🔑 Key Takeaways
- Taking proactive measures such as using PCSK9 inhibitors and undergoing regular screenings can minimize the risks of FH. The latest CTEP inhibitors show promise in treating cardiovascular disease, Alzheimer's disease, and type 2 diabetes. Understanding the role of APOE4 can help identify high-risk patients and potential therapeutic options.
- FH is a genetic condition that can lead to cardiovascular disease. Early identification through history and genetic testing is important to differentiate between phenotype and genotype and prevent serious manifestations like heart attacks. Education about FH is crucial.
- FH is a genetic disorder causing high LDL cholesterol and premature coronary diseases. It can be diagnosed through family history and elevated LDL levels. Genetic testing and child testing are crucial for accurate diagnosis.
- Mutations in LDL receptor, ApoB, or PCSK9 protein can cause elevated LDL cholesterol levels, leading to downstream health issues. These mutations, prevalent in about 1 in 250 people, make FH the most common autosomal dominant disorder in men.
- Elevated levels of Cytosterol and Compesterol can result in physical signs of cholesterol accumulation, including xanthomas and cholesterol deposits. A diagnosis of FH can be made based on LDLC levels and family history, even without physical manifestations.
- LDL cholesterol levels alone are not enough to diagnose FH. Family history, clinical observation, and other factors should be considered for accurate diagnosis and treatment.
- FH is a genetic condition resulting in high LDL cholesterol, raising the risk of heart disease. Early diagnosis and treatment are crucial, while smoking increases the risk for men with FH.
- Not all individuals are equally affected by LDL and HDL cholesterol, and primary prevention of ASCVD is rare. For those with FH, starting healthy habits early and restricting saturated fats is crucial.
- Heterozygous FH can be managed with statins as early as childhood, offering potential for drastic lifespan extension without known major risk.
- Early identification and treatment of familial hypercholesterolemia (FH) with statins and PCSK9 inhibitors can help prevent premature death and coronary disease, with evinacumab as a potential option for severe cases with high starting LDL levels.
- High levels of LDL cholesterol are a major risk factor for heart disease, regardless of metabolic health. Even if some individuals with high LDL cholesterol do not have heart disease, the link between LDL and heart disease is not diminished. CTEP inhibitors show potential for treating atherosclerosis, which is caused by the CTP protein and loss of function of CTP is linked to better health outcomes.
- Pfizer's CTAP Inhibitor, Torcetropip, developed to reduce the activity of CTP, failed due to side effects, emphasizing the importance of careful understanding of potential complications before progressing to phase three in drug development.
- CTP inhibition found in drugs like statins and obesetropib can lower heart attacks by lowering LDL, validated by the largest cardiovascular outcome trial, while the preservation of ApoB has an evolutionary explanation for our species-wide transition.
- Our genetic adaptations in response to scarce resources may not always serve us well in modern environments where resources are plentiful and can lead to health problems. While drugs like Obisibatrib can help manage LDL cholesterol levels, a balanced approach is still required to prevent heart attacks and strokes.
- Inhibiting CTP reduces heart disease, Alzheimer's, macular degeneration, septicemia, and diabetes by lowering LDL levels and increasing HDL levels. It also prevents lipotoxicity and reduces the risk of becoming insulin dependent. Further research is required for the potential of CTP inhibitors for septicemia patients.
- Maintaining high HDL levels and inhibiting CTP can protect against negative health effects, including septicemia and type 2 diabetes. Obesetrapib shows promising results in clinical trials but cardiovascular outcomes must still be evaluated.
- A new drug that is cheaper with fewer side effects than statins is currently being tested in phase three trials known as Broadway, Brooklyn, and Prevail. It has the potential to offer significant reduction in ASCVD cases.
- PCS canine inhibitors are proving to be a viable alternative to heavily medicated patients in reducing LDL and Lp(a) cholesterol levels with minimal side effects. The Prevail trial shows promise for wider use.
- Genetic variations in CTEP can impact lipid profile and blood pressure, potentially affecting longevity. Further research is needed to determine the clinical significance of reducing LPa levels and the potential role of ASO inhibitors.
