High HDL cholesterol levels
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High HDL Cholesterol Levels and Cardiovascular Risk
U-Shaped Association Between HDL Cholesterol and Mortality
Recent research shows that the relationship between high-density lipoprotein cholesterol (HDL-C) levels and health outcomes is not straightforward. Multiple large studies have found a U-shaped association, where both low and extremely high HDL-C levels are linked to increased risks of all-cause and cardiovascular mortality. This pattern has been observed in the general population, in people with hypertension, in those with type 2 diabetes, and across different ethnic groups, including Japanese and Korean cohorts Hirata2018Trimarco2022Li2025+4 MORE.
Extremely High HDL Cholesterol and Increased Mortality
Extremely high HDL-C levels (often defined as ≥80 or ≥90 mg/dL) are paradoxically associated with higher risks of death from all causes, as well as from cardiovascular and non-cardiovascular diseases. This increased risk is seen in both men and women, though some studies suggest it may be more pronounced in men Hirata2018Trimarco2022Li2025+2 MORE. The risk is also evident in specific groups, such as hypertensive patients and those with type 2 diabetes, where both low and high HDL-C levels are associated with more adverse events compared to moderate HDL-C levels Trimarco2022Lui2024.
No Additional Benefit at Very High HDL Cholesterol Levels
While moderate HDL-C levels are generally associated with lower risk of coronary heart disease (CHD), studies show that increasing HDL-C beyond a certain point does not provide further protection. In men, the benefit plateaus at HDL-C levels above 90 mg/dL, and in women, above 75 mg/dL. Beyond these levels, there is no additional reduction in CHD risk, and in some cases, risk may increase Wilkins2014Franczyk2021Razavi2023.
HDL Cholesterol Function and Quality
The traditional view that higher HDL-C is always better is being challenged. Some genetic conditions can cause very high HDL-C without reducing cardiovascular risk, suggesting that the function and composition of HDL particles may be more important than the cholesterol level itself. Dysfunctional HDL may lose its protective effects or even become harmful at very high concentrations Franczyk2021Razavi2023.
Special Populations and Confounding Factors
In people with primary hypercholesterolemia, high HDL-C was not independently associated with lower mortality after adjusting for other risk factors, indicating that the relationship may be influenced by additional variables . Lifestyle factors, such as alcohol consumption, may also modify the risk associated with high HDL-C .
Conclusion
Extremely high HDL cholesterol levels are not always protective and may be linked to increased risks of death and cardiovascular events, especially in men and in people with certain health conditions. The relationship between HDL-C and health outcomes is U-shaped, with both low and very high levels associated with higher risk. These findings highlight the importance of considering HDL function and overall cardiovascular risk, rather than focusing solely on raising HDL-C levels.
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