Relationship of Lipoproteins to CV Events: The AIM-HIGH Trial

Editor's Note: Commentary based on Guyton JR, Slee AE, Anderson T, et al. Relationship of Lipoproteins to Cardiovascular Events: The AIM-HIGH Trial (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes). J Am Coll Cardiol 2013;62:1580-1584.

Background

In the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes) trial,1 addition of extended release (ER) niacin to aggressive low-density lipoprotein-cholesterol (LDL-C) lowering did not reduce cardiovascular (CV) events. In this article, the authors evaluated the following questions among AIM-HIGH trial participants: 1. Are there patient subsets with specific lipid profile who may derive a benefit from ER niacin? 2. What is the effect of baseline and in-trial lipids on CV events among those receiving ER niacin + lipid lowering therapy (LLT) or placebo +LLT.

Methods

Traditional lipids were measured in 3,414 trial participants before randomization (baseline) and at one, three, six months and each year after randomization. The authors compared the impact of ER niacin +LLT vs. placebo +LLT on the primary outcome (time to first occurrence of death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, hospitalization for acute coronary syndrome, or symptoms driven coronary or cerebral revascularization) across each baseline lipid tertile. The authors then compared the association between baseline or in-trial lipids and the primary outcome in the ER niacin +LLT or placebo +LLT groups and a p value for interaction was described. All models were adjusted for sex and diabetes.

Results

ER niacin treatment did not reduce the primary end point across tertiles of any baseline lipid parameters (LDL-C, triglycerides [TG], high-density lipoprotein-cholesterol [HDL-C], non-high-density lipoprotein-cholesterol [non-HDL-C], total cholesterol/HDL-C ratio, or TG/HDL-C ratio). A prespecified analysis among 522 subjects (15.3%) who simultaneously had baseline TGs in the highest tertile (≥198 mg/dl) and HDL-C in the lowest tertile (<33 mg/dl) showed a nonsignificant trend toward reduction in primary outcome in the niacin group (HR: 0.74, p = 0.073). In a smaller group (n =439) of participants meeting the stricter criteria of TGs ≥200 mg/dl and HDL-C <32 mg/dl, the trend toward reduced events in the niacin group was stronger (HR: 0.64, p = 0.032).

Most baseline lipids (LDL-C, triglycerides, HDL-C, non-HDL-C, triglycerides/HDL-C ratio) were not associated with the primary outcome in either treatment group. Among the in-trial lipids, only LDL-C and non–HDL-C levels showed a significant treatment interaction (p for interaction = 0.01 and 0.008 for LDL-C and non-HDL-C, respectively). LDL-C and non-HDL-C were associated with the primary outcome in the placebo +LLT group (HR = 1.39, 95% CI = 1.16-1.67 for LDL-C, HR = 1.31, 95% CI 1.13-1.52 for non-HDL-C), but not in the ER niacin +LLT group (HR = 1.01, 95% CI 0.83-1.22 for LDL-C, HR 0.98, 95% CI 0.83-1.15 for non-HDL-C). None of the other lipid parameters showed a significant treatment interaction.

Conclusion

Niacin treatment was not associated with benefit or harm in tertiles of baseline lipids except for a possible benefit in the high TG/low HDL-C subgroup. ER niacin therapy attenuated the expected association between various lipid parameters and adverse CV outcomes.

