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I always tell patients we have tools today that we couldn't even fathom 20 years ago. 20 years ago, if you needed to have your apoB slammed, there was only one way to do it, which was megadose statins. I don't believe any patient needs to be on a megadose of a statin today because we just have too many other tools.
One of the most common questions we get is how do you lower your apoB, and what's realistic with and without pharmacology? So first of all, exercise has no meaningful impact on ASCVD risk factors through lipoproteins. It does in other ways, but if you're just talking about managing lipoprotein risk, it really comes down to pharmacology, hands down the most potent way to do it, and then nutrition, a far less potent but not insignificant way to do it.
On the nutrition front, you basically have two levers to pull. You can dramatically reduce carbohydrates, which will lower triglycerides, and all things equal, the lower the triglycerides, the lower the apoB burden, because you have to traffic fewer triglycerides with the cholesterol. The other way to do it is to dramatically cut saturated fat, which will do two things. It will reduce cholesterol synthesis, and in a high saturated fat diet, what typically happens in addition to an increase in cholesterol synthesis is the liver sues through something called the sterol regulatory element binding protein, which says, "I don't need any more fat brought in, I don't need any more cholesterol brought in," so it downregulates LDL receptors, so it pulls fewer LDL out of circulation, and LDL will skyrocket. So the reverse is true: if you cut saturated fat, the liver is going to want more LDL coming in. It will upregulate LDL receptors and pull more LDL out of circulation.
So if you were on a really low carbohydrate, really low saturated fat diet, you would indeed lower your apoB. Would you lower it to the levels that I think are necessary to make ASCVD irrelevant? Most people probably not. And then would that be a diet that for most people is sustainable long term? That's probably a very individual decision. For someone like me, who has very low triglycerides, I don't go out of my way to eat saturated fat, but I'm also not restricting it either. I would say I'm probably in line with where the average person is. My apoB at baseline would still be, I don't know, 90 to 100 milligrams per deciliter, which puts me at about the 50th percentile of the population. So that's my normal apoB, which is far, far too high for someone who has a genetic predisposition to ASCVD, and be just somebody who wants to take the one horseman that can be taken off the table and take it off the table.
So my target for apoB is 30 to 40 milligrams per deciliter. Obviously, that would require pharmacology, and so I take three drugs to do that. I take a PCSK9 inhibitor called Repatha, and I take a combo drug called Nexlizet, which is bempedoic acid and ezetimibe combined into a single pill. The mechanism of action of ezetimibe, not to get too technical, is that it blocks the NPC1L1 transporter in both hepatocytes and enterocytes of the gut. It prevents non-esterified cholesterol from coming back into the gut after you've recirculated it through your liver and into bile, so it prevents you from reabsorbing your cholesterol.
Of the three drugs I'm taking, that's far and away the least potent. Bempedoic acid is a prodrug. What that means is by itself it is inactive. When you ingest it, it goes to the liver, it gets activated, and there it is a cholesterol synthesis inhibitor. It acts on a different enzyme from statins, and what makes bempedoic acid special, for lack of a better word, is that it only inhibits cholesterol synthesis in the liver, whereas statins, which are very potent inhibitors of cholesterol synthesis, do so throughout the body because they don't have this prodrug trick. When the liver senses less cholesterol, it increases LDL receptor expression on its surface and pulls more LDL out of circulation. So that's how both statins and bempedoic acid work: they work indirectly. The difference is bempedoic acid is less potent than a statin and more selective in that way.
So the combination of those three drugs will keep my apoB negligible, and more importantly, or at least I would say equally importantly, there are no side effects associated with that for me personally.
When it comes to lipid management, it's certainly one of my favorite topics. I always tell patients we have tools today that we couldn't even fathom 20 years ago. 20 years ago, if you needed to have your apoB slammed, there was only one way to do it, which was megadose statins. I don't believe any patient needs to be on a megadose of a statin today because we just have too many other tools. I do have some concern about megadose statins, because, one, the efficacy curves show that statins hit their maximum efficacy at about a quarter dose. The curve for the efficacy of a statin looks like this. For example, if you look at rosuvastatin, you're getting 85% of its maximum apoB reduction at 5 milligrams. You hit the maximum around 10 milligrams, and it's a drug typically dosed up to 40 milligrams, so once you hit 10 milligrams there's no need to go any higher, because all you're really doing is buying side effects and getting very little in the way of increased efficacy.
So we're very quick to pivot patients off statins if we can't get great efficacy with no side effects at low dose on those drugs, including statins. If you can get the efficacy at a low dose, often times people who are younger, in their 30s, 40s, even 50s, will reach out and ask whether there are any concerns about taking those drugs for such a long period of time. Yes and no. I think it depends on the alternative. There are some people who poo-poo the side effects of statins and say they're nonexistent. I think that's a ridiculous thing to say. There are well-documented side effects of statins, at least three, that shouldn't be ignored. One is muscle aches. The second is elevations of transaminases, or liver function tests. The third is insulin resistance. All of these are relatively small, but they're not zero, and two of the three are objectively measurable. Why would we ignore that? So I really like it when you have objectively measurable side effects.
I would say that if a young person is in a situation where perhaps they can't afford bempedoic acid, Nexlizet, or PCSK9 inhibitors, because to be clear, those drugs are expensive at this time and statins are not, your alternative might be: well, I'm going to be on a statin, but at least go through the trouble of trying to find the right one that produces the fewest side effects. We think pitavastatin, or rosuvastatin, and Crestor are probably the best places to go, but it's also so highly individualized that I think you just have to try a couple until you find the ones doing the best without any collateral damage.
You've talked about PCSK9 before, but do you think we're any closer to those being more widely available, and by widely available, I mean at a potentially lower cost to individuals? I think so, because through a different mechanism you now have a shot that can be administered once every six months. The twice-monthly shot that I take for the PCSK9 inhibitor, which has already come down in price by more than 50% since that drug came out eight years ago, I think there will be continued price pressure on these drugs as more and more other drugs become available.
Speaking of drugs, you mentioned before that for the future of Lp(a), there's a drug in the pipeline that you're pretty optimistic about being available for people who have a high Lp(a), which could be anywhere from 8 to 12 up to 20% of people. We've had podcasts on that before, and with the number of people who have a high Lp(a), they often reach out, because up until now there hasn't really been a drug that can lower it. Could you talk a bit more about what's on the future horizon for Lp(a) medications?
Truthfully, I haven't been following anything for the last few months, so I don't have anything new to say on this since I last spoke about it. But there is a drug being made by a company, I think in San Diego, that is an antisense oligonucleotide. The drug disrupts the process of DNA making RNA to make apo(a), so it interrupts the synthesis of the protein that turns an LDL into an Lp(a). The drug worked very well in phase two. In phase two studies, which don't have clinical hard outcomes, the question is just whether the biomarker is improving, and there was a complete obliteration of Lp(a), with no side effects over the short haul. What matters now is the phase three trial, which is ongoing, and that's testing the more important question: does eliminating Lp(a) via this mechanism reduce clinical events? Does it reduce major adverse cardiac events? The answer to that question will determine whether or not this drug is approved and therefore becomes available.
But I will say this: it is unlikely that drug will be approved to treat patients for primary prevention, because the manner in which it's being tested is for secondary prevention. This is very common in drug development. You first test the drug in the highest-risk patients, so you get the answer relatively quickly. This trial is looking at people who have already had major adverse cardiac events, and it's essentially seeing whether we can prevent subsequent events. If the answer is yes, I believe the drug gets approved for that use case. It would still be able to be used by anybody for primary prevention, but it's not likely that an insurance company would pay for that yet.