Relationship of apolipoproteins A-1 and B, and lipoprotein(a) to cardiovascular outcomes: the AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglyceride and Impact on Global Health Outcomes)

Abstract

Objectives: This study sought to examine the relationship between baseline and on-study apolipoproteins (apo) A-1 and B and lipoprotein(a) [Lp(a)] levels and the development of subsequent cardiovascular (CV) events in the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglyceride and Impact on Global Health Outcomes) trial.

Background: Niacin has been reported to lower apoB and Lp(a) and to raise apoA-1.

Methods: Individuals with CV disease and low baseline levels of high-density lipoprotein cholesterol were randomized to simvastatin plus placebo or simvastatin, plus extended-release niacin ([ERN], 1,500 to 2,000 mg/day), with ezetimibe added as needed, in both groups, to maintain an on-treatment low-density lipoprotein cholesterol in the range of 40 to 80 mg/dl. Hazard ratios (HRs) were used to evaluate the relationship between levels of apoA-1, apoB, and Lp(a), and CV events in each treatment group.

Results: Baseline apoB and the apoB/apoA-I ratio were significantly predictive of CV events only for the placebo group (HR: 1.17 [p = 0.018] and HR: 1.19 [p = 0.016]). Baseline and on-study Lp(a) were predictive of CV events in both simvastatin plus placebo (baseline HR: 1.24 [p = 0.002] and on-study HR: 1.21 [p = 0.017]) and the simvastatin plus ERN group (baseline HR: 1.25 [p = 0.001] and on-study HR: 1.18 [p = 0.028]). The ERN modestly increased 1-year apoA-1 (7%), decreased apoB (13%), decreased the ApoB/ApoA-1 ratio (19%), and decreased Lp(a) 21%, but did not reduce CV events.

Conclusions: Lp(a) was associated with increased CV risk in both treatment groups indicating that it contributes to residual CV risk. However, there was no evidence that ERN reduced CV risk, despite favorable lipoprotein changes.

Keywords: Apo; CV; ELISA; ERN; HDL-C; HR; LDL; LDL-C; Lp(a); apolipoprotein; apolipoproteins; cardiovascular; cardiovascular risk; enzyme-linked immunoadsorbent assay; extended-release niacin; hazard ratio; high-density lipoprotein cholesterol; lipoprotein(a); low-density lipoprotein; low-density lipoprotein cholesterol; niacin; simvastatin.

Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1. Comparison of AIM-HIGH and Framingham baseline Lp(a) distribution

Histogram of baseline Lp(a) [nmol/L] for each study. Lp(a) distributions are compared using the Wilcoxon test.

Figure 2. Time to first cardiovascular event for statin + placebo arm by baseline Lp(a) quartile

Kaplan-Meier curves show time to first CV event for quartiles of baseline Lp(a) [nmol/L] in patients randomized to LDL-lowering therapy + placebo. HR and 95% CI are based on Cox Proportional Hazards regression, including terms for gender and diabetes. HR = Hazard Ratio; CI = Confidence Interval

Figure 3. Time to first cardiovascular event for statin + niacin arm by baseline Lp(a) quartiles

Kaplan-Meier curves show time to first CV event for quartiles of baseline Lp(a) [nmol/L] in patients randomized to LDL-lowering therapy + niacin. HR and 95% CI are based on Cox Proportional Hazards regression, including terms for gender and diabetes. HR = Hazard Ratio; CI = Confidence Interval