Could New Drug Lower Cholesterol in lean people on a Keto diet?

Summary

This video explores the potential for a new drug, resmon, to treat high cholesterol levels in lean people on ketogenic diets who experience the 'lean mass hyper-responder' phenomenon. The presenter discusses the drug's effects on fatty liver disease and cholesterol levels, and hypothesizes that it could either significantly lower or raise LDL cholesterol in this specific population. By testing this drug in a different metabolic context, the results could provide valuable insights into fat metabolism, the lipid energy model, and offer new treatment options for high LDL cholesterol beyond traditional approaches.

Takeaways

• 📚 A new drug called Resmon, a liver-directed thyroid hormone receptor beta selective agonist, shows promise in treating fatty liver disease (NASH) and reducing LDL cholesterol, according to a phase 3 trial published in the New England Journal of Medicine.
• 📌 Lean mass hyperresponders (LMHRs), individuals on ketogenic diets with high LDL cholesterol, high HDL, and low triglycerides, might benefit from exploring the effects of Resmon, despite not being the original target demographic for this drug.
• 🧭 The lipid energy model and the role of thyroid hormone in energy metabolism provide a theoretical basis for investigating Resmon's potential impact on LMHRs.
• 🔥 Free T3, a thyroid hormone, has been identified as independently predictive of elevated LDL cholesterol in lean individuals on low-carb diets, suggesting a link between thyroid function and lipid metabolism.
• ⚡️ There's an interesting possibility that Resmon could either significantly lower or, alternatively, increase LDL cholesterol in LMHRs, based on its mechanism of action on liver metabolism.
• 📡 The drug's effect on cardiac risk markers and LDL cholesterol reduction in fatty liver patients raises provocative questions about its potential use and effectiveness in LMHRs.
• 🛠 Mechanistic insights into fat metabolism and the lipid energy model could be gained from a hypothetical trial of Resmon in LMHRs, offering a new perspective on managing high LDL cholesterol levels.
• 🏦 LMHRs typically do not have fatty liver or high visceral fat levels, highlighting the need for tailored research into the drug's effectiveness in this unique population.
• 💻 The concept of changing metabolic context affecting drug outcomes underscores the importance of targeted interventions in nutrition and metabolism research.
• 🚩 The potential for Resmon to provide alternative LDL lowering strategies for LMHRs beyond traditional methods like statins or dietary adjustments is a key area of interest.

Q & A

What is the new drug mentioned in the script for treating fatty liver disease?

The new drug mentioned for treating fatty liver disease is called Resmetirom (referred to as 'resmon' in the script), which is a liver-directed thyroid hormone receptor beta selective agonist.

Can Resmetirom be used to treat high cholesterol levels in lean people on ketogenic diets?

The script raises the question of whether Resmetirom, initially used for treating fatty liver disease, could also lower high cholesterol levels in lean people on ketogenic diets, known as the lean mass hyper-responder phenotype. However, it suggests that further research is needed to confirm this potential use.

What is the lean mass hyper-responder phenotype?

The lean mass hyper-responder phenotype refers to lean individuals on low carbohydrate diets who experience high LDL cholesterol levels, alongside high HDL and low triglycerides, potentially influenced by energy metabolism and thyroid hormone levels.

How does free T3 predict LDL cholesterol levels?

Free T3, a thyroid hormone, has been shown to independently predict elevated LDL cholesterol levels in lean individuals on low carbohydrate diets, suggesting a link between thyroid hormone levels and cholesterol metabolism.

What are the potential effects of Resmetirom on lean mass hyper-responders?

The script hypothesizes that Resmetirom could either significantly lower LDL cholesterol in lean mass hyper-responders or, alternatively, increase it due to enhanced liver fat metabolism, indicating the need for specific trials to determine the actual outcome.

What are the results of Resmetirom in its phase 3 trial?

In its phase 3 trial, Resmetirom resolved fatty liver in a significant percentage of patients, reduced LDL cholesterol by 13.6% or more depending on the dose, and positively affected other cardiac risk markers.