- Carriership of ApoE4 molecule can cause sterols accumulation and lead to brain-related issues. ApoA1 can replace ApoE4's functions with the help of CTP inhibitors, essential for brain health.
- Understanding the Apo E4 gene can help individuals prevent Alzheimer's disease by taking preventative measures like increasing Apo A1 levels and participating in clinical trials aimed at normalizing cholesterol synthesis, removal, and reducing inflammation.
- APOE4 may have been beneficial during the Ice Age, but now it is linked to higher LDL, inflammation, and heart disease due to its effects on the LDL receptor and chronic pro-inflammatory state. While controlling for APOE may help reduce risk, other factors like diabetes and insulin resistance can amplify differences in risk. Non-HDL and APOE may be better indicators of cardiovascular disease than LDL cholesterol.
- Developing drugs with the right biomarkers and conducting effective clinical trials with the right approach are essential to reduce the cost of drug development and save lives. Strong Mendelian randomization evidence is crucial in phase one and two trials before phase three trials.
📝 Podcast Summary
Insights on Familial Hypercholesterolemia and New Treatment Options
Familial hypercholesterolemia is a hereditary heart disease that affects a significant number of people. The risks of FH can be minimized by taking proactive measures such as using PCSK9 inhibitors. Additionally, the latest CTEP inhibitors may be game-changers in treating not only cardiovascular disease but also Alzheimer's disease and type 2 diabetes. The discussion also highlights the role of APOE, particularly in understanding why the protein coded by the APOE4 isoform produces a higher risk of Alzheimer's disease and cardiovascular disease. It is optimistic that in the next five years, therapeutic molecules for high-risk patients such as those with APOE4 may become available.
Familial Hypercholesterolemia (FH) and Its Relationship to Cardiovascular Disease
Cardiovascular disease is the leading cause of death globally, with familial hypercholesterolemia (FH) being a genetic condition that affects thousands of people. FH is a true autosomal dominant disease that starts very early in life and becomes symptomatic in the teenage years, with physical manifestations such as cholesterol depositing on tendons, Arcus in the eye, and deposits on eyelids. Angina or a heart attack is the first serious manifestation of FH, and the plaque that one gets in FH is a soft plaque, making it dangerous. It is important to educate people about FH, and with an objective metric of history and genetic testing, we can differentiate between phenotype and genotype.
Identifying Familial Hypercholesterolemia through Genetic Testing
Familial hypercholesterolemia (FH) is a genetic disorder that causes elevated LDL cholesterol, leading to premature coronary diseases. FH can be identified through family history and elevated LDL levels in first-degree relatives, and genotyping can confirm the diagnosis. Children are more likely to have a genetic cause for elevated LDL levels, making them a good diagnostic linchpin. FH has a heterogeneous genetic set of causes, with over 3500 different mutations that can cause the condition. Most cases of FH are caused by the LDL receptor gene, and FH diagnosis in adults is not as good as in children, as there may be mutations we do not yet know about.
Understanding the Causes of Elevated LDL Cholesterol Levels
The elevation of LDL cholesterol is caused by mutations in LDL receptor, ApoB, or PCSK9 protein, which lead to a lack of LDL receptors for the LDL particles to bind onto. This results in higher biomarker levels and downstream health issues. To anthropomorphize these mutations, imagine the LDL with ApoB as a baseball, the LDL receptor as a mitt, and PCSK9 as something that smacks the mitt closed. FH or familial defective ApoB is caused by a mutation in the binding domain of ApoB or the LDL receptor, while an overactive PCSK9 can degrade all LDL receptors. These mutations are prevalent in about 1 in 250 people in the general population and make FH the most common autosomal dominant disorder in men.
Cytosterolemia and Compesterol Disorders: More Common Than Expected
Cytosterolemia and Compesterol disorders are more common than originally thought, with a frequency of about 1 in 150,000. These disorders can coincide frequently because both of them have increased Cytosterol and Compesterol levels. Physical signs of cholesterol accumulation, such as xanthomas and cholesterol deposits, occur in areas of the body with frequent movements such as extensor tendons. The deposits on the eyes may also be linked to movement, as blinking throughout the day can cause a deposit of cholesterol in the cornea. The physical manifestation of xanthomas is not always required for a diagnosis of FH, as high levels of LDLC and family history of elevated cholesterol can be enough to diagnose.
