LDL: Lower Is Better, but How Low Should We Go?
By Harold L. Karpman, MD
Many risk factors contribute to the complex metabolic process which leads to atherosclerosis development. In an atherogenic environment, oxidized LDL infiltrates the vascular intima resulting in inflammation, endothelial dysfunction and eventually in the development of significant atherosclerosis even in those individuals with "normal" LDL levels (ie, 90-130 mg/dL.4 At least 7 statin mega-trials (with control LDL levels of 120-180 mg/dL and treatment LDL values of between 100-140 mg/dL) demonstrated remarkable reductions in CHD events and in all cause mortality.5-11 The National Cholesterol Education Program Adult Treatment Panel-III targeted the optimal low-density glycoprotein (LDL) level for patients with established coronary artery disease or coronary heart disease (CHD) risk equivalents (ie, diabetes, peripheral or cerebral vascular disease, and/or predicted 10-year CHD risk of > 20%) at < 100 mg/d.1 The European guidelines for this group of patients recommended a target LDL of < 115 mg/dL.
O’Keefe and colleagues3 reviewed published reports regarding the hunter-gatherer populations that existed before the introduction of agriculture and animal husbandry 10,000 years ago and which revealed no evidence for atherosclerosis even in individuals living into the seventh and eighth decades of life.12,13 These populations had total cholesterol levels of 100-150 mg/dL and LDL cholesterol levels estimated to be 50-75 mg/dL. Even today, the LDL levels of healthy neonates are in the 30-70 mg/dL range and healthy, wild adult primates usually have LDL levels of 40-80 mg/dL; in fact, modern humans are currently the only adult mammals, excluding some domesticated animals, with a mean average LDL level over 80 mg/dL and a total cholesterol over 160 mg/dL.12,13
Multiple, prospective, randomized controlled trials have demonstrated that the rate of angiographic progression of atherosclerosis was closely related to the chronic LDL level and that the threshold for progression appears to be at an LDL level at or above approximately 67 mg/dL (see Figure 1).14-20
Atherosclerosis progression varies directly with low-density lipoprotein cholesterol.
This regression line indicates that atherosclerosis does not progress when LDL is
67 mg/dL or below. All Figures adapted from O’Keefe, JH, et al. J Am Coll Card
More recently, an intra coronary ultrasound study even demonstrated atherosclerotic regression when LDL levels were reduced to a mean level of 79 mg/dL.20 More than 100,000 patients have been randomized to statin therapy in CHD event reduction trials which have clearly demonstrated a direct relationship between the level of on-treatment LDL values and the absolute risk of CHD events.5-11 The LDL level at which the cardiovascular event rate is predicted to approach zero is 57 mg/dL for primary prevention (see Figure 2) and 30 mg/dL for secondary prevention (see Figure 3). Inflammation and endothelial dysfunction have both been shown to be improved if the LDL is lower to < 80 mg/dL.20 Finally, statin therapy with improved LDL levels have been associated with reductions in the incidence of symptomatic peripheral vascular disease, stroke, dementia, macular degeneration, aortic stenosis, and osteoporosis, and, as result, some investigators have suggested that statins be considered for routine use in individuals over the age of 55 years.21
Coronary heart disease event rates in primary prevention trials (4-5 years duration)
are directly proportional to the on-treatment low-density LDL cholesterol levels. The
event rate is predicted to approach 0 at an LDL level of about 57 mg/dL.
Coronary heart disease event rates in
secondary prevention trials (5 years in duration
except the PROVE-IT study, which was 2 years) were directly proportional to low-
density LDL cholesterol levels. The event rate is predicted to approach 0 at LDL of
The newer, more potent, statin drugs are capable of reducing LDL cholesterol safely and tolerably in most patients thus making a target LDL of 50-70 mg/dL a practical goal, but, how low is too low? Since the cumulative experience with statin therapy has demonstrated impressive cardiovascular benefits that are directly proportional to the degree of LDL lowering with no increase in adverse events and, since on the other hand cholesterol is an essential component of the cell membrane and a needed precursor for bile acid, steroid hormones, and vitamin D synthesis, there must be a physiologically ideal range of blood cholesterol and LDL levels above and below which adverse health consequences might be expected. Patients with heterozygous hypobetalipoproteinemia with cholesterol levels as low as 80 mg/dL and LDL levels as low as 30 mg/dL live long lives presumably due to the absence of atherosclerosis and have no increase in adverse effects.22
Finally on July 13, 2004, most newspapers nationwide published a report issued by a panel from the National Institutes of Health’s National Cholesterol Education Program which recommended that reduction of LDL cholesterol to < 70 mg/dL is a "therapeutic option" (ie, a reasonable clinical strategy) on the basis of available clinical evidence. Furthermore, they extended this therapeutic option recommendation to patients at very high risk who even have achieved the previously recommended goal of a baseline LDL < 100 mg/dL.23
In summary, although an LDL level of 50-70 milligrams/dL may seem excessively low by recent American standards, it appears to be precisely the correct or normal range for individuals living the lifestyle and eating the diet for which we are genetically adapted and it would appear to be the goal that we should achieve in order to prevent the progression and even to promote regression of coronary atherosclerosis.
Dr. Karpman, Clinical Professor of Medicine, UCLA School of Medicine, is Associate Editor of Internal Medicine Alert.
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.
2. Law, MR, Wald NJ. BMJ. 2002;324:1570-1576.
3. O’Keefe, JH, et al. Jour Am Coll of Card. 2004;43: 2142-2146.
4. Akosh KO, et al. J Am Coll Cardiol. 2003;41: 1475-1479.
5. Shepherd J, et al. N Engl J Med. 1995;333:1301-1307.
6. Downs JR, et al. JAMA. 1998;279:1615-1622.
7. Sever PS, et al. Lancet. 2003;361:1149-1159.
8. Heart Protection Study Collaborative Group. Lancet. 2002;360:7-22.
9. Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) Study Group. N Engl J Med. 1998; 339:1349-1357.
10. Sacks FM, et al. N Engl J Med. 1996; 335:1001-1009.
11. Scandinavian Simvastatin Survival Study Group. Lancet. 1994; 344:1383-1389.
12. Cordain L, et al. Eur J Clin Nutr. 2002; 56(Suppl 1):S42-52.
13. O’Keefe JH, et al. Mayo Clin Proc. 2004;79:101-108.
14. Jukema JW, et al. Circulation. 1995;91:2528-2540.
15. Blankenhorn DH, et al. Ann Intern Med. 1993; 119:969-976.
16. MAAS Investigators. Lancet. 1994;344:633-638.
17. Waters D, et al. Circulation. 1994;89:959-968.
18. Pitt B, et al. J Am Coll Cardiol. 1995;26:1133-1139.
19. Herd JA, et al. Am J Cardiol. 1997;80:278-286.
20. Nissen S, et al. JAMA. 2004;291:1071-1080.
21. Wald NJ, Law MR. BMJ. 2003;326:1419.
22. Glueck CJ, et al. Metabolism. 1997;46:625-633.
23. Grunely SM, et al. Circulation. 2004;110:227-229.