Why might lean mass hyper-responders not be the intended use population for Resmetirom?

Lean mass hyper-responders typically do not have fatty liver disease; they tend to have very low levels of liver fat and visceral fat, differing from the phenotypic profile for which Resmetirom is initially intended.

What could a trial of Resmetirom in lean mass hyper-responders reveal about fat metabolism?

A trial of Resmetirom in lean mass hyper-responders could provide mechanistic insights into fat metabolism and the lipid energy model, potentially offering new options for LDL cholesterol management beyond traditional methods.

What is the significance of thyroid hormone receptor beta in the context of the script?

Thyroid hormone receptor beta, expressed in the liver, plays a crucial role in energy metabolism and intersects with pathways involved in ketosis, suggesting its involvement in the effects observed with Resmetirom treatment.

What are the broader implications of the script's discussion on nutrition, metabolism, and medicine?

The script emphasizes the importance of exploring new therapeutic uses for existing drugs in different metabolic contexts, potentially leading to innovative treatments and a deeper understanding of nutrition, metabolism, and medicine.

Outlines

00:00

🔍 Exploring a New Fatty Liver Drug's Potential for Treating High Cholesterol

The video introduces a groundbreaking study on a new drug potentially effective for treating fatty liver disease, as reported in a major scientific journal. The narrator speculates on the drug's ability to treat high cholesterol levels in lean individuals on ketogenic diets, known as the lean mass hyperresponder phenotype. With a foundation in the lipid energy model and thyroid hormone's role in cholesterol metabolism, the discussion centers around the drug's mechanism of action—specifically targeting the liver's thyroid hormone receptor beta. Initial findings suggest the drug not only resolves fatty liver in a significant percentage of patients but also reduces LDL cholesterol and other cardiac risk markers. However, the applicability to lean mass hyperresponders, who typically don't exhibit fatty liver or visceral fat, remains speculative. The video delves into the biological pathways linking thyroid hormone and ketosis, raising provocative questions about the drug's potential effects on cholesterol levels in different metabolic contexts.

05:01

🤔 Potential Outcomes of Fatty Liver Drug on Lean Mass Hyperresponders

In the second part of the video, the focus shifts to the hypothetical effects of the discussed drug on lean mass hyperresponders. Given the drug's mechanism of action on liver metabolism through the thyroid hormone receptor beta, there's speculation on whether it could either significantly lower LDL cholesterol or paradoxically increase it by enhancing VLDL export and turnover. The only way to determine the actual outcome is through clinical testing. This exploration into the drug's alternative uses extends to broader implications for understanding fat metabolism and the lipid energy model. The narrator emphasizes the importance of experimental interventions in different metabolic contexts to uncover unexpected results and insights, advocating for a scientific and open-minded approach to nutrition and metabolic health research. The video concludes with a call for community and citizen science engagement in these intriguing and complex topics.

Keywords

💡Fatty liver disease

Fatty liver disease, also known as non-alcoholic steatohepatitis (NASH), is a condition characterized by the accumulation of excess fat in the liver. In the video, it is mentioned that a new drug called Resmon, designed to treat this disease, has shown promising results in a phase 3 trial. This drug's relevance to the discussion lies in its potential application beyond its intended use for NASH, specifically regarding its effects on lowering LDL cholesterol, which could have implications for people with the 'lean mass hyper-responder' phenotype on ketogenic diets.

💡Lean mass hyper-responders

Lean mass hyper-responders (LMHR) are individuals who exhibit significantly elevated levels of LDL cholesterol when consuming a low-carbohydrate, high-fat diet, despite having a lean body mass and generally good metabolic health. The video explores the hypothesis that the drug Resmon, while intended for treating fatty liver disease, might also affect LDL cholesterol levels in LMHRs, raising questions about the underlying mechanisms of fat metabolism and cholesterol management in different dietary contexts.

