By Michael H. Crawford, MD

Professor of Medicine, Chief of Clinical Cardiology, University of California, San Francisco

Dr. Crawford reports no financial relationships relevant to this field of study.

SYNOPSIS: A meta-analysis of 29 cholesterol-lowering outcome studies with baseline average low-density lipoprotein (LDL) cholesterol levels ≤ 70 mg/dL showed consistent major adverse cardiovascular event risk reductions down to average LDL levels of 21 mg/dL without any increase in adverse events.

SOURCES: Sabatine MS, Wiviott SD, Im K, et al. Efficacy and safety of further lowering of low-density lipoprotein cholesterol in patients starting with very low levels: A meta-analysis. JAMA Cardiol 2018:3:823-828.

Gotto AM Jr. Low-density lipoprotein cholesterol and cardiovascular risk reduction. How low is low enough without causing harm? JAMA Cardiol 2018:3:802-803.

With the advent of PCSK9 inhibitors, low-density lipoprotein cholesterol (LDL-C) now can be reduced to very low levels. The current guidelines recommend high-intensity statins regardless of the LDL-C level in patients with vascular disease or at high risk for developing it.

Investigators sought to evaluate the efficacy and safety of further lowering LDL-C in patients with average levels of ≤ 70 mg/dL at baseline by performing a meta-analysis of 29 randomized, double-blind, controlled trials of aggressive LDL-C-lowering therapy when the average baseline LDL-C was ≤ 70 mg/dL. The primary outcome was a combination of coronary death, myocardial infarction, ischemic stroke, or coronary revascularization over five years. Safety outcomes included myalgias/myositis, elevated liver enzymes, new onset diabetes, hemorrhagic stroke, and cancer. Three trials concerned non-statin drugs (ezetimibe, evolocumab, anacetrapib) added to statins. The other 26 were statin trials.

The statin trials reduced LDL-C from 66 mg/dL to levels not reported. The three non-statin plus a statin trials lowered LDL-C from a baseline of 63-70 mg/dL to 11-45 mg/dL. The overall relative risk of the primary endpoint was 0.79 (95% confidence interval, 0.71-0.87; P < 0.001). None of the safety endpoints were altered significantly by LDL-C lowering to median levels of 21 mg/dL.

The authors concluded that there was a consistent reduction in major adverse cardiovascular (CV) events in high CV risk patients with median LDL-C levels of 63 mg/dL, with further LDL-C reduction to a median of 21 mg/dL, without any observed adverse effects.


The latest cholesterol management guidelines (2013) abandoned LDL-C target levels in favor of using risk of CV events as the determinant of therapy. This was understandable given the lack of data or consensus on LDL-C targets. Also, it was well known that LDL-C levels alone do not predict risk of CV events accurately for primary prevention. Also, it was known that secondary prevention was driven by the mantra that whatever the LDL-C reading, it was too high. However, age heavily influenced the risk calculator to the point that most men > 65 years of age would qualify for statin therapy. Thus, many cardiologists have used a hybrid system that still considers LDL-C levels, favoring treatment for higher levels. Even the guidelines abandoned the risk equation if LDL-C was > 190 mg/dL.

This meta-analysis demonstrates that there is a 22% reduction in CV events for every 39 mg/dL reduction in LDL-C, down to LDL-C levels of about 20 mg/dL, regardless of baseline LDL-C. However, the higher the LDL-C, the greater the benefit. Also, this study showed that the benefit was independent of the drug used at the same LDL-C level. In addition, the results were remarkably consistent across the 29 trials included, which strengthens the validity of this meta-analysis. Finally, the reduction in CV events was accomplished without an increase over placebo in adverse effects. On the other hand, the non-statin trials were of a relatively short duration. Some adverse events with statins were not observed for more than 20 years. Thus, long-term surveillance of newer drugs still is necessary.

Unfortunately, this study did not establish new targets for LDL-C. However, the authors demonstrated at least short-term safety to a median LDL-C level of about 20 mg/dL. But there were few subjects with very low levels in the meta-analysis. Data from newborns reveal LDL-C levels of 22-45 mg/dL. Perhaps this should be our target range, especially for secondary prevention. Accordingly, some have recommended < 50 mg/dL but > 20 mg/dL for secondary prevention, which this study would support. What the levels should be for primary prevention is not considered.

Current belief is < 100 mg/dL or < 70 mg/dL, but the results of this study suggest lower may be better. We await more studies and the expected revision of the 2013 guidelines to answer these questions.