#1045

Is everyone taking their SGLT2 with breakfast or with dinner? I do breakfast but might switch to dinner just so it’s away from my workouts (no idea if it matters though). I just don’t want it to impact sleep.

#1046

I take it in the morning.

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#1047

It’s more than “point”: SGLT2i are approved in people without diabetes who have CKD or heart failure. So we know it protects the kidneys and heart irrespective of diabetes status. For people without diabetes, SGLT2i don’t lower HbA1c much (that’s what papers say, that’s my experience, even though you do pee a lot of sugar), so these benefits are not related to lower glucose levels. There’s something else happening.

Does it mean that someone without T2D, CKD or HF would benefit from SGLT2i? No one knows. But is there any other class of drugs that have 2 compounds proved to extend lifespan in healthy mice (canagliflozin ITP and empagliflozin that obscure Chinese paper)?

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#1048

My guess is that SGLT2I improve kidney efficiency and slow down kidney aging. Kidneys are very important and if you can keep them in better shape for longer, you will live longer.

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#1049

I also haven’t noticed any reduction in A1C with Empagliflozin either. I guess it is better at preventing it from going up when not diabetic.

I also haven’t gotten a A1C reduction with Acarbose either.

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#1050

https://www.medscape.com/viewarticle/new-atrial-fibrillation-guidelines-confront-underlying-2024a1000fvd

“Sodium-glucose cotransporter-2 (SGLT2) inhibitors “should be offered to all patients with AF,” according to Van Gelder, who identified this as a new class I recommendation.”

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#1051

SGLT2i even better than GLP1-RAs for neuroprotection? => Parkinson's disease - #250 by adssx

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#1052

I found this Japanese study (high quality country) which discusses empagliflozin and sarcopenia. It hints at muscle loss (about 1% vs placebo over 52 weeks) but muscle loss is not statistically significant.

I guess the counter to this is to hit the gym.

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#1053

It’s quite clear to me that a calorie deficit can cause a decrease in muscle mass, I’ve noticed this measurably already at a young age and in strength levels as well. As far as I understand, there is also clear research evidence for this. SGLT2i reduces the absorption of calories because glucose is excreted with the urine, if the diet remains the same and you were in caloric balance, now you are in a caloric deficit. If you’re in a calorie deficit, you’re in a catabolic state, making it harder to maintain muscle mass. However, preserving muscle mass is also possible with a small calorie deficit, but many factors affect it. Since fat mass has decreased in these studies, that is a strong indication of a caloric deficit, so these studies tell me nothing personally (you can always add more calories to balance it out). It would be a clear indication of a calorie-independent effect if the fat mass does not decrease, but still the muscle mass decreases.

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#1054

I would add that it will most probably cause a decrease in muscle mass, barring a few specific cases of overweight people starting to train with weights.

mTOR apparently rules it all. By taking SGLT2-inhibitors, all other things being equal (no overfeeding to balance the loss) many upstream signals are lowered (energy, glucose, insuline/IGF1…). Even by keeping active the mechanic signal, it may not be enough, mTOR will shut off and autophagy/catabolism will prevail. This state will include both muscle cells and adipocytes, since lipid metabolism as well is ruled by mTOR.

In my n=1 anecdote, every time I go even moderately low carb, I invariably loose weight, both muscle mass and fat.

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#1055

Do you notice any differences in maximal strength? Reducing carbohydrates decreases the amount of water bound to muscles (if you reduce carbs enough, although the threshold may vary slightly between individuals).

#1056

Actually I can’t tell you much about max strength since I’ve been training light to avoid nagging pains and aches at ribs, joints and tendons. I’ve been unable to eliminate them and I have to spare myself to do household chores and gardening. Surely I lose water when doing a fast mimicking diet. Last time I went low carb (I mean 100-150 grams carbs per day) I lost 22 pounds in 2 years. After months, I could only regain 4 pounds.

