#522

I totally agree with you that the “why” is important.

But I thought that BOTH SGLT2 and 1 decrease obesity and diabetes… so the question is if the delta (where we so far have decreased death from SGLT1 but not 2) is doing something positive?

I also think @adssx has showed that there is a lot in the studies that suggests that many of the health benefits are separate from T2D (and obesity) effects?

We know that positive remodeling of gut microbiome, minimizing glucose spikes, etc might be good for longevity also in the leanest too

But - yeah, a lot of questions where we only partially can infer.

Perhaps someone could look at the MR study and see if the death down also holds if one controls for weight/BMI or something T2D.

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#523

This I think is an argument that I might work in lean individuals - that it helps act as a calorie restriction “mimetic”. I think a few of the papers on SGLTi (including SGLT2i) and longevity make that argument in a strong way.

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#524

You’d have to control for reduction in obesity and diabetes if you want to tease out effect on mortality outside it for SGLT1i. My guess is there is a much smaller effect then.

It’s not a mimetic since it reduces calorie absorption. Hence you are basically on CR.

Yes.

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#525

This paper may be interesting for you to read in this context

Caloric restriction promotes longevity in multiple animal models. Compounds modulating nutrient-sensing pathways have been suggested to reproduce part of the beneficial effect of caloric restriction on aging. However, none of the commonly studied caloric restriction mimetics actually produce a decrease in calories. Sodium-glucose cotransporter 2 inhibitors (SGLT2-i) are a class of drugs which lower glucose by promoting its elimination through urine, thus inducing a net loss of calories. This effect promotes a metabolic shift at the systemic level, fostering ketones and fatty acids utilization as glucose-alternative substrates, and is accompanied by a modulation of major nutrient-sensing pathways held to drive aging, e.g., mTOR and the inflammasome, overall resembling major features of caloric restriction.

And on things outside of just diabesity:

In addition, preliminary experimental data suggest that SGLT-2i might also have intrinsic activities independent of their systemic effects, such as the inhibition of cellular senescence. Consistently, evidence from both preclinical and clinical studies have also suggested a marked ability of SGLT-2i to ameliorate low-grade inflammation in humans, a relevant driver of aging commonly referred to as inflammaging.

Considering also the amount of data from clinical trials, observational studies, and meta-analyses suggesting a tangible effect on age-related outcomes, such as cardiovascular diseases, heart failure, kidney disease, and all-cause mortality also in patients without diabetes, here we propose a framework where at least part of the benefit provided by SGLT-2i is mediated by their ability to blunt the drivers of aging. To support this postulate, we synthesize available data relative to the effect of this class on: 1- animal models of healthspan and lifespan; 2- selected molecular pillars of aging in preclinical models; 3- biomarkers of aging and especially inflammaging in humans; and 4- COVID-19-related outcomes. The burden of evidence might prompt the design of studies testing the potential employment of this class as anti-aging drugs.

IJMS | Free Full-Text | Repurposing SGLT-2 Inhibitors to Target Aging: Available Evidence and Molecular Mechanisms

#526

Yes - I said exactly that? See my exact language

“Perhaps someone could look at the MR study and see if the death down also holds if one controls for weight/BMI or something T2D”

Above

#527

I’m talking specifically about SGLT1i and not SGLT2i.

Yes, we agree.

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#528

That seems like semantics - if anyone if it actually helps get us into that state without it being as painful then it might be even more positive than if a successful mimetic

See also the paper above that I think goes in the direction of choosing mimetic language here, but I don’t remember perfectly as it was about a year ago I read the paper

#529

Ok. I think the choices we have today are basically

  • SGLT2i
    Or
  • SGLT1&2i

Don’t think there are drugs available only do SGLT1i

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#530

It’s not semantics. A CR mimetic enables the same pathways as CR but without the calorie restriction. If you eat less calories, or absorb less calories, that is CR, and not a mimetic, as the mechanism of action is still the same. It will probably be equally painful, except you feel more full when you bottleneck absorption. I don’t think that is the problem with CR.

I don’t see the reason to target SGLT1i based on that MR paper if the mechanism of action is on obesity and diabetes risk, unless someone has high risk of either. But we don’t know for sure how much it affects mortality, my guess is a lot. Then it’s just better to select a SGLT2 inhibitor that has pleiotropic effects outside of lowering glucose, like it does for heart failure.

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#531

@AnUser Do you think that the hypothesis that a large part of acarbose comes from the gut remodeling effects has any weight?

That seems to be one thing that SGLT1i but not 2i helps with.

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#532

Perhaps people on SGLTi’s could comment

My understanding is that a lot of people have trouble or at least feel a cost of traditional diet based CR(on) - but I have not really heard people on SGLTi say that when asked about side effects.

@RapAdmin can you perhaps comment as someone who has done CR and also used several SGLTis?

