How to lower your apoB

Summary

This script discusses advancements in managing apolipoprotein B (apoB) levels, a key risk factor for atherosclerotic cardiovascular disease (ASCVD). The speaker emphasizes the shift from high-dose statins to a variety of pharmacological and nutritional tools, including PCSK9 inhibitors and dietary adjustments. They also highlight the importance of individualized treatment, the potential of new drugs in the pipeline, and the considerations for long-term statin use, balancing efficacy with potential side effects.

Takeaways

• 😲 Today's medical tools for managing apolipoprotein B (apoB) are far more advanced than 20 years ago, offering alternatives to high doses of statins.
• 🏃 Exercise does not significantly impact apoB levels or lipoprotein risk factors, but it can affect cardiovascular health in other ways.
• 💊 Pharmacological interventions are the most potent method for lowering apoB levels, with nutrition being a less potent but still significant approach.
• 🍚 Reducing carbohydrates can lower triglycerides and, consequently, apoB burden, as fewer triglycerides need to be transported with cholesterol.
• 🥩 Cutting saturated fat intake can reduce cholesterol synthesis and upregulate LDL receptors, leading to a decrease in LDL and apoB levels.
• 🥗 A low-carb, low-saturated-fat diet could theoretically lower apoB to levels that might make atherosclerotic cardiovascular disease (ASCVD) less of a concern.
• 💡 Individual dietary choices and sustainability are important, with the speaker noting their own apoB levels and how they manage them without extreme restrictions.
• 🎯 The speaker's target apoB level is 30 to 40 milligrams per deciliter, which requires pharmacological intervention due to their genetic predisposition to ASCVD.
• 🤒 Concerns about high doses of statins include potential side effects such as muscle aches, liver function test elevations, and insulin resistance.
• 💊 The speaker takes a combination of three drugs, including a PCSK9 inhibitor and a combo drug containing bempedoic acid and aetam, to manage their apoB levels.
• 💰 The cost of PCSK9 inhibitors has decreased over time, and the availability of alternative drugs, such as a once-every-six-months injection, may further reduce costs.
• 🔬 A drug in development targets the synthesis of APO(a), potentially offering a new treatment for high Lp(a) levels, which are associated with an increased risk of cardiovascular events.

Q & A

What has changed in the medical field regarding the treatment of high apob levels over the past 20 years?

Over the past 20 years, there has been a significant advancement in the tools available for treating high apob levels. Previously, the only option was high doses of statins, but now there are various other pharmacological options available.

What is the impact of exercise on managing lipoprotein risk factors?

Exercise has no meaningful impact on managing lipoprotein risk factors directly through lipoproteins. Its benefits are seen in other ways, but for managing lipoprotein risk, pharmacology and nutrition are more effective.

How does reducing carbohydrates affect apob levels?

Reducing carbohydrates can lower triglycerides, which in turn can lower the apob burden because fewer triglycerides need to be trafficked with cholesterol.

What is the effect of cutting saturated fat on cholesterol synthesis and LDL levels?

Cutting saturated fat reduces cholesterol synthesis and can also upregulate LDL receptors, leading to more LDL being pulled out of circulation, which can lower apob levels.

What are the two main dietary approaches to lowering apob levels as mentioned in the script?

The two main dietary approaches to lowering apob levels are reducing carbohydrates to lower triglycerides and cutting saturated fat to reduce cholesterol synthesis and upregulate LDL receptors.

What is the speaker's target apob level and why?

The speaker's target apob level is 30 to 40 milligrams per deciliter. This target is set because the speaker has a genetic predisposition to ASCVD and wants to minimize the risk factor.

What pharmacological treatments does the speaker take to manage their apob levels?

The speaker takes a PCSK9 inhibitor called Batha, a combo drug called NEXletapide which contains bempedoic acid and ezetimibe, and possibly a statin, although they prefer to avoid high doses.

How does bempedoic acid work differently from statins in cholesterol synthesis inhibition?

Bempedoic acid is a prodrug that is only active in the liver, where it inhibits cholesterol synthesis. Unlike statins, which inhibit cholesterol synthesis throughout the body, bempedoic acid is more selective and less potent.

