My thoughts are that this response is a very good example of why “Consensus” belongs in the circular file and subsequent wastebasket. Other posters have already indicated the laughable lack of evidence being incorporated from easily available studies. But with performance this bad, why would anyone ever use this, when there is no way to know when it’s being actively informationally destructive. It’s like going to the doctor whose job it is to cure you, but you never know when he might randomly shoot you in the head. I’d guess that the number of his patients would be zero.
3 Likes
Beth
#1539
@Virilius and @CronosTempi
Yes! I sent the information to my vet because, while my cats don’t have diabetes, they do have CKD, so I asked her if I can share my stash of dapagliflozin! (She approves of me sharing my rapa with them). Stay tuned !
3 Likes
Appreciate the responses. I think consensus is probably just overly conservative. This is what it said about some of those other studies mentioned:
Despite all these promising mechanisms, here’s the key:
• Clinical benefit has only been proven in people with specific risk factors—CKD, heart failure, or diabetes.
• In healthy individuals:
• You may not have enough physiological “stress” (e.g., high glomerular pressure, sodium retention, inflammation) for these mechanisms to meaningfully engage.
• There’s no safety data or long-term outcome studies.
• Side effects (e.g., dehydration, infections, rare DKA) are real and may outweigh any theoretical benefit.
⸻
Conclusion:
Yes—SGLT2 inhibitors work through multiple mechanisms that go far beyond glucose lowering. These explain their powerful benefits in people with heart failure or CKD, even without diabetes. But no studies show that these benefits translate to healthy people, so use in that context remains speculative and unadvised for now.
1 Like
It’s perfectly reasonable to come to that conclusion based on your age, current health status and risk tolerance.
3 Likes
If you have perfectly healthy kidneys in your 90s, SGLT2i most likely won’t be ueseful to you. If you expect your bodily functions to eventually decline in your 60s-70s, you can extrapolate from existing clinical trials and figure that SGLT2i will have a protective effect on your kidneys.
6 Likes
adssx
#1543
Dapagliflozin mitigates cognitive deficits in a rat model of chronic restrained stress by addressing insulin resistance and mitochondrial dysfunction 2025
Egyptian paper…
Chronic stress is recognized as a risk factor for neurodegeneration. Sodium glucose co-transporter 2 receptors (SGLT2) have been found in various brain regions, suggesting the potential neuroprotective properties of SGLT2 inhibitors as dapagliflozin (DGF). This study aimed to investigate the effect of DGF on behavioral, and neurodegenerative changes in chronic restraint stress (CRS) as an animal model of cognitive impairment. Forty-eight male rats were allocated into four groups: Control; CRS-subjected group, rats were subjected to chronic restraint stress for 6 weeks to induce cognitive impairment; DGF-treated CRS group, dapagliflozin was given daily by oral gavage; and DGF-administered group. Behavioral tests were performed and fasting serum glucose, insulin, and corticosterone levels were measured. Hippocampal oxidative markers, insulin signaling, mitochondrial function, amyloid beta, p-tau, and brain-derived neurotrophic factor (BDNF) gene expression were evaluated. DGF significantly prevented CRS-induced cognitive dysfunction (Y maze and Morris water maze tests). Also, DGF ameliorated hippocampal neurodegenerative changes by decreasing tau and amyloid beta levels, while increasing BDNF gene expression. DGF reduced hippocampal phosphorylated mammalian target of rapamycin (p-mTOR) and protein kinase B (p-Akt) levels. In addition to its antioxidant effects, DGF increased ATP levels and cytochrome C oxidase activity. These findings were confirmed by transmission electron microscopic (TEM) examination. The current study demonstrates a biological link between chronic stress, insulin resistance, and cognitive impairment. Dapagliflozin has therapeutic potential in alleviating cognitive deficits and neurodegeneration primarily due to its insulin-sensitizing and antioxidant properties, along with its capacity to enhance mitochondrial function.
So we have a BBB-crossing mTOR inhibitor @John_Hemming?
4 Likes
adssx
#1544
Not a single drug is approved for longevity so of course Consensus can’t recommend anything.
By the way, can we please stop sharing copy-paste of random AIs that don’t cite their source? It doesn’t have any value to our discussions.
13 Likes
Fair enough. But in this case I was sharing it only to get a better understanding of why it’s wrong
1 Like
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.
8 Likes
jnorm
#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.
5 Likes
Genja
#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
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?
jnorm
#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.
6 Likes
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!
1 Like
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.
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.
1 Like
adssx
#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).
13 Likes
SGLT-2 Inhibitors in Cancer Treatment—Mechanisms of Action and Emerging New Perspectives
6 Likes
jnorm
#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.
7 Likes
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
8 Likes
