Canagliflozin – Another Top Longevity Drug

Damn, even after 1280 posts in a thread loaded with information. You’re tough.

I’d be happy to be convinced… if someone can simply link a genetic study showing that SGLT2 inhibition makes your kidneys immortal from eGFR decline.

There’s 224 PCKS9 mendelian randomization papers, 145 HMGCR, but only 34 SGLT2.

I don’t think it will happen.
There’s barely any good data… (MR for long term and early use).

And many recent MR papers basically took 3 minutes to create the data with two sample MR, and then in some cases some generated text to make it all sound good… Compared to the older NEJM paper I posted earlier.

33 out of 34 of the SGLT2 papers are from >=2022.

It’s over?

Well I probably can’t convince you because you’re not exactly wrong. As far as I know, there aren’t studies done on healthy people. However, if they are great for people with heart failure and kidney failure, it would make sense that using it would help prevent those conditions. If you have a good heart and kidneys now, then perhaps the benefits would be small, especially if you’re younger.

I did some not-so-smart things in the past and had hypertension for a while, so I have to watch out for my cardiovascular health. It’s a nice security blanket for me in that regard.

Anecdotally, for what it’s worth, I had my cystatin C checked and it was bottom of the range 0.65, so I was quite happy. My eGFR seems higher each time I test it than in years past too (Cystatin c is a much better test)

I’m taking empagliflozin for the kidney benefits. I hope to see a higher eGFR when I test next. Here’s hoping!

I haven’t looked closely at the numbers, but assuming that genetic variance in the MR studies isn’t sufficient to explain the effect size of empagliflozin in RCTs, that’s evidence that the protection is (at least partially) SGLT2-independent. Which is an emerging consensus anyways (e.g EMPA-KIDNEY trial showed kidney protection in normoglycemic indivudals+mechanistic data that empagliflozin inhibits TGF-β signaling, which is the central mediator of fibrosis, which is turn is a major driver of CKD progression).

I am prediabetic, FBG usually around 110-115 in the morning, A1c 5.7 – 5.9. This has been going on for many years despite my best lifestyle exercise, diet efforts (exercise actually always raises my blood sugar significantly, if transiently). I tried metformin 500mg/day for a year – it did absolutely nothing for my glucose control.

Under these circumstances, I saw empagliflozin as a reasonable intervention for BG, without reference to any other benefits – just hoping to get me to normal non-prediabetic blood sugar levels. If it can do that without negative side effects, that will be a win in my book.

I have commenced a daily 12.5mg dose starting on December 1. So far, no negative side effects that I can detect. I do fingerprick blood glucose monitor tests every morning. It’s been less than three weeks (18 days), and the highest readings on my monitor have been 99 on two occasions; the lowest 88. In general, while not stellar levels so far, it is definitely – so far – a distinct lowering of FBG in the morning. Whether this will persist, and whether this will translate into lower A1c, I won’t know for another 3 months or so, when I intend to get a comprehesive blood panel, including the A1c.

If I continue to tolerate empagliflozin well, with no detectable negative side effects, I will escalate the dose to 25mg/day in case my blood glucose levels are not in optimal range (and I don’t anticipate that suddenly my A1c will go down to 5.0 – 5.2 levels, and FBG to 80-85 in the morning consistently).

So from my point of view, any possible life extension benefits are icing on the cake, which I am not counting on. I am hoping empagliflozin might provide healthspan benefits, though that might be hard to impossible to prove. I am hoping it addresses some weak links in my health, rather than directly affect aging pathways. FWIW, all my kidney numbers are pretty stellar, and if empa can help keep it that way for longer, I’ll be more than satisfied. YMMV.

I sent you this above. (OR for CKD 0.11, 1.01 in the CI but CKD is multifactorial so not surprising).

Have you tried using MR Base to do the MR you want?

Is Peter Attia taking dapagliflozin btw? (I was told that but can’t find confirmation) I wouldn’t be surprised if Bryan Johnson starts canagliflozin and lowers his metformin dose in the future.