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#1057

Yet another longitudinal study on SGLT2 pointing to neuroprotection (and all-cause mortality!): Association of sodium-glucose cotransporter 2 inhibitors with risk of incident dementia and all-cause mortality in older patients with type 2 diabetes: A retrospective cohort study using the TriNetX US collaborative networks 2024

Our first cohort comprised 193 948 patients treated with metformin and SGLT-2 inhibitors and an equal number of patients treated with metformin and DPP-4 inhibitors. In this cohort, the risk of dementia and all-cause mortality was lower in patients treated with SGLT-2 inhibitors than in those treated with DPP-4 inhibitors (hazard ratio [HR]: 0.62, 95% confidence interval [CI]: 0.59-0.65, for dementia; HR: 0.54, 95% CI: 0.52-0.56, for all-cause mortality). Our second cohort comprised 165 566 patients treated with metformin and SGLT-2 inhibitors and an equal number of patients treated with metformin and GLP-1 RAs. In this cohort, the risk of dementia and all-cause mortality was lower in those treated with SGLT-2 inhibitors than in those treated with GLP-1 RAs (HR: 0.92, 95% CI: 0.87-0.98, for dementia; HR: 0.88, 95% CI: 0.85-0.91, for all-cause mortality).

Poke @DrFraser

@Guest: Given that the glucose-lowering effect of SGLT2i is modest and that the comparators here are other potent glucose-lowering drugs (DPP-4i & GLP-1 RAs), I find papers like that compelling (and there are dozens of papers like this, looking at various databases and all finding similar HRs). More compelling than similar articles on bipolar disorder: 1/ smaller population and 2/ lithium is the main medicine used to treat bipolar disorder (at least in the UK), so someone with BD who is not on lithium might be intrinsically different for their doctor to choose another drug. And it might be that these other drugs are neurotoxic rather than lithium being neuroprotective (at least at the high BD doses). What do you think? I think it’s also one of the first papers looking at all-cause mortality: impressive as well (because you can always have the problem that people have a lower rate of dementia because they die sooner and don’t have “time” to develop dementia).

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#1058

And now a similar paper and finding for PD: Sodium-glucose cotransporter 2 inhibitors and the risk of Parkinson disease in real-world patients with type 2 diabetes 2024

Of 89 330 eligible Medicare beneficiaries (mean age: 75 ± 7 years, 52% women), 0.6% (n = 537) had incident PD over the follow-up. After 1:1 propensity matching, the PD incidence was 2.5 and 3.5 events per 1000 person-years in the SGLT2 inhibitor group and DPP4 inhibitor group, respectively. The SGLT2 inhibitor group was associated with a significantly lower risk of incident PD than the DPP4 inhibitor group (hazard ratio: 0.70 [95% confidence interval: 0.55–0.89]). There is a potential trend that the risk reduction in incident PD was profound in non-Hispanic Black individuals and insulin users.

My two cents: all these papers suggest that either DPP4 inhibitors are neurotoxic or SGLT2 inhibitors are neuroprotective, beyond glycemic control in people with T2D.

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Parkinson's disease
#1059

I’ve now been taking dapagliflozin 5mg for a week (splitting a 10mg tablet). Is there a big difference in potential longevity benefits between 5mg and 10mg? Of course, no one can know for sure, but what do you think? It seems like 5mg doses haven’t really been studied from this perspective?

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#1060

Very interesting. Given the large cohort sizes, did they break out the HRs for individual SGLT2i, in particular cana vs pure SGLT2i?

#1061

“There is a potential trend that the risk reduction in incident PD was profound in non-Hispanic Black individuals and insulin users.”

If you posit that “either DPP4 inhibitors are neurotoxic or SGLT2 inhibitors are neuroprotective”, why is this true for Black individuals and insulin users. That tells me that it would be tricky to extend this possible “neuroprotection” hypothesis/result to the general healthy population. Perhaps it’s something to do with T2D and insulin that is ameliorated or enhanced by SGLT2i. Again unfortunately the limitation is that we’re dealing with comparisons among cohorts all of which have morbidities. Same as the other one about all cause mortality - we have to be particularly cautious with this metric in sick people; a drug addressing a disease in sick people lowers death rates, duh. Now show the same drug effect in healthy people.

#1062

Interesting data. I guess the question is whether the DPP4’s are actually detrimental, or could they be protective, but just less so than the GLPs? It’s always a challenge when we don’t have a control group.

I’ll be interested to see if they can get data together for people taking it for heart failure, vs. those on other medications for heart failure and see what that pattern looks like (or of renal protection).

#1063

I don’t have access to the full text, I’m sorry. @AnUser do you still have access?

No it’s not that: it’s “a drug addressing a disease in sick people lowers death rates two times more than another drug addressing a disease in sick people”

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#1064

Right, one drug is better than another drug in sick people, but the healthy people are wondering what about us?

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