#1007

Also, when you buy Indian Empagliflozin, you can buy the original brand made in Europe and not a generic made in India.

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#1008

Anyone experienced random cold sweats or slight sensation of fever while on empagliflozin? I’m taking 12.5mg irregularly and noticed this happens more often if taking it two days in a row

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#1009

My body temperature is elevated on it.

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#1010

Mendelian randomization study of sodium–glucose cotransporter 2 inhibitors in cardiac and renal diseases 2024
:warning: Chinese paper :warning:

SGLT2i had a significant protective effect against nephrotic syndrome (odds ratio [OR] 0.0011, 95% confidence interval [CI] 0.000–0.237), chronic glomerulonephritis (OR 0.0002, 95% CI 0.000–0.21), and hypertensive nephropathy (OR 0.0003, 95% CI 0.000–0.785). No causal effects were observed between SGLT2i and cardiac diseases or potential adverse events.

If I understand correct, this finding suggests that SGLT2 inhibition is highly nephroprotective but that SGLT2 inhibitors might not be cardioprotective via SGLT2 inhibition but via another off-target pathway.

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#1011

I apologize if this was already discussed, but are there any ideas on why cana led to a more significant increase in mice lifespan in the ITP study than empa did in the study below?

Cana extended median survival of male mice by 14%.

Empagliflozin extended the median survival of male mice by 5.9%

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#1012

Perhaps it’s overly cautious, but the empag paper is from Chinese institutions that are not of the first order. I think that’s worth noting. Btw., here is Matt Kaeberlein about Chinese papers, having spent a lot of time there on scientific exchanges. He’s very diplomatic, but states outright that once you step outside the few major research centers in Beijing and Shanghai, the quality plunges precipitously, and any smaller regional paper he looks extra cautiouly at - from 4:50 on:

I’d look for confirmation of these results first before going all in on this. YMMV.

6 Likes
Everolimus instead of Sirolimus / Rapamycin? Anyone else trying?
#1013

Excellent question! Which dose did the Chinese study use? From which age? Which route of administration?

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#1014

OK, so the Chinese paper says:

To observe the effect of empagliflozin on the lifespan of mice, 100 13-month-old C57BL/6 J male mice were randomly divided into two groups (n = 50 in each group). Mice received water and standard AIN-93G diet (Ctrl) or standard AIN-93G diet plus empagliflozin 30 mg/kg/day body weight (Empa) ad libitum. Mice were observed daily, and their mortality was recorded. In addition, mice were euthanized for humane reasons if they were found to be in a severely distressed state by an experienced professional technician and unlikely to survive more than 48 h.

And they found “Empagliflozin extended the median survival of male mice by 5.9%”, log-rank survival test analysis, P = 0.0274

The ITP using canagliflozin:

  • 2016: 180 ppm (equivalent to 30 mg/kg mouse body weight), from 7 mo: +14% median survival of male mice, log-rank test yielded P < 0.001, 150 male controls + 150 male cana
  • 2020, 180 ppm (idem), from 16 mo: +14% median survival of male mice, p = 0.004, same numbers?

The ITP uses “genetically heterogeneous (UM-HET3) mice born in 2016 were placed on a chow diet”.

So:

  1. The types of mice and diet might influence the results.
  2. The Chinese study was 3x smaller. It’s possible that the “real” lifespan extension is not that different between empa and cana.
  3. The ITP paper notes that the cana dose used is “similar to the human therapeutic dose of 100–300 mg/d for a 70 kg person”. The Chinese study used the same mg/kg/day dose of empa. However, in humans the typical dose (DDD) is 200 mg for cana vs 17.5 mg for empa. 11x more! So they should have tested empa 3 mg/kg/day.

However, assuming the Chinese study is correct, it’s still interesting: empagliflozin, contrary to canagliflozin, is a pure SGLT2 inhibitor so it shows that SGLT2 inhibition alone might have life extension properties (or it’s an off-target mechanism common to canagliflozin and empagliflozin?). poke @Neo.

4 Likes
Everolimus instead of Sirolimus / Rapamycin? Anyone else trying?
#1015

Empagliflozin has still shown significant benefit in protecting kidney function in human clinical trials so regardless of how well it works in male mice, everyone should still be using it.

#1016

My own experience with Jardiance has not been encouraging. Have only been using it for a short time, and already had two bladder infections that involved a week of frequent urination, painful urination, and extreme fatigue. Going to talk to my cardiologist next week about it. As I’m not diabetic I don’t “need” to be on it and I’m wondering if perhaps a lower dose or cycling on/off would be more viable.

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#1017

Interesting. Even when I had severe prostate hyperplasia with severe urinary retention, I never had a single UTI while taking empagliflozin.

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#1019

You are not diabetic, have you tried taking it at a lower dose and only a few days a week?

#1020

This is already approved for non diabetic who have CKD or heart failure so it shouldn’t be a problem.