I think CKD is much like other diseases of aging. The mitochondria get damaged this gradually pushes more and more cells in to a senescent state whilst also causing certain proteins not to be produced and aberrant splicing to occur.

It will be multifactoral as lots of things damage mitochondria.

This is a search on o1. I have not checked any of the assertions.

Thought about CKD and splicing for 13 seconds

Chronic Kidney Disease (CKD) is a complex, progressive disorder characterized by the gradual loss of kidney function and the development of extensive fibrosis, inflammation, and metabolic imbalances. In recent years, mounting evidence has highlighted the role of post-transcriptional gene regulation—especially alternative and aberrant splicing—in shaping the molecular landscape that drives CKD pathogenesis.

Key Links Between CKD and Aberrant Splicing

1. Disruption of Normal Splicing Machinery:
   In both early and advanced stages of CKD, changes in the expression and activity of core splicing factors (e.g., members of the SR and hnRNP families) have been documented. Alterations in these regulatory proteins can disrupt normal splice site recognition and exon inclusion/exclusion patterns, leading to the production of aberrant RNA transcripts. Such dysregulated splicing machinery contributes to the misregulation of numerous downstream genes critical for kidney homeostasis.
2. Influence on Fibrogenic Pathways:
   One of the hallmarks of CKD progression is chronic tubulointerstitial fibrosis driven largely by activated myofibroblasts, inflammatory cells, and persistent pro-fibrotic signaling (e.g., TGF-β signaling). Aberrant splicing can affect key components of these pathways:

• TGF-β Signaling Components: Splicing alterations in transcripts encoding TGF-β receptors, co-factors, or downstream effectors can yield isoforms that either enhance or diminish fibrogenic responses. For instance, certain alternative isoforms may have higher stability or stronger receptor-binding affinities, exacerbating the fibrotic cascade.
• Extracellular Matrix (ECM) Proteins: Collagens, fibronectin, and other ECM constituents are often subject to complex splicing regulation. Aberrantly spliced ECM protein isoforms can be more fibrogenic, less easily degraded, or improperly assembled, fueling scar formation and kidney structural deterioration.

3. Impact on Inflammatory and Immune Responses:
   Chronic inflammation is a key driver of CKD. Aberrant splicing can alter cytokine, chemokine, and adhesion molecule isoforms, potentially influencing leukocyte infiltration, macrophage polarization, and the intensity and persistence of inflammatory responses. Splicing changes that lead to pro-inflammatory transcript variants may thus help perpetuate low-level, chronic inflammation in the kidney milieu.
4. Altered Splicing of Transporters and Channels:
   The kidney’s primary functions—filtration, reabsorption, secretion, and electrolyte balance—depend on a precise array of ion channels, transporters, and receptors. Aberrant splicing of these genes can yield dysfunctional isoforms that either fail to localize correctly to the cell membrane or have altered transport kinetics. Such isoforms can contribute to dysregulated solute handling, hypertension, and metabolic disturbances characteristic of CKD.
5. Contribution to Podocyte Injury and Epithelial-to-Mesenchymal Transition (EMT):
   Podocyte damage is an early feature in many forms of CKD, and the progression to a fibrotic phenotype often involves epithelial and endothelial cells undergoing EMT or EndoMT. Aberrant splicing events can influence the expression of splice variants of critical cytoskeletal regulators, adhesion molecules, and signaling proteins that govern podocyte integrity and EMT processes. By altering the balance of isoforms that promote or inhibit EMT, aberrant splicing can accelerate kidney scarring and functional decline.
6. Involvement in Diabetic Nephropathy and Other CKD Etiologies:
   Diabetic nephropathy, a leading cause of CKD, also exhibits splicing-related dysregulations. For instance, insulin receptor and growth factor-related genes may produce isoforms that amplify metabolic stress or reduce the protective pathways in renal cells. Similarly, hereditary or rare CKD variants associated with mutations in splicing factors, splice-site mutations, or unusual exon skipping highlight the fundamental importance of correct splicing in kidney function.
7. Biomarker and Therapeutic Potential:
   As the understanding of aberrant splicing in CKD deepens, certain mis-spliced transcripts have emerged as potential biomarkers for disease stage, progression, or response to therapy. In the future, correcting splicing errors—via antisense oligonucleotides, small molecules targeting splicing regulators, or RNA-binding proteins—may provide a novel therapeutic angle. By restoring normal splicing patterns, it may be possible to halt or even reverse CKD progression.

