#255 ‒ Latest therapeutics in CVD, APOE's role in Alzheimer's disease and CVD, familial hypercholesterolemia, and more | John Kastelein, M.D., Ph.D.
John Kastelein, a genetic researcher and clinician, discusses familial hypercholesterolemia (FH), the history and compelling potential of CETP inhibitors, and the intricate role of ApoE in Alzheimer's and cardiovascular disease. He shares optimism for future targeted therapies.
Deep Dive Analysis
15 Topic Outline
Introduction to Familial Hypercholesterolemia (FH)
Differentiating FH Phenotype and Genotype
Pathophysiology of FH-Causing Gene Mutations
Clinical Presentations and Diagnosis of FH
Why Some FH Patients Avoid Premature ASCVD
Treatment Strategies for FH in Children and Adults
Addressing the 'LDL is Not Causal' Argument
History and Failures of CETP Inhibitors
The Thrifty Gene Hypothesis and CETP's Evolutionary Role
Potential of the Latest CETP Inhibitor: Obicetrapib
Obicetrapib's Impact on Diabetes and Sepsis
Obicetrapib's Effect on Lp(a) and Phase 3 Trials
APOE4, Brain Lipid Metabolism, and Alzheimer's Disease
APOE's Role in Cardiovascular Disease and Inflammation
Optimism for Future Targeted Therapies
7 Key Concepts
Familial Hypercholesterolemia (FH)
A genetic disorder characterized by very high levels of LDL cholesterol from birth, significantly increasing the risk of premature atherosclerotic cardiovascular disease (ASCVD). It is the second most common form of hereditary heart disease.
LDL Receptor Pathway
This pathway involves LDL particles, each with an ApoB protein, binding to LDL receptors on liver cells for internalization and clearance. PCSK9 protein degrades LDL receptors, maintaining a natural balance in LDL clearance.
Tendon Xanthomas
Physical manifestations of FH, these are cholesterol deposits that accumulate on tendons, most frequently the extensor tendons of the hands and the Achilles tendon. Their formation is theorized to be linked to frequent movement and macrophage activity.
Arcus Cornealis
A physical sign of FH, appearing as a cholesterol deposit in the cornea of the eye, forming a visible ring. It is also conjectured to be linked to the constant movement of blinking.
Thrifty Gene Hypothesis
An evolutionary theory suggesting that genes selected for survival during periods of resource scarcity (like the Ice Age) by promoting energy and cholesterol conservation can become detrimental in modern, resource-abundant environments, contributing to diseases like high LDL cholesterol and diabetes.
CETP (Cholesteryl Ester Transfer Protein)
A protein that facilitates the transfer of cholesterol esters from HDL particles to LDL particles. High CETP activity leads to lower HDL cholesterol and higher LDL cholesterol, which was beneficial for energy conservation in ancestral environments but is now associated with increased disease risk.
APOE4
A specific isoform of the APOE gene that codes for a protein that is inefficient at transporting cholesterol in the brain. This inefficiency leads to the accumulation of oxidized sterols in neurons, driving inflammation and cell death, and significantly increasing the risk for Alzheimer's disease and cardiovascular disease.
10 Questions Answered
FH is a genetic disorder characterized by very high levels of LDL cholesterol from birth, significantly increasing the risk of premature atherosclerotic cardiovascular disease (ASCVD).
FH is diagnosed based on a combination of family history of premature coronary disease, elevated LDL cholesterol (typically >190 mg/dL) without other abnormalities, and sometimes physical manifestations like tendon xanthomas or arcus cornealis. Genetic testing can confirm the diagnosis in about 95% of cases.
The vast majority (95%) of FH cases are due to mutations in the LDL receptor gene, with smaller percentages attributed to mutations in the APOB gene (4.5%) or gain-of-function mutations in the PCSK9 gene (0.5%).
Approximately 5% of FH patients, predominantly women, seem immune to disease symptoms, often characterized by high HDL cholesterol, absence of smoking, and lack of diabetes, suggesting protective genetic or environmental factors.
Yes, evidence from FH patients, who have a single gene mutation causing only elevated LDL cholesterol and experience premature heart attacks, strongly supports the causal role of LDL cholesterol in atherogenesis.
This hypothesis suggests that genes promoting cholesterol and energy conservation, beneficial during periods of famine, now contribute to diseases like high LDL cholesterol, diabetes, and heart disease in modern, resource-rich environments.
