#1118

@adssx any thoughts on this? It does seem like Empa (and Dapa) may not affect complex 1 in the same way as Cana?

#1119

Thanks @Madhacker. Have you seen any other discussion about this hypothesis?

#1120

Based on this, I plan to continue taking Empa until I get a cancer diagnosis, then switch to Cana. I plan to get an annual whole body MRI scan (SimonOne for $650 for cancer only scan, $1250 with MRA and NeuroQuant and higher-res Prostate/Ovarian cancer scan SimonOne Pricing) so I get early warning.

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#1121

In theory that would seem to make some sense:

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#1122

I have no idea sorry.

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#1123

No, I came to this website as this is the place to do it. Empa and other SGLT2 do not share the same direct effect on complex-1. It’s an independent and personal hypothesis that I’ve been thinking about the past 18 months. My business is seasonal, I’ve just finished up so I have time to review the data.

Mitochondrial Respiratory Complex I is a target for specific types of cancer research and it looks promising. Empa and other SGLT2 inhibitors targets AMPK, and cancer outcomes are less impressive to say the least. To note, canagliflozin targets AMPK at a significantly higher level- It will be a no brainer when I specify the mechanism- inhibiting mitochondrial function, complex 1. As we all know, mice are vulnerable and prone to cancer; humans having much more complex systems than mice so far from equal models for ITP outcomes, but the cancer specific outcomes in humans are measurable.

Beyond, autoimmune targets for age-related, generalized autoimmunity is of interest as we currently cannot target the aging immune system in all its complexity- increasing immune responses is a problem leading to many diseases- presently, canagliflozin but not other SGLT2 inhibitors have shown to target adaptive related modulating effects rather than suppressing.

Empa has numerous benefits for mitochondrial function and metabolic functions increasing ATP etc. which are primary reasons for its efficacy in HF. Numerous other targets of course.

We have been blindly taking Empa for aging indication based on the fact that it has more promising data in humans for numerous drug indications, which in some context “aging is the sum of all diseases” but fundamentally I question it’s efficacy compared to Cana for aging indication. It looks like Cana can meet primary end-points for some adaptive related autoimmunity downstream >mTOR1 and the cancer target of complex 1 while benefiting CV, CKD and HF but not to the degree of Empa.

We know that preventive measure is the best measure and I think that’s what cana can provide, possibly more than other molecules in the class. That’s my hypothetical Interpretation as how it can increase healthspan.

@RapAdmin Would you like to start a thread on this and move this over? I’m failing to discuss various other details that are involved and many could benefit from the discussion.

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SGLT2 Inhibitor Canagliflozin eliminates senescent cells and alleviates pathological aging (in mice)
SGLT2 Inhibitor Canagliflozin eliminates senescent cells and alleviates pathological aging (in mice)
#1124

Empa’s benefits have been clinically proven.
Canagliflozin’s impact on cancer and autoimmune regulation is so far only a hypothesis underlined by some ex vivo cell tests. It is not even clear if clinical relevant concentrations could be achieved in the T-cells in vivo for example.
I will happily switch to Canagliflozin if the hypothesis turns out to be true, but so far I will stick to Empa.
Or maybe I will take both alternatively then.

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#1125

Sodium-glucose co-transporter 2 inhibitors for all-cause and cardiovascular death in people with different stages of CKD: A systematic review and meta-analysis 2024

In people with CKD, treatment with SGLT2is compared to placebo reduced the risk of cardiovascular death by 14% (hazard ratio [HR] .86; 95%CI .79-.94), all-cause death by 15% (HR .85; 95%CI .79-.91) and MACEs by 13% (HR .87; 95%CI .81-.93). A consistent treatment effect was observed across eGFR-subgroups (≥60 mL/min/1.73 m2: HR .82, 95%CI .65-1.02; <60 mL/min/1.73 m2: HR .86, 95%CI .77-.96, p-subgroup difference = .68) and KDIGO risk-categories (low, moderate, high and very high) (p-subgroup difference = .69) for cardiovascular death; reduction in the risk of all-cause death tended to be greater in the highest KDIGO risk categories.

That’s good news!

Worldwide burden of antidiabetic drug-induced sarcopenia: An international pharmacovigilance study

Antidiabetic drugs showed significant associations with sarcopenia, with SGLT2 inhibitors exhibiting the strongest association. Notably, despite numerous reports, GLP-1 RAs, did not show a significant association.

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#1126

That’s quite bad that SGLT2I and Metformin are associated with sarcopenia. That’s very very bad unless I’m missing something here?

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#1127

It’s one paper based on about 500 cases of sarcopenia and they note: “This signal was not observed in older individuals (≥ 65 years) but was significant in the 18–64 age groups.”

So we need more data but at least it’s reassuring regarding GLP-1RAs.

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#1128

Seems logical to me. If you’re constantly lowering glucose levels with something like SGLT2 inhibitors without giving your body enough fuel to rebuild, muscle loss could be the outcome, especially in “healthy” individuals who don’t necessarily need glucose lowering to that degree. Muscle needs glycogen to recover and grow, so if you’re not managing the refeeding process properly, sarcopenia makes sense as a risk.

That’s why I limit moderate dose empagliflozin to just 3-4 days a week around cardio, where the glucose burn is more beneficial, and I avoid it completely on weightlifting days when glucose is key for muscle recovery. Working so far…

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#1129

In my mind, it’s quite the opposite. In endurance training, glucose is key for recovery, while in strength training, protein is crucial. This is also reflected in the diets of endurance athletes compared to bodybuilders/strength athletes. When I was younger, I was able to build muscle quite well even though I was in ketosis for over a year, with no issues. Of course, calories need to be in a surplus.

