It’s also good that basically SLGT2i cancels out the BD excess mortality (based on the 2.02 you sent). That’s combining two different papers using different methodologies and databases, etc. But potentially if you look at the same database and if you’d see that BD + SGLT2i has a lower ACM than no BD (and no SGLT2i) then that would be a strong signal.
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Absolutely. Note, the paper I posted is very robust, with huge data set, so we can be pretty confident in those numbers. At this point, the class effect of SGLT2i in various contexts is well established, and now what is of interest is which individual SGLT2i has the biggest impact on a given outcome and risk profile. After all, we as individuals take a specific drug, so we are interested in “is it dapaglifozin, or empagliflozin, or canagliflozin best for my vulnerability X”.
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So, we should develop rudimentary guidelines for which flozin to take. @CronosTempi @adssx want to give it a shot?
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That doesn’t make the result correct. A friend of mine who’s doing that kind of data mining studies told me that there were so many methodology details that can change the outcomes. Since then I don’t trust anything anymore 
(such as excluding or not those who study abroad!)
But in this particular case, they founs “All‐cause mortality was increased in people with BD (RR = 2.02, 95% CI: 1.89–2.16, k = 39)”. If it’s 1.89 and if the other paper is correct then potentially SGLT2i lower ACM vs non BD people. Not if it’s 2.16.
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I take dapagliflozin. I don’t think we have much data to conclude. Those who love mice might prefer canagliflozin. Those who love mechanistic reasoning and MR studies might prefer sotagliflozin (dual SGLT1 + 2 inhibitor).
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I don’t see how the Simpson’s paradox is related to what I said.
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People with BD have a certain ACM, as do people with other morbidities. It’s very hard to group them together with all SGLT2i and try to compare ACMs across all these disparate cohorts.
And also, if you look at ACM itself, what is that composed of? They try to separate cause specific to BD, such as suicide, death from unnatural causes etc., but really we should just look at deaths from “natural causes”, here given as - (RR = 1.90, 95% CI: 1.75–2.06, k = 17).
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Use of Sodium-glucose cotransporter 2 (SGLT 2) inhibitor is associated with reduced emergency room visits and hospitalizations in patients with Chronic obstructive pulmonary disease (COPD) and type 2 Diabetes Mellitus
https://www.sciencedirect.com/science/article/abs/pii/S0954611124002944
SGLT-2 Inhibitors and the Risk of Chronic Obstructive Pulmonary Disease Exacerbations and Mortality in Chronic Obstructive Pulmonary Disease Patients
The clinical effectiveness of sodium-glucose co-transporter-2 inhibitors on prognosis of patients with chronic obstructive pulmonary disease and diabetes
https://www.nature.com/articles/s41467-025-60582-y
Sodium–Glucose Cotransporter 2 Inhibitor Use and Risk of Liver-Related Events in Patients With Type 2 Diabetes: A Meta-analysis of Observational Cohort Studies
Here is a list of top 10 causes of death in the USA in 2024:
- Heart disease: 683,491
- Cancer: 619,876
- Accidents (unintentional injuries): 197,449
- Stroke (cerebrovascular diseases): 166,852
- Chronic lower respiratory diseases: 145,643
- Alzheimer’s disease: 116,022
- Diabetes: 94,445
- Nephritis, nephrotic syndrome, and nephrosis: 55,081
- Chronic liver disease and cirrhosis: 52,274
- Suicide: 48,824
Try to evaluate how many of these are impacted by SGLT2i. Question: should SGLT2i be added to the water supply?
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New paper (pay walled), mouse model, apparently shows damage and scarring of distal renal tubules due to the high concentration of glucose being excreted from the kidneys.
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Sounds like you should hydrate well if on an SGLT2i - at least you can try to dilute the kidney output. I figured as much anyway.
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Interesting paper but one surprising bit: “Empagliflozin induced hyperglucosuria that persisted post-cessation”
This is not something that happens in humans so the results might not be translatable to humans. Even more so as they go against the massive amount of evidence showing SGLT2i renal benefits. Including preclinical literature showing that SGLT2i reduce, not worsen, renal inflammation/fibrosis/EMT pathways. For instance: Renal protective effects of empagliflozin via inhibition of EMT and aberrant glycolysis in proximal tubules - PMC
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The paper you linked is in proximal tubules. Has anyone examined empagliflozin’s effects on distal tubules in humans?
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Could this be because to date they’ve only been looking at proximal as opposed to distal renal tubules, and/or overall renal function as opposed to zooming in specifically on the distal tubules?
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Holly molly are these convos ever scientific where I have no clue what to make of them. I started Empa about year ago on suggestions from these boards and do 1/2 pill =12.5mg per day. Are we still in agreement that SGLT2i are beneficial or should I damn stop all the meds and never look at anything until I’m in my death bed LOL. Btw, I started it more so for benefits to other organs (and hopefully as synergetic to rapa) than to lower my glucose which is a bit high mid 90’s but still within normal range.