Potent CETP inhibition not only lowers LDL and raises HDL but also changes lipoprotein metabolism, potentially protecting against type 2 diabetes by promoting cholesterol efflux from pancreatic beta cells and offering protection against septicemia by maintaining high HDL levels.
APOE4 codes for a protein that is inefficient at transporting cholesterol in the brain, leading to accumulation of oxidized sterols in neurons, which triggers inflammation and cell death, contributing to neurodegeneration.
Yes, CETP inhibitors significantly raise ApoA1 levels in circulation, and ApoA1 can traverse the blood-brain barrier to take over the dysfunctional cholesterol transport roles of APOE4, potentially mitigating Alzheimer's risk.
APOE4 is associated with higher LDL cholesterol because it acts as a better ligand for the LDL receptor on VLDL and VLDL remnants, leading to their rapid clearance and subsequent down-regulation of LDL receptors, which then increases circulating LDL. It is also associated with a chronic pro-inflammatory state.
22 Actionable Insights
1. Initiate Early FH Treatment in Children
If a child is diagnosed with definite Familial Hypercholesterolemia (FH) based on rigorous criteria, initiate treatment as early as 6-8 years of age to significantly improve long-term outcomes and prevent premature cardiovascular disease.
2. Aggressively Treat Adult FH
For adults with FH, especially those transitioning from pediatric care, aggressively treat with high-intensity statins, ezetimibe, PCSK9 inhibitors, and potentially inclisiran, striving for the lowest possible LDL cholesterol levels to minimize cardiovascular risk.
3. Utilize Dutch Lipid Clinic Criteria for FH
To ensure the most accurate diagnosis of Familial Hypercholesterolemia, utilize the Dutch Lipid Clinic Network (DLCN) criteria, which have been externally and internally validated as highly predictive for FH.
4. Rule Out Secondary Causes of High LDL
Before diagnosing FH, always rule out other medical conditions that can cause elevated LDL cholesterol, such as high triglycerides, type 2 diabetes, untreated thyroid disease, or renal disease.
5. Be Aware of FH Physical Signs
Look for physical manifestations of FH, including tendon xanthomas (cholesterol deposits on tendons, especially extensor tendons of hands and Achilles), arcus cornealis (a cholesterol ring in the cornea), and xanthelasmata (deposits on eyelids), as these can aid in early diagnosis.
6. Consider Genetic Testing for FH
If clinical diagnosis of FH is strong, pursue genetic testing to definitively confirm the presence of a mutation, as this provides an unambiguous diagnosis without overlap, unlike cholesterol levels alone.
7. Implement Healthy Lifestyle for FH Children
For children with heterozygous FH, establish a very healthy lifestyle early on, including extensive anti-smoking education, comprehensive dietary counseling for healthy food choices, and regular physical exercise.
8. Start Statin Therapy for FH Children
Despite lifestyle interventions, statin therapy should be initiated in children with FH, typically around age six, as lifestyle measures alone are insufficient to cure the condition.
9. Consider Rosuvastatin for Pediatric FH
When prescribing statins for children with FH, rosuvastatin can be a preferred option due to its ability to be dosed at a low 2.5 mg, making it a tiny, manageable pill for a child.
10. Aim for Lower LDL in FH Children
While conservative guidelines suggest an LDL cholesterol goal of at least below 130 mg/dL for children with FH, recognize that a healthy endothelium ideally has much lower LDL levels, suggesting potential benefit from more aggressive treatment.
11. Utilize Quadruple Therapy for Homozygous FH
For individuals with homozygous FH, implement a state-of-the-art quadruple therapy consisting of high-dose statins, ezetimibe, evolocumab (or similar PCSK9 inhibitor), and evinacumab (an NGPTL3 monoclonal antibody) to achieve relatively normal LDL levels.
12. Advocate for Evinacumab in Pediatric Homozygous FH
For children with severe homozygous FH, advocate for the use of evinacumab, as it is a ‘golden rescue’ that can significantly reduce LDL levels and often obviate the need for LDL apheresis, though currently approved for adults.
13. Do Not Dismiss LDL’s Causal Role in ASCVD
Do not dismiss the causal link between elevated LDL cholesterol and atherosclerotic cardiovascular disease (ASCVD), as evidenced by the severe and often premature outcomes in FH patients with single-gene mutations that solely raise LDL.
