Peter Salgo, MD: We, now, are seeing the dawn of these inhibitors. If the early research is born out going forward, this is the dawn of a new era—new cholesterol levels that are so low that we couldn’t conceive of getting stuff down before. But where are we going from here? What’s next? What are some of the more interesting areas of research in cholesterol management going forward?
Howard Weintraub, MD: Now, there are medicines that work by inhibiting DNA—essentially, messenger RNA (mRNA) inhibitors. These are medicines that prevent the proteins from being made, and there are certain kinds of dyslipidemias that can be horribly damaging; many of them involve triglycerides. Triglycerides are fats. It’s the way we store energy in the body. We used to think of them as not much to have to deal with. It’s a company they keep. It’s obesity and blood sugar. But now, it turns out from Mendelian genetics that they have very big importance.
There are several new drugs that are going to address that, and one of them is a lipoprotein that we’ve been ignoring for years, called Lp(a) [L-p-little-a] that is present in about 20% of people and ups your risk by 3- to 4-fold. A lot of the people that we see, who are the ones who need the PCSK9s (proprotein convertase subtilisin/kexin type 9s), are people with LDLs with levels around 80 mg/dL who keep having events. And these are the people, when you measure them (we did a study that’s in press), 45% of these people that keep coming back have high LP(a)s.
Peter Salgo, MD: What is this ORION-1 trial?
Howard Weintraub, MD: ORION-1 is second-generation PCSK9. It’s a mRNA inhibitor, which means you can get it every 3 months. You get the exact same degree of LDL reduction—55% at the highest dose. One group got it at 3 months, 1 group got 2 injections. And at 3 and 6 months, they did very, very well. They had some injection site reactions, which was much more than what you see with the monoclonal antibodies, so they’re going to have to work that out. And, in general, this has been a problem with other mRNA inhibitors that have come to market. But you get the benefit of 4 injections a year versus 12, and also, it’s cheaper. These are cheaper to make than monoclonal antibodies.
Peter Salgo, MD: When you’re dropping LDL cholesterol as rapidly and as dramatically as you are, some people, looking at the early statin trials and the effects on cognition and word finding, were blaming cholesterol. They were saying, “You need some cholesterol in your brain to make this work.” What about these drugs? They’re so low.
Seth J. Baum, MD: You do need cholesterol in the brain. The brain is highly dependent upon cholesterol, but all the brain cells make their own cholesterol. So, the brain does not get cholesterol from LDL. LDL does not deliver cholesterol from the brain.
Peter Salgo, MD: Is it rational to say this that this will not affect it?
Seth J. Baum, MD: This will not affect it. And, in fact, in the trials, it did not.
Howard Weintraub, MD: Right. And there’s another trial, which was a partner to FOURIER, where they looked at cognitive issues in people in the FOURIER study and they found no consequences of getting LDL down into the 30 mg/dL and 20 mg/dL range. They were concerned it would make people goofy, and it did not happen.
Peter Salgo, MD: So, in fact, what was making people goofy on the statins may not have had anything to do with cholesterol at all?
Howard Weintraub, MD: Exactly.
Seth J. Baum, MD: Right.
Peter Salgo, MD: What do you see as the unmet needs here?
Seth J. Baum, MD: Although, in theory, you could say that the statins, the HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme) reductase inhibitors do block cholesterol production in a cell. And if they do cross the blood-brain barrier, they do limit, somewhat, the internal cellular capacity to manufacture cholesterol.
Peter Salgo, MD: And the newer drugs don’t do that?
Howard Weintraub, MD: They do not. They’re a big protein.
Seth J. Baum, MD: They don’t cross.
Peter Salgo, MD: They don’t cross the blood-brain barrier.
Seth J. Baum, MD: Right, and they have no impact on a cell’s manufacture of its own cholesterol.
Peter Salgo, MD: That’s fascinating, because the peripheral effect of the statins is at the hepatic level—reabsorption, not in terms of assembly of cholesterol. That’s interesting.
Seth J. Baum, MD: Yes.
Howard Weintraub, MD: Right.
Peter Salgo, MD: It’s fascinating.