#240 ‒ The confusion around HDL and its link to cardiovascular disease | Dan Rader, M.D. | The Peter Attia Drive

Intro

In this episode of “The Peter Attia Drive” podcast, Peter Attia discusses the confusion surrounding HDL (high-density lipoprotein) and its link to cardiovascular disease with Dr. Dan Rader. They delve into the biology, origin, metabolism, and function of HDL, debunking common misconceptions and shedding light on the complexities of this lipoprotein. They also explore the role of HDL in atherosclerosis and the potential for HDL-based therapies.

Main Takeaways

HDL Biology and Function

• HDLs are complex and their biology is not well understood.
• HDLs are known as “good cholesterol” but this designation is oversimplified.
• Lipoproteins are the mechanism for transporting lipids in the blood, as lipids do not mix well with water.
• There are two families of lipoproteins: the Apo B family and the Apo A family.
• Apo B family primarily transports triglycerides and is directly linked to cardiovascular disease.
• HDL is a complex lipoprotein that transports cholesterol and some other complex lipids.
• APOA1 is the key protein with HDL, and there are several molecules of APOA1 in any given HDL particle.
• HDL is formed when APOA1 is put into the blood by either the intestine or the liver.
• ABCA1 is a key transport protein that helps HDL acquire lipid, particularly phospholipid and cholesterol.
• Humans that lack ABCA1 have virtually undetectable HDL.

HDL and Cardiovascular Disease

• Having high HDL does not guarantee protection against cardiovascular disease.
• Manipulating the ApoB side of the equation has been more successful in treating atherosclerosis than the ApoA side.
• HDLs are much smaller and denser than LDLs and have less lipid.
• There are different types of lipoproteins, including VLDLs, IDLs, LDLs, and chylomicrons.
• Standard lipid panels provide limited information and do not account for the complexity of HDL metabolism.
• Companies have developed drugs to raise HDL cholesterol levels, but their effectiveness in reducing cardiovascular events has been limited.
• Raising HDL cholesterol levels may not reduce cardiovascular disease events as it is not the particle driving the e-flux process of cholesterol from foam cells and macrophages.

HDL Function and Risk Prediction

• Measuring HDL functionality is important for assessing risk and targeting therapies.
• Clinical assays for measuring HDL function are under development and may be available in the next 2-3 years.
• HDL function is a predictor of incident cardiovascular events.
• The directional flux of cholesterol in the blood is more from HDL to APOB-containing lipoproteins rather than the other way around.
• Composite metrics of biomarkers may predict E-flux capacity rather than measuring it directly.
• HDL cholesterol is an inverse barometer of triglyceride metabolism and reflects 24-hour triglyceride metabolism better than fasting triglyceride measurement.

Summary

HDL Biology and Function

HDLs, often referred to as “good cholesterol,” are complex lipoproteins involved in the transport of lipids in the blood. They are composed of various proteins, including APOA1, and play a crucial role in cholesterol metabolism. HDL particles are formed when APOA1 is released into the blood by either the intestine or the liver. ABCA1, a transport protein, helps HDL acquire lipids, particularly phospholipids and cholesterol. However, the exact biology and function of HDLs are still not fully understood.

HDL and Cardiovascular Disease

Contrary to popular belief, having high HDL does not guarantee protection against cardiovascular disease. Manipulating the ApoB side of the equation, which primarily transports triglycerides and is directly linked to cardiovascular disease, has been more successful in treating atherosclerosis. HDL particles are smaller and denser than LDL particles and have less lipid. Standard lipid panels provide limited information and do not account for the complexity of HDL metabolism. Despite efforts to develop drugs to raise HDL cholesterol levels, their effectiveness in reducing cardiovascular events has been limited.

HDL Function and Risk Prediction

Measuring HDL functionality is crucial for assessing cardiovascular risk and targeting appropriate therapies. Clinical assays for measuring HDL function are currently under development and may be available in the next few years. HDL function, such as cholesterol efflux capacity, has been shown to be a predictor of incident cardiovascular events. The directional flux of cholesterol in the blood is more from HDL to APOB-containing lipoproteins, highlighting the importance of understanding the e-flux process. Composite metrics of biomarkers may provide better predictions of HDL function than measuring it directly. HDL cholesterol levels reflect 24-hour triglyceride metabolism better than fasting triglyceride measurements.

Conclusion

While HDL has been traditionally labeled as “good cholesterol,” its biology and function are much more complex than commonly believed. High HDL levels do not guarantee protection against cardiovascular disease, and manipulating the ApoB side of lipid metabolism has shown more success in treating atherosclerosis. The development of clinical assays to measure HDL function may provide better risk predictions and guide targeted therapies. Further research is needed to fully understand the complexities of HDL and its role in cardiovascular health.