls?

I don’t know if the comparison makes sense (I know nothing about phosphate) but SGLT2i are approved for kidney disease and they prevent eGFR decline and yet after starting them many people experience a dip in eGFR (so a worsening of their kidney function!). Most of these people go back to their baseline after a few weeks, but some don’t and yet even those are still better off 12 months later compared to controls (who caught them up in terms of decline)!

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