LDL—Lower is Better, But How Low Should We Go?

By Harold L. Karpman, MD, FACC, FACP, Clinical Professor of Medicine, UCLA School of Medicine. Dr. Karpman reports no financial relationship to this field of study.

Synopsis: Statin therapy in patients with a very low LDL Cholesterol level (ie, less than 60 mg/dL) appears to be safe and is associated with improved survival.

Source: Leeper NJ, et al. Statin use in patients with extremely low low-density lipoprotein levels is associated with improved survival. Circulation. 2007;116:613-618(10).

Many risk factors contribute to the complex metabolic process that leads to atherosclerosis development. In an atherogenic environment one of these risk factors, LDL-cholesterol (LDL), becomes oxidized and infiltrates the vascular intima, resulting in inflammation, endothelial dysfunction and eventually in the development of significant atherosclerosis (occurring often even in those individuals with "normal" LDL levels [ie 90-130 mg/dL]). Intervention trials using statins to lower LDL levels have consistently demonstrated substantial reductions in major cardiovascular events in the treated group.1-7 Furthermore, it would appear that the magnitude of the reduction in and the frequency of events is a function of the extent of LDL lowering, with each decrease of 40 mg/dL corresponding to a 24% reduction in major cardiovascular events.8 The National Cholesterol Education Program Adult Treatment Panel-III targeted the optimal LDL levels for patients with coronary heart disease (CHD) risk equivalents (ie, diabetes, peripheral or cerebral vascular disease, and/or predicted 10 year CHD risk of greater than 20%) at less than 100 mg/dL.9 Finally, on July 13, 2004, a panel from the National Institutes of Health's National Cholesterol Education Program stopped short of an all-out recommendation that high risk CHD patients reduce their LDL below 70 mg/dL, pending the results of ongoing studies on the benefits of aggressive LDL lowering. However, the panel did suggest a new lower LDL level would be a "therapeutic option" for patients who had recently suffered a myocardial infarction or who were considered to be at high risk for the development of symptomatic CHD.

Recent research has once again focused on identifying the optimal level to which lipids, including LDL, should be reduced safely. A large meta-analysis revealed a near-linear relationship between cholesterol reduction and improvement in cardiovascular outcomes when initial cholesterol levels ranging from 73.1 to 150.4 mg/dL were reduced.13 Leeper and his colleagues from Stanford University attempted to investigate the safety and clinical outcomes of statin treatment in patients with LDL levels below 60 mg/dL.9 They studied the 4295 patients who had at least one prescription filled for statin medication during the 150 day observation period after the low LDL value had been obtained. The study was an observational study, designed primarily to evaluate associations between statin use in patients with very low cholesterol levels, and clinical outcomes. The results of the study suggested that statin therapy can safely be prescribed to patients with very low LDL levels (ie less than 60 mg/dL) and that treatment is associated with a survival benefit even when the LDL level is below 40 mg/dL.

Commentary

Evidence compiled from hunter-gatherer populations which existed before the introduction of agriculture and animal husbandry over 10,000 years ago suggested that there was no evidence of atherosclerosis even among individuals living into their seventh and eighth decades of life. These populations had total cholesterol levels of 100-150 mg/dL and LDL 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, non-domesticated mammals with a mean average LDL level over 80 mg/dL and a total cholesterol over 160 mg/dL. Multiple studies in over 100,000 patients who had been randomized to statin therapy in CHD event reduction trials have clearly demonstrated a direct relationship between the level of statin therapy and LDL values and the absolute risk of CHD events. The LDL level at which the cardiovascular event rate is predicted to approach zero is about 57 mg/dL for primary prevention and 30 mg/dL for secondary prevention. The mechanism by which statin therapy improves survival in patients by producing very low LDL levels is unclear. Although continued plaque stabilization and prevention of atheroma development are the most likely biological events which produce these positive results, other unmeasured effects of these drugs may also may contribute to the results observed in the Leeper study.9-12

The new, more potent statin drugs are capable of reducing LDL levels 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 acids, 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 hypobetal ipoproteinemia with cholesterol levels as low as 80mg/dL and LDL levels as low as 30 milligrams/dL live long lives, presumably due to the absence of atherosclerosis, and these patients exhibit no increase in adverse effects. In summary, although an LDL level of 50-70 mg/dL may seem excessively low by recent American guidelines, it appears to be precisely the correct "normal" range for individuals living the lifestyle and eating diets to which we are genetically adapted, and it would appear to be the goal that we should aim to achieve in order to prevent the progression and even to promote regression of coronary atherosclerosis.

The results of the Leeper study suggest that statin therapy can safely be prescribed to patients with even very low LDL levels (ie less than 60 mg/dL) and that statins in that group of patients, in fact, resulted in improved survival benefit even when the LDL level initially was below 40 mg/dL In addition statin therapy in these circumstances appears to be both safe and associated with improved mortality figures for patients without documented coronary artery heart disease. However, because the trial was not randomized, unmeasured clinical factors may have affected any physician's decision to prescribe or not to prescribe the drug. Therefore, although the results of the study suggest that statin therapy in patients with very low LDL levels appear to be safe and is associated with significantly improved survival even in those patients with initial LDL levels below 40 mg/dL, statistically significant prospective randomized studies must be performed in patients with very low LDL values in order to confirm these findings before they are proposed and/or recommended as practice guidelines.

References

1. Sever PS, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA0: a multicenter randomized controlled trial. Lancet. 2003; 361:1149-1158.

2. Sacks FM, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med. 1996;335: 1001-1009.

3. Shepherd J, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med. 1995;333:1301-1307.

4. Downs JR, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. JAMA. 1998;279:1615-1622.

5. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study. Lancet. 1994;344: 1383-1389.

6. The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in the incidence of coronary heart disease. JAMA. 1984;251:351-364.

7. Baigent C, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomized trial of statins. Lancet. 2005;366:1267-1278.

8. Sacks FM, et al. Effect of pravastatin on coronary disease events in subgroups defined by coronary risk factors: the Prospective Pravastatin Pooling Project. Circulation. 2000;102:1893-1900.

9. Leeper NJ, et al. Statin use in patients with extremely low low-density lipoprotein levels is associated with improved survival. Circulation. 2007;116:613-618. (10).

10. Grundy SM, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines (published erratum in Circulation. 2004;110:763). Circulation. 2004;110:227- 239.

11. Ray KK, et al. Beyond lipid lowering: what we have learned about the benefits of statins from the acute coronary syndrome trials? Am J Cardiol. 2006;98:S18-S25.

12. Fisman, et al. Statins research unfinished saga: desirability versus feasibility. Cardiovasc Diabetol. 2005; Jun 7;4(1):8.

13. Baigenbt C, et al. Cholesterol Treatment Trialists (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomized trials of statins. Lancet. 2005;366:1267-1278.