Conclusion:
Aberrant splicing is intricately woven into the pathophysiology of CKD, influencing fibrosis, inflammation, metabolism, and cell differentiation processes. Rather than being a byproduct of disease, splicing dysregulation is increasingly recognized as a driver and modulator of CKD progression. As research advances, understanding these splicing alterations opens new avenues for early diagnosis, prognostication, and targeted interventions aimed at restoring the delicate balance of RNA isoforms that maintain kidney health.

The title says it all: SGLT2 Inhibition Induces Cardioprotection by Increasing Parasympathetic Activity 2024

This is really interesting. When I ran out of empagliflozin while on tirzepatide a few months ago, I almost immediately noticed increased anxiety, heart palpitations, HR and even lower HRV than I already had from low dose tirzepatide. I couldn’t think of a mechanism by which empagliflozin would have made a difference (until now), so I wasn’t sure what to think, but it all got better very quickly after restarting the empagliflozin. I still have elevated HR compared to baseline, but it just doesn’t bother me or seem nearly as noticeable as it was during that window of time when I wasn’t taking empagliflozin.

This makes the SGLT2 + GLP1-RA combination even more interesting!

Doesn’t all of the SGLT2 inhibitors have a similar effect?

SGLT2 independent effect does not mean glucose-independent effect.

He has said he takes a SGLT2 inhibitor but I don’t know which.

No, but I’d like to see some expert do it, It’s a shame the pharma companies doesn’t do it.

Not necessarily, but as SGLT2i increases glucose excretion, it’s a reasonable hypothesis that an SGLT2-dependent mechanism would revolve around this.

Doesn’t all of the SGLT2 inhibitors have a similar effect?

I believe so, although I think empaglifozin generally performs the best in humans. It’s been shown that empagliflozin can protect against TGF-β signaling in isolated human cardiomyocytes (which don’t express SGLT2), and although the heart and kidney protection could be independent of this mechanism, it seems unlikely.

Anti-diabetic agents and the risks of dementia in patients with type 2 diabetes: a systematic review and network meta-analysis of observational studies and randomized controlled trials 2024

A total of 41 observational studies (3,307,483 participants) and 23 RCTs (155,443 participants) were included. In the network meta-analysis of observational studies, compared with non-users, sodium glucose cotransporter-2 inhibitor (SGLT-2i) (OR = 0.56, 95%CI, 0.45 to 0.69), glucagon-like peptide-1 receptor agonist (GLP-1RA) (OR = 0.58, 95%CI, 0.46 to 0.73), thiazolidinedione (TZD) (OR = 0.68, 95%CI, 0.57 to 0.81) and metformin (OR = 0.89, 95%CI, 0.80 to 0.99) treatments were all associated with reduced risk of dementia in patients with T2D. The surface under the cumulative ranking curve (SUCRA) evaluation conferred a rank order as SGLT-2i > GLP-1RA > TZD > dipeptidyl peptidase-4 inhibitor (DPP-4i) > metformin > α-glucosidase inhibitor (AGI) > glucokinase activator (GKA) > sulfonylureas > glinides > insulin in terms of the cognitive benefits. Meanwhile, compared with non-users, SGLT-2i (OR = 0.43, 95%CI, 0.30 to 0.62), GLP-1RA (OR = 0.54, 95%CI, 0.30 to 0.96) and DPP-4i (OR = 0.73, 95%CI, 0.57 to 0.93) were associated with a reduced risk of Alzheimer’s disease while a lower risk of vascular dementia was observed in patients receiving SGLT-2i (OR = 0.42, 95%CI, 0.22 to 0.80) and TZD (OR = 0.52, 95%CI, 0.36 to 0.75) treatment. In the network meta-analysis of RCTs, the risks of dementia were comparable among anti-diabetic agents and placebo.