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#1021

What about UTI vaccine before using SGLT2i? I see no mention of Uromune here: Uromune - Wikipedia

There is also a UTI vaccine trial which is possible to enroll in following certain criteria.

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#1022

Two (naive?) questions I’ve been wondering about:

  1. Do we know anything about the body’s adaptations during the time SGLT2 inhibitors are taken that may impact what happens after discontinuing them? In other words, what would happen if one tried these drugs for several months or years but then discontinued them? Would the body revert to “business as usual”, or is it possible that there would be some residual (especially unwanted) effects due to some feedback mechanisms?
  2. Somewhat related, most of the studies are relatively short-term. Is there reason to believe that the positive effects discussed in the thread would continue compounding if the drugs are taken long-term (5+ years, 10+ years, etc.), or is there a risk that the trend would eventually reverse?
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#1023

There is no reason to believe that the body would not reverse to its default state after SGLT2 inhibition is stopped. At the very least there are no case reports pointing to such a thing.

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#1024

Not yet, I’m going to see what the doc says next week.

#1025

My biggest concern about SGLT2Is is that they take a lot out of your blood and send it to your urine. For instance, it helps excrete glucose (good), sodium (good), and lithium (bad). I wonder if it also affects other blood trace minerals such as magnesium, iron, copper, boron, etc… If so, you may lose many of the benefits from supplementing these other minerals. Would it also act on amino acids, proteins, or other food/supplements?

I’ve already upped my dose of lithium orotate to compensate (5 mg to 10 mg) due to the 70% increased excretion of lithium by empagliflozin. And, I’m still only getting 3 mg with the new higher dose.

It does appear to increase potassium levels due to the increased excretion of sodium.

In a pooled analysis of heart failure patients with reduced or preserved ejection fraction, empagliflozin reduced the composite of investigator-reported hyperkalemia or initiation of K±binding drugs without increasing the incidence of hypokalemia.7

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#1026

I hear you DeStrider, very valid concerns.

But here is an odd thought - what exactly is the primary function of SGLT2i drugs? It gets rid of glucose. What is the most frequent cause of excess glucose? It could be insulin insensitivity or insulin insufficiency, but often both have a common cause - a long period of excess calorie consumption which results in insulin resistance, then insulin underproduction, and all from a consistence overabundance of glucose. In other words overfeeding.

What SGLT2i are countering, is the first consequence of overfeeding - excessive glucose levels. In other words, SGLT2i acts as if you are not overfeeding. As if you are eating less, because food enters your mouth but before the resulting glucose can wreak havoc, it is removed, effectively as if a portion of your food was removed from your mouth.

Curtailing food intake is another name for Calorie Restriction. Perhaps SGLT2i can be called crypto CR agents. From anecdotal reports you hear people say they can eat alot, yet not gain weight.

Yet, what is the effect of CR? Very healthy, seemingly. Undernutrition is healthy, while overnutrition is unhealthy. Now, if you are on CR, you expect all aspects of the food you take in to be at lower levels. It’s not as if when you consume lithium in your food and water intake, the CR only cuts out glucose, and leaves the lithium behind. No. CR cuts out ALL of the food, including ALL of the constituents, salt, lithium and everything else. So if SGLT2i cuts down on lithium, perhaps we can take our complaint not just against SGLT2i, but also CR. Yet, CR is healthy. Now, we can speculate that SGLT2i gets rid of nutrients unevenly, unlike CR that simply gets rid of it all, so perhaps some kind of unhealthy imbalance results… but…

In fact, doesn’t the same “losing micronutrients” rule that happens with SGLT2i in humans also apply to rodents? Yet, the mice on cana as tested in the ITP seemed to live longer. How hurt were those mice by all that micronutrient loss and imbalance - not much, and not more than CR, both of which extended lifespan. Let us remember, why SGLT2i were developed in the first place - to get rid of excess glucose. But if you are on CR, you never have excess glucose in the first place! So, CR is superior to SGLT2i and as Matt Kaeberlein says, CR is superior to rapa, because it takes care of many other pathways of aging compared to rapa. And CR gets rid of ALL extra nutrients - one can quibble but that’s the gist of it.

Bottom line, I’m not sure what to make of this, but perhaps - PERHAPS - loss of nutrients or molecules from using SGLT2i is not quite as worrisome as may seem at first glance. But hey, it’s just some crazy speculation - either way, for or against SGLT2i. YMMV.

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#1027

@CronosTempi I agree with you. I’m not going to stop empagliflozin because the benefits are amazing. As you said, I can eat more AND lose weight and not have it affect my insulin resistance. That’s a win-win. However, if it is causing a nutrient deficiency, I want to be aware of it and address it.

I want my cake and eat it too… And not gain the weight from eating it.

That’s why I’ll continue with empagliflozin no matter what. But, I’ll be upping my lithium dose to compensate. Now I just need to be aware of what else I may have to adjust.

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