Limitations of LDL cholesterol testing in diagnosing FH
Elevated LDL cholesterol alone cannot be used as a 100% certain marker for heterozygous FH or homozygous FH; it is a syndrome diagnosis that requires consideration of family members' history and Arcus. Heterozygous FH and polygenic hypercholesterolemia show an overlap in the Gaussian distribution of cholesterol levels, but the risk of premature MI with heterozygous FH is higher. Homozygous FH is the most severe form of inherited hypercholesterolemia caused by LDL receptor gene mutations. The Dutch lipid clinic criteria are the most rigorous in predicting FH and involve a score of one if a first-degree relative has premature coronary disease. Elevated triglycerides and low HDL require consideration of other factors.
Familial Hypercholesterolemia and Its Impact on Heart Health
Familial hypercholesterolemia (FH) is a genetic condition that results in very high levels of LDL cholesterol, which increases the risk of early heart disease. For diagnosis, there are different categories ranging from definite FH to unlikely FH. People with definite FH need treatment from the age of six, and it is important to diagnose the condition as early as possible to prevent premature onset of heart disease. Approximately 5% of people with FH seem immune to the phenotype and do not go on to develop early heart disease. These cases are mostly observed in women who have highly efficient reverse cholesterol transport system that takes care of deposited LDL. Smoking is particularly dangerous for men with FH who smoke, as it significantly increases their risk of heart disease.
The Complexities of Cholesterol and Prevention of ASCVD
Some people, mostly healthy women, seem immune to the negative effects of LDL cholesterol, due to an alignment of factors that offset the damage. The HDL cholesterol story is more complicated than LDL cholesterol, and sometimes elevated HDL may be a biomarker of dysfunctional HDL, but not in all cases. Primary prevention of ASCVD is rare and secondary prevention involves treating someone who already has discernible signs of disease. In heterozygous FH, it is important to start with anti-smoking training, healthy dietary counseling, and physical exercise from an early age. Saturated fat restriction is recommended for people with FH, who are more sensitive to dietary saturated fat.
Early Intervention with Statins Can Prolong Life in Heterozygous FH
Heterozygous FH is driven by LDL and early intervention with statins can add 15 to 20 years to a patient's life compared to doing nothing. Children with FH can be treated with a statin, with guidelines recommending starting treatment between 6 and 8 years of age. There is no strong preference for a particular statin, but some physicians prefer rosuvastatin due to its low starting dose. The goal LDL for children with FH is below 130, though some experts believe that the healthy LDL level for endothelium is much lower. There has been no negative effect found in kids of statins, but some people are still conservative about treating children with medication.
Early Treatment of FH Reduces Risk of Premature Death and Coronary Disease in Children
Treating familial hypercholesterolemia (FH) from an early age protects children against premature death and premature coronary disease, according to observations. Statins and PCSK9 inhibitors are effective against FH in the adult population. However, about 10% of heterozygous FH patients who are on triple therapy cannot achieve a reasonable LDL level, making them severe heterozygous FH patients. Moreover, Severe heterozygous FH is linked to the starting LDL, which if above 300, requires evinacumab as a quadruple therapy option that may obviate the need for LDL apheresis in many instances. It is hoped that the subcutaneous formulation of evinacumab will become available for kits to use.
LDL cholesterol and the link to heart disease
LDL cholesterol is causally related to ASCVD and is a major risk factor for heart disease, regardless of metabolic health. The author argues that the existence of individuals who smoke their whole lives without getting lung cancer does not diminish the causal link between smoking and lung cancer, similarly the existence of individuals with high LDL cholesterol who do not have heart disease does not diminish the link between LDL and heart disease. The discussion also covers the potential of CTEP inhibitors for treating atherosclerosis, which is caused by the CTP protein that is present in rabbits and promotes atherosclerosis. Loss of function of CTP has been linked to longevity and better health outcomes.
The Evolving Role of Genes: From Energy Conservation to Health Complications.
