How is FH diagnosed, especially in children?

Diagnosis of FH primarily relies on family history of premature coronary disease and elevated LDL cholesterol without other abnormalities. In children, where other causes for elevated LDL are rare, it serves as a diagnostic linchpin. Genetic testing for mutations in LDL receptor, APOB, or PCSK9 genes confirms the diagnosis in about 95% of cases, making the Dutch Lipid Clinic criteria the most rigorous.

What are the physical signs of FH?

Physical manifestations often include tendon xanthomas, which are cholesterol deposits on frequently used tendons like the extensor tendons of the hands and Achilles tendon. Other signs include Arcus cornealis (a cholesterol deposit in the cornea) and xanthelasma (deposits on eyelids). These physical symptoms can sometimes lead to immediate diagnosis by simple observation.

At what age should children with FH begin treatment?

Children with definite FH, confirmed by rigorous diagnostic criteria and often severe family history, should begin treatment between six and eight years of age. This involves extensive anti-smoking, dietary counseling, and physical exercise training, followed by statin therapy.

Why are some individuals with FH resistant to the disease's typical progression?

Approximately 5% of FH patients, predominantly women, escape severe disease symptoms. These individuals often have very high HDL cholesterol, suggesting a highly efficient reverse cholesterol transport system that handles deposited LDL. They are typically non-smokers, active, thin, and do not have diabetes, indicating a protective alignment of lifestyle and possibly other genetic factors.

How effective are statins in children with FH, and do they have side effects?

Statin therapy in children with FH, starting as early as 6-8 years old, has been shown to protect against premature death and coronary disease, delaying progression of atherosclerosis. Interestingly, children with FH generally do not experience statin-related muscle symptoms (myalgias) as commonly as adults.

What is the aggressive treatment approach for adults with FH?

Adults with FH, especially after transitioning from pediatric care, are treated aggressively, often immediately starting with PCSK9 monoclonals, inclisiran, and ezetimibe. For homozygous FH, high-dose statins, ezetimibe, evolocumab, and evinacumab (a Regeneron monoclonal antibody) are used to achieve the lowest possible LDL levels.

What is the 'Thrifty Gene Hypothesis' in relation to cholesterol metabolism?

The Thrifty Gene Hypothesis suggests that during ice ages and times of famine, genes promoting energy and cholesterol conservation were favored. CETP, PCSK9, and ANGPTL3 are examples of such genes, which now, in an abundance of resources, contribute to metabolic diseases and atherosclerosis.

What is Obicetrapib, and why is it different from previous CETP inhibitors?

Obicetrapib is a potent, next-generation CETP inhibitor discovered at Mitsubishi Tanabe Pharma. Unlike its predecessors, it is highly effective at lowering LDL (by about 50% on top of statins) and significantly raising HDL (by 165%) without off-target side effects like blood pressure elevation. It aims for broad therapeutic benefits beyond cardiovascular disease, including Alzheimer's and type 2 diabetes.

How does Obicetrapib impact new-onset type 2 diabetes and septicemia?

Obicetrapib, by significantly raising HDL through CETP inhibition, is believed to protect beta-islet cells in the pancreas from apoptosis, leading to a 16-20% reduction in new-onset type 2 diabetes. Furthermore, individuals with low CETP activity (mimicking the drug's effect) show increased protection against septicemia mortality due to HDL's scavenging function.

What are the key Phase 3 trials for Obicetrapib?

The three main Phase 3 trials are Broadway (2,400 high-risk ASCVD patients, 1 year), Brooklyn (300 heterozygous FH patients), and Prevail (9,000 hardcore ASCVD patients). Prevail is powered for cardiovascular outcomes with a median follow-up of 3.5 to 4 years, aiming for a significant reduction in MACE.

Does Obicetrapib reduce LP(a) levels?

Yes, Obicetrapib has shown a significant reduction in LP(a) levels, by about 56% at a 10mg dose. This is substantially higher than other CETP inhibitors and PCSK9 inhibitors, although the exact mechanism for this reduction is not yet fully understood.

What is the connection between APOE4, cholesterol metabolism, and Alzheimer's disease?

APOE4 is an insufficient protein for moving cholesterol in the brain, leading to sterol accumulation and oxidative damage in neurons, promoting inflammation and cell death. CETP inhibitors, by raising APOA1 concentrations in the circulation, can help APOA1 traverse the blood-brain barrier to compensate for dysfunctional APOE4, potentially normalizing cholesterol synthesis and removal in the brain and reducing inflammation.

How does APOE4 influence cardiovascular disease risk?

APOE4 is associated with higher LDL levels and a more pro-inflammatory state, both contributing to heart disease. The APOE4 protein has a higher affinity for LDL receptors on remnants and VLDL, leading to their rapid clearance, which in turn downregulates LDL receptors and drives up LDL cholesterol, initiating a chain of events that increases atherosclerosis risk.

