<p><a href="https://peterattiamd.com/danrader/?utm_source=podcast-feed&utm_medium=referral&utm_campaign=230130-pod-danrader&utm_content=230130-pod-danrader-podfeed"> View the Show Notes Page for This Episode</a></p> <p><a href="https://peterattiamd.com/subscribe/?utm_source=podcast-feed&utm_medium=referral&utm_campaign=230130-pod-danrader&utm_content=230130-pod-danrader-podfeed"> Become a Member to Receive Exclusive Content</a></p> <p><a href="https://peterattiamd.com/newsletter/?utm_source=podcast-feed&utm_medium=referral&utm_campaign=230130-pod-danrader&utm_content=230130-pod-danrader-podfeed"> Sign Up to Receive Peter's Weekly Newsletter</a></p> <p>Dan Rader is a Professor at the Perelman School of Medicine at the University of Pennsylvania, where he conducts translational research on lipoprotein metabolism and atherosclerosis with a particular focus on the function of high-density lipoproteins (HDLs). In this episode, Dan goes in-depth on HDL biology, including the genesis of HDL, its metabolism, function, and how this relates to atherosclerotic cardiovascular disease (ASCVD). He explains why having high HDL-C levels does not directly translate to a low risk of cardiovascular disease and reveals research pointing to a better way to measure the functionality of HDL and predict disease risk. He also goes into detail on the role of HDL in reverse cholesterol transport and the benefits this has for reducing ASCVD. Additionally, Dan discusses the latest thinking around the association between HDL cholesterol and neurodegenerative diseases and ends the conversation with a discussion of how the latest research on HDL provides a promising outlook for ongoing trials and future therapeutic interventions.</p> <p><strong>We discuss:</strong></p> <ul type="disc"> <li>The lipidology of apoB and apoA [4:00];</li> <li>A primer on the high-density lipoprotein (HDL): genesis, structure, and more [9:30];</li> <li>How the lipoprotein system differs in humans compared to other mammals [20:00];</li> <li>Clarifying the terminology around HDL and apoA [25:30];</li> <li>HDL metabolism [31:45];</li> <li>CETP inhibitors for raising HDL-C: does it reduce CVD risk? [34:45];</li> <li>Why it's so important to have hard outcome trials in the field of cardiovascular medicine [42:30];</li> <li>SR-B1: an HDL receptor important for cholesterol efflux [48:00];</li> <li>The association between HDL levels and atherosclerosis: are they causally linked? [53:15];</li> <li>How insulin resistance is impacting HDL, and how HDL-C provides insights into triglyceride metabolism [58:00];</li> <li>Disappointing results from the studies of niacin—a drug that raises HDL-C and lowers apoB [1:08:15];</li> <li>HDL lipidation, dilapidation, and reverse cholesterol transport [1:12:00];</li> <li>Measuring the cholesterol efflux capacity of HDL: a better predictor of ASCVD risk than HDL-C? [1:22:00];</li> <li>A promising new intervention that may promote cholesterol efflux and reverse cholesterol transport [1:32:45];</li> <li>The association between HDL cholesterol and neurodegenerative diseases [1:34:00];</li> <li>Challenges ahead, a promising outlook, and the next frontier in lipidology [1:44:45]; and</li> <li>More.</li> </ul> <p>Connect With Peter on <a href="https://twitter.com/PeterAttiaMD">Twitter</a>, <a href="https://www.instagram.com/peterattiamd/">Instagram</a>, <a href="https://www.facebook.com/peterattiamd/">Facebook</a> and <a href="https://www.youtube.com/channel/UC8kGsMa0LygSX9nkBcBH1Sg">YouTube</a></p>
Actionable Insights
1. Do Not Rely on High HDL-C
Understand that HDL cholesterol itself is not directly and causally protective against atherosclerotic cardiovascular disease, as demonstrated by genetic studies and failed drug trials. Therefore, do not use a high HDL cholesterol level as a reason to forgo necessary preventive therapies like statins if other risk factors warrant treatment.
View a low HDL cholesterol level as an integrator of information related to insulin resistance, triglycerides, and inflammation, signaling increased cardiovascular risk even if not directly causal. In cases where treatment decisions are borderline, a low HDL can contribute to tilting towards more aggressive preventive therapy.
3. Understand HDL-C & Triglyceride Link
Recognize that HDL cholesterol levels reflect 24-hour triglyceride metabolism and postprandial triglyceride excursions more comprehensively than a single overnight fasting triglyceride measurement. Higher chronic triglyceride levels lead to lower HDL cholesterol.
4. Aim for Lower ApoB
Consider that humans are less efficient at clearing ApoB-containing lipoproteins compared to other mammals, leading to higher ApoB concentrations and increased risk of atherosclerotic cardiovascular disease. Aiming for lower ApoB levels, potentially around 20 mg/dL, could significantly reduce lifetime ASCVD risk.
5. Avoid HDL Fractionation
Do not rely on HDL fractionation metrics (e.g., HDL1, HDL2, HDL3, or various NMR sizes) for clinically valuable information or to predict cardiovascular risk, as current evidence does not support their utility for this purpose.
6. Exercise Caution with Clomid
If using clomiphene (Clomid) for testosterone replacement, be aware that it can significantly increase desmosterol levels, which may be associated with adverse cardiovascular outcomes, similar to the historical drug triparanol. Monitor desmosterol levels and consider long-term risks, especially with prolonged use.
7. Advocate for HDL Functional Assays
Be aware that cholesterol efflux capacity, a measure of HDL function, is a better predictor of cardiovascular risk than simply measuring HDL cholesterol. As these assays become more widely available clinically in the next 2-3 years, consider using them for a more sophisticated assessment of risk.
8. Consider HDL Particle Number
If available, HDL particle number (HDLP) may offer a slightly better prediction of cardiovascular risk compared to HDL cholesterol, though it remains a static measure.