During the last Ice Age, our evolutionary funnel led to the selection of genes that were meant to conserve energy and cholesterol. However, these genes like PCSK9, CTP, and HPTL3 are now bad for us. All Mendelian randomization studies have shown that people with high activity of CTP have more heart disease, heart failure, kidney disease, diabetes, and Alzheimer. Pfizer developed the CTAP inhibitor called Torcetropip to reduce the activity of CTP. However, the drug failed in the phase three trial due to side effects. It increased blood pressure and promoted aldosterone and cortisol production, which led to water and sodium retention, low potassium, and high blood pressure. In essence, careful understanding of side effects should be considered before progressing to phase three.
Exploring the Pharmaceutical Industry's Failures and Successes in Cardiovascular Drug Development.
The pharmaceutical industry has a history of epic failures that resulted in loss of drugs that could have been beneficial, like Vioxx. The failure of dorsetrapib ended the HDL hypothesis and validated that CTP inhibition only lowers heart attacks by lowering LDL. The largest cardiovascular outcome trial ever conducted with 30,000 patients validated that CTP inhibition answers to the same law as statins, zidimibe, and PCSK9 monoclonals. To find a CTAP inhibitor that doesn't have the off-target effect of dorsetropib and lowers LDL, Mitsubishi developed obesetropib. Evolutionary explanation suggests that our species-wide transition to the preservation of ApoB makes more sense than any other teleologic explanation.
The Consequences of Evolutionary Adaptations in Modern Times
Our bodies have evolved to be highly efficient at clearing LDL cholesterol because preservation of resources was a crucial priority for millions of years. However, with the shift to an environment with more than enough resources in the last 150 years, this same gene that we worked to preserve is now causing health problems. For example, the thrifty gene hypothesis explains why people in Asia get type 2 diabetes at a much lower BMI than other parts of the world. Scientists discovered a new drug called Obisibatrib that is effective at lowering LDL cholesterol by 50% on top of high-intensity statins, but it's important to remember that an HDL cholesterol increase alone won't prevent heart attacks and strokes.
Inhibiting CTP for Overall Health Benefits
Inhibiting CTP can not only reduce heart disease, but also prevent Alzheimer’s, macular degeneration, septicemia, and diabetes. This is because inhibiting CTP lowers LDL levels and increases HDL levels, and also produces more ApoA1, which can clear away cholesterol. This is proven for all four CTP inhibitors. Additionally, inhibiting CTP can suck cholesterol out of beta cells in the pancreas, preventing lipotoxicity and reducing the risk of becoming insulin dependent. There are also indications that FH patients untreated may have a lower mortality rate due to septicemia, however, further research is required. Researchers in Vancouver and Leiden are testing CTP inhibitors on septicemia patients. The mechanism behind this is very complex.
The Role of HDL and CTP Inhibition in Septicemia and Diabetes
Maintaining high HDL levels during septicemia and raising HDL levels through CTP inhibition can protect against negative health effects. HDL acts as a sink for endotoxins and raises cholesterol efflux from macrophages, providing protection against apoptosis. CTP inhibition also helps in protecting against newly onset type 2 diabetes by up to 16-20%, almost as much as the negative effect of statins on diabetes. Obesetrapib is a CTP inhibitor that impacts both heterotypic and homotypic exchange and has completed phases one, two, and is currently in phase three with promising results. The main risk is that results may not pan out as expected in the cardiovascular outcomes trial.
A Promising New Drug to Replace Statins
If the new drug proves to be effective in phase three trials, it has the potential to replace all statins due to its cheaper cost and reduced risk of type two diabetes. The drug is easy to consume and has low or no side effects which makes it an ideal supplement to existing lipid-lowering therapies. The ongoing phase three trials- Broadway, Brooklyn, and Prevail- provide hope for the drug's efficacy, though they are not powered for MACE. Prevail is the largest trial, and the patients with existing ASCVD in this trial are also tested for other risk factors. The drug has the potential to offer more than 20% mass reduction in ASCVD cases, making it a much-awaited solution.
