Yes, of course, it’s the expected answer. I too have read the studies. My whole point here is that in medicine (and biology) we have especially good reasons to practice epistemic humility. There are literally thousands of examples of when we thought we understood the MOA of something only to later discover that it’s far more complicated, sometimes to the opposite effect. This is why in medicine we put so much emphasis on outcomes. Because it tells us “what” the outcome is in a measurable way, whereas the “why” is the mechanism, which we are far more prone to be wrong about. It’s very common to say “this medication works, though we don’t fully understand why”. Which is why I try to adopt the black box paradigm to medicine. We have inputs (the intervention), and we have the output (the outcomes), but how you get from input to output is through a black box of MOA which is opaque. Yes, in many cases we can speculate accurately as to what happens inside of the black box. But very often we don’t - we make a small change in inputs (in that we think the change is irrelevant based on what happens inside to black box), only to be surprised when the output changes too.
What are the situations when our spidey sense tells us to be careful in asserting we understand the full MOA? It’s when the effects are complex. For example SGLT2i effects are extremely pleiotropic. They affect not just kidneys, but brain and heart among other tissues. And we really do not have a full explanation of the MOA of SGLT2i positive effects on CVD for example. When it comes to kidney health, we have a whole bunch of mechanisms by which we think SGLT2i manage their good effects: glomelular hypertension, diuretic anithypertensive effects, antifibrotic, tubular hypoxia, metabolic efficiency, anti-inflammatory effects etc., and so on down the line. And that is exactly when our spidey sense should kick in. When the MOA is simple or unitary, odds are it’s correct. We see that in elegant experiments, for example with infectious agents, where the presence or absence of the agent gives the precise outcomes we observe. There is no ambiguity. That’s true of many molecules. But when it comes to many others, where the effects are diffuse and pleiotropic, all bets are off. The more ways a drug acts and along more pathways, the less confident we can be about the MOA - some of these we call “dirty” drugs, because they have such scattershot effects where we are not sure at all about the MOA or the weight of impact we can assign to any particular aspect of a multi-effect drug - which precise mechanism is more important than another.
And that’s the situation with SGLT2i. Yes, we think we understand many MOA of how SGT2i achieve their health benefits in the kidneys, but it’s actually along many pathways and we can’t be sure we’ve mapped out all of them. In such a scenario, how do we know we have not missed one, including - pure speculation - lithium disposal? Epistemic humility.
My point is not to assert that lithium disposal is part of the MOA in kidney benefits of SGLT2i. That would be the opposite of epistemic humility, lol! My point is simply to say - epistemic humility compells me to point out that the causality chain is not transparent here, and not complete. I don’t know. In that I’m not just pronouncing simple ignorance, but a more socratic one of consciously thought through skepticism, “I know that I don’t know” precisely because I have read so much of the relevant literature. More knowledge alerts you to how much more knowledge gaps there are.
To bring it back to brass tacks. I’m not saying Li is not the bee’s knees. I’m saying that settling on a good dose of LiO is dependent on an understanding of the effects. And there is a ton we don’t know about lithium in the context of longevity and health effects. Meanwhile SGLT2i are a class of medications that tell us something about lithium levels and health - even if exclusively “low levels are not necessarily deleterious to health”. But the fact that we are faced with such a paradox when it comes to Li and NDDs with SGLT2i impact tells us unequivocally that there is A LOT we do not understand here. The idea here is that we should take LiO for NDDs and brain health. Shouldn’t we understand the effects more before we can select the appropriate dose? And shouldn’t we be troubled by the existence of that paradox of SGLT2i being good against dementia in people while drastically lowering Li that in turn is also supposedly good against dementia? So which is it? Low levels, or high levels? Isn’t that relevant when trying to settle on a dose?
That was the context of my idle speculation - to say that there is too little information and that the disparate effects, including on the kidney might alert us that “that way danger lay”, and angels fear to tread - should we rush in? Again - like I said it’s pure speculation, not assertion. I don’t know. YMMV.
