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:
SGLT2i drugs still prevent and treat heart failure in non-diabetics. You don’t need hyperglycaemia to benefit.
SGLT2i drugs prevent HF in mice which have been genetically edited to remove the SGLT2 receptor.
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
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!
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.
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.
They also showed SGLT2i activity on isolated cardiomyocytes. Adding the drug revs them up, makes them generate more ATP, and contract harder.
This is very cool, thanks for sharing! Although there are previous papers showing effects of SGLT2i in cells that don’t transcribe the SGLT2 gene. For example, empagliflozin exerts putative antifibrotic effects in cardiac myofibroblasts, despite their lack of SLC5A2 expression.
Ha! Cool that you found two articles. And yeah, I agree with the commentary that MR are very powerful but always need to be considered with mechanisms in mind. And to be honest, it’s relatively easy to massage the methods in order to find a result you want, which unfortunately is the case.
Very cool!
I learned a bit about the history of these drugs, and yet again it’s a natural molecule (phlorizin) discovered 200+ years ago in apple tree root bark. Obviously we’ve tidied up the molecule since then. But I do like the overall “lesson” here that there are tons of highly-potent bioactive molecules all around us. I learned that this is something called the “privileged scaffold hypothesis” because for a plant to synthesise these molecules it needs to interact with a bunch of different enzymes. Thus the molecule is already well-adapted for binding to proteins.
Think about it: aspirin, lovastatin, rapamycin, cyclosporine, paclitaxel, artemisinin, berberine, astaxanthin, metformin, colchicine - all highly-potent natural molecules which are very good at binding with lots of proteins across different species.