Commentary/Perspective

These findings highlight and complement several recent observations. First, combination therapy with niacin was not associated with a reduction in CV events across most baseline lipid parameters. However, a nonsignificant trend towards benefit was seen among those with elevated TGs and low HDL-C. Similar results have been noted in trials of fibrate therapy,2-5 which like niacin, lowers triglycerides and raises HDL-C. Unfortunately, none of these clinical trials recruited patients based on this combined dyslipidemia pattern, with most analyses being post-hoc and therefore, the results are hypothesis generating. Second, prior statin trials have shown various on-treatment lipids like LDL-C, non-HDL-C (and apolipoprotein B) to be associated with future CV events.6 In contrast, none of these atherogenic lipid variables predicted CV events in the group receiving niacin in the AIM-HIGH trial. As authors pointed out, this could suggest that nonlipoprotein effects of niacin therapy may influence CV events, obscuring the effect of atherogenic lipids. These nonlipoprotein effects of niacin could be both beneficial (suppression of inflammatory response, increased cholesterol efflux from the macrophages) or detrimental (inhibition of adipocyte TG lipolysis leading to impaired fuel supply and counter regulatory increase in hormones like catecholamines). The net effect of multiple nonlipoprotein actions of niacin, together with a relatively small 15% HDL-C increase seen in the AIM-HIGH trial could have brought about a balance leading to no overall change in CV events (as also seen in the HPS2-THRIVE trial).7 Some could argue that evaluating the efficacy of niacin therapy using apolipoproteins or lipoprotein(a) [Lp(a)] could be more informative. In that respect, a concurrent publication8 from the AIM-HIGH trial showed that despite favorable changes with ER niacin; apoB, apoA-1 or Lp(a) did not identify any patient subgroup who might benefit from niacin. Third, neither baseline nor in-trial HDL-C levels were associated with CV events in either the ER niacin or the placebo arm of the AIM-HIGH trial (mean baseline LDL-C = 74 mg/dl). This suggests that HDL-C may not be the best clinical measure of various functions of the HDL. It is important to note that in the statin-treated arm of the primary prevention JUPITER trial9 or the statin-treated secondary prevention population of dal-OUTCOMES trial,10 no relationship between baseline HDL-C levels and subsequent CV events was seen. Some of the recent studies have also shown HDL particle concentration to be a better marker of residual CV risk in statin treated patients (with low LDL-C levels) compared with HDL-C.11 Interestingly, the ability of HDL to promote cholesterol efflux (an integrated measure of both HDL quantity and quality) from macrophages has also been shown to have a more robust association with subclinical atherosclerosis and obstructive coronary artery disease compared with HDL-C or apoA-1.12 These studies question whether HDL-C is a good marker of reverse cholesterol transport (RCT) and whether we need better functional markers of RCT that could be used to screen patients who may potentially derive benefits from HDL raising therapies.

References

  1. AIM-HIGH Investigators, Boden WE, Probstfield JL, Anderson T, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011;365):2255-67.
  2. ACCORD Study Group, Ginsberg HN, Elam MB, Lovato LC, Crouse JR 3rd, Leiter LA, Linz P, Friedewald WT, Buse JB, Gerstein HC, Probstfield J, Grimm RH, Ismail-Beigi F, Bigger JT, Goff DC Jr, Cushman WC, Simons-Morton DG, Byington RP. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010;362:1563-74.
  3. Scott R, O'Brien R, Fulcher G, et al. Effects of fenofibrate treatment on cardiovascular disease risk in 9,795 individuals with type 2 diabetes and various components of the metabolic syndrome: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. Diabetes Care 2009;32:493-8.
  4. Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease: the Bezafibrate Infarction Prevention (BIP) study. Circulation 2000;102:21-7.
  5. Manninen V, Tenkanen L, Koskinen P, et al. Joint effects of serum triglyceride and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki Heart Study: implications for treatment. Circulation 1992;85:37-45.
  6. Kastelein JJ1, van der Steeg WA, Holme I, Gaffney M, Cater NB, Barter P, Deedwania P, Olsson AG, Boekholdt SM, Demicco DA, Szarek M, LaRosa JC, Pedersen TR, Grundy SM; TNT Study Group; IDEAL Study Group. Lipids, apolipoproteins, and their ratios in relation to cardiovascular events with statin treatment. Circulation 2008;117:3002-9.
  7. HPS2-THRIVE Collaborative Group. 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 2013;34:1279-1291.
  8. Albers JJ1, Slee A, O'Brien KD, Robinson JG, Kashyap ML, Kwiterovich PO Jr, Xu P, Marcovina SM. 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). J Am Coll Cardiol 2013;62:1575-9
  9. Ridker PM, Genest J, Boekholdt SM, Libby P, Gotto AM, Nordestgaard BG, Mora S, MacFadyen JG, Glynn RJ, Kastelein JJ; JUPITER Trial Study Group. HDL cholesterol and residual risk of first cardiovascular events after treatment with potent statin therapy: an analysis from the JUPITER trial. Lancet 2010;376:333-339.
  10. Schwartz GG, Olsson AG, Abt M, Ballantyne CM, Barter PJ, Brumm J, Chaitman BR, Holme IM, Kallend D, Leiter LA, Leitersdorf E, McMurray JJ, Mundl H, Nicholls SJ, Shah PK, Tardif JC, Wright RS; dal-OUTCOMES Investigators. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med 2012;367:2089-2099.
  11. Mora S1, Glynn RJ, Ridker PM. High-density lipoprotein cholesterol, size, particle number, and residual vascular risk after potent statin therapy. Circulation 2013;128:1189-97.
  12. Khera AV, Cuchel M, de la Llera-Moya M, et al. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N Engl J Med 2011;364:127-35.

Clinical Topics: Diabetes and Cardiometabolic Disease, Clinical Topic Collection: Dyslipidemia, Lipid Metabolism, Nonstatins

Keywords: Cholesterol, Cholesterol, LDL, Dyslipidemias, Global Health, Hypertriglyceridemia, Lipids, Lipoproteins, LDL, Niacin, Metabolic Syndrome X, Triglycerides


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