Watch the full episode and view show notes here: https://bit.ly/3MKk0Er Become a member to receive exclusive content: https://peterattiamd.com/subscribe/ Sign up to receive Peter's email newsletter: https://peterattiamd.com/newsletter/ John Kastelein is a renowned expert in lipoprotein metabolism and atherosclerotic cardiovascular disease (ASCVD) research. In this discussion, John delves deep into familial hypercholesterolemia (FH), a genetic disorder characterized by high levels of LDL cholesterol in the blood that increases the risk of developing heart disease. He covers its definition, genetic underpinnings, and clinical identification. He then explores the therapeutic options available for the prevention and treatment of cardiovascular disease, including the captivating history of CETP inhibitors. He explains the past shortcomings of previous CETP inhibitors before underscoring the compelling potential of the latest iterations, not only for cardiovascular disease but also for conditions like Alzheimer's disease and type 2 diabetes. Moreover, he unveils the intricate role of APOE, shedding light on why the APOE4 isoform codes for a protein that significantly increases the risk of Alzheimer's disease and cardiovascular disease. Concluding the discussion, John shares a profound sense of optimism, envisioning the possibility of targeted therapeutic interventions for high-risk patients in the near future. We discuss: Intro [0:00] Familial hypercholesterolemia (FH): a genetic condition [4:30]; Differentiating between phenotype and genotype when it comes to FH [9:45]; The pathophysiology related to mutations of FH [15:30]; Clinical presentations, physical manifestations, and diagnosis of FH [22:00]; Criteria used to make a formal diagnosis of FH [30:15]; Why a small fraction of people with FH do not develop premature ASCVD [34:15]; Treatment and prevention for those with FH [39:45]; Addressing the assertion by some that elevated LDL is not casual in cardiovascular disease [52:45]; The history of CETP inhibitors and the role of the CETP protein [55:45]; The thrifty gene hypothesis and why genes underlying FH may have been preserved [1:09:00]; The compelling potential of the latest CETP inhibitor (obicetrapib) [1:13:00]; Promising results from phase 3 trials exploring obicetrapib [1:27:45]; Why the APOE4 allele increases the risk of Alzheimer’s disease, and the connection to blood lipids [1:41:30]; The role of APOE in cardiovascular disease [1:51:45];  Takeaways and looking ahead [1:57:00]; and More. -------- About: The Peter Attia Drive is a deep-dive podcast focusing on maximizing longevity, and all that goes into that from physical to cognitive to emotional health. With over 60 million episodes downloaded, it features topics including exercise, nutritional biochemistry, cardiovascular disease, Alzheimer’s disease, cancer, mental health, and much more. Peter Attia is the founder of Early Medical, a medical practice that applies the principles of Medicine 3.0 to patients with the goal of lengthening their lifespan and simultaneously improving their healthspan. Learn more: https://peterattiamd.com Connect with Peter on: Facebook: http://bit.ly/PeterAttiaMDFB Twitter: http://bit.ly/PeterAttiaMDTW Instagram: http://bit.ly/PeterAttiaMDIG Subscribe to The Drive: Apple Podcast: http://bit.ly/TheDriveApplePodcasts Overcast: http://bit.ly/TheDriveOvercast Spotify: http://bit.ly/TheDriveSpotify Google Podcasts: http://bit.ly/TheDriveGoogle Disclaimer: This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing, or other professional healthcare services, including the giving of medical advice. No doctor-patient relationship is formed. The use of this information and the materials linked to this podcast is at the user's own risk. The content on this podcast is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Users should not disregard or delay in obtaining medical advice for any medical condition they have, and they should seek the assistance of their healthcare professionals for any such conditions. I take conflicts of interest very seriously. For all of my disclosures and the companies I invest in or advise, please visit my website where I keep an up-to-date and active list of such companies. For a full list of our registered and unregistered trademarks, trade names, and service marks, please review our Terms of Use: https://peterattiamd.com/terms-of-use/