Physicians' Academy for Cardiovascular Education

Addition of ER niacin to intensive LDL-c lowering therapy does not reduce CV events

Literature - Guyton JR, Slee AE, Anderson T et al. - J Am Coll Cardiol. 2013 Jul 20


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

1. Aim-High Investigators. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. New Engl J Med 2011;365:2255-67.
2. Haynes R, Jang L, Hopewell JC et al. HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment. Eur Heart J 2103;34:1279-91..
3. Armitage J. HPS2-THRIVE: Randomized placebo-controlled trial of ER niacin and laropiprant in 25,673 patients with pre-existing cardiovascular disease. American College of Cardiology Annual Scientific Sessions. San Francisco, 2013.
4. Coronary Drug Project Research Group. Clofibrate and niacin in coronary heart disease. J Am Med Assoc 1975;231:360-381.
5. Lee JM, Robson MD, Yu LM et al. Effects of high-dose modified-release nicotinic acid on atherosclerosis and vascular function: a randomized, placebo-controlled, magnetic resonance imaging study. J Am Coll Cardiol 2009;54:1787-94.
6. Taylor AJ, Villines TC, Stanek EJ et al. Extended-release niacin or ezetimibe and carotid intima-media thickness. New Engl J Med 2009;361:2113-2122.
7. Carlson LA, Rosenhamer G. Reduction of mortality in the Stockholm Ischaemic Heart Disease Secondary Prevention Study by combined treatment with clofibrate and nicotinic acid. Acta Med Scand 1988;223:405-418.
8. Brown BG, Zhao XQ, Chait A et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. New Engl J Med 2001;345:1583-1592.
9. Whitney EJ, Krasuski RA, Personius BE et al. A randomized trial of a strategy for increasing high-density lipoprotein cholesterol levels: effects on progression of coronary heart disease and clinical events. Ann Intern Med 2005;142:95-104.
 

Find this article on Pubmed

Share this page with your colleagues and friends: