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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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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adssx
#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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Rob01
#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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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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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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LukeMV
#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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Davin8r
#1320
Any body weight, lean mass, fat % before-and-after measurements?
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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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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tj_long
#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?
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adssx
#1324
More recent papers:
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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.”
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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.”
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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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adssx
#1325
Dapagliflozin plus calorie restriction for remission of type 2 diabetes: multicentre, double blind, randomised, placebo controlled trial 2025
Interventions Calorie restriction with dapagliflozin 10 mg/day or placebo.
Remission of diabetes was achieved in 44% (73/165) of patients in the dapagliflozin group and 28% (46/163) of patients in the placebo group (risk ratio 1.56, 95% confidence interval (CI) 1.17 to 2.09; P=0.002) over 12 months, meeting the predefined primary endpoint. Changes in body weight (difference −1.3 (95% CI −1.9 to −0.7) kg) and homoeostasis model assessment of insulin resistance (difference −0.8, −1.1 to −0.4) were significantly greater in the dapagliflozin group than in the placebo group. Likewise, body fat, systolic blood pressure, and metabolic risk factors were significantly more improved in the dapagliflozin group than in the placebo group. In addition, no significant differences were seen between the two groups in the occurrence of adverse events.
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LukeMV
#1326
Anecdotally, my eGFR is consistently better now after having been on Empagliflozin a few years compared to what it was before. It wasn’t bad to begin with, but it is higher now most of the time. EGFR heavily fluctuates though.
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Have you noticed any changes in your resting heart rate or HRV while using Mounjaro?
RHR went up a few bpm for a couple of months and then decreased back to baseline. I did start taking Ivabradine, but in theory it shouldn’t be the reason my RHR decreased since I’m typically ~50bpm and afaict from the research Ivabradine won’t lower RHR unless it’s significantly elavated.
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PBJ
#1329
My experience is quite similar to dicarlo2’s. Initially, I noticed a slight increase in resting heart rate (RHR), but over time, it has decreased significantly, likely due to weight loss. In my opinion, most people wouldn’t notice a meaningful increase in RHR unless the dosage exceeds 5 mg. However, at 10 mg, I experienced a noticeable rise, which led me to reduce my dose to 7.5 mg.
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LukeMV
#1330
So no benefit from the Ivabradine? I started it and it seems to be lowering RHR slightly.
Beth
#1331
And @CronosTempi
I was just going to comment on this, too
I’ve been on an sglt2 for a couple of months and I keep waiting to have to urinate more often, but nope, nothing is different
I’m not diabetic
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I’m much more confident that it helps with POTS, my tachycardia issues (and related POTS symptoms) on standing are completely resolved.
My comment about it probably not working for GLP1 induced heart rate increases was based on this post and also another that I can’t find regarding a study on ivabradine and starting RHR (I could be misremembering this one though, perhaps they looked at a different drug with heart rate lowering effects)
It could be that it helped, or my RHR just went back down on its own. Either way I continue to take it because I don’t have any side effects.
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