Key Moments

255-Latest therapeutics in CVD, APOE’s role in Alzheimer’s disease, familial hypercholesterolemia

Peter Attia MD

Science & Technology4 min read125 min video

May 22, 2023|29,980 views|544|124

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Key Moments

TL;DR

Familial hypercholesterolemia, APOE's role in Alzheimer's, and novel CTP inhibitors with therapeutic promise.

Key Insights

Familial Hypercholesterolemia (FH) is a common genetic disorder causing high LDL from birth, requiring early intervention.

APOE4 gene isoform is linked to increased risk of Alzheimer's disease due to impaired brain cholesterol transport.

CTEP inhibitors like obicetrapib show promise for cardiovascular disease, Alzheimer's, and type 2 diabetes.

FH diagnosis relies on a combination of clinical history, LDL levels, family history, and genetic testing.

Early statin treatment in children with FH is crucial for preventing premature cardiovascular disease.

Novel CTP inhibitors, like obicetrapib, appear safe and effective, potentially revolutionizing lipid management.

UNDERSTANDING FAMILIAL HYPERCHOLESTEROLEMIA (FH)

Familial Hypercholesterolemia (FH) is a prevalent, autosomal dominant genetic disorder characterized by significantly elevated LDL cholesterol levels from birth. This condition, often overlooked, leads to premature cardiovascular disease. Diagnosis involves a combination of clinical manifestations like xanthomas and arcus cornealis, elevated LDL cholesterol, family history of premature heart disease, and genetic testing. Early identification, particularly in children who form the backbone of diagnosis due to the absence of secondary causes for elevated LDL, is critical for effective management and preventing life-threatening events.

THE GENETICS AND PATHOPHYSIOLOGY OF FH

FH arises from mutations in genes responsible for LDL metabolism, primarily the LDL receptor, apolipoprotein B (APOB), and PCSK9. Mutations in the LDL receptor impair its ability to bind and internalize LDL particles. APOB mutations affect the binding site for the LDL receptor, while PCSK9 mutations can lead to overactivity, degrading LDL receptors. These defects converge at the liver cell surface, resulting in reduced clearance of LDL from the circulation and a consequent increase in plasma LDL cholesterol, driving atherosclerotic plaque formation.

CLINICAL MANIFESTATIONS AND DIAGNOSTIC CRITERIA

Physical signs of FH include tendon xanthomas (deposits on tendons like the Achilles) and xanthelasmas (cholesterol deposits on eyelids), as well as arcus cornealis (a ring around the iris). While these signs are indicative, diagnosis can be made even in their absence, especially with a strong family history and consistently high LDL. The Dutch Lipid Clinic Network criteria are highlighted as particularly rigorous, assigning points for various factors, with a high score indicating definite FH. This comprehensive approach is essential for accurate diagnosis and timely treatment.

THE ROLE OF APOE IN ALZHEIMER'S DISEASE

The APOE gene has three common isoforms: E2, E3, and E4. While APOE3 is considered neutral, APOE4 significantly increases the risk of late-onset Alzheimer's disease. This predisposition is linked to APOE4's inefficiency in transporting cholesterol within the brain. It poorly accepts cholesterol from cells with excess and fails to deliver it effectively to cells that need it. This impairment leads to cholesterol accumulation and oxysterol formation in neurons, triggering inflammation and apoptosis, thus contributing to neurodegeneration and Alzheimer's pathology.

CTEP INHIBITORS: A NEW ERA IN THERAPEUTICS

Cholesteryl ester transfer protein (CTEP) inhibitors are a class of drugs that have evolved significantly. Early attempts, like Pfizer's torcetrapib, failed due to off-target effects causing hypertension and increased cardiovascular events. Subsequent trials for other CTEP inhibitors showed no cardiovascular benefit, undermining the HDL hypothesis. However, newer agents like obicetrapib have demonstrated significant LDL lowering, robust safety profiles, and potential benefits beyond cardiovascular disease, including in Alzheimer's and diabetes.

OBICETRAPIB AND ITS THERAPEUTIC POTENTIAL

Obicetrapib, a potent and selective CTEP inhibitor, shows remarkable promise. It effectively lowers LDL cholesterol (up to 50% on top of statins) and significantly increases HDL cholesterol, while avoiding the adverse effects seen with earlier CTEP inhibitors. Importantly, obicetrapib also reduces Lp(a), a known cardiovascular risk factor. Preclinical and early clinical data suggest potential benefits in Alzheimer's disease by increasing ApoA1, which can cross the blood-brain barrier and help manage brain cholesterol metabolism, and in type 2 diabetes by protecting pancreatic beta cells.