What are the common side effects of statins mentioned in the script?

The common side effects of statins mentioned are muscle aches, elevations of transaminases (liver function tests), and insulin resistance.

What is the speaker's view on the future availability and cost of PCSK9 inhibitors?

The speaker believes that the availability and cost of PCSK9 inhibitors will improve due to the introduction of a new drug with a different mechanism that can be administered less frequently and as more drugs become available, there will be continued price pressure.

What is the drug being developed to target high LP(a) levels and how does it work?

The drug being developed for high LP(a) levels is an antisense oligonucleotide that disrupts the process of DNA making RNA to make APO(a), thereby interrupting the synthesis of the protein that turns an LDL into an LP(a).

What is the current status of the drug for high LP(a) levels and what is being tested in phase three trials?

The drug for high LP(a) levels has shown promising results in phase two trials with no side effects and complete obliteration of LP(a). The ongoing phase three trials are testing whether eliminating LP(a) via this mechanism reduces clinical events and major adverse cardiac events.

Outlines

00:00

💊 Advancements in Lipid Management Tools

The speaker discusses the evolution of tools for managing apolipoprotein B (apoB) levels, which is a key indicator of cardiovascular risk. They emphasize that while high doses of statins were once the only option, today there are various pharmacological and nutritional approaches available. Exercise is noted to have minimal direct impact on apoB levels, with pharmacology being the most potent method. Nutrition can also play a role, particularly through reducing carbohydrates to lower triglycerides and cutting saturated fat to reduce cholesterol synthesis and increase LDL receptor activity. The speaker shares their personal apoB target and the combination of drugs they take to achieve it, including a PCSK9 inhibitor and a combination drug of bempedoic acid and ezetimibe, highlighting the importance of individualized treatment plans.

05:02

🚫 Concerns Over High-Dose Statins and Future Medications

The speaker expresses concern over the use of high-dose statins, pointing out that their efficacy plateaus at a much lower dosage, beyond which the risk of side effects increases without significant additional benefits. They discuss the side effects of statins, including muscle aches, liver function test elevations, and insulin resistance, and stress the importance of considering these when prescribing. The conversation then shifts to the potential of new drugs, such as a PCSK9 inhibitor administered every six months, and the possibility of more affordable options becoming available. The speaker also addresses the future of LP(a) medications, mentioning a drug in phase three trials that could potentially lower LP(a) levels, but notes that its approval will likely first be for secondary prevention rather than primary prevention.

10:03

🔬 Drug Trials and Insurance Coverage for Cardiovascular Medications

In this paragraph, the speaker delves into the process of drug trials, particularly for a drug aimed at reducing LP(a) levels, which are associated with cardiovascular risk. They explain that the drug is being tested in patients who have already experienced major adverse cardiac events to determine if it can prevent subsequent events. If successful, the drug is expected to be approved for secondary prevention use cases, but its use for primary prevention may not be covered by insurance due to the cost and the trial's focus. The speaker also touches on the importance of insurance coverage in making new medications accessible to patients who need them for preventive care.

Keywords

💡ApoB

ApoB, short for Apolipoprotein B, is a protein found in lipoproteins, including low-density lipoprotein (LDL), which carries cholesterol in the blood. It is a key indicator of cardiovascular risk. In the video, the speaker emphasizes the importance of managing ApoB levels to reduce the risk of atherosclerotic cardiovascular disease (ASCVD), and discusses various methods to achieve this, including pharmacological and nutritional approaches.

💡Statins

Statins are a class of drugs that inhibit cholesterol synthesis in the liver, thereby reducing the levels of LDL cholesterol in the blood. The script mentions that high doses of statins were once the primary method to manage ApoB levels, but today, there are more tools available, and the speaker suggests that mega doses of statins are not necessary due to the availability of alternative treatments.

💡Pharmacology

Pharmacology is the branch of science concerned with the study of drugs and their effects on the body. In the context of the video, the speaker discusses the use of pharmacological interventions to lower ApoB levels, highlighting that while exercise does not have a significant impact on lipoproteins, drugs are the most potent way to manage lipoprotein risk factors.

