Effects of Extended-Release Niacin on Quartile Lp-PLA 2 Levels and Clinical Outcomes in Statin-treated Patients with Established Cardiovascular Disease and Low Baseline Levels of HDL-Cholesterol: Post Hoc Analysis of the AIM HIGH Trial

Abstract

Background:

Lipoprotein-associated phospholipase A₂ (LpPLA₂) is an inflammatory marker that has been associated with the presence of vulnerable plaque and increased risk of cardiovascular (CV) events.

Objective:

To assess the effect of extended-release niacin (ERN) on Lp-PLA₂ activity and clinical outcomes.

Methods:

We performed a post hoc analysis in 3196 AIM-HIGH patients with established CV disease and low baseline levels of high-density lipoprotein cholesterol (HDL-C) who were randomized to ERN versus placebo on a background of simvastatin therapy (with or without ezetimibe) to assess the association between baseline Lp-PLA₂ activity and the rate of the composite primary end point (CV death, myocardial infarction, stroke, hospitalization for unstable angina, and symptom-driven revascularization).

Results:

Participants randomized to ERN, but not those randomized to placebo, experienced a significant 8.9% decrease in LpPLA₂. In univariate analysis, the highest quartile of LpPLA₂ activity (>208 nmol/min/mL, Q4) was associated with higher event rates compared to the lower quartiles in the placebo group (log rank P = .032), but not in the ERN treated participants (log rank P = .718). However, in multivariate analysis, adjusting for sex, diabetes, baseline LDL-C, HDL-C, and triglycerides, there was no significant difference in outcomes between the highest Lp-PLA2 activity quartile versus the lower quartiles in both the placebo and the ERN groups.

Conclusion:

Among participants with stable CV disease on optimal medical therapy, elevated Lp-PLA₂ was associated with higher CV events; however, addition of ERN mitigates this effect. This association in the placebo group was attenuated after multivariable adjustment, which suggests that Lp-PLA₂ does not improve risk assessment beyond traditional risk factors.

Keywords

extended-release niacin high density lipoprotein cardiovascular disease atherogenic dyslipidemia

Introduction

Lipoprotein-associated phospholipase A₂ (Lp-PLA₂) is a known inflammatory marker that has been associated with the presence of vulnerable plaque and increased risk of cardiovascular (CV) events.¹ The Lp-PLA₂ is an enzyme produced by macrophages and lymphocytes, which hydrolyzes oxidized phospholipids in low-density lipoprotein cholesterol (LDL-C), leading to the generation of lysophosphatidylcholine and oxidized non-esterified fatty acids² These particles play an important pathogenetic role in both plaque inflammation and vulnerability, causing expansion of the necrotic core and thinning of the fibrous cap that may make such plaques prone to rupture.^3
-5

A number of epidemiologic and observational studies have shown an association between elevated levels of Lp-PLA₂ activity and CV events.^6

-14 In addition, several meta-analyses have found a positive correlation between Lp-PLA₂ and CV risk.^1,15,16 These findings resulted in a recommendation from an expert panel of lipid specialists to consider Lp-PLA2 testing in initial clinical assessment of patients with coronary heart disease (CHD), but did not recommend it for on-treatment management decisions.¹⁷

Preclinical studies with the Lp-PLA₂ inhibitor darapladib demonstrated that it prevented necrotic core expansion and, thus, decreased plaque vulnerability to rupture,¹⁸ as well decreasing plasma interleukin-6 and high sensitivity C-reactive protein levels, which suggest a possible reduction in inflammatory burden.¹⁹ However, these positive effects with darapladib in preliminary studies did not translate into significant beneficial clinical outcomes in 2 randomized clinical trials, Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy (STABILITY) and Stabilization of Plaques Using Darapladib-Thrombolysis in Myocardila Infarction (SOLID-TIMI 52).^20,21

As Lp-PLA₂ circulates attached to lipoproteins, mainly LDL-C, it remains unclear if the attenuation of Lp-PLA₂ activity with lipid lowering medications (principally statins) is associated with improved clinical outcomes, independent of the change in total cholesterol, triglycerides (TG), LDL-C, or high-density lipoprotein cholesterol (HDL-C). It is unclear if niacin can affect Lp-PLA₂ activity levels.

The purpose of this study was to evaluate the effect of adding extended-release niacin (ERN) versus placebo on a background of simvastatin therapy, with or without additional ezetimibe, on Lp-PLA₂ activity among patients with established atherosclerotic CV disease in the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High triglycerides and Impact on Global Health Outcomes (AIM-HIGH) trial. We further sought to assess the correlation between Lp-PLA₂ activity levels and clinical outcomes in ERN versus placebo groups.

