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U-shaped association between HDL cholesterol and mortality

By Bianca Nogrady
Extremely high levels of high-density lipoprotein (HDL) cholesterol – the so-called ‘good cholesterol’ – and extremely low levels are both linked to higher all-cause and cardiovascular (CV) mortality, new Danish research suggests.

Data from 52,268 men and 64,240 women enrolled in two prospective population-based studies showed a U-shaped association between HDL cholesterol and mortality, according to a paper published in the European Heart Journal.

Over a median follow up of six years, the lowest all-cause mortality was seen in men with an HDL cholesterol concentration of 1.9 mmol/L and women with a concentration of 2.4 mmol/L.

Compared with the reference level of 1.5 to 1.99 mmol/L, men with HDL cholesterol concentrations of 3 mmol/L or greater had a two-fold higher risk of all-cause mortality, and those with a concentration below 1 mmol/L had a 27% greater risk.

Women with an HDL cholesterol concentration of 3.5 mmol/L or above had a 68% higher all-cause mortality risk than the reference point of 2.0 to 2.49 mmol/L, and those with a concentration below 1 mmol/L had a 78% higher all-cause mortality.

‘The observed associations in this study could also be an epiphenomenon where there is a pathophysiologic abnormality, perhaps genetic, which increases risk in ways we do not understand and also increases HDL, suggesting that the physiology of HDL is complex and perhaps not well understood,’ the study authors wrote.

This U-shaped association between extremely low or extremely high HDL cholesterol was also seen for CV mortality in both men and women. Men with extremely high HDL had a 2.5-fold higher CV mortality while women had a 2.9-fold higher CV mortality compared with the reference groups.

Commenting on the study, Professor Garry Jennings, Chief Medical Advisor for the National Heart Foundation said the idea of ‘good’ and ‘bad’ cholesterol has been useful but was an over-simplification of lipid biology and its role in atherosclerosis.

‘It has been known for some time that genetic variants can be associated with high circulating HDL cholesterol but paradoxically high CV disease,’ Professor Jennings told Cardiology Today.

Professor Jennings suggested that while the occurrence of these extremely high rates of HDL cholesterol was relatively rare, it emphasised the need to look beyond the absolute level of HDL cholesterol.

‘People with very high and unexplained levels of HDL cholesterol may be referred to a lipid clinic for further evaluation, especially if there is a strong family history of CVD.’
Eur Heart J 2017; 38: 2478-2486. doi:10.1093/eurheartj/ehx163.

Picture credit: © Medical Illustration of high-density lipoprotein.