#329

Looks like it is in open access now, and it’s well worth a read!

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#330

@adssx may I ask what your own SGLT2i protocol is, if anything? Is it purely for longevity or in context of other health context?

#331

So far, none. I have significant reactive (postprandial) hypoglycemia, diagnosed after a 6-hour oral glucose tolerance test (OGTT)… I tried acarbose to treat my reactive hypo, and it helps a lot, but:

  1. It decreases Hb A1c, and mine is already low,
  2. Acarbose only prevents the degradation of complex carbohydrates, so it doesn’t work for simple carbs, and I still have reactive hypo when I eat those,
  3. The amount of complex carbs in the meal determines the effectiveness of acarbose, so I feel like I need to guess and adjust how much acarbose I take before each meal, depending on the expected carb content (and at friends or at the restaurant you never know :slight_smile: ).

So, my doctor recommended trying SGLT2i (dapagliflozin, but there are also ongoing trials of empagliflozin for reactive hypo); I’ll report the results… The longevity aspects would be a (great) bonus, but it’s not my main goal.

I’m also interested in SGLT2i because I like drug repurposing. I think there are many low-hanging fruits among existing drugs that are not exploited because of a lack of commercial incentives. The EU wants to create a new incentive scheme for repurposed drugs. If big enough (so far, their proposal is too weak IMHO), these incentives could trigger a new industry: you identify promising candidates for repurposing (let’s say, “empagliflozin for Parkinson’s”, “semaglutide for Alzheimer’s”, etc.), run a cheap trial (you can often skip phase 1 for repurposed drug and then combine 2 & 3), get approved, and cash in the gov money/incentives. Here’s our policy note on the topic: EU Pharma Directive & Regulation Drug repurposing incentives - Google Docs (Feedback welcome!)

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#332

Antoine,

I love your group’s efforts at encouraging drug repurposing… definitely a huge opportunity to help people. The balance is always to incentivize the Pharma/biotech groups to do the trials on the new indication, but balance that with the need to keep prices as low as possible. Have you and your group reviewed the A4LI proposals in this area? The Advanced Approval Pathway for Longevity Medicines - a4li.org

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#333

In an ideal world, you could say that repurposed drugs (or any drug or intervention, including nonpharmaceutical ones actually) get x% of how much they help the healthcare system save over the next n years. It could take the form of an advance market commitment between the payer (private or public healthcare insurers) and the pharma company before the trial starts.

Savva wrote a fantastic article on similar concepts: Leveraging Pharmacoeconomics and Advance Market Commitments to Reduce Healthcare Expenditures - Federation of American Scientists

I checked the A4LI proposals; they’re great. I emailed them on Sept 10 about our lobbying efforts at the EU level, but they never got back to me.

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#334

Effects of SGLT2 inhibitors on clinical cancer survival in patients with type 2 diabetes

Taiwanese researchers found that SGLT2 use divided death by about 5 in cancer patients (adjusted hazard ratio (aHR) for all-cause mortality in SGLT2i users compared with nonusers of 0.22 (95 % CI: 0.21–0.23)) and that “mortality was noted to significantly decrease with increases in dosage”.

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Crazy… (365 cDDD = daily use over a year, with the defined dose defined by the WHO, so for instance 10 mg/d for dapagliflozin or 17.5 mg/d for empagliflozin: WHOCC - ATC/DDD Index )

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#335

Thanks. Thats a gigantic effect. I couldn’t find info about variation between SLGT2 drugs. Would the SLGT2 and SLGT1 inhibitors (Cana) have a greater effect than SLGT2 only (dapa, empa)? I wonder.

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#336

Yes, it’s almost too good to be true. Even a few months of use (cDDD < 90) have a massive impact. There may be biases in the study, or maybe SGLT2 inhibitors are more potent in the Taiwanese population? In any case, we need more studies to confirm these protective (or even curative?) effects. AstraZeneca is running a massive cohort retrospective study about this with more than 1 million people, results expected in 2025: Cancer in Patients on Dapagliflozin and Other Antidiabetic Treatment

There are other ongoing trials on SGLT2i + cancer:

I couldn’t find a comparison of the various SGLT2i for cancer either.

There’s only one combined SGLT2 + SGLT21 inhibitor: Sotagliflozin (I don’t think that canagliflozin has any SGLT1 inhibition effects).

However, sotagliflozin was only approved in the EU in 2019, only for type 1 diabetes, and it was then withdrawn in 2022 (voluntarily by the pharma behind it). It was approved in the US in May 2023 for heart failure. So we have almost 0 longitudinal data on sotagliflozin. The only study I found comparing sotagliflozin to empagliflozin showed that their effects are identical, with only one exception: post-breakfast glucose and insulin response. Sotagliflozin is way better at reducing the post-breakfast AUC. (Metabolic, Intestinal, and Cardiovascular Effects of Sotagliflozin Compared With Empagliflozin in Patients With Type 2 Diabetes: A Randomized, Double-Blind Study) Is this enough to prefer sotagliflozin to empagliflozin? I don’t know.

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#337

“Canagliflozin, the other dual SGLT inhibitor, is more selective to SGLT2 than SGLT1 compared with sotagliflozin (250-fold vs 20-fold, respectively). “

It looks like Cana does have a smaller (order of magnitude less) effect on sglt1 than sotagliflozen. I don’t think the other popular SGLT2 inhibitors have any sglt1 inhibition. Is the the sglt1 effect important to the longevity benefits? I wonder…

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#338

You’re right: “At approved doses, canagliflozin, but not dapagliflozin or empagliflozin, inhibits renal SGLT1, which may reconcile the differences in clinical efficacy and safety among gliflozins. […] At approved doses, SGLT1 inhibition by canagliflozin but not dapagliflozin or empagliflozin contributed to ~ 10% of daily urinary glucose excretion.” (Differentiating the Sodium‐Glucose Cotransporter 1 Inhibition Capacity of Canagliflozin vs. Dapagliflozin and Empagliflozin Using Quantitative Systems Pharmacology Modeling)

Is this relevant? Could be, see Does SGLT1 Inhibition Add Benefit to SGLT2 Inhibition in Type 2 Diabetes?.

