EDITORIAL COMMENT
Are You Targeting Non–High-Density Lipoprotein Cholesterol?*
Jennifer G. Robinson, MD, MPH*
Departments of Epidemiology and Medicine, Lipid Research Clinic, University of Iowa, Iowa City, Iowa
* Reprint requests and correspondence: Dr. Jennifer G. Robinson, Associate Professor, Departments of Epidemiology and Medicine, Director, Lipid Research Clinic, University of Iowa, 200 Hawkins Drive SE 223 GH, Iowa City, Iowa 52242 (Email: jennifer-g-robinson{at}uiowa.edu).
Key Words: low-density lipoprotein cholesterol • non–high-density lipoprotein cholesterol • triglycerides • total cholesterol/high-density lipoprotein cholesterol ratio • coronary heart disease risk
Non–high-density lipoprotein cholesterol (HDL-C) was defined as the second lipid target of therapy in the 2001 National Cholesterol Education Program-Adult Treatment Panel III guidelines (1), yet is not yet widely used in clinical practice. At no additional cost, non–HDL-C measures all atherogenic apolipoprotein B–containing lipoproteins, including low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein cholesterol, and to a lesser extent, intermediate-density lipoprotein cholesterol, lipoprotein (a), chylomicrons, and chylomicron remnants (Fig. 1) (2). Not surprisingly, non–HDL-C predicts cardiovascular risk better than LDL-C alone. Non–HDL-C is simply calculated by subtracting HDL-C from total cholesterol. When triglycerides are 200 to 500 mg/dl, non–HDL-C is  30 mg/dl higher than LDL-C due to elevated levels of triglyceride-rich lipoproteins. For this reason, the National Cholesterol Education Program Adult Treatment Panel III set the goal for non–HDL-C 30 mg/dl higher than the LDL-C goal (1).
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Figure 1 Targets of Therapy
Low-density lipoprotein cholesterol (LDL-C) and non–high-density lipoprotein cholesterol (non–HDL-C) are recommended as the first and second targets of lipid therapy. Non–HDL-C includes LDL-C and atherogenic triglyceride-rich lipoproteins. Very low-density lipoproteins (VLDLs) are often elevated when triglyceride levels exceed 200 mg/dl. Estimated LDL-C calculated by the Friedewald formula also includes intermediate-density lipoproteins (IDLs) and lipoprotein (a) [Lp(a)]. Plasma triglyceride level reflects the triglyceride content of all lipoproteins. Clinical assays measure both apolipoprotein B (Apo B) 100 and Apo B48 particles (Barter P, Ballantyne C, Carmena R, et al. Apo B versus cholesterol in estimating cardiovascular risk and in guiding therapy: report of the thirty-person/ten-country panel. J Intern Med 2006;259:247–58). Each LDL-C, IDL cholesterol, VLDL cholesterol, and Lp(a) particle contains 1 Apo B100 molecule, and each chylomicron or chylomicron remnant contains 1 Apo B48 molecule. Chylomicrons and remnants are rapidly metabolized and contribute little to total Apo B levels. Adapted in part, with permission, from Miller et al. (2).
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In this issue of the Journal, the study by Arsenault et al. (3) is a welcome addition to the growing body of support for non–HDL-C as a target of therapy and extends the contribution of non–HDL-C to cardiovascular risk to even lower LDL-C levels. This study evaluated 11-year follow-up data from the EPIC (European Prospective Investigation Into Cancer and Nutrition)-Norfolk study, which included a primary prevention population of over 21,000 men and women age 45 to 79 years at baseline. A non–HDL-C 30 mg/dl higher than LDL-C was found to predict increased coronary heart disease (CHD) risk compared with non–HDL-C <30 mg/dl higher than the LDL-C level. Excess risk attributable to non–HDL-C occurred across increasing LDL-C categories for both men and women. Even when LDL-C was <100 mg/dl, those with non–HDL-C 130 mg/dl had excess CHD risk 1.8-fold higher than when non–HDL-C was <130 mg/dl. Notably, this analysis was not confined to those with triglyceride levels 200 to 499 mg/dl, as recommended by the National Cholesterol Education Program Adult Treatment Panel III (1).
