The Courage to Recognize that HDL Cholesterol is Only a Biomarker of Risk

Editor's Note: Based on Acharjee S, Boden WE, Hartigan PM, et al. Low levels of high-density lipoprotein cholesterol and increased risk of cardiovascular events in stable ischemic heart disease patients: A post-hoc analysis from the COURAGE Trial (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation). J Am Coll Cardiol 2013;62:1826-33.

The COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial investigated optimal medical therapy in patients with stable ischemic heart disease who were randomized to initial treatment with or without percutaneous coronary intervention (PCI) as the initial management strategy.1 In this post hoc analysis of COURAGE, Acharjee and colleagues investigate the risk of cardiovascular events associated with high density lipoprotein cholesterol (HDL-C) levels in patients with low density lipoprotein cholesterol (LDL-C) levels <70 mg/dL.2

This analysis included 2,193 men and women with stable ischemic heart disease who were treated with optimal medical therapy (OMT). The primary lipid goals for LDL-C were 60-85 mg/dL, and secondary lipid targets for HDL-C were >40 mg/dL and triglycerides <150 mg/dL. After six months OMT, the association between HDL-C levels and the rate of cardiovascular events (composite of death from any cause or nonfatal MI) was assessed.

At 6 months of OMT (baseline values for this analysis), HDL-C levels were stratified into quartiles (<34.8, 34.9 to <40.7, 40.7 to <48.0, and 48.0 to 94.0 mg/dL, respectively). Utilization of statins in the quartiles of HDL-C (low to high) was 92.6, 94.4, 95.5, 94.2 and 94.2 percent respectively. Other lipid-lowering agents (niacin, fibrates, ezetimibe) were more commonly used in low HDL-C subgroups. The respective utilization of other lipid-lowering agents was 35.4, 27.4, 20.1, and 16.2% respectively. Lower HDL-C groups included more individuals with body mass index (BMI) (30.8 5.2, 30.2 5.0, 29.2 4.6, and 28.1 4.8 kg/m2, respectively; diabetes 41.4, 33.4, 32.1, and 28.0 percent, respectively, other features of the metabolic syndrome (higher triglycerides [197.2 128.2, 160.6 86.8, 148.6 101.5, and [25.9 67.6, respectively] and hypertension [74.2, 69.1, 62.3 and 63.2%, respectively); and current smokers (35.6, 26.7, 27.8, and 22.6%, respectively). The use of beta-blockers was also more common among individuals in the lowest to highest HDL-C groups (73.0, 72.9, 69.9 and 68.5%, respectively).

After multivariate analysis for age, sex, BMI, hypertension, diabetes, current smoking and triglycerides, the highest HDL-C subgroup in patients with achieved LDL-C<70 mg/dL had a 33% lower risk of the primary endpoint (HR: 0.67, 95% confidence interval 0.47 to 0.95; p=0.02). Within quartiles of HDL-C levels, the second lowest (HR 0.75 [0.55, 1.04]) and third lowest (HR 0.84 [0.62, 1.16] had no significant difference in risk compared to the highest HDL-C group. only the lowest HDL-C group. Using actual values of LDL-C at 6 months, there was no significant effect on the inverse association of HDL-C on the primary end-point.


This post-hoc analysis of COURAGE confirms that a prior reports from the Treating to New Targets (TNT) trial in stable CHD patients that a low HDL-C is associated with increased risk of death and nonfatal MI even among statin-treated patients who achieve LDL-C<70 mg/dL.3 In COURAGE, the risk of death and nonfatal MI remained higher even when efforts were made to increases HDL-C to >40 mg/dL and lower triglycerides <150 mg/dL.2 Thus, this analysis provides continued to support that a low HDL-C is a biomarker of increased cardiovascular risk.

Similar conclusions can be made from clinical trials of HDL-C the raising therapy with niacin that failed to reduce cardiovascular events among CHD patients with LDL-C levels <70 mg/dL.4,5 Similarly, cholesteryl ester transfer protein (CETP) inhibitors that increased HDL-C levels by 72% in ILLUSTRATE6 and about 30% in Dal-Outcomes7 have not had a favorable impact on cardiovascular events. Thus, it is important to consider reasons that low HDL-C levels are biomarkers of risk but not effective targets of therapy.

Thus, there are multiple unresolved issues include the reason for the increased risk associated with low HDL-C levels. Two major issues are discussed. The cholesterol content in HDL is not an adequate biomarker of HDL functionality.8 Large cholesterol carrying HDL particles have different interactions with macrophage cholesterol efflux pathways than small particles;9 and through changes in the HDL proteome and lipidome, critical anti-oxidant, anti-inflammatory, anti-apoptotic and anti-infective proteins are less abundant in large HDL particles.8,9 Second, low HDL cholesterol is inversely associated with the concentration of atherogenic lipoproteins (triglyceride-remnants, small and total LDL particles). In the Framingham Offspring Study, low levels of HDL-C were associated with progressively higher concentrations of small and total LDL particles10; and in the AFACAPS/TexCAPS trial, HDL-C was inversely associated with apolipoprotein B (apoB) concentrations.11 In TNT, low HDL-C levels in atorvastatin-treated patients with LDL-C<70 mg/dL were associated with high apoB concentrations.3

