Just an opinion piece based on the research I've done so far...
Global inflammation effects HDL in two ways... high inflammation decreases HDL, but also morphs the structure of existing HDL.
HDL only functions correctly (reverse cholesterol transport and protects LDL from oxidation) when there are low levels of global inflammation in the body. In other words, you can have high HDL, but if none of it is functional, you effectively have low HDL. Particle size is important too, but not relevant to this specific discussion.
Results for trials using Nicotinic Acid (NA) have been pretty poor, and I think the reason is that most people on statins have really high levels of inflammation. Statins work because they have an anti-inflammatory component to their mechanism of action, they change the functionality of the HDL that exists in circulation.
So my hypothesis is that NA-only therapy would be much more successful if taken in conjunction with strong anti-inflammatory compounds, and that the success of NA+anti-inflammatory would depend on how much a problem lipid-based cvd risk and inflammation is for the particular person.
Take butyrate as an example of NIACR1 agonism functioning properly. Butyrate is strongly anti-inflammatory, and lowers cholesterol through the same receptor mechanism as NA, and I think it would be a really good therapy for people with dyslipidemia and high risk of cvd, if only the right dosage could be administered cheaply and easily. The reason people don't use butyrate over NA is that it's less potent at the receptor, so you need grams and grams of the stuff vs miligrams of NA... so, can we make an NA stack function like butyrate? Perhaps if we co-administered anti-inflammatory HDAC inhibitors, we'd see good results with NA.
Or perhaps we just find a cheap and comfortable way to megadose butyrate?
Enjoy my brainfarts,
Adam