The EPIC-Norfolk analysis also found that at each LDL-C level, those with nonfasting triglycerides 150 mg/dl were at greater CHD risk than those with lower triglyceride levels, which was most notable when LDL-C was <100 mg/dl (hazard ratio: 1.6 [95% confidence intervals: 1.02 to 2.59]). None of the analyses were adjusted for the presence of diabetes, insulin resistance, or HDL-C level. Therefore, conclusions regarding the strength of the association between hypertriglyceridemia and CHD risk in this study may be limited, especially as previous analyses of the EPIC-Norfolk and other populations found that the relationship between triglycerides and CHD risk was substantially attenuated after adjustment for these factors (4). On the other hand, more pertinent to statin-treated patients, the PROVE IT–TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis In Myocardial Infarction 22) study found those with fasting triglycerides 150 mg/dl were still at increased CHD risk after more complete adjustment for confounders (5). The PROVE IT–TIMI 22 study further found excess risk due to elevated triglycerides persisted even when on-treatment LDL-C levels are <70 mg/dl.
The EPIC-Norfolk study is consistent with other studies in finding that nonfasting triglycerides have recently been shown to be better predictors of cardiovascular risk than fasting levels (6). However, lack of a standardized protocol for quantitation of post-prandial hypertriglyceridemia limits its clinical application. In contrast, post-prandial chylomicronemia minimally influences the relationship between non–HDL-C levels and CHD risk (Fig. 1) and is another strength of non–HDL-C as a target of therapy (5).
What are the implications for clinical practice? We have shown that non–HDL-C lowering predicts CHD risk reduction in a 1:1 relationship in trials of drugs used as monotherapy and that non–HDL-C was twice as good as LDL-C for predicting risk reduction (7). Individual-level analysis of the TNT (Treating to New Targets) and IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering) trials comparing atorvastatin 80 mg to pravastatin 40 mg or simvastatin 20 to 40 mg, respectively, also confirmed that non–HDL-C was a superior risk predictor to LDL-C (8). Clearly, non–HDL-C should be routinely used as a target of therapy to reduce cardiovascular risk. Whether non–HDL-C should replace LDL-C as the sole target of therapy will need to be addressed in future guidelines.
In contrast to the clear relationship between non–HDL-C lowering and cardiovascular risk reduction, drug therapy to lower triglycerides per se has not yet been shown to provide incremental risk reduction beyond that obtained from LDL-C or non–HDL-C–directed therapy (9). Results from the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial will be reported soon and should help to clarify whether the addition of fenofibrate to simvastatin therapy will provide incremental benefit beyond that expected from the degree of non–HDL-C lowering (10). The ongoing AIM HIGH: Niacin Plus Statin to Prevent Vascular Events trial is evaluating whether lowering triglycerides and raising HDL-C with extended-release niacin will provide incremental benefit over simvastatin therapy when both treatment groups achieve similar LDL-C levels (11). In the meantime, in light of a recent meta-analysis showing that changes in triglycerides (or HDL-C) from statins, niacin, or fibrates failed to predict CHD risk (9), there is no compelling reason to specifically target therapy to triglycerides or HDL-C. This should be kept in mind when evaluating recent marketing campaigns identifying triglyceride and HDL-C abnormalities as targets for reducing "residual risk" in statin-treated patients. Triglyceride and HDL-C abnormalities are certainly markers of obesity, insulin resistance, and physical inactivity, and lifestyle modification may be the most appropriate risk reduction strategy (12). Smoking, hypertension, and the thrombotic state are proven targets of evidence-based therapy. Indeed, we have suggested that such therapies may result in greater reduction in risk than efforts to drive LDL-C to very low levels, given the log linear relationship between LDL-C and cardiovascular risk (13).
Some have advocated apolipoprotein B as an additional target or replacement for LDL-C and non–HDL-C levels, especially in those with diabetes (14). Given the added expense, lack of availability, and in some cases measurement quality issues of apolipoprotein B, non-HDL has numerous advantages over apolipoprotein B and other measures of particle size and number (15). Because statins are first-line therapy for cardiovascular risk reduction, it is important to note that apolipoprotein B, although superior to LDL-C, provides virtually no additional information over that obtained from non–HDL-C in statin-treated individuals (8,16). Efforts are underway to have non–HDL-C reported on all routine lipid panels (14).
Given the superiority of non–HDL-C to other lipid measures for risk prediction, and the proven benefit of non–HDL-C–lowering therapies, future guidelines will no doubt continue to emphasize the importance of non–HDL-C for guiding cardiovascular prevention strategies. Ultimately, it may be desirable to move toward non-HDL as the primary target of therapy once non–HDL-C has been routinely incorporated into clinical practice.