Note: α-glucosidase inhibitor (AGI) = acarbose

From the study:

“The network meta-analyses for RCTs did not yield any positive results. Further dedicated RCTs directly evaluating the association between anti-diabetic agents and dementia event risks are required to enrich the evidence.”

In the limitations section:

“Meanwhile, in this study, it was indicated that previous RCTs lacked attention to the risks of dementia events in patients with T2D. Subsequent RCTs designating the primary outcome as dementia event risks in patients with T2D are needed to effectively evaluate the impacts of anti-diabetic agents on the risks of dementia events in patients with T2D with high-quality evidence.”

So there is discordance between observational and RCT studies, but perhaps the RCTs were poorly focused on dementia outcomes. I find such a strong discordance nonetheless concerning, because RCTs are the gold standard.

These odds ratios are CRAZY, very impressive

Many people take multiple drugs that affect kidney health. How do SGLT2i drugs (especially empagliflozin) interact with RAS blockers, diuretics, CCB, NSAIDs, in the context of renal health in T2DM patients:

https://www.kidney-international.org/article/S0085-2538(19)30317-5/pdf

Some trials found cognitive improvements on empagliflozin in elderly.

Chinese paper in a mid-tier journal but seems legitimate. The YAP/TAZ-inhibition they observed with dapagliflozin has interesting implications for the mechanism of gliflozin-mediated fibrosis prevention.

Fibrosis is responsible for up to 45% of deaths in the developed world (see Fibrosis: from mechanisms to medicines | Nature), making pan-organ anti-fibrotic drugs promising longevity therapies. Given that fibrosis especially affects the liver, kidneys, and heart (the organs we know empagliflozin protects), it wouldn’t be surprising if gliflozin geroretardant activity is largely independent of blood sugar. If true, rapamycin+acarbose+empagliflozin being superior to rapamycin+acarbose is likely. Rapamycin activates TGF-β signaling—which is the master auto/paracrine regulator of fibrosis—so another potential reason to stack it with an anti-fibrotic drug.

Also intriguing—multiple gliflozins (including cana, empa, and dapa) inhibit the sodium-hydrogen pump NHE1, and there’s evidence that this underlies empa’s anti-fibrotic effects.

Mechanical variables like cell volume are NHE1-dependent, and with YAP/TAZ being a downstream transcriptional effector of mechanotransduction, an NHE1-YAP/TAZ axis is a plausible gliflozin anti-fibrotic mechanism. See Cytoskeletal activation of NHE1 regulates mechanosensitive cell volume adaptation and proliferation and The Hippo Pathway: Biology and Pathophysiology

Bonus relevant papers:

SGLT2 promotes pancreatic cancer progression by activating the Hippo signaling pathway via the hnRNPK-YAP1 axis

Empagliflozin Reduces the Progression of Hepatic Fibrosis in a Mouse Model and Inhibits the Activation of Hepatic Stellate Cells via the Hippo Signalling Pathway

YAP/TAZ Are Mechanoregulators of TGF-β-Smad Signaling and Renal Fibrogenesis

And since the least popular cytokine on this site is probably IL-11, also see YAP promotes the malignancy of endometrial cancer cells via regulation of IL-6 and IL-11. Not surprising to see a pro-fibrotic transcriptional effector like YAP linked with IL-11, considering the central role of TGF-β in fibrosis, and the necessity of IL-11 in TGF-β-mediated fibrosis in the heart and other tissues, e.g IL-11 is a crucial determinant of cardiovascular fibrosis | Nature