Physicians' Academy for Cardiovascular Education

Role of LDL as the most important blood lipids CHD risk factor challenged

Literature - Eliasson B, Gudbjörnsdottir S, Zethelius B, et al.; on behalf of the NDR - Eur J Prev Cardiol. 2013 Jun 17

LDL-cholesterol versus non-HDL-to-HDL-cholesterol ratio and risk for coronary heart disease in type 2 diabetes.

Eliasson B, Gudbjörnsdottir S, Zethelius B, et al.; on behalf of the NDR.
Eur J Prev Cardiol. 2013 Jun 17 [Epub ahead of print]


The benefits of lowering LDL-c for risk reduction of coronary heart disease (CHD) have been well-established, and guidelines recommend a primary target for treatment of <2.5 mmol/L LDL in patients with diabetes at lower CHD risk, and LDL<1.8 mmol/L at very high CHD risk. However, a growing body of evidence suggest that non-HDL-c [1-8] and the non-HDL-c-to-HDL- c (non-HDL:HDL)ratio [9,10]  are stronger CHD predictors than LDL in the general population.
The inverse relationship between HDL-c and CHD risk is well-described, including stratified for patients with elevated, normal or low LDL [11]. Guidelines have incorporated HDL targets accordingly, despite insufficient scientific evidence for any HDL-c value to be considered as a goal of therapy.
This study compared the clinical usefulness of LDL with non-HDL, HDL and non-HDL:HDL with regard to their predictive value for CHD risk, in a large observational study of 46786 patients with type 2 diabetes.  Patients were followed for until a CHD event, death or the censor date.

Main results

  • 2590 nonfatal or fatal CHD events occurred, based on 193182 person-years during a mean follow-up of 5.8 years.
  • HR for fatal/nonfatal CHD increased with higher baseline quartiles 2-4 as compared to quartile 1, for non-HDL, HDL and non-HDL:HDL (p<0.001 for all).
  • Mathematical polynomial spline construction of 6-year absolute CHD rates by increase in baseline lipid values showed an increase in CHD rate only with LDL above 3 mmol/L, and more rapidly above 3.5 mmol/L. In the non-HDL spline, CHD rate increased progressively from the lowest levels, and more pronounced above 4 mmol/L. The rate also decreased progressively from the lowest HDL-value (0.5 mmol/L), which attenuated at the highest levels >2.5 mmol/L. Non-HDL:HDL showed a linear CHD increase from the lowest levels, throughout the whole range.
  • Decrease in baseline HDL or updated HDL per 1 SD (0.4 mmol/L) yielded an adjusted HR for CHD of 1.14-1.17 (P<0.001). Adjustment for LDL gave HR: 1.13-1.16, and HR: 1.08-1.13 with further adjustment for non-HDL.
  • The 40097 patient without showed a similar picture to the 6689 patients with a history of CVD with respect to CHD risk by quartiles of baseline LDL. Only quartile 4, and quartile 3 among those without previous CVD, had significantly higher risk than quartile 1.


This observational study challenges the current role of LDL as the most important CHD risk factor among blood lipids in treatment guidelines. The almost linear splines for CHD by non-HDL:HDL, as opposed to the nonlinear splines by LDL demonstrate that non-HDL:HDL might be a better risk marker, specifically when LDL<3 mmol/L, where LDL did not differentiate CHD risk, and non-HDL:HDL did.


1. 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). Circulation 2002; 106: 3143–3421.
2. The Task Force for the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). ESC/EAS Guidelines for the management of dyslipidaemias. Eur Heart J 2011; 32: 1769–1818.
3. Simon A, Chironi G, Gariepy J, et al. Differences between markers of atherogenic lipoproteins in predicting high cardiovascular risk and subclinical atherosclerosis in asymptomatic men. Atherosclerosis 2005; 179: 339–344.
4. Ndumele CE, Matsushita K, Astor B, et al. Apolipoproteins do not add prognostic information beyond lipoprotein cholesterol measures among individuals with obesity and insulin resistance syndromes: The ARIC study. Eur J Prev Cardiol. October 29 2012.
5. Frontini MG, Srinivasan SR, Berenson G, et al. Utility of non-high-density lipoprotein cholesterol versus other lipoprotein measures in detecting subclinical atherosclerosis in young adults (The Bogalusa Heart Study). Am J Cardiol 2007; 100: 64–68.
6. Orakzai SH, Nasir K, Blaha M, et al. Non-HDL cholesterol is strongly associated with coronary artery calcification in asymptomatic individuals. Atherosclerosis 2009; 202: 289–295.
7. Toth PP, Simko RJ, Rao Palli S, et al. The impact of serum lipids on risk for microangiopathy in patients with type 2 diabetes mellitus. Cardiovasc Diabet 2012; 11: 109–119.
8. Brunzell JD, Davidson M and Furberg CD. Lipoprotein management in patients with cardiometabolic risk. J Am Coll Cardiol 2008; 51: 1512–1524.
9. Ingelsson E, D’Agostino RB, Vasan RS, et al. Clinical utility of different lipid measures for prediction of coronary heart disease in men and women. JAMA 2007; 298: 776–785.
10. Nam B-H, Kannel WB and D’Agostino RB. Search for an optimal atherogenic lipid risk profile: From the Framingham Study. Am J Cardiol 2006; 97: 372–375. deGoma EM, Leeper NJ and Heidenreich PA. Clinical significance of high-density lipoprotein cholesterol in patients with low low-density lipoprotein cholesterol. J Am Coll Cardiol 2008; 51: 49–55.

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