Lowering Your ApoB: A Comprehensive Guide

This article is a summary of the YouTube video ‘How to lower your apoB’ by Peter Attia MD

Written by: Recapz Bot

Written by: Recapz Bot

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How does it work?
Exercise does not impact ASCVD risk factors; drugs lower ApoB levels. Cutting carbs reduces triglycerides. Sat fat reduction boosts LDL levels. Drugs effectively lower ApoB. Speaker uses PCSK9 inhibitor and combo drug. Pitavastatin and Rosuvastatin have fewer side effects. Statins have small side effects. Med costs may decrease. Research on LP little A drug ongoing. Phase three trial to determine efficacy. Drug tested for secondary prevention initially. Approval for primary prevention unlikely, limited insurance coverage.

Key Insights

  • Exercise has no significant impact on ASCVD risk factors through lipoproteins.
  • Pharmacology is the most potent way to lower ApoB levels, followed by nutrition.
  • Lowering triglycerides by reducing carbohydrates can lower ApoB burden.
  • Cutting saturated fat can decrease cholesterol synthesis and LDL receptors, resulting in increased LDL levels.
  • Pharmacological drugs, such as PCSK9 inhibitors (e.g., Repatha) and combination drugs (e.g., Nexlazet), can effectively lower ApoB levels.
  • The speaker takes three drugs, including a PCSK9 inhibitor and a combo drug, to keep ApoB levels negligible.
  • Certain statin drugs, such as Pitavastatin or Rosuvastatin, produce fewer side effects.
  • Statins can have side effects like muscle aches, elevated liver function tests, and insulin resistance, though they are relatively small.
  • The cost of medications, such as PCSK9 inhibitors, may decrease in the future with the availability of other drugs and continued price pressure.
  • There is ongoing research on an antisense oligonucleotide drug that disrupts synthesis of LP little A, a biomarker associated with cardiovascular events.
  • The phase three trial of the drug will determine its efficacy in reducing clinical events.
  • The drug is being tested for secondary prevention initially, targeting high-risk patients who have already experienced major adverse cardiac events.

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Transcript

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 a megadose of 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 triglycerides, the lower the ApoB burden because you have to traffic fewer triglycerides with the cholesterol. The other way to do it is 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, through something called the sterile regulatory binding protein, 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 probably am in line with sort of where the average person is. My ApoB at a 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. That’s far, far too high for someone who A, has a genetic predisposition to ASCVD, and B, just somebody who wants to take the one horseman that can be taken off the table and take it off. My target for ApoB is 30 to 40 milligrams per deciliter. Obviously, therefore that would require pharmacology. And so I take three drugs to do that. I take a PCSK9 inhibitor called Brapatha, and I take a combo drug called Nexlozet, which is benpendoic acid and ezetimibe combined into a single pill.

And the mechanism of action of ezetimibe, not to get too technical, but it blocks the Niemann-Pick C1-like-1 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. Benpendoic acid is a pro-drug. What that means is by itself it is inactive. So 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 benpendoic 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, they do so throughout the body because they don’t have this pro-drug trick. So 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 benpendoic acid work. They work indirectly. The difference is benpendoic 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. And again, 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 a megadose of 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.

And I do have some concern about mega dose of statins because one, the efficacy curves show that statins hit their maximum efficacy at about quarter dose. Like the curve for the efficacy of a statin looks like this, right? So you know, for example, if you look at Resuvastatin, you’re getting 85% of its maximum ApoB reduction at five milligrams, roughly 85% of you hit the maximum. And by the way, it’s a drug that is 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 you’re 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, let’s say, if you can get the efficacy at the low dose, oftentimes we’ll have people who are younger in their 30s, 40s, even 50s kind of reach out and say, do you have 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 kind of poo-poo the side effects of statins and say they’re non-existent. Well, 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, right? One is muscle aches. The two is elevations of transaminases or liver function tests. And the third is insulin resistance. Now all of these are relatively small, but they’re not zero. Two of the three are objectively measurable. Like why would we ignore that, right? So I really like 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 benpendoic acid, Nexlazet, PCSK9 inhibitors, because to be clear, those drugs are expensive at this time and statins are not, yeah, your alternative might be, well, I’m going to be on a statin, at least go through the trouble of trying to find the right one that produces the fewest side effects. We think that probably Pitavastatin or Livalo, Razuvastatin or Crestor, 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 that are doing the best without any collateral damage.

You’ve talked about PCSK9s before, but do you think we’re any closer to those being more widely available and by widely available, just meaning at a potential lower cost to individuals? I think so because we now have, through a different mechanism, you have a shot that can be administered once every six months. So I think that the twice-monthly shot that I take for 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 just be continued price pressure on these drugs as more and more other drugs become available.

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This article is a summary of the YouTube video ‘How to lower your apoB’ by Peter Attia MD