14. Reject the HDL Hypothesis for ASCVD Prevention
Do not rely on high HDL cholesterol as a primary protective factor against ASCVD, as clinical trials with CETP inhibitors that only raised HDL without lowering LDL or ApoB showed no reduction in heart attacks or strokes.
15. Prioritize Potent CETP Inhibitors for LDL Lowering
When considering CETP inhibitors, prioritize those that robustly lower LDL cholesterol (e.g., by 50% on top of high-intensity statins) and have a clean safety profile, as LDL lowering is the validated mechanism for cardiovascular benefit.
16. Consider Obicetrapib for Type 2 Diabetes Risk Reduction
Recognize the potential of potent CETP inhibitors like obicetrapib to reduce the risk of type 2 diabetes by improving pancreatic beta-cell function and reducing lipotoxicity, an effect observed across multiple CETP inhibitor trials.
17. Consider Obicetrapib for Sepsis Protection
Understand that potent CETP inhibition may offer protection against septicemia by maintaining high HDL levels, which can function as a sink for endotoxins and other inflammatory mediators during infection.
18. Consider Obicetrapib for Lp(a) Reduction
If you have elevated Lp(a), consider the potential of obicetrapib to significantly lower Lp(a) levels (e.g., by 56% at a 10mg dose), although clinical outcome data specifically for Lp(a) lowering with this drug are still pending.
19. APOE4 Carriers: Raise ApoA1 for Neuroprotection
For APOE4 carriers, consider strategies that substantially raise ApoA1 levels (such as potent CETP inhibitors), as ApoA1 can traverse the blood-brain barrier and potentially offset the detrimental effects of dysfunctional APOE4 on brain cholesterol metabolism and Alzheimer’s risk.
20. APOE4 Carriers: Proactively Manage Risk Factors
If you are an APOE4 carrier, proactively take steps to prevent exacerbating risk factors for Alzheimer’s and cardiovascular disease, as early intervention and comprehensive management can significantly improve your long-term outcomes.
21. APOE4 Carriers: Be Aware of Cardiovascular Risk
If you are an APOE4 carrier, be aware of your increased risk for cardiovascular disease due to higher LDL cholesterol and a pro-inflammatory state, and manage these factors aggressively.
22. Prioritize ApoB and Non-HDL-C as Biomarkers
Prioritize non-HDL cholesterol and ApoB as superior prognostic markers and measures of therapeutic efficacy compared to LDL cholesterol calculated by the Friedewald formula, as they more accurately reflect the total burden of atherogenic lipoproteins.
6 Key Quotes
FH is a true autosomal dominant disease, meaning it's not sex linked. You don't need two parents to get it. You only need one parent to get it. It's almost 100% penetrant, meaning that if you have a robust mutation in one of the genes that cause FH, you're almost certain to get the phenotype.
John Kastelein
If you're a man and you smoke and you have FH, it's a death sentence.
John Kastelein
That drug was the end of the HDL hypothesis because there was no effect on LDL, no effect on FOB, no effect on non-HDL, but there was a 35% raising of HDL cholesterol. And that did not translate into one less heart attack or stroke.
John Kastelein
It's called the thrifty gene hypothesis, and it's more often used to explain, for example, that people in Asia get type 2 diabetes at a much lower BMI than we Caucasians because they've gone through much more famine when the rice failed, huge famine in the Far East.
John Kastelein
If you carry an E4, you have like a list this long of things that go wrong in your brain.
John Kastelein
I have been too down on CTEP inhibitors, and I'm very hopeful that Obisetrabib not only redeems the field, but also gives me something to be excited about clinically in my practice.
Peter Attia
2 Protocols
Treatment Protocol for Heterozygous FH in Children (Dutch Guidelines)
John Kastelein- Start with a very healthy lifestyle, including extensive anti-smoking training, dietary counseling for healthy choices, and physical exercise.
- Initiate statin therapy (e.g., rosuvastatin at 2.5 mg) at age six.
- Add ezetimibe if needed to achieve an LDL goal below 130 mg/dL.
State-of-the-Art Therapy for Homozygous FH
John Kastelein- High-dose statin therapy.
- Ezetimibe.
- Evalocumab (PCSK9 monoclonal antibody).
- Evinacumab (ANGPTL3 monoclonal antibody).