Relationship of Lipoproteins to Cardiovascular Events in the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes (AIM-HIGH) Trial.

Guyton JR, Slee AE, Anderson T et al.
J Am Coll Cardiol. 2013 Jul 20. doi:pii: S0735-1097(13)02835-0. 10.1016/j.jacc.2013.07.023

Background

Adding extended release (ER) niacin to intensive LDL-c lowering therapy did not reduce atherothrombotic events in the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes (AIM-HIGH) trial [1]. Similarly, the Heart Protection Study 2, Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trial showed no benefit for addition of ER niacin/laropriprant to statin therapy [2,3]. However, some other studies have shown beneficial effects of niacin monotherapy [4] or combination therapy [5-9].
Niacin has both lipoprotein effects, thought to be mediated through the liver, and nonlipoprotein effects mediated by a G-protein coupled receptor on adipocytes, macrophages and dermal dendritic cells or by a direct action on endothelial cells. The present study analyses the interaction between plasma lipoproteins, niacin treatment and atherothrombotic events in AIM-HIGH. Patients enrolled in AIM-HIGH had established stable atherosclerotic disease with HDL-c<40 mg/dL for men, <50 mg/dL for women, high triglyceride (TG)(150-400 mg/dL) and LDL-c<180 mg/dL (adjusted for LDL-lowering treatment)[1].

Main results

• Treatment assignment did not significantly affect the rate of first major CV event in any baseline tertile of lipoprotein. Only for the 522 patients (15.3%) who had baseline TG in the highest tertile (>198 mg/dL) as well as HDL-c in the lowest tertile (<33 mg/dL) a trend was observed towards a reduced CV risk was observed in the ER niacin group (HR: 0.74, P=0.073).
• Baseline and in-trial HDL-c levels were not significantly associated with CV events.
• In trial LDL-c, non-HDL-c and TG/HDL-c significantly predicted events in the control group only. In-trial LDL-c (HR: 1.39) and non-HDL-c (HR: 1.31) were associated with CV events in the control group, but not in the ER niacin group (HR: 1.01 and 0.98).
• The overall predictive impact of in-trial lipoprotein variables was found to differ among treatment groups, suggesting that the use of ER niacin in patients treated with intensive LDL-c lowering therapy reduces the overall impact of lipoproteins on CV events.

Conclusion

Adding ER niacin to intensive LDL-c lowering therapy did not lead to a reduction of CV events, despite a 15% higher HDL-c level. This confirms earlier observations that HDL-c levels shows no correlation with events.
Only in the control group, in-trial atherogenic lipoprotein variables predicted atherothrombotic events , thus niacin appears to affect the relationship between lipoproteins and CV events. This could mean that niacin induces a change in lipoproteins that makes them less atherogenic, or that niacin has an effect on CV events independent of lipoproteins, or both. The authors find the second hypothesis the most likely.

References

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