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HDL-C Levels and Adverse CV Outcomes in High-Risk Populations
Quick Takes
- A paradoxical association between very elevated HDL-C (>80 mg/dL) and increased all-cause or cardiovascular mortality in patients with CAD has been suggested.
- Findings need to be further explored and incorporated into risk scoring models for patients with CAD.
Study Questions:
Is there an association between very elevated high-density lipoprotein cholesterol (HDL-C) levels in patients with coronary artery disease (CAD) and all-cause and cardiovascular (CV) mortality?
Methods:
Data were analyzed from two subsets of patients: The UK Biobank (UKB) included 14,478 patients aged 40-72 years from the UK general population with CAD between 2006–2010, and the Emory Cardiovascular Biobank (EmCAB) included a prospective cohort of 5,647 patients aged ≥18 years with confirmed CAD in the United States. Both models were adjusted for factors such as age, sex, race and ethnicity, body mass index, comorbidities, estimated glomerular filtration rate, alcohol use, triglycerides, low-density lipoprotein cholesterol (LDL-C), among others. A genetic risk score (GRS) was created for patients in the UKB. Five categories of HDL-C were assessed: <30 mg/dL, 30-40 mg/dL, 40-60 mg/dL (reference range), 60-80 mg/dL, and >80 mg/dL (very-high HDL-C). The primary outcome was all-cause death and the secondary outcome was CV death.
Results:
In the UKB, a total of 1.8% of patients had an HDL-C >80 mg/dL and these patients were more likely to be older, female, with frequent alcohol use (consumption ≥3 times per week), a lower prevalence of CV risk factors (hypertension, diabetes, and myocardial infarction [MI]), lower mean triglycerides, and higher mean LDL-C compared to those with lower HDL-C. In adjusted models, very-high HDL-C was also associated with increased risk of both all-cause death (hazard ratio [HR], 1.95; 95% confidence interval [CI], 1.42-2.71; p < 0.001) and CV death (HR, 1.71; 95% CI, 1.09-2.68; p = 0.02) compared to patients with the reference HDL-C. Additionally, in adjusted models, patients with HDL-C between 60-80 mg/dL also had an increased risk of all-cause death compared to those with the reference HDL-C (HR, 1.27; 95% CI, 1.08-1.5; p = 0.005). A positive linear association between the HDL-C GRS and HDL-C levels was observed; however, the HDL-C GRS was not associated with the risk of all-cause death or CV death in the adjusted or unadjusted models.
In the EmCAB, 1.6% of patients had HDL-C >80 mg/dL and these patients were more likely to be Black, female, with greater alcohol intake (consumption of ≥8 drinks per week), lower mean triglyceride levels, less likely to have a history of MI, and less likely to be using a statin, aspirin, beta-blocker, angiotensin-converting enzyme inhibitor, or angiotensin receptor blocker compared to those with lower HDL-C. Patients with HDL-C >80 mg/dL had a higher risk of all-cause death (HR, 1.62; 95% CI, 1.09-2.43; p = 0.02), but not a significantly increased risk of CV mortality (HR, 1.57; 95% CI, 0.95-2.61; p = 0.08). A U-shaped association between HDL-C and outcomes was demonstrated in both cohorts.
Conclusions:
This cohort study suggests that patients with CAD and very-high HDL-C (>80 mg/dL) have a higher risk of all-cause and CV death compared to those with normal HDL-C. HDL-C genetic variations in the GRS did not contribute substantially to the risk of all-cause or CV mortality nor did traditional risk factors.
Perspective:
This large multicenter cohort study using data from two independent high-risk populations with CAD in different countries demonstrated a U-shaped association with HDL-C and all-cause and CV mortality. These findings support that in addition to the known risk of low HDL-C, there is a paradoxical increase in mortality risk associated with elevated HDL-C. Further studies are needed to evaluate interactions such as gender, age, diabetes, and other risk factors and allow for addition of these findings to CV risk scores. Notably, this study is not generalizable to patients with nonatherosclerotic CV disease.
Clinical Topics: Cardiovascular Care Team, Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Atherosclerotic Disease (CAD/PAD), Hypertriglyceridemia, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Hypertension
Keywords: Alcohol Drinking, Angiotensin Receptor Antagonists, Angiotensin-Converting Enzyme Inhibitors, Aspirin, Patient Care Team, Cholesterol, HDL, Cholesterol, LDL, Coronary Artery Disease, Diabetes Mellitus, Dyslipidemias, Genetic Variation, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypertension, Myocardial Infarction, Myocardial Ischemia, Outcome Assessment, Health Care, Primary Prevention, Risk Factors, Triglycerides
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