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@jnorm @Davin8r: it’s true that most papers looked at proximal rather than distal tubules but some did:
- SGLT2 inhibitors mitigate kidney tubular metabolic and mTORC1 perturbations in youth-onset type 2 diabetes 2023 (Michigan, Ann Arbor): “However, transcriptional alterations with SGLT2i treatment were seen across nephron segments, particularly in the distal nephron. […] Decreased levels of phosphorylated S6 protein in proximal and distal tubules in T2Di(+) patients confirmed changes in mTORC1 pathway activity. […] Conversely, no differences in fractional interstitial area were observed among the 3 groups, suggesting that transcriptomic differences observed in PT are not directly related to observable interstitial changes.” No signs of distal injury/fibrosis.
- Glucose/Fructose Delivery to the Distal Nephron Activates the Sodium-Chloride Cotransporter via the Calcium-Sensing Receptor 2023 (Mexican National Institute of Health Sciences + one Oregon Health and Science University co-author): they looked at cells, mice, ex vivo kidney, and healthy humans, they reported increased NCC/SPAK phosphorylation rather than a senescence/EMT/fibrosis.
- Inhibition of Sodium Glucose Cotransporter 2 Attenuates the Dysregulation of Kelch-Like 3 and NaCl Cotransporter in Obese Diabetic Mice 2019 (University of Tokyo): looked at distal convoluted tubule cells in diabetic mice. Found that ipragliflozin lowered PKC activity in DCT cells and reduced KLHL3 phosphorylation and NCC levels. No reports of distal tubular senescence, EMT, or fibrosis.
Surely the above would have noticed if fibrosis was present?
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One point in favor of the 2026 paper: “This study is the first to show that acute empagliflozin treatment induces senescence in distal tubular cells of wild-type mice, but not in diabetic mice. Additionally, the long-term effects of empagliflozin promote senescence, EMT, and renal interstitial fibrosis in the distal tubules of both wild-type and diabetic mice.”
Maybe previous papers only looked at diabetic mice and therefore missed “senescence in distal tubular cells”? However, the second sentence applies to both types. Also, ITP found life extension in wild type with canagliflozin and a Chinese paper replicated the result with empagliflozin (but smaller effect).
It’s also surprising that the 2026 paper did not cite or discuss the three papers above. When you make such an extraordinary claim vs all previous literature, you should discuss it a bit, shouldn’t you?
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What about ARBs used either alone or in conjunction with SGLT2i wrt. distal tubular cell impact? I haven’t performed any extensive literature search, but I might try later, time allowing. A very general look at kidneys:
Observations of the Effects of Angiotensin II Receptor Blocker on Angiotensin II-Induced Morphological and Mechanical Changes in Renal Tubular Epithelial Cells Using Atomic Force Microscopy
“Renal fibrosis, characterized by increased extracellular matrix (ECM) accumulation on the kidney parenchyma, is the final common manifestation of chronic kidney disease (CKD), regardless of the primary causes [1, 2]. Previous studies reported that renal tubular epithelial cells (TECs) played an important role in the development of renal tubulointerstitial fibrosis [3]. TECs release chemokines and profibrogenic cytokines and undergo epithelial to mesenchymal transition (EMT) in pathological conditions [4–6]. Therefore, understanding the changes of TECs are important for the prevention and effective treatment of renal fibrosis.”
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SGLT2i use was associated with lower risk of LOE (HR = .55, 95% CI = .44–.68), status epilepticus (HR = .38, 95% CI = .21–.69), and antiseizure medication initiation (HR = .63, 95% CI = .58–.69)
One more benefit…
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Some other papers against SGLT2i, make whatever you want of it:
- Canagliflozin mediated dual inhibition of mitochondrial glutamate dehydrogenase and complex I: an off-target adverse effect 2018
- Differential In Vitro Effects of SGLT2 Inhibitors on Mitochondrial Oxidative Phosphorylation, Glucose Uptake and Cell Metabolism 2022: “The results confirmed cana´s inhibition of mitochondrial activity and GU at supra-pharmacological and pharmacological concentrations, whereas the dapa, ertu, and empa did not show effects even at supra-pharmacological concentrations.”
- SGLT2-independent effects of canagliflozin on NHE3 and mitochondrial complex I activity inhibit proximal tubule fluid transport and albumin uptake 2024: “We found that canagliflozin, but not empagliflozin, reduced NHE3-dependent fluid transport and endocytic uptake in cultured proximal tubule cells. These effects were independent of SGLT2 activity and resulted from inhibition of mitochondrial complex I and NHE3.”
- Effect of Dapagliflozin on the Functioning of Rat Liver Mitochondria In Vitro 2021: “Dapagliflozin in concentrations of 10-20 μM had no effect on the parameters of respiration and oxidative phosphorylation of rat liver mitochondria. Increasing dapagliflozin concentration to 50 μM led to a significant inhibition of mitochondrial respiration in states 3 and 3UDNP.”
- The Influence of Empagliflozin on the Expression of Mitochondrial Regulatory Proteins in Human Myocardium in an Ex Vivo Model of Short-Term Atrial Tachypacing 2025: “Furthermore, empagliflozin increased mitochondrial respiration with a fatty acid substrate but decreased it when it was not available.”
The above are mostly about canagliflozin and/or not high-quality papers.
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