So, name a class of prescription drugs that lots of people have been taking daily over a period of decades: how about statins? From a distance, the story is completely understandable: statins inhibit the enzyme HMG-CoA reductase, which shuts down a key step in cholesterol biosynthesis. That lowers the amount of cholesterol in the body, and that lowers the blood levels of low-density lipoprotein (LDL), and that leads to lower rates of cardiovascular mortality. There you have it.
But step up closer and look again. We’ve already had some puzzling results about the cardiovascular benefits of lowering LDL per se, not to mention several whalloping failures in seeing good effects by raising HDL, which is (from that same distance above) just as solid a hypothesis. This is why the current PCSK9 therapies are still involved in large outcomes studies. No one doubts that they lower LDL, but no one’s completely sure if this is going to be one of those lowers-LDL-and-does-good stories or lowers-LDL-and-something-else-happened stories. You’d think the former, but you’d think a lot of things (I know I do).
OK, come over and look at this story from that same closer distance, but from another vantage point. So what do statins actually do? There have been reports over the years of decreases in some forms of cancer in statin patients versus matched control populations, and reports of similar effects in Alzheimer’s (see this new paper for more on that). These studies are not easy to do, because they’re mostly observational, but the flip side is that you can potentially use observational data collected from tens of millions of people. Over the years, more and more people have come to think that statins as a class do more than just lower LDL.
One of these things is almost certainly to affect prenylation. That’s one of the many post-translational modifications to proteins, and its availability is also tied to the mevalonate pathway that’s affected by statin effects of HMG-CoA reductase. Messing around with prenylation can have a number of effects, including tumor progression and modulation of the immune system. Prenylation is thought to be the mechanism by which statin treatment makes fruit flies live significantly longer – interestingly, it appears that the effect works through improvements in their small fruit fly hearts, which might well be a mechanism by which statins improve cardiovascular mortality in humans completely outside the LDL pathway. There’s a lot of argument about that last point, but it’s more about how large these beneficial pleiotropic effects are than whether they exist.
But if you go ask a thousand people how statin drugs work, to the extent that you’ll get any answers at all, they’re almost certainly going to be “They lower your cholesterol”. Lots of people are surprised to find out that cholesterol is necessary for life, although that certainly doesn’t mean that having heaps of it in your body = more life (although having extremely low levels is actually correlated with early mortality). The story is more complicated, and it’s more complicated at every level.
Take as another example that link above to the new paper on statin effects on the incidence of Alzheimer’s disease. It will be easy to write a headline (someone probably will) that Cholesterol Drugs Fight Alzheimer’s, but it’s tricky. The paper found varying results depending on which statin was used in which population (by ethnicity and gender). Even with the huge Medicare data set the authors used, it’s hard to say just what’s going on, and hard (as yet) to made any recommendations. Pharmacokinetics (including blood-brain barrier penetration), metabolic differences between different groups, and who knows how many other variables are affecting the data.
So that brings us back around to the opening paragraph: here are some of the most widely taken, most well-studied drugs in the industrialized world, and we’re still trying to figure out what they do and how they do it. This is worth a thought whenever someone tries to pretend that drug discovery and development isn’t ( or shouldn’t be) so complicated. It is, it is.