Statins are the most efficacious approved class of lipid altering agents that reduce atherogenic (apoB-containing) lipoproteins; however, in the TNT trial low HDL-C levels were associated with progressively higher apoB levels. Thus, the residual risk associated with a low HDL-C cannot be distinguished from the higher concentrations of apoB-containing lipoproteins. LDL-C is a less accurate measure of LDL particle concentration in patients with disorders of insulin resistance (metabolic syndrome, type 2 diabetes). As shown in a cross sectional study of type 2 diabetes patients treated with LDL-C levels <50 mg/dL and non-HDL-C levels <80 mg/dL on treatment with statin therapy, 84% had elevated LDL-P.12 The discordance between LDL-C and LDL-P is relevant for this analysis of the COURAGE trial in which 41.4% of the lowest HDL-C group had type 2 diabetes or 13.4% more than the highest HDL-C group. Moreover, more patients had characteristics of the metabolic syndrome that would be anticipated to increase the number of LDL discordant patients.


Low HDL-C is a biomarker of increased risk of all-cause mortality and nonfatal MI in COURAGE. This report is consistent with another trial of CHD patients with stable CHD, but it differs from a large primary prevention trial with rosuvastatin. Further information on the lipid associated risk of HDL and LDL may be clarified with lipoprotein analyses and in the future functional assays of HDL. Meanwhile, high-intensity statin therapy is implemented for CHD patients, and in accordance with other expert consensus documents, a measure of apoB or LDL-P should be considered to determine if further intensification of LDL lowering therapy is warranted.


  1. Boden WE, O'Rourke RA, Teo KK, et al., for the COURAGE Trial Research Group. Optimal Medical Therapy with or without PCI for stable coronary disease. N Engl J Med 2007; 356:1503-16.
  2. Acharjee S, Boden WE, Hartigan PM, et al. See.Low levels of high-density lipoprotein cholesterol and increased risk of cardiovascular events in stable ischemic heart disease patients: A post-hoc analysis form the COURAGE Trial (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation. J Am Coll Cardiol 2013;62:1826-33.
  3. Barter P, Gotto AM, LaRosa JC, Maroni J, Szarek M, Grundy SM, Kastelein JJ, Bittner V, Fruchart JC, Treating to New Targets Investigators. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med 2007;357:1301-1310.
  4. Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-Nickens P, Koprowicz K, McBride R, Teo K, Weintraub W for the AIM-HIGH Investigators. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011;365:2255-2267.
  5. HPS2-Thrive Collaborative Group. HPS2-THRIVE: Randomized placebo-controlled trial of ER niacin and laropiprant in 25,673 patients with pre-existing cardiovascular disease. American College of Cardiology 2013 Scientific Sessions. March 9, 2013 presentation by Jane Armitage. Accessed May 7, 2014
  6. Barter PJ, Caulfield M, Eriksson M, Grundy SM, Kastelein JJ, Komajda M, Lopez-Sendon J, Mosca L, Tardif JC, Waters DD, Shear CL, Revkin JH, Buhr KA, Fisher MR, Tall AR, Brewer B; ILLUMINATE Investigators. Effects of torcetrapib inpatients at high risk for coronary events. N Engl J Med 2007;357:2109-22.
  7. Schwartz GG, Olsson AG, Abt M, Ballantyne CM, Barter PJ, Brumm J, Chaitman BR, Holme IM, Kallend D, Leiter LA, Leitersdorf E, McMurray JJ, Mundl H, Nicholls SJ, Shah PK, Tardif JC, Wright RS; dal-OUTCOMES Investigators. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med 2012;367:2089-2099.
  8. Rosenson RS, Brewer HB Jr, Ansell B, Barter P, Chapman MJ, Heinecke JW, Kontush A, Tall AR, Webb NR. Translation of high-density lipoprotein function into clinical practice: current prospects and future challenges. Circulation 2013; 128: 1256-67.
  9. Rosenson RS, Brewer HB Jr, Davidson WS, Fayad ZA, Fuster V, Goldstein J, Hellerstein M, Jiang XC, Phillips MC, Rader DJ, Remaley AT, Rothblat GH, Tall AR, Yvan-Charvet L. Cholesterol efflux and atheroprotection: advancing the concept of reverse cholesterol transport. Circulation 2012;125:1905-19.
  10. Otvos JD, Jeyarajah EJ, Cromwell WC. Measurement issues related to lipoprotein heterogeneity. Am J Cardiol 2002;90:22i-29i.
  11. Gotto AM Jr, Whitney E, Stein EA, Shapiro DR, Clearfield M, Weis S, Jou JY, Langendörfer A, Beere PA, Watson DJ, Downs JR, de Cani JS. Relation between baseline and on-treatment lipid parameters and first acute major coronary events in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS). Circulation 2000;101:477-484.
  12. Malave H, Castro M, Burkle J, Voros S, Dayspring T, Honigberg R, Pourfarzib R. Evaluation of low-density lipoprotein particle number distribution in patients with type 2 diabetes mellitus with low-density lipoprotein cholesterol <50 mg/dl and non-high density lipoprotein cholesterol <80 mg/dL. Am J Cardiol 2012;110:662-5.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Lipid Metabolism, Nonstatins, Interventions and Coronary Artery Disease

Keywords: Cholesterol, HDL, Cholesterol, LDL, Coronary Artery Disease, Drug Evaluation, Myocardial Ischemia, Percutaneous Coronary Intervention

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