Very Low Levels of Atherogenic Lipoproteins and the Risk for Cardiovascular Events: A Meta-Analysis of Statin Trials

Study Questions:

What is the range in lipoprotein levels achieved with statin therapy and the cardiovascular disease risk reduction associated with very low levels of atherogenic lipoproteins achieved with statin therapy?


This was a meta-analysis, which included individual patient data from eight randomized controlled trials of statin therapy. Trials were included if conventional lipids and apolipoproteins were measured in all study participants at baseline and at 1-year follow-up. Trials with a mean follow-up for cardiovascular events <2 years and those including <1,000 participants were excluded. Investigators were contacted and asked to provide individual patient data including sex; age; smoking status; body mass index; diabetes mellitus status; blood pressure; fasting glucose, total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides, and apolipoprotein (apo) A-I and B concentrations at baseline and at 1-year follow-up and past medical history. The following outcomes (and times to events) were also collected: fatal and nonfatal myocardial infarction, fatal “other coronary heart disease,” hospitalization for unstable angina, fatal and nonfatal stroke, fatal and nonfatal hemorrhagic stroke, peripheral artery disease, and congestive heart failure.


A total of 38,153 study participants were randomized to a statin arm and had a complete set of lipid and apo levels during statin treatment available. During 155,573 person-years of follow-up, a total of 6,286 major cardiovascular events occurred in 5,387 study participants. There was large interindividual variability in the reductions of LDL-C, non–HDL-C, and apoB achieved with a fixed statin dose. More than 40% of trial participants assigned to high-dose statin therapy did not reach an LDL-C target <70 mg/dl. Compared with patients who achieved an LDL-C >175 mg/dl, those who reached an LDL-C of 75 to <100 mg/dl, 50 to <75 mg/dl, and <50 mg/dl had adjusted hazard ratios for major cardiovascular events of 0.56 (95% confidence interval [CI], 0.46-0.67), 0.51 (95% CI, 0.42-0.62), and 0.44 (95% CI, 0.35-0.55), respectively. Similar associations were observed for non–HDL-C and apoB.


The authors concluded that reductions of LDL-C, non–HDL-C, and apoB levels achieved with statin therapy displayed large interindividual variation. Among trial participants treated with high-dose statin therapy, >40% did not reach an LDL-C target <70 mg/dl. Patients who achieve very low LDL-C levels have a lower risk for major cardiovascular events than do those achieving moderately low levels.


This meta-analysis suggests that many patients do not achieve low LDL-C levels, which were recommended in guidelines prior to 2013. Furthermore, lower LDL-C levels were associated with lower risk for cardiovascular disease events. Understanding the implications of current changes in guidelines on specific outcomes, including coronary events, should be an important research priority.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Hypertriglyceridemia, Lipid Metabolism, Nonstatins, Acute Heart Failure, Diet, Smoking

Keywords: Myocardial Infarction, Stroke, Follow-Up Studies, Cholesterol, LDL, Coronary Disease, Peripheral Arterial Disease, Blood Pressure, Smoking, Glucose, Lipoproteins, LDL, Body Mass Index, Research Personnel, Heart Failure, Confidence Intervals, Triglycerides, Lipoproteins, HDL, Diabetes Mellitus, Fasting

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