However, according to SGLT inhibitors for improving Healthspan and lifespan: “Empagliflozin, dapagliflozin, and sotagliflozin are the agents in the SGLTi drug class with the strongest safety and efficacy for improving healthspan and lifespan.”

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#339

Thanks for the info. The last link you provided should be read by everyone on this forum. I had no idea of the wide range of benefits for Sglt2 inhibitors… and I’m taking one (Farxiga).

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#340

I think it was shared by @RapAdmin previously, and it is indeed an amazing paper.

This recent one is also great: On the wake of metformin: Do anti-diabetic SGLT2 inhibitors exert anti-aging effects?.

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#341

Would note that the NIH / NIA ITP life extension effects were with Cana and hence some SGLT1i

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#342

We should maybe suggest them to test sotagliflozin or empagliflozin next year: Suggestions for ITP drugs to test - #113 by RapAdmin

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#343

It must be the potential for negative effects that kept Cana off the list. But I’m guessing.

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#344

Yes, the risk/reward ratio seems better with empa and dapa.

Regarding sota, if anyone has access to this comment, I’d love to read it: Dual SGLT1 and SGLT2 inhibitor sotagliflozin achieves FDA approval: landmark or landmine?. It starts with:

“No one knows what the benefits or risks of inhibiting SGLT1 in the heart might be.”

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#345

Just found this recent comparison: Comparative Cardiovascular Benefits of Individual SGLT2 Inhibitors in Type 2 Diabetes and Heart Failure: A Systematic Review and Network Meta-Analysis of Randomized Controlled trials

Based on surface under the cumulative ranking curve (SUCRA), the top ranked SGLT2i for reducing HFH were canagliflozin (95.5%), sotagliflozin (66.0%) and empagliflozin (57.2%). Head-to-head comparisons found no significant differences between individual SGLT2i in reducing CV death. “Add-on” SGLT2i reduced all-cause mortality compared with SoC alone, although only dapagliflozin was statistically significant. […] Among them, canagliflozin may be considered the preferred treatment for patients with diabetes and a history of heart failure, but it may also be associated with an increased risk of any adverse events compared to other SGLT2i. However, a sensitivity analysis focusing on HF-specific trials identified sotagliflozin as the most likely agent to reduce CV-death/HFH, followed by empagliflozin and dapagliflozin.

The journal seems OK, but there’s an ongoing scandal regarding Thai publications ( Surge in number of ‘extremely productive’ authors concerns scientists ), so I don’t know how reliable this study is…

Also this: Sotagliflozin: Efficacy, Safety, and Potential Therapeutic Applications in Heart Failure

Where sotagliflozin will be adopted into the treatment of HF is unclear due to the evidence and benefits of already established SGLT2 inhibitors and the need for comparison with SGLT2 inhibitors. […] Given the limitations of currently available evidence, including difficulty in fully interpreting the trial results due to changes in primary endpoints, not adjudicating the events, and not reaching the original power calculations, more investigation is warranted to determine the benefit of sotagliflozin compared with SGLT2 inhibitors.

SGLT2 inhibitors and risk reduction for mortality in high-risk patients: a meta-analysis of randomized controlled trials

No differences were observed in the effect of empagliflozin and dapagliflozin on CV death (HRempagliflozin: 0.81; 95% CI 0.68-0.97, HRdapagliflozin: 0.88; 0.82-0.95, p=0.39) and all-cause death (HRempagliflozin: 0.86; 95% CI 0.73-1.02, HRdapagliflozin: 0.87; 0.78-0.97, p=0.94).

My two cents based on all the above: the differences don’t seem massive between the various SGLT2i, empa and dapa seem safer and as efficient if not more than cana, and sota is promising but hasn’t been tested enough.

By the way, this computational drug repurposing paper identified dapagliflozin and canagliflozin as top candidates for Alzheimer’s disease (see Figure 3): [2311.09596] Generating Drug Repurposing Hypotheses through the Combination of Disease-Specific Hypergraphs

I asked the authors why sotagliflozin is not ranked; it could be because it was not yet FDA-approved when they ran the algorithm.

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#346

FWIW:
"We found similar reductions in worsening HF with empagliflozin, canagliflozin and dapagliflozin. However, *empagliflozin was associated with a greater reduction in all-cause and cardiovascular mortality.

“Comparative efficacy of sodium-glucose cotransporter-2 inhibitors (SGLT2i) for cardiovascular outcomes in type 2 diabetes: a systematic review and network meta-analysis of randomised controlled trials”

全文：
https://sci-hub.se/10.1007/s10741-020-09954-8

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#347

Thanks. One caveat: it’s based on data “up to August 12, 2019”. Given how recent SGLT2i are (first approved in 2012 in the EU and 2013 in the US), newer papers may lead to different results.

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#348

I like this idea… I am shocked that the ITP only had 28 submissions last year, so I think we need to increase the suggestions given all the compounds we see that are interesting. It would be interesting to tease out the benefits of SGLT2 vs. SGLT1 inhibition in longevity.

And we should scrape our forums for other good compounds to suggest they test. We have about 3 months to do this.

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