Fascinating information about SGLT2i and heart failure

#1

I was at a big cardiovascular meeting recently and learned something which I’ve not seen discussed here, which I want to share.

I think we all know that SGLT2i drugs are goo for the heart, right? I assumed that this related to the glucose lowering effects. On these drugs, you pee out something like 60 to 90 grams of glucose (300kcal worth) per day. Considering that your blood has only around 5g (a teaspoon) of glucose in your blood at any given point, 60-90g per day is actually really very significant.

However, I learned some really interesting things:

  1. SGLT2i drugs still prevent and treat heart failure in non-diabetics. You don’t need hyperglycaemia to benefit.
  2. SGLT2i drugs prevent HF in mice which have been genetically edited to remove the SGLT2 receptor.
  3. There is no known SGLT2 receptor in normal heart tissue.

Cutting a long story short, it turns out there is a completely different mechanism of action for these drugs:

  • SGLT2i drugs directly activate an enzyme called pantothenate kinase 1 (PANK1).

  • PANK1 is a rate-limiting enzyme that initiates conversion of pantothenate (vitamin B5) into coenzyme A. (If you recall your high school biochemistry, CoA is basically central to all major ATP generation pathways, and especially so in the heart which is extremely ATP hungry.)

  • PANK1 expression is suppressed in failing human hearts.

  • SGLT2i drugs significantly boost CoA levels and stimulate fuel use in the heart.

  • In this study, the authors showed incredibly strong evidence. They showed rising CoA both in mice, and also using human ex vivo hearts. In other words, the heart is removed from the body, kept alive on a perfusion system, and the drug was infused. So this means the SGLT2i drugs work directly on heart tissues, and this has nothing to do with the kidney, glucose levels or anything else.

  • They also showed SGLT2i activity on isolated cardiomyocytes. Adding the drug revs them up, makes them generate more ATP, and contract harder.

So this is an extremely “lucky” off-target effect, and IMO makes these drugs even more appealing. The good news is that these findings (according to the speaker) apply to all of the “flozin” drugs. They can be used to actually treat heart failure, and by this logic should be preventative.

@adssx I know you’re interested in this topic and these drugs, so tagging you

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Vitamin B5: pantethine vs pantothenic acid (calcium pantothenate)
Canagliflozin - Another Top Longevity Drug
#2

Thanks for sharing. PANK1 is one of the potential off-target pathways but there are others being studied: Canagliflozin - Another Top Longevity Drug - #1252 by adssx (ref 27 is your article, Forelli et al.).

The July 2024 article you shared (Forelli et al.) is a preprint, though, and it doesn’t seem to have been published yet. No one has really written on the topic since then. Why?

Anyway, I’m sure @John_Hemming will be interested by this pathway!

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#3

Ah, cool that you were already aware of this. I only learned it recently.

According to the speaker, I believe it will be published in Nature some time soon.

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#4

Very nice, that will trigger a good discussion on this hypothesis then!

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#5

There probably is a reason for a rate limit on CoA production. It looks like sglt2i and pantethine have similar effects here.

#6

Yeah other glucose lowering drugs haven’t had this effect, and it was initially an incidental finding from CVD safety trials.

Does this mean that SGLT2i MR studies can’t detect HF outcomes and PANK1 activation MR or similar is needed? I guess that’s a way to validate this hypothesis if it’s the case.

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#7

Oh wow, yeah that’s a very good point!! Since it’s a completely off-target effect, MR studies of SGLT2 receptor variants would not account for that, you are right.

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#8

And yet: https://www.sciencedirect.com/science/article/abs/pii/S0014299925007113

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#9

Another one: Frontiers | SGLT2 inhibition, plasma proteins, and heart failure: a proteome-wide Mendelian Randomization and colocalization study

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