Extremely high HDL – beneficial or harmful?

Extremely high HDL – beneficial or harmful?

Too much of something good can be harmful, so goes the saying. Is this true in case of high density lipoprotein cholesterol (HDL) also? HDL represents reverse cholesterol transport and is considered a marker of cardiovascular protection. But this view was challenged partly by a large study involving 631,762 individuals using “big-data” approach [1].

It was an observational study using CANHEART (Cardiovascular Health in Ambulatory Care Research Team) dataset which had 17 different individual level data sources. Study population had an age range of 40 to 105 years. They were residents of Ontario, Canada, without previous cardiovascular disorders or severe comorbidities.

Mean follow up period was 4.9 years and all cause mortality was 8.1 per 1000 person-years in males and 6.6 per 1000 person-years in females. Those with lower HDL levels were likely to have low incomes, unhealthy lifestyle, higher triglyceride levels and other cardiac risk factors and medical comorbidities. Low HDL levels were associated with higher risk of cardiovascular, cancer and other mortality. The interesting finding was that those with higher HDL levels (above 70 mg/dl in males and more than 90 mg/dl in females) had increased hazard for non cardiovascular mortality. This has been called the U curve in case of HDL. Another important observation is that low HDL levels are associated with poor general health and unhealthy lifestyle.

An earlier study in male smokers had shown that all-cause and alcohol and violence related mortality was positively associated with HDL among younger men in the study population which had an age range of 50-69 years. U-shaped dose response was noted in men 60 years or more in all cause mortality [2]. So  there was view that increased HDL in this study was due to increased alcohol intake.

The EPOCH-JAPAN study checked the association of extremely high HDL with cardiovascular mortality in a pooled analysis of 9 cohort studies which included 43,407 individuals [3]. Extremely high HDL in this study was defined as HDL levels of 90 mg/dl or more. 4995 all-cause deaths and 1280 deaths due to cardiovascular cause were identified during the 12.1 year follow up. Extremely high levels of HDL were significantly associated with increased atherosclerotic cardiovascular disease mortality with a hazard ratio of 2.37 in this study.  There was increased risk for coronary heart disease and ischemic stroke. Risk of extremely high HDL was more evident among current drinkers.

Another longitudinal study of 83,100 participants having mean age of 45.4 years had 4475 participants with extremely high HDL above 90 mg/dl [4]. This study showed extremely high HDL was associated with lower risks for all-cause mortality and cardiovascular events compared to low HDL. But they had higher risks compared to very high HDL.

Paradoxically high all-cause mortality in those with extremely high HDL has also been reported in another study of 52 268 men and 64 240 women [5].

Though most of these studies showed a negative role for extremely high HDL, there is recent study from Korea which showed that extremely high HDL was not associated with increased risk of mortality, myocardial infarction and stroke [6]. That study with 343,687 subjects also defined extremely high HDL as 90 mg/dl or more. The median follow up period was 6 years.

So to conclude the final word on extremely high HDL is still not available. We need large scale population studies of longer period, across multiple countries to say whether the U shaped dose response relationship noted in several studies is actually due to HDL or some other associated confounding factors.

References

  1. Ko DT, Alter DA, Guo H, Koh M, Lau G, Austin PC, Booth GL, Hogg W, Jackevicius CA, Lee DS, Wijeysundera HC, Wilkins JT, Tu JV. High-Density Lipoprotein Cholesterol and Cause-Specific Mortality in Individuals Without Previous Cardiovascular Conditions: The CANHEART Study. J Am Coll Cardiol. 2016 Nov 8;68(19):2073-2083. doi: 10.1016/j.jacc.2016.08.038. PMID: 27810046.
  2. Paunio M, Heinonen OP, Virtamo J, Klag MJ, Manninen V, Albanes D, Comstock GW. HDL cholesterol and mortality in Finnish men with special reference to alcohol intake. Circulation. 1994 Dec;90(6):2909-18. doi: 10.1161/01.cir.90.6.2909. PMID: 7994838.
  3. Hirata A, Sugiyama D, Watanabe M, Tamakoshi A, Iso H, Kotani K, Kiyama M, Yamada M, Ishikawa S, Murakami Y, Miura K, Ueshima H, Okamura T; Evidence for Cardiovascular Prevention from Observational Cohorts in Japan (EPOCH–JAPAN) Research Group. Association of extremely high levels of high-density lipoprotein cholesterol with cardiovascular mortality in a pooled analysis of 9 cohort studies including 43,407 individuals: The EPOCH-JAPAN study. J Clin Lipidol. 2018 May-Jun;12(3):674-684.e5. doi: 10.1016/j.jacl.2018.01.014. Epub 2018 Feb 8. PMID: 29506864.
  4. Kobayashi D, Noto H, Shimbo T, Ino T, Osugi Y, Takahashi O, Asai K. Repeated measures of extremely high levels of high-density lipoprotein cholesterol and subsequent all-cause mortality and cardiovascular events: A longitudinal study. Atherosclerosis. 2019 Sep;288:17-25. doi: 10.1016/j.atherosclerosis.2019.06.918. Epub 2019 Jun 29. PMID: 31295627.
  5. Madsen CM, Varbo A, Nordestgaard BG. Extreme high high-density lipoprotein cholesterol is paradoxically associated with high mortality in men and women: two prospective cohort studies. Eur Heart J. 2017 Aug 21;38(32):2478-2486. doi: 10.1093/eurheartj/ehx163. PMID: 28419274.
  6. Yang Y, Han K, Park SH, Kim MK, Yoon KH, Lee SH. High-Density Lipoprotein Cholesterol and the Risk of Myocardial Infarction, Stroke, and Cause-Specific Mortality: a Nationwide Cohort Study in Korea. J Lipid Atheroscler. 2021 Jan;10(1):74-87. doi: 10.12997/jla.2021.10.1.74. Epub 2020 Dec 3. PMID: 33537255; PMCID: PMC7838511.