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Footnotes
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Dr. Robinson has received grants to the institution from Abbott, Aegerion, Bristol-Myers Squibb, Daiichi-Sankyo, GlaxoSmithKline, Hoffman La Roche, Merck, and Merck/Schering-Plough; and has also served as a consultant on the advisory board for AstraZeneca.
* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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1. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III) JAMA 2001;285:2486-2497.[Free Full Text]2. Miller M, Ginsberg HN, Schaefer EJ. Relative atherogenicity and predictive value of non–high-density lipoprotein cholesterol for coronary heart disease Am J Cardiol 2008;101:1003-1008.[CrossRef][Web of Science][Medline] 3. Arsenault BJ, Rana JS, Stroes ESG, et al. Beyond low-density lipoprotein cholesterol: respective contributions of non–high-density lipoprotein cholesterol levels, triglycerides, and the total cholesterol/high-density lipoprotein cholesterol ratio to coronary heart disease risk in apparently healthy men and women J Am Coll Cardiol 2010;55:35-41.[Abstract/Free Full Text] 4. Sarwar N, Danesh J, Eiriksdottir G, et al. Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 Western prospective studies Circulation 2007;115:450-458.[Abstract/Free Full Text] 5. Miller M, Cannon CP, Murphy SA, Qin J, Ray KK, Braunwald E. Impact of triglyceride levels beyond low-density lipoprotein cholesterol after acute coronary syndrome in the PROVE IT-TIMI 22 trial J Am Coll Cardiol 2008;51:724-730.[Abstract/Free Full Text] 6. Bansal S, Buring JE, Rifai N, Mora S, Sacks FM, Ridker PM. Fasting compared with nonfasting triglycerides and risk of cardiovascular events in women JAMA 2007;298:309-316.[Abstract/Free Full Text] 7. Robinson JG, Wang S, Smith BJ, Jacobson TA. Meta-analysis of the relationship between non–high-density lipoprotein cholesterol reduction and coronary heart disease risk J Am Coll Cardiol 2009;53:316-322.[Abstract/Free Full Text] 8. Kastelein JJP, van der Stieg W, Holme I, et al. Lipids, apolipoproteins, and their ratios in relation to cardiovascular events with statin treatment Circulation 2008;117:3002-3009.[Abstract/Free Full Text] 9. Briel M, Ferreira-Gonzalez I, You JJ, et al. Association between change in high density lipoprotein cholesterol and cardiovascular disease morbidity and mortality: systematic review and meta-regression analysis BMJ 2009;338:b92.[Abstract/Free Full Text] 10. Ginsberg HN, Bonds DE, Lovato LC, et al. ACCORD Study Group Evolution of the lipid trial protocol of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial Am J Cardiol 2007;99:S56-S67. 11. AIM-HIGH: Niacin plus statin to prevent vascular events( NCT00120289)National Heart Lung and Blood Institute; 2006Available at: http://www.clinicaltrials.gov/show/NCT00120289. Accessed November 21, 2006. 12. Mozaffarian D, Wilson PWF, Kannel WB. Beyond established and novel risk factors: lifestyle risk factors for cardiovascular disease Circulation 2008;117:3031-3038.[Free Full Text] 13. Robinson JG, Stone NJ. Identifying patients for aggressive cholesterol lowering: the risk curve concept Am J Cardiol 2006;98:1405-1408.[CrossRef][Web of Science][Medline] 14. Sniderman AD. The case against ApoB and the ApoB:ApoA-I ratio: are they right? Future Lipidol 2008;3:257-264.[CrossRef][Web of Science] 15. Blaha M, Blumenthal R, Brinton E, Jacobson T, National Lipid Association Taskforce on Non-HDL Cholesterol The importance of non-HDL cholesterol reporting in lipid management J Clin Lipidol 2008;2:267-273.[CrossRef][Web of Science][Medline] 16. Ballantyne CM, Raichlen JS, Cain VA. Statin therapy alters the relationship between apolipoprotein B and low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol targets in high-risk patients: the MERCURY II (Measuring Effective Reductions in Cholesterol Using Rosuvastatin therapY II) trial J Am Coll Cardiol 2008;52:626-632.[Abstract/Free Full Text]
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