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#533

My questions about whether we want SGLT1i is based on the totally of data I’ve seen and shared, including for instance that the ITP - in more than one study - showed effects on lifespan so far only if SGLT1i was part of it, and we have no such data for SGLT2i alone.

Can I ask you what you think about the main parts of this post [click on the link so you can see it with better formatting than how it gets embedded here].

#534

I don’t remember exactly, but yeah maybe.

I’ve looked a bit more into this, and I am becoming more certain that SGLT1i is simply unnecessary - and all of the effects in humans is based on SGLT2i - why?

Simply, look at the dosage difference of the different flozins. The ones more selective for SGLT1, has a higher dosage. Which implies that they are dosed for the effect on SGLT2, which can also be the reason why they are withdrawing marketing for them in EU, and study them less. I don’t know about this, @J0hn thoughts?

#535

Since the weight loss effect is so modest (at best) for the SGLT2i drugs, are they really acting via caloric restriction to any real-world degree? Yes, some glucose is lost in the urine, but the calories lost is nothing compared to the classic “caloric restriction” studies.

#536

The weight loss with SGLT2i is surprisingly high (although I haven’t lost one gram so far), almost as good as oral semaglutide: Oral Semaglutide Versus Empagliflozin in Patients With Type 2 Diabetes Uncontrolled on Metformin: The PIONEER 2 Trial

image

Not as good as injected semaglutide, but still impressive: Efficacy of Once-Weekly Semaglutide vs Empagliflozin Added to Metformin in Type 2 Diabetes: Patient-Level Meta-analysis 2020

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And to continue the SGLT1 debate: SGLT inhibitors on weight and body mass: A meta-analysis of 116 randomized-controlled trials 2022

In total, 116 randomized-controlled trials were included, with a combined cohort of 98,497 patients. Overall, patients had a mean weight reduction of -1.79 kg (95% CI: -1.93 to -1.66, p < 0.001) compared with placebo. This effect was observed across diabetes status, duration of follow-up, various comorbidities, and all SGLT drug types. Mean BMI changes were -0.71 kg/m2 (95% CI: -0.94 to -0.47, p < 0.001) compared with placebo. Canagliflozin, empagliflozin, sotagliflozin, and licogliflozin showed a dose-response relationship for mean weight change. Compared with SGLT2 inhibitors, SGLT1/SGLT2 inhibitors had a significantly larger reduction in weight.

They only considered sotagliflozin and licogliflozin as “combined SGLT1/SGLT2 inhibitors” but canagliflozin is somewhat between “pure” SGLT2 inhibitors and combined SGTL1/SGLT2 inhibitors in terms of mean weight change (luseogliflozin as well, but with a wide 95%CI):

  • Remogliflozin: –1.27 kg (p = 0.003)
  • Ipragliflozin: –1.35 kg (p < 0.001)
  • Dapagliflozin: –1.69 kg (p < 0.001)
  • Empagliflozin: –1.70 kg (p < 0.001)
  • Ertugliflozin: –1.99 kg (p < 0.001)
  • Canagliflozin: –2.05 kg (p < 0.001)
  • Sotagliflozin: –2.29 kg (p < 0.001)
  • Luseogliflozin: –2.38 kg (p = 0.03)
  • Licogliflozin: –2.71 kg (p < 0.001)

Interestingly, Novartis did not pursue the development of licogliflozin: ClinicalTrials.gov

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#537

Same for me! I haven’t seen any excitement about these drugs as significant weight loss meds anywhere, despite the fact that they’re widely available, orally bioavailable and have been around for years. IMO if they worked so well for weight loss, they’d be more popular.

#538

SGLTi might only have weight loss effects for people with a BMI > 30 and/or with T2D. In the same way that “In normotensive, nonobese individuals, SGLTi-induced changes in BP and weight are minimal to absent.” whereas “SGLT2i is effective in reducing blood pressure compared with placebo in patients with type 2 diabetes and hypertension” (5/2 mmHg).

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#539

Would be interesting to see the net caloric loss in obese type 2 diabetics vs “healthy” adults from SGLT2i meds. Would also have to control for dietary intake as well. I still doubt in either case it would be enough to compare to typical anti-aging levels of caloric restriction (30%?), although anything is likely better than nothing.

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#540

I think there may be effects in humans that are meaningful already around 10% or perhaps lower CR.

See the CALORIE trial from Yale if I recall correctly.

(And Bryan Johnson has changed his CR to now only be around 10%).

@adssx wonder if one your groups could access any of the before and during/after blood of people on SGLT from any of the trials that already where conducted (or even just UK biobank people on SGLTi vs controls) and run some of the epigenetic and other biological aging clocks on…

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#541

Interesting. That fits with one of @AnUser ’s observation from a different context.

Thanks for providing the data and papers in your overall post.

I think I’m going to have to do a Dexa and get other body composition data before I start taking SGLT. (Thought it’s tough for me too keep my exercise and diet the same as I’m frequently trying to optimize different things there too…)

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