Very high HDL-c levels associated with higher mortality in patients with CAD

Association Between High-Density Lipoprotein Cholesterol Levels and Adverse Cardiovascular Outcomes in High-risk Populations

Literature - Liu C, Dhindsa D, Almuwaqqat Z, et al. - JAMA Cardiol. 2022 May 18:e220912. doi: 10.1001/jamacardio.2022.0912.

Introduction and methods


Historically, HDL-c is regarded as the ‘good’ cholesterol: indeed, higher HDL-c levels confer a lower CVD risk [1]. However, recent epidemiological studies in populations free of CVD show that very high HDL-c levels are related to higher mortality [2,3]. It is unknown whether this also applies to patients with CVD and whether a genetic cause underlies this relationship.

Aim of the study

The aim of this study was to examine the relationship between very high HDL-c levels (> 80 mg/dl) and mortality in patients with coronary artery disease (CAD). The relationship between known HDL-c genotypes and outcomes of very high HDL-c levels was also investigated.


The researchers conducted a multicenter, prospective cohort study based on data from the UK Biobank and the Emory Cardiovascular Biobank. The UK Biobank contains data from over 500,000 Britons recruited at the age of 40-69 years from 2006-2010. From this biobank, the researchers selected all patients with CAD (n=14,478). The Emory Cardiovascular Biobank is an ongoing prospective cohort study of American adults who require left hart catheterization because of suspected or confirmed CAD. Patients without CAD were excluded from participation (5467 patients were included).


The primary outcome measure was all-cause mortality. The secondary outcome measure was CV mortality.

The analyses were adjusted for potential confounders, including age, sex, ethnicity, BMI, smoking, and alcohol consumption. In addition, the analyses of data from the UK Biobank were adjusted for a genetic risk score, which was based on 142 single nucleotide polymorphisms that were independently related to HDL-c levels in a large-scale genome-wide association study [4].

Main results

  • Over a median follow-up of 8.9 years in the UK Biobank, a U-shaped association was found between HDL-c levels and both all-cause and cardiovascular mortality; a similar association was observed over a median follow-up of 6.7 years in the Emory Cardivascular Biobank.
  • In the UK Biobank, very high HDL-c levels (> 80 mg/dl) were related to an increased all-cause mortality (adjusted HR: 1.96; 95%CI: 1.42-2.71; P<0.001) and cardiovascular mortality (adjusted HR: 1.71; 95%CI: 1.09-2.69; p = 0.02), compared with an HDL-c level of 40-60 mg/dl. These results were replicated in the Emory Cardiovascular Biobank.
  • In the UK Biobank, the associations between HDL-c and outcomes persisted after adjustment for the HDL-c genetic risk score.


The results of this cohort study suggest that very high HDL-c levels are associated with higher mortality in patients with CAD. This association was independent of genetic variants related to HDL-c levels. According to the researchers, the study results have important implications for risk prediction.


1. Wilson PW, Abbott RD, Castelli WP. High-density lipoprotein cholesterol and mortality: the Framingham Heart Study. Arteriosclerosis. 1988;8(6):737-741. doi:10.1161/01.ATV.8.6.737

2. Madsen CM, Varbo A, Nordestgaard BG. Extreme high high-density lipoprotein cholesterol is paradoxically associated with high mortality in men and women: 2 prospective cohort studies. Eur Heart J. 2017;38(32):2478-2486. doi:10.1093/eurheartj/ehx163

3. Ko DT, Alter DA, Guo H, et al. High-density lipoprotein cholesterol and cause-specific mortality in individuals without previous cardiovascular conditions: the CANHEART Study. J AmColl Cardiol. 2016;68(19):2073-2083. doi:10.1016/j.jacc.2016.08.038

4. Klarin D, Damrauer SM, Cho K, et al; Global Lipids Genetics Consortium; Myocardial Infarction Genetics (MIGen) Consortium; Geisinger-Regeneron DiscovEHR Collaboration; VA Million Veteran Program. Genetics of blood lipids among ~300,000 multi-ethnic participants of the Million Veteran Program. Nat Genet. 2018;50(11):1514-1523. doi:10.1038/s41588-018-0222-9

Find this article online at JAMA Cardiol.

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