💡LDL cholesterol

LDL cholesterol, often referred to as 'bad' cholesterol, is a lipoprotein responsible for transporting cholesterol to cells throughout the body. High levels of LDL cholesterol are associated with an increased risk of cardiovascular diseases. The video discusses how Resmon, a drug for fatty liver disease, also impacts LDL cholesterol levels, and speculates on its potential effects in individuals with high LDL cholesterol due to a ketogenic diet, particularly lean mass hyper-responders.

💡Ketogenic diets

Ketogenic diets are high-fat, adequate-protein, low-carbohydrate diets that induce ketosis, a metabolic state in which the body burns fat rather than carbohydrates for energy. The video mentions ketogenic diets in the context of their potential to significantly increase LDL cholesterol in some individuals, specifically lean mass hyper-responders, and explores how interventions like the drug Resmon might interact with this dietary-induced metabolic state.

💡Thyroid hormone

Thyroid hormones, particularly free T3 (triiodothyronine), play a crucial role in regulating metabolism, including lipid metabolism. The video highlights research suggesting that free T3 levels can predict elevated LDL cholesterol in individuals on low-carbohydrate diets, positioning thyroid hormone activity as a key factor in the discussion of cholesterol management and the potential effects of treatments like Resmon in different metabolic contexts.

💡Energy flux

Energy flux refers to the rate at which energy is transferred within the body, impacting metabolic processes including fat metabolism and the regulation of lipid levels in the blood. The video invokes the concept of energy flux to explain the lipid energy model, which provides a framework for understanding the high LDL cholesterol levels seen in lean mass hyper-responders on ketogenic diets, and how thyroid hormone activity might intersect with this process.

💡Resmon

Resmon is introduced in the video as a liver-directed thyroid hormone receptor beta selective agonist. It's a new drug designed to treat fatty liver disease by targeting specific pathways in the liver to reduce liver fat and improve related metabolic markers, including lowering LDL cholesterol. The discussion about Resmon centers on its potential application for lowering LDL cholesterol in lean mass hyper-responders, raising intriguing questions about its mechanism of action and broader implications for fat metabolism.

💡Thyroid hormone receptor beta

Thyroid hormone receptor beta is a protein that mediates the effects of thyroid hormones in the liver and other tissues. It is highlighted in the video as the target of the drug Resmon, which acts to stimulate this receptor specifically in the liver. This receptor's role in metabolic regulation is central to the discussion of how thyroid hormone activity influences cholesterol levels and how Resmon might affect this process in the context of fatty liver disease and potentially in lean mass hyper-responders.

💡Lipid energy model

The lipid energy model is a theoretical framework mentioned in the video that seeks to explain the metabolic adaptations and changes in lipid profiles, particularly LDL cholesterol, in response to low-carbohydrate, high-fat diets. It suggests that these dietary patterns lead to an increased reliance on lipids for energy, influencing LDL levels. The model is used to contextualize the potential effects of Resmon on LDL cholesterol in individuals following ketogenic diets, especially those identified as lean mass hyper-responders.

💡Phase 3 trial

A phase 3 trial is a crucial stage in the clinical testing of new drugs, involving large groups of patients to assess the effectiveness and monitor adverse reactions of the medication. The video discusses a phase 3 trial for Resmon, which showed promising results in treating fatty liver disease and lowering LDL cholesterol. This trial's findings serve as a foundation for the speculative exploration of Resmon's potential effects on individuals with high LDL cholesterol due to their dietary choices, particularly those on ketogenic diets.

Highlights

Introduction to exploring the potential use of a new drug for treating fatty liver disease to also treat high cholesterol levels in lean people on ketogenic diets.

Background knowledge assumption on lean mass hyperresponders and the lipid energy model.

Link between free thyroid hormone, specifically free T3, and elevated LDL cholesterol in lean people on low carbohydrate diets.

Introduction of the lipid energy model explaining high LDL on low carb diets with high HDL and low triglycerides.

Clarification that hypothyroidism does not completely explain the lean mass hyperresponder phenotype.

Discussion on thyroid hormone receptor beta and its role in liver and intersection with ketosis pathways.

Introduction of Resmon, a liver-directed thyroid hormone receptor beta selective agonist, from a new phase 3 trial.