TREATMENT STRATEGIES FOR VARIOUS POPULATIONS

Treatment for FH begins early, often at age six, with lifestyle modifications (diet, exercise) and statins. While pediatric guidelines suggest LDL goals around 130 mg/dL, there's a scientific argument for lower targets due to the naturally low LDL levels in children. In adults, the treatment intensifies, often including PCSK9 inhibitors, ezetimibe, and potentially newer agents like obicetrapib, aiming for the lowest possible LDL. Homozygous FH requires even more aggressive multi-drug therapy, sometimes necessitating apheresis.

APOE'S IMPACT ON CARDIOVASCULAR RISK

Beyond its role in Alzheimer's, APOE4 also contributes to cardiovascular disease risk. Although counterintuitive, APOE4's higher affinity for LDL receptors primarily affects VLDL remnants, leading to their accelerated clearance. This process downregulates LDL receptors, paradoxically increasing circulating LDL levels. Furthermore, APOE4 is associated with a pro-inflammatory state, adding another layer of risk for atherosclerosis, even when LDL levels are controlled, suggesting multiple pathways linking APOE4 to adverse cardiovascular outcomes.

Mentioned in This Episode

●Companies

●Organizations

●Books

●Studies Cited

●Concepts

●People Referenced

Common Questions

Familial Hypercholesterolemia (FH) is the second most common form of hereditary heart disease, after elevated LP(a). It is a true autosomal dominant disease, meaning only one parent needs to carry the mutation, making it almost 100% penetrant. It is probably as frequent as 1 in 250 in the general population.

Topics

Health & Longevity Neuroscience & the Brain Drug Discovery Medicine & Clinical Familial Hypercholesterolemia (FH)Cardiovascular Disease Prevention Lipid Metabolism Alzheimer's Disease Risk Statin Therapy Type 2 Diabetes Prevention

Mentioned in this video

personTom Dayspring

A mentor of Peter Attia who introduced him to John Kastelein's work.

drugVIXX

A COX-2 inhibitor, mentioned by Peter Attia as another example of a drug removed prematurely due to perceived toxicity, although a subset of patients may have benefited.

locationLeiden

One of two locations with research groups showing that loss of function in CETP protects against septicemia.

studyFourier and Odyssey trials

Large cardiovascular outcome trials for PCSK9 inhibitors, initially doubted by Peter Attia for their ability to show difference given low baseline LDL, but proved successful.

personSam Tsimikas

A researcher on ASO inhibitors for LP(a) who Peter Attia plans to have on the show.

conceptClotho (KLVS) variants

Genetic variants that seem to offer almost complete protection from the APOE4 gene's effects, a remarkable finding.

personMax Verstappen

A Dutch athlete used by John Kastelein as a humorous analogy for Dutch leadership in research.

companyMitsubishi Tanabe Pharma

Japanese pharmaceutical company where Obicetrapib (TA-8995) was discovered; John Kastelein consulted for them.

personChris Hemsworth

An actor who publicly disclosed his APOE4 carrier status during the 'Limitless' series, raising awareness about genetic risk for Alzheimer's.

studyOdyssey long-term study

A clinical trial led by John Kastelein that helped establish the safety and efficacy of PCSK9 inhibitors.

organizationJama

A medical journal where research on FH diagnosis in children was published.

conceptLDL Receptor

A protein on the liver cell surface that binds and internalizes LDL particles.

drugRosuvastatin

A Statin with a low starting dose that some pediatricians prefer for treating FH in children.

drugAtorvastatin

A statin used in children with FH, also not associated with myalgias.

drugEvinacumab

A Regeneron ngptl3 monoclonal antibody used as state-of-the-art therapy for homozygous FH, considered a "golden rescue" for children.

drugAnacetrapib

Merck's CETP inhibitor which, despite only moderately lowering LDL, confirmed that CETP inhibition reduces heart attacks by lowering LDL, fitting the CTT meta-regression line.

conceptFoxO gene

A gene identified as a longevity gene.

organizationUniversity of Amsterdam

Where John Kastelein is currently a professor of genetic medicine and leads the department of vascular medicine.

studyOdyssey outcomes study

A clinical trial led by John Kastelein that helped establish the safety and efficacy of PCSK9 inhibitors.

conceptType 2 Diabetes

A metabolic disease that a new CETP inhibitor might also help treat.

organizationDutch government

Provided a significant grant to actively find FH patients in the Netherlands.

studyLancet

A medical journal where research on FH diagnosis in children was published.

personPeter Landsberg

A co-worker of John Kastelein who developed the Dutch Lipid Clinic criteria for FH diagnosis.

drugpravastatin

A Statin initially preferred for its mildness in treating FH in children, shown to attenuate progression of atherosclerosis.

