Too much of a good thing: very high HDL-C levels and increased mortality risk

By Dr Emily Lathlean MB BS, FRACGP
A prospective, multicentre cohort study has found a paradoxical association between very high HDL-cholesterol (HDL-C) and all-cause mortality in patients with coronary artery disease (CAD).

The study, published in JAMA Cardiology, recruited 14,478 patients with CAD from the UK Biobank and 5467 patients from the US Emory Cardiovascular Biobank in Atlanta, Georgia.

Over a median follow up of nine and seven years, respectively, a U-shaped association with all-cause and cardiovascular mortality was observed, with higher risk in patients with low and very high (>80 mg/dL [≈2.1 mmol/L]) HDL-C levels compared with patients with midrange values (40 to 60 mg/dL [≈1.0 to 1.6 mmol/L]). Those with very high HDL-C had a 96% higher risk of all-cause mortality and a 71% higher risk of cardiovascular mortality than those with midrange HDL-C values.

HDL-C has previously been termed ‘good cholesterol’, with low HDL-C levels associated with higher CAD risk and high HDL-C levels often viewed as being protective. However, emerging evidence suggests that a U-shaped association might be present with higher mortality in patients who have very high levels of HDL-C, a finding previously found in the general population and now also in this study of patients with CAD.

‘It is important to note that elevated HDL was noted in just 1.8% of the UK cohort and 1.6% of the US cohort, so this is quite a rare phenomenon,’ said Professor Leon Simons, Conjoint Associate Professor of Medicine at UNSW, Sydney.

Higher cardiovascular mortality risk was more prominent in younger patients with high HDL-C levels compared with patients aged 65 years or older in both cohorts. The association between very high HDL-C levels and mortality risk was stronger among patients with diabetes in the US cohort but not in the UK cohort. Researchers suggested more studies with large sample sizes were needed to further evaluate these findings.

‘While I believe the findings are genuine, there are inconsistencies in the data,’ Professor Simons said. ‘Both cohorts are predominantly male, yet those with elevated HDL-C are predominantly female. In the UK cohort, higher HDL was clearly related to higher alcohol intake, yet no such relationship was present in the US cohort. In addition, the risk of all-cause mortality was increased in males versus females in the UK cohort, yet this was not so in the US cohort.’

Professor Simons said that although HDL-C levels were an important cardiovascular risk factor, there were generally no specific guidelines to treat low or high HDL-C levels, and that the findings were unlikely to influence the management of patients with CAD.
JAMA Cardiol 2022; doi: 10.1001/jamacardio.2022.0912.