Key Moments
255-Latest therapeutics in CVD, APOE’s role in Alzheimer’s disease, familial hypercholesterolemia
Peter Attia MDKey Moments
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
●Drugs & Medications
●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
Mentioned in this video
A mentor of Peter Attia who introduced him to John Kastelein's work.
A researcher on ASO inhibitors for LP(a) who Peter Attia plans to have on the show.
A Dutch athlete used by John Kastelein as a humorous analogy for Dutch leadership in research.
An actor who publicly disclosed his APOE4 carrier status during the 'Limitless' series, raising awareness about genetic risk for Alzheimer's.
A co-worker of John Kastelein who developed the Dutch Lipid Clinic criteria for FH diagnosis.
A genetic researcher and clinician scientist specializing in familial hypercholesterolemia and lipid-modulating drugs, professor at the University of Amsterdam.
Host of The Drive podcast, focused on longevity science and health education.
A professor in Vancouver where John Kastelein trained and was a visiting professor, known for his work in genetics and FH.
A researcher previously discussed on Peter Attia's podcast, mentioned in the context of FH and CETP inhibitors.
Australian KOL who discovered the CETP protein in rabbits.
Implied co-worker of John Kastelein with whom he wanted to develop an ethical cholesterol-lowering drug. Also involved in Clotho research.
A researcher known for his work on chronic pro-inflammatory states and their association with E4 carrier status.
Cited for his view that APOB is the primary driver of cardiovascular disease statistics, with other risk factors falling away once APOB is controlled.
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.
A Statin with a low starting dose that some pediatricians prefer for treating FH in children.
A statin used in children with FH, also not associated with myalgias.
A Regeneron ngptl3 monoclonal antibody used as state-of-the-art therapy for homozygous FH, considered a "golden rescue" for children.
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.
A Statin initially preferred for its mildness in treating FH in children, shown to attenuate progression of atherosclerosis.
Often added to statin therapy in children with FH to further lower LDL-C.
A PCSK9 inhibitor used aggressively in adult FH patients.
A class of drugs with a history of failures initially, but with new promise for lowering LDL and impacting other diseases.
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.
Another lipid-lowering drug with a good safety profile, comparable to newer agents.
A class of drugs whose safety and efficacy were established in trials led by John Kastelein, used to treat FH and other hypercholesterolemia.
A statin used in trials for children with heterozygous FH.
Pfizer's CETP inhibitor that failed due to off-target effects, increasing blood pressure and aldosterone, leading to higher mortality.
One of two locations with research groups showing that loss of function in CETP protects against septicemia.
Location of John Kastelein's work and the large pediatric lipid clinic.
One of two locations with research groups showing that loss of function in CETP protects against septicemia.
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.
A clinical trial led by John Kastelein that helped establish the safety and efficacy of PCSK9 inhibitors.
A clinical trial led by John Kastelein that helped establish the safety and efficacy of PCSK9 inhibitors.
Recent study results indicating that lower LDL levels beyond current targets are beneficial.
Genetic variants that seem to offer almost complete protection from the APOE4 gene's effects, a remarkable finding.
A protein on the liver cell surface that binds and internalizes LDL particles.
A gene identified as a longevity gene.
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.
A gene with three isoforms (APOE2, APOE3, APOE4) that codes for the APOE protein, influencing risk for Alzheimer's and cardiovascular disease.
The protein coded by the APOE gene, with different isoforms impacting the risk of Alzheimer's and cardiovascular disease.
A protein cringled around every LDL particle, containing a binding domain for the LDL receptor.
A gene whose hypofunctioning variant is considered a longevity gene.
A condition resulting from a mutation in the binding domain of APOB, leading to elevated LDL cholesterol similar to FH.
Genes whose loss-of-function mutations lead to increased plant sterols in circulation and can cause sitosterolemia, a rare lipid disorder.
A disorder associated with mutations in ABCG5/G8, characterized by increased plant sterols; its prevalence may be underestimated.
Japanese pharmaceutical company where Obicetrapib (TA-8995) was discovered; John Kastelein consulted for them.
Pharmaceutical company that produced a CETP inhibitor which lowered LDL by only 17%, confirming CETP's effect on heart attacks through LDL lowering.
Pharmaceutical company that developed Evinacumab.
Pharmaceutical company that developed the first CETP inhibitor, torcetrapib, which failed due to off-target effects and increased mortality.
A medical journal where research on FH diagnosis in children was published.
Where John Kastelein is currently a professor of genetic medicine and leads the department of vascular medicine.
Provided a significant grant to actively find FH patients in the Netherlands.
Conducted the large 30,000-patient cardiovascular outcome trial for Merck's CETP inhibitor.
Guidelines from this organization have influenced the exclusion criteria for the Prevail trial, setting lower LDL thresholds for eligibility.
An organization that provides guidelines for treating FH in children.
A scientific journal where research on Obicetrapib was published.
Does not allow statistical analysis on non-powered endpoint data in early phase trials.
A journal where John Kastelein published research on CETP activity and coronary angiography.
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