Resmon's effects on resolving Nash fatty liver and reducing LDL cholesterol as well as other cardiac risk markers.

Highlighting that lean mass hyperresponders do not have fatty liver, indicating they are not the intended use population for Resmon.

Questioning whether Resmon could lower LDL cholesterol in lean mass hyperresponders and its potential effects.

Speculation on whether increasing liver fat metabolism with Resmon could actually increase LDL in lean mass hyperresponders.

Hypothesis on the possible outcomes of a trial of Resmon on lean mass hyperresponders - either significantly lowering or raising LDL cholesterol.

Potential for new insights into fat metabolism and lipid energy model from hypothetical trial findings.

Discussion on expanding treatment options for lean mass hyperresponders beyond traditional methods.

Closing remarks on the importance of hypothesis-driven research in understanding metabolic context impacts.

Transcripts

there's a new drug that could be used to

treat fatty liver disease that was

published in a major news study in the

world's highest impact factor Journal

now here's a question could that same

fatty liver drug be used to treat very

high cholesterol levels and lean people

on ketogenic diets the so-called lean

mass Hypes phenotype and in exploring

that question what might we

learn welcome to my channel where we

navigate the data with Nuance I am going

to go over some of the results from the

study mentioned and some of our own

trial results blend them and bring forth

some provocative questions but before I

do that I want to acknowledge that I'm

going to assume some background

knowledge in terms of lean mass

hyperresponders and the lipid energy

model so if those are terms that are

completely new to you I really do

suggest you watch The Links below first

and then come back to this video but

with that I'll move forward we've

recently demonstrated in our own

Interventional trials that free thyroid

hormone free T3 is independently

predictive of elevated LDL cholesterol

the bad cholesterol all in lean people

on low carbohydrate diets this is in

addition to lean BMI so we know that

lean people on low carbohydrate diets

they're the ones susceptible to high LDL

cholesterol when they go low carb but in

addition to that thyroid hormone can be

a predictor of specifically free T3 a

predictor of high LDL on low

carbohydrate diets and from a 50,000

foot view this makes sense the lipid

energy model explains the lean mass

Hypes phenotype high LDL on low carb

diets with high HDL and low

triglycerides lipid energy model it's

all about energy flux so wouldn't it

makes sense that a marker of energy

metabolism thyroid hormone could be

Associated or involved with that I do

want to take a second to provide an

interpretive caution I'm not saying that

hypothyroidism low thyroid can

completely explain the lean mass Hypes

phenotype lean mass Hypes patients tend

to be U thyroid normal TSH have normal

or even elevated basil metabolic rates

and generally have absent clinical

symptoms of hypothyroidism so they don't

have reduced body temperature feel cold

all the time constipated etc etc that

said thyroid hormon metabolism is likely

involved as some contributing feature of

the lean mass Hypes Triad the high LDL

the high HDL and the L triglycerides so

including the high LDL now delving into

the mechanism a little bit thyroid

hormone receptor it comes in a couple

flavors the thyroid hormone receptor

beta is expressed in the liver and

interestingly actually has Pathways that

intersect with ketosis I'll give a

couple examples they're not particularly

important but just as examples of

overlapping biology both ketosis and the

thyroid hormone receptor beta pathway

they can converge on epigenetic

Regulators like histone deacetylases hxs

and they can also affect particular

histone and DNA epigenetic motifs things

like lysine 27 trimethylation of histone

3 that's mouthful you don't need to know

what it means point being there's

overlapping biology in this thyroid

pathway and in the ketosis pathway with

that let's move on to the trial a new

phase 3 trial published in the highest

impact factor journal in the world the

New England Journal of Medicine found

that this new drug it's called reton

it's a liver directed thyroid hormone

receptor beta selective Agonist that

means that it acts on the thyroid

hormone receptor beta to activate that

pathway in particular on the liver and

it's a drug that's being used to treat

fatty liver disease or Nash in the trial

this drug resmon resolved Nash fatty

liver in 26 or more per of patients

depending on dose and it also reduced

LDL cholesterol by 13.6% or more

depending on dose it also affected other

