Here's yet another chance to play the human biology game that might as well be called "Now what?" That's when we find that what we thought we knew is actually wrong, more complicated, or a sign of something else entirely.
Today's entry is niacin. As many readers know, it looks like it should be a promising therapy for patients whose lipoproteins are out of whack. It lowers LDL, raises HDL, lowers free fatty acids, and lowers triglycerides, and all those things are supposed to be good. (As came up in the comments yesterday's post, though, the evidence is pretty strong for that first proposition, but not as solid for the others). Still, if you went around to thousands of cardiologists and asked them if they'd be interested in a therapy that did those four things, you'd get a resounding "Yes".
So why hasn't niacin taken over the world? Because of the side effects. It has to be taken in rather stiff doses to show the lipid effects, and those tend to cause a nasty skin flush reaction, which is apparently unpleasant enough that most people won't put up with it. Various attempts have been made to abrogate this, with the most direct assault being Merck's (failed) Cordaptive.
The flushing is thought to be mediated through the receptor GPR109A, via a prostaglandin pathway. Unfortunately, it's also believed that niacin's beneficial effects are mediated through that receptor, too, via some mechanism that starts with the lowering of free fatty acids. If you knock out the receptor in mice, you get no skin flushing, but no FFA lowering, either.
We must now revise that idea. A new paper tests that hypothesis with two non-niacin agonists, MK-1903 (a compound via Arena Pharmaceuticals, I believe) and SCH900271, and their effects in humans. They also report niacin's effects in the receptor knockout mice, claiming that although the FFA lowering does indeed disappear, that the downstream lipid effects remain. (That surprises me; I'd thought that had already been studied).
But the human data are especially revealing. The two new agonists do indeed show FFA effects, as you'd expect from compounds hitting GPR109A. But they do not show chronic free fatty acid lowering, nor do they have the desired downstream effects on blood lipids. So it appears inescapable that niacin's effects are going through some other pathway, one that doesn't depends on GPR109A or its (transient) free fatty acid lowering. Back to the drawing board everyone gets to go.
But niacin has been heading there already. Readers may remember a trial of a niacin-and-statin combination had to be stopped early because the cardiovascular effects were (alarmingly) going in the other direction. Not only was there no benefit, but there seemed to be active harm. Taken together, all this tells us that we have an awful lot to learn about some things that we thought we were starting to understand. . .