💡Nutrition

Nutrition refers to the process by which the body obtains and utilizes nutrients from food. The script discusses the role of nutrition in managing ApoB levels, suggesting that reducing carbohydrates can lower triglycerides and, consequently, ApoB burden, while cutting saturated fat can reduce cholesterol synthesis and increase LDL receptor expression.

💡Triglycerides

Triglycerides are a type of fat found in the blood, often associated with an increased risk of heart disease. The video explains that reducing triglycerides can lower the ApoB burden because fewer triglycerides need to be transported with cholesterol, which is an important consideration in managing cardiovascular risk.

💡Saturated Fat

Saturated fat is a type of fat found primarily in animal products and some plant-based oils. The speaker in the video explains that reducing saturated fat intake can decrease cholesterol synthesis and increase LDL receptor expression, which can help lower LDL cholesterol levels and, by extension, ApoB levels.

💡PCSK9 Inhibitor

PCSK9 inhibitors are a relatively new class of drugs that lower LDL cholesterol by increasing the number of LDL receptors on the liver's surface, thus enhancing the liver's ability to remove LDL cholesterol from the bloodstream. The script mentions that the speaker takes a PCSK9 inhibitor called 'Batha' as part of their pharmacological regimen to manage ApoB levels.

💡Bempedoic Acid

Bempedoic acid is a drug that inhibits cholesterol synthesis in the liver, acting on a different enzyme from statins. The script describes it as a prodrug, meaning it is inactive until it reaches the liver, where it is activated and reduces cholesterol synthesis. It is part of a combination drug called 'NEXletz' that the speaker takes to manage their ApoB levels.

💡Efficacy

Efficacy refers to the effectiveness of a drug or treatment in achieving the desired outcome. The video discusses the concept of maximum efficacy, noting that statins reach their peak effectiveness at about a quarter of their maximum dose, suggesting that higher doses do not significantly increase efficacy but do increase the risk of side effects.

💡LPA

LPA, or Lipoprotein(a), is a type of lipoprotein that is considered a risk factor for cardiovascular disease. The script mentions that there is a drug in development that targets LPA, aiming to reduce its levels and potentially decrease the risk of major adverse cardiac events. The drug works by disrupting the synthesis of the protein that turns an LDL into an LPA.

💡Primary Prevention

Primary prevention refers to measures taken to prevent a disease or condition from occurring in the first place. In the context of the video, the speaker suggests that a new drug targeting LPA is unlikely to be approved for primary prevention due to the nature of clinical trials, which typically focus on secondary prevention in higher-risk patients first.

Highlights

20 years ago, the only way to manage high apob levels was through high doses of statins.

Today, there are numerous tools available for managing apob levels beyond just statins.

Exercise has no significant impact on managing lipoprotein risk factors.

Pharmacology is the most potent method for managing lipoprotein risk factors.

Nutrition can be a less potent but still significant method for managing lipoprotein risk factors.

Reducing carbohydrates can lower triglycerides and apob burden.

Cutting saturated fat can reduce cholesterol synthesis and increase LDL receptor upregulation.

A low carbohydrate and low saturated fat diet can significantly lower apob levels.

Individual sustainability of a low carbohydrate and low saturated fat diet varies.

The speaker's apob target is 30 to 40 milligrams per deciliter, requiring pharmacological intervention.

The speaker takes a PCSK9 inhibitor, a combo drug, and a cholesterol synthesis inhibitor for apob management.

Bempedoic acid is a selective and less potent cholesterol synthesis inhibitor compared to statins.

Statins and bempedoic acid work indirectly by increasing LDL receptor expression when cholesterol is low.

The combination of three drugs keeps the speaker's apob levels negligible without side effects.

Statins have a maximum efficacy at about a quarter of their typical dose, with diminishing returns and increased side effects at higher doses.

The speaker is concerned about the long-term use of high-dose statins and their side effects.

There are well-documented side effects of statins, including muscle aches, liver function test elevations, and insulin resistance.

Finding the right statin with minimal side effects is important for long-term management.

The future of LPA management includes a drug that disrupts the synthesis of the protein that turns LDL into LP(a).