cardiac wrist markers rmon decreased LP

little a APO C3 and Appo B at the 80 Mig

there were significant reductions from

Baseline versus placebo in LP delay by

5% in Appo C3 by 12% and an Appo B by

14% this is actually coming from the

October nature medicine paper related to

this drug but nonetheless there are

improvements in a broad spectrum of

markers and reductions in lthl

cholesterol with that I do want to note

or at least highlight that lean mass

hyperr patients do not have fatty liver

actually they tend to to have very low

levels of liver fat and very low

visceral fat so they wouldn't really be

the intended use population for this

medication in fact in very many ways

they be the opposite of the phenotypic

profile you generally use this drug in

however lean mass hyperresponders do

have very very high LDL cholesterol so

I'm curious whether resmon would lower

LDL cholesterol in lean mass

hyperresponders and if so by how much so

if free thyroid hormone predicts LDL

cholesterol in lean mass hyperresponders

lean people on ketogenic diets if

thyroid hormone impacts LDL receptor

expression on the liver which we know it

does and if liver targeting of thyroid

hormone receptor beta activity this drug

lowers ldlc in fatty liver would it do

so in lean mass hyperresponders and

because the magnitude of LDL and lmhr is

so high would it drop the LDL massively

it's a possibility it's a very

interesting possibility for an

alternative use of the same drug for an

alternative use case but here's the rub

and here's really why I made this video

there's an alternative possibility a

provocatively alternative possibility

could it be maybe maybe that by

increasing liver fat metabolism or

metabolism in the liver in general

resmon could rather than lower LDL as it

does in fatty liver patients could it

actually increase LDL in lean mass

hyperr patients that would be like okay

if we're saying the lipid energy model

is all about energy flux and you're kind

of turning up the flywheel so to speak

with this thyroid hormone receptor beta

Agonist on liver metabolism could rather

than lowering LDL cholesterol you

increased vldl export and increased vldl

turnover peripherally and increase LTL

it's actually possible so we have these

two really interesting distinct

possibilities this drug if given to lean

mass hyperresponders could lower LDL

significantly substantially it could

smash it into the floor or it could

raise it how do we know which would be

the case the only way we would know is

to test it so thus this findings or this

not this findings they haven't been

findings the findings that could arise

from a hypothetical trial for this new

fatty liver drug in a very different

population from fatty liver lean mass

hyperresponders could provide

mechanistic insight into fat metabolism

and the lipid energy model it could if

it lowers LDL create new creat creative

options for LDL lowering in lean mass

hyperresponders Beyond carb

reintroduction be it Oreos or sweet

potatoes or standard LDL lowering drugs

like statins or pcsk9 Inhibitors so it

expand the pool of options available for

patients this trial that I'm

hypothesizing in my mind that definitely

hasn't happened that I don't have the

resources for the reason I want to

highlight it is the same reason I did

the Oreo versus Statin study in which I

showed I could lower my LDL cholesterol

with Oreo Cookies by a massive amount

it's because when you take an

intervention intervention X be it Oreos

or this new drug published in the New

England Journal of Medicine and you take

that intervention and you put it in an

entirely different metabolic context

what results do you get there's no way

to know until you test it and the

results can be incredibly interesting

like it was for the Oreo versus Statin

study and we can learn so much in my

opinion this shouldn't be something that

is polarizing or politicizing in the

social media space this should be of

interest to everyone everyone with a

mind towards nutrition metabolism and

medicine so I'm really excited about

this new paper for probably a reason

other people aren't I hope you found

this video interesting and that maybe it

gave you some insight into how I think

about these sort of things and why we we

colleagues studying lean mass hyper

responders are doing what we're doing

it's really fun and really interesting

to hypothesize and think about how

changing metabolic context can change

the way that our environment interacts

with our bodies this was a particularly

nerdy one I hope you followed along I'd

love to get your comments your thoughts

your hypotheses Community input citizen

science input is really valuable to us

so thanks for following along bye