supplementezetimibe

Often added to statin therapy in children with FH to further lower LDL-C.

drugInclisiran

A PCSK9 inhibitor used aggressively in adult FH patients.

drugCETP inhibitors

A class of drugs with a history of failures initially, but with new promise for lowering LDL and impacting other diseases.

companyMerck

Pharmaceutical company that produced a CETP inhibitor which lowered LDL by only 17%, confirming CETP's effect on heart attacks through LDL lowering.

bookNature Medicine

A scientific journal where research on Obicetrapib was published.

supplementBempedoic Acid

Another lipid-lowering drug with a good safety profile, comparable to newer agents.

conceptAPOA1

A crucial molecule for cholesterol efflux, which CETP inhibitors stimulate the liver to produce more of, driving the reduction of cholesterol from peripheral tissues and beta-islet cells.

personJohn Kastelein

A genetic researcher and clinician scientist specializing in familial hypercholesterolemia and lipid-modulating drugs, professor at the University of Amsterdam.

conceptAPOE gene

A gene with three isoforms (APOE2, APOE3, APOE4) that codes for the APOE protein, influencing risk for Alzheimer's and cardiovascular disease.

conceptAPOE protein

The protein coded by the APOE gene, with different isoforms impacting the risk of Alzheimer's and cardiovascular disease.

locationAmsterdam

Location of John Kastelein's work and the large pediatric lipid clinic.

conceptAPOB protein

A protein cringled around every LDL particle, containing a binding domain for the LDL receptor.

studyFourier Olay results

Recent study results indicating that lower LDL levels beyond current targets are beneficial.

organizationOxford

Conducted the large 30,000-patient cardiovascular outcome trial for Merck's CETP inhibitor.

drugObicetrapib

A potent CETP inhibitor from Mitsubishi Tanabe Pharma that lowers LDL by 50% on top of statins and dramatically increases HDL, showing promise for various diseases including Alzheimer's, septicemia, and diabetes.

organizationAmerican College of Cardiology

Guidelines from this organization have influenced the exclusion criteria for the Prevail trial, setting lower LDL thresholds for eligibility.

conceptAPOC3 gene

A gene whose hypofunctioning variant is considered a longevity gene.

personPeter Attia

Host of The Drive podcast, focused on longevity science and health education.

supplementPCSK9 Inhibitors

A class of drugs whose safety and efficacy were established in trials led by John Kastelein, used to treat FH and other hypercholesterolemia.

conceptAlzheimer's disease

A neurodegenerative disease that a new CETP inhibitor might also help treat.

personMichael Hayden

A professor in Vancouver where John Kastelein trained and was a visiting professor, known for his work in genetics and FH.

conceptFamilial Defective Apob

A condition resulting from a mutation in the binding domain of APOB, leading to elevated LDL cholesterol similar to FH.

conceptATP-binding cassette G5/G8

Genes whose loss-of-function mutations lead to increased plant sterols in circulation and can cause sitosterolemia, a rare lipid disorder.

conceptSitosterolemia

A disorder associated with mutations in ABCG5/G8, characterized by increased plant sterols; its prevalence may be underestimated.

personDan Rader

A researcher previously discussed on Peter Attia's podcast, mentioned in the context of FH and CETP inhibitors.

organizationAmerican College of Pediatrics

An organization that provides guidelines for treating FH in children.

drugSimvastatin

A statin used in trials for children with heterozygous FH.

companyRegeneron

Pharmaceutical company that developed Evinacumab.

personPhil Barter

Australian KOL who discovered the CETP protein in rabbits.

companyPfizer

Pharmaceutical company that developed the first CETP inhibitor, torcetrapib, which failed due to off-target effects and increased mortality.

drugTorcetrapib

Pfizer's CETP inhibitor that failed due to off-target effects, increasing blood pressure and aldosterone, leading to higher mortality.

locationVancouver

One of two locations with research groups showing that loss of function in CETP protects against septicemia.

studyThe Lancet

A scientific journal where research on Obicetrapib was published.

organizationFDA

Does not allow statistical analysis on non-powered endpoint data in early phase trials.

studyNew England Journal of Medicine

A journal where John Kastelein published research on CETP activity and coronary angiography.

mediaLimitless series

A series where Chris Hemsworth discussed his APOE4 status, bringing awareness to genetic risk factors.

personMike Davidson

Implied co-worker of John Kastelein with whom he wanted to develop an ethical cholesterol-lowering drug. Also involved in Clotho research.

personPaul Ridker

A researcher known for his work on chronic pro-inflammatory states and their association with E4 carrier status.

personAlan Snyderman

Cited for his view that APOB is the primary driver of cardiovascular disease statistics, with other risk factors falling away once APOB is controlled.