LDL Cholesterol: How Low Do We Go?
November 30, 2018
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.
COMMENTARY
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.
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.
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