The drug has shown promising results in phase two trials with no side effects and complete obliteration of LP(a).

The phase three trial will determine if eliminating LP(a) via this mechanism reduces clinical events.

The drug is unlikely to be approved for primary prevention but could still be used off-label.

Transcripts

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 Mega do of

statins I don't believe any patient

needs to be on a mega do 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 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 um 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 Su 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 while 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 longterm you know

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 like restricting it either I I would

say 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 Mig per

deciliter which puts me at about the

50th percentile of the population so

that's my normal

apob um that's far far too high for

someone who a has 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 the

table so my target for apob is 30 to 40

milligrams per deciliter obviously that

therefore that would require

pharmacology and so I take three drugs

to do that I take a pcsk9 inhibitor

called Batha and I take a combo drug

called NEX lazette which is bempedoic

acid and aetam combined into a single

pill and the mechanism of action of aami

not to get too technical but it blocks

the Neiman pixie1 like one transporter

in both hepatocytes and ocytes 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 prevents you

from reabsorbing your cholesterol of the

three drugs I'm taking that's far and

away the least potent uh bendic acid is

a prodrug 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 bendic acid

uh 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 when the liver

senses less

cholesterol it increases LDL uh receptor

expression on its surface and pulls more

LDL out of circulation so that's how

both statins and bidic acid work they

work indirectly the difference is bidic

acid is less potent than a Statin uh and

more selective in that way so the

combination of those three drugs

uh will will will keep my apob

negligible and more importantly or at

least I would say equally importantly uh

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 Mega do of statins I

don't believe any patient needs to be on

a mega dose of a Statin today because um

we just have too many other tools and I

do have some concern about Mega do of

statins because one the efficacy curves

show that Statin hit their maximum

efficacy at about quarter dose like the

the curve for the efficacy of a Statin

looks like this right so you know for

example if you look at rzua Statin

you're getting

85% of its

maximum APO reduction at 5 milligrams 80

roughly 85% of you hit 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

often times while 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 poooo 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 bempedoic acid NEX lazette PCS

Inhibitors because to be clear those

drugs are expensive at this time and

statins are not yeah your alternative

ative might be well I'm going to be on a

Statin um 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 lielo uh

rosuvastatin 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 them doing the best without any

collateral damage you Ted about pcsk9

before but do you think we're any closer

to those being more widely available and

by widely available just meaning add a

potential lower cost to individuals I

think so because you know we now have

through a different mechanism you have a

a shot that can be administered once

every six months um so I think that the

twice monthly shot that I take for pcs9

inhibitor which has already come down in

price by more than 50% since that drug

came out 8 years ago uh I think there

will just be continued price pressure on

these drugs as more and more other drugs

become available speaking of drugs you

mentioned before you think for the

future of LP little a that there's a

drug in the pipeline that you're pretty

optimistic about being available for

people who have a high LP little a which

could be anywhere from 8 to 12 up to 20%

of people and we've had podcasts on that

before and so just with the amount of

people that have a high LP little a

often they'll reach out because up until

now there's not really a drug that can

lower that so do you just maybe want to

talk a little bit more about what's on

the future for LPA medications yeah

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 probably last spoke about it but

there is a drug being made by a company

I think in San Diego that is an anti-

sensolo nucleotide so the drug disrupts

the process of DNA making RNA to make

APO little a so it interrupts the

synthesis of the protein that turns an

LDL into an LP little a the drug worked

very well in phase two so in phase two

studies which don't have clinical hard

outcomes the outcome is just is the

biomarker improving there was a a a

complete obliteration of LP little a and

there were no side effects over the

short Hall so what matters now is the

phase three trial which is ongoing and

that's test ing the the more important

question which is does eliminating LP

little 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 for me to imagine that that

drug will be approved to treat patients

with primary prevention because the

manner in which it's being tested under

understandably is for secondary

prevention this is very common in drug

development where you first test the

drug the clinical indication is in the

highest risk patient so you get the

answer relatively quickly so this is a

trial that is looking at people who have

already had major adverse cardiac events

and it's basically seeing can we prevent

subsequent events and if the answer is

yes I believe the drug gets approved it

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

[Music]

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