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#1130

Interesting perspective! For me, the focus on cardio days is more about depleting ATP and activating AMPK. By lowering glucose availability with moderate-dose empagliflozin, I aim to enhance this process. When glucose is limited, the body is forced to rely more on fatty acid oxidation, which depletes ATP stores more quickly and triggers AMPK activation along with other cascades such as FOXO, H2S, and p53. This shift improves mitochondrial efficiency, and supports long-term metabolic health. So, I am not focused on 40km under 2 hours, but rather on creating hormetic stress on body in a most “convenient” way.

However, when it comes to weightlifting and muscle recovery, I prefer to keep glucose levels available to fuel glycogen replenishment and muscle protein synthesis (mTOR up, AMPK down).

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#1131

Yes, my previous response was written entirely from the perspective of recovery/performance. Glucose does have its benefits for muscle growth, but for me personally, its effect doesn’t seem to be significant—individual differences are possible. Glucose triggers insulin secretion, and insulin promotes an anabolic state, but for example, a high-quality whey protein induces a strong insulin response even without glucose.

But back to the topic. I asked ChatGPT about this, and according to it, one mechanism for sarcopenia could be that, based on animal studies, glucosuria can also lead to the excretion of amino acids in the urine. I didn’t get any sources, so it could be ‘hallucination’ or pure mechanistic speculation.

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#1132

My educated guess is if we lift weights, it’ll probably offset any minimal risk of sarcopenia, bone loss, etc

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#1133

You could also just up your calorie intake while on SGLT2i, although how much of the benefits are then lost? Maybe still there are benefits, as the anti-fibrotic effects (at least for heart) are present in the absence of diabetes:

Methods: The EMPATROPISM clinical trial (NCT 03485222) investigated the efficacy and safety of EMPA in non-diabetic HFrEF patients. 84 patients were randomized to EMPA 10mg daily for 6 months or placebo on top of optimal medical treatment, and were evaluated with cardiac magnetic resonance (CMR). IMF was assessed by CMR using extracellular volume (ECV) by T1 mapping. Aortic stiffness was quantified by pulse wave velocity (PWV) by CMR. The primary endpoint was change in LVEDV. Prespecified secondary endpoints were changes in ECV (ΔECV) and PWV (ΔPWV) at 6 months between both arms
Results: 80 patients completed the follow up period. There were no differences at baseline in LVEDV (220±75 vs 209±68mL for EMPA vs placebo, p=0.5) or LVEF (36±8 vs 37±8%, p=0.7). There were no differences at baseline in both groups in either ECV or PWV (Table). In the primary endpoint, EMPA-treated patients showed decrease in LVEDV and increase in LVEF (ΔLVEDV -25±25 vs -1±25mL, p<0.001; and ΔLVEF 6±4 vs 0±4%, p<0.001 for EMPA vs placebo). EMPA-treated patients exhibited a reduction in ECV (ΔECV -1.25±1.5 vs 0.3±1.4% for EMPA vs placebo, p<0.001), which demonstrates IMF regression with SGLT2i. EMPA-treated patients exhibited a reduction in PWV (ΔECV -0.6±1 vs 0.6±1.4 m/s for EMPA vs control, p<0.001), which indicates amelioration of aortic stiffness with SGLT2i
Conclusions: In HFrEF patients without diabetes, treatment with empagliflozin ameliorates IMF and aortic stiffness. This may explain the benefits of SGLT2i in HFrEF even in the absence of diabetes [ref]

Also some evidence that these effects are SGLT2-independent

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#1134

That’s my experience as well. Every time I try to moderate carbs, I go catabolic. No matter the amount of protein (although I could never go much above the quantity of 1.6 g/kg/d).

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#1135

An interesting study that looked into empa and klotho:
https://www.sciencedirect.com/science/article/pii/S0753332222010666

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#1136

Are you compensating for the lower amount of carbs by increasing fat in your diet? Simply increasing protein probably won’t work - At least that’s been my experience.

Similarly, if I do endurance training for several weeks with too few carbs, I start to experience symptoms of overtraining. Maybe people are just different.

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#1137

tj_long, yes, I tried to keep the regime isocaloric with plenty of fats, using cronometer as a daily tracker. Probably the energy intake drifted downward when I ceased using cronometer.
Here is where the individual genetic makeup probably makes the difference.
I’m not usually hungry, and sometimes, I eat less than usual. Periods with some caloric deficit might have sent a strong inhibitory signal via the AMPK cascade.
Also, I have an hypothesis supported by a single blood draw, which I’ll have to repeat.
That analysis showed very low fasting insulin and pretty low IGF-1, so it may be that I need carbs to keep these signals above the threshold needed to switch up mTOR to phosphorylate the downstream anabolic targets.
Even if carbs are substituted by fats, this takes the energy signal (AMPK) theoretically constant, but it may dim the Insulin-IGF1/PI3K/AKT signal. Which signal prevails probably depends on a host of individual factors too complex to clarify.
All the above, of course, keeping constant the mechanical signal given by resistance exercise.

Last but not least, let’s remember that the typical buildup diet of bodybuilders, also advised by Brad schoenfeld in his book, is based on carbs and protein, with not so much fats.
So, I presume it is not impossible to gain muscle mass on a low carb diet, only it’s not so easy and it depends probably on individuals.