Do mixed sglt2 inhibitors synergize with each other

#1

Eg is halving the dose of canagliflozin and empagliflozin more effective than one pure strategy effective dose of each

[their activity is not EXACTLY identical]. Some are better at one thing than the other…

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#2

Do they have different mechanisms of action?

#3

yes, one is a sglt1 inhibitor and the second is an sglt2 inhibitor

#4

Canagliflozin is also an SGLT2 inhibitor.

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#5

Both of these are SGLT2 inhibitors.

#6

I think Alex is interested in finding out if adding some of the SGLT1 inhibition from canagliflozin will complement a pure SGLT2I such as empagliflozin, or is it just best to stick to one or the other.

I’d hazard a guess that most of the benefits come from SGLT2I, and I don’t really need the SGLT1I.

#7

That is a bold guess…

… since the only ITP or other actual longevity studies and data are all with Cana / SGLT1, there are mechanistic reasons to think the gut effects (which you don’t get from just 2-inhibition) are important for longevity, and it’s only for SGLT1 that we have Mendelian Randomization data for mortality.

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#8

True. I could be wrong. However I do like the results for empagliflozin, so I’m going to give that a try first. As more data is available, it may change my mind.

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#9

My understanding is that cana inhibites both 1 and 2

#10

Totally. Anything I said make it sound like I think otherwise?

#11

dapagliflozin and empagliflozin have much lower rates of dementia than canagliflozin. I have no idea why… this is just one study, but I’d imagine it would be better to use a combination of both spread out amongst each other (canagliflozin is better at blocking immediate glucose spikes from strawberries)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8659196/ says SGLT1 in the brain too… (also flozins can increase gluconeogenesis too…)

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#12

I recall reading that sglt1 was everywhere (brain and heart as I vaguely recall; not just the gut) and that too much sglt1 inhibition could be problematic.

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#13

UGE ~100 g/dayk ~70 g/day Empagliflozin 10 mg: ~64 g/day
Empagliflozin 25 mg: ~78 g/day See note
Caloric Lossa (1 g =~4 kcal) ~400 kcal/day ~280 kcal/day ~256 - 312 kcal/day See note
Food Effects &

Comparison of INVOKANA to Other SGLT2 Inhibitors

Chat gpt convert to table

#14

Canagliflozin has off target effects interfering with mitochondrial respiration that the others don’t. This occurs within or close to the range of clinical exposures. Whether this is bad or good is unknown (metformin also inhibits one of the targets: complex I). Canagliflozin also had some unique adverse events (eg limb amputations) in clinical trials that the others don’t know have - don’t know whether this is related to SGLT1 or mitochondrial inhibition or random.

I don’t see why mixing drugs would have synergies. Just go with canagliflozin if you want to max out UGE. SGLT2 will already have been maximally inhibited as you ramp up SGLT1 inhibition.