PCS Canine Inhibitors Proven Safe and Effective in Reducing Cholesterol
The PCS canine inhibitors were believed to be safe and effective in reducing cholesterol, but the trial was expected to fail as the patients included in the study were heavily medicated. However, the study succeeded even with patients having an LDL cholesterol level of 70 milligrams per deciliter. The Prevail trial, which will determine the efficacy of PCS canine inhibitors, has already randomized 9,000 patients who are actively taking high LDL medication, and the baseline LDL for these patients is already around 100. Furthermore, the PCS canine inhibitors have been found to be safe, with no side effects identified in phase 1 and phase 2 clinical trials. Drug classes like bumpindoic acid, azetamide, obesetrapib, and PCS canine inhibitors are effective in reducing LDL and Lp little a and have relatively fewer side effects than statins.
The Role of CTEP Concentration in Health Outcomes and Longevity.
A genetically determined decrease in CTEP concentration leads to reductions in LDLC, triglyceride, LPa, and blood pressure but an increase in HDL cholesterol. Hypo-functioning CTEP has been added to the list of longevity genes like ApoE2, FOXO, and ApoC3. However, the link between CTEP activity and blood pressure remains unknown. Elevated LP little a is hands down the most common genetic finding leading to premature ASCVD, but it is yet to be known if a 50% reduction is clinically enough to reduce outcomes. ASO inhibitors may be the lifeline there.
ApoE4 Molecule's Role in Brain Health and Importance of ApoA1
Carriership of APO E4 molecule is bad for the brain as it fails to remove or bring cholesterol, leading to the accumulation of sterols in neurons that get oxidized and generate oxysterols. ApoA1 can take over the functions of ApoE4 and raise in ApoA1 concentration can be achieved by using CTP inhibitors that enhance HDLs. ApoA1 can get through the blood-brain barrier and replaces the dysfunctional ApoE4. A Hollywood actor, Chris Hemsworth, disclosed that he is an E4 carrier. APO E4 is pro-inflammatory and insufficient in lipoprotein metabolism, leading to various brain-related issues. Raising ApoA1 concentration is crucial, and CTP inhibitors can help achieve it.
Taking preventative measures for Alzheimer's disease through Apo E4 gene knowledge.
having the Apo E4 gene does not necessarily mean that someone will develop Alzheimer's disease, as it is high risk but not deterministic. However, knowing about the gene can allow individuals to take steps to prevent exacerbating risk factors early on, in order to increase their odds of avoiding the disease. One potential preventative measure is increasing Apo A1 levels, which can offset the damaging effects of a defective Apo E in response to Apo E4. To understand the potential benefit of this, a proof of concept trial is being conducted where researchers will measure biomarkers such as desmosterol and leftosterol to see if cholesterol synthesis and removal can be normalized and inflammation reduced. In addition to its role in the brain, APOE is also involved in cardiovascular disease.
The Negative Association Between APOE4 and Heart Disease
APOE4, once advantageous in the Ice Age, is now associated with higher LDL, inflammation, and heart disease. APOE4 sits on VLDL and on VLDL remnants, where it is a better ligand for the LDL receptor, leading to down-regulation of the LDL receptor and less clearance of LDL. APOE4 is also associated with a chronic pro-inflammatory state and other negative factors. While controlling for APOE may make the association with risk disappear, APOE has several properties that cannot be completely knocked out statistically or biologically with APOE lowering. Other factors, such as type 2 diabetes, NAFLD, and insulin resistance, may amplify the differences in risk between individuals with the same APOE. Non-HDL and APOE may be better prognostic markers for cardiovascular disease than LDL cholesterol.
The Consequences of Developing Drugs Based on the Wrong Biomarker and Lack of Understanding the Mechanism of CTEP inhibition.
The field lost its way in developing a drug based on the wrong biomarker and understanding the mechanism of CTEP inhibition. Lives were lost and billions of dollars were wasted. Strong Mendelian randomization evidence and lots of phase one and two trials are needed before phase three trials. It's important to have the right biomarker to develop drugs that have no bizarre side effects. Clinical trials should be done with a DSMB and not with a blood pressure effect. Reducing the cost of drug development and saving lives require a different approach to clinical trials and biomarker discovery.