Methods

Study Population and Trial Design

This is a post hoc substudy of the AIM-HIGH trial, which was a prospective, randomized, placebo-controlled clinical trial sponsored by the National Heart, Lung, and Blood Institute (NHLBI) and supported in part by research grant from AbbVie Pharmaceuticals. Details of the rationale, design, and inclusion/exclusion criteria for AIM-HIGH have been published previously.²² Eligible participants with established CV disease and evidence of atherogenic dyslipidemia and who could tolerate at least 1500 mg of ERN per day during a 4 to 8 week open label run-in period were then randomly assigned, in a 1:1 ratio, to ERN or matching placebo. All participants received simvastatin, with the possible addition of ezetimibe, in order to maintain an on-treatment LDL-C between 40 mg/dL and 80 mg/dL.

The primary end point was the composite of the time to first event for death from CHD, nonfatal myocardial infarction (MI), ischemic stroke, hospitalization for acute coronary syndrome (ACS), or symptom-driven coronary or cerebral revascularization. Upon the recommendation of the independent Data and Safety Monitoring Board, the NHLBI decided to stop the trial prematurely after mean follow up period of 3 years, based on convincing evidence of a lack of benefit of ERN on the primary outcome.²³

Laboratory Measurements and Stratification

The Lp-PLA₂ activity was measured at baseline and 1 year after enrollment. Lipid profiles were measured at baseline, and for Lp-PLA₂ activity levels, groups were stratified into quartiles (Q). For baseline Lp-PLA₂ activity, quartiles of measurements of all participants were as follows: Q1 < 154.2 nmol/min/mL, Q2: 154.2-179.3 nmol/min/mL, Q3: 179.3-208.1 nmol/min/mL, Q4 > 208.1 nmol/min/mL. For Lp-PLA₂ activity at year 1, quartiles of measurements of all participants were: Q1 < 143.2 nmol/min/mL, Q2: 143.2-167.95 nmol/min/mL, Q3: 167.95-195 nmol/min/mL, Q4 > 195 nmol/min/mL. Laboratory analyses were performed by Northwest Lipid Metabolism and Diabetes Research Laboratories at the University of Washington, a central core laboratory. Diadexus (Poway, California) provided the laboratory kits for analysis of Lp-PLA₂.

Statistical Analyses

Statistical analyses were performed at the Data Coordinating Center (Axio Research, LLC; Seattle, Washington). Only patients who were on statins prior to randomization were included in this analysis. The effect of statin plus placebo versus statin plus ERN on the activity of Lp-PLA₂ was evaluated by linear regression analysis, ANCOVA. The relationship of baseline Lp-PLA₂ activity on the primary end point was analyzed using Kaplan-Meier curves comparing 4-year survival rates among quartiles of baseline Lp-PLA₂ activity independently in both control and ERN groups. The effect of baseline Lp-PLA₂ activity on the primary end point was also estimated using a multivariable Cox proportional hazard model in each treatment arm, adjusted for the presence of diabetes mellitus, sex, baseline LDL-C, HDL-C, and TG. For all analyses a 2-sided P value <.05 was considered significant. All statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC)

Results

Baseline Characteristics by Treatment Group

Among 3414 participants enrolled in the AIM-HIGH trial, a total of 3196 (94%) were receiving statin therapy at study entry, of whom 1601 were assigned to the control (statin plus placebo) group and 1595 to the intervention (statin plus ERN) group.²³ The baseline characteristics were well-balanced between ERN and placebo treatment groups, as published previously.²³ The baseline lipid profile was comparable between groups, with a mean LDL-C of 71 mg/dL, TG of 179 mg/dL, HDL-C of 35 mg/dL, and non-HDL-C of 107 mg/dL. In addition, the mean baseline Lp-PLA₂ activity levels in both groups were Identical (183 nmol/min/mL).

Baseline Characteristics by Quartile of Lp-PLA₂ Activity

Baseline Lp-PLA₂ activity was measured in 3088 (90%) AIM-HIGH participants. Baseline characteristics of participants, divided by Lp-PLA₂ activity quartiles, showed similar distribution by age, but there were some notable differences among the 4 groups (Table 1). There was a higher proportion of women in the lowest quartile (30% in Q1), which gradually decreased with each higher quartile (14% in Q2, 9% in Q3, and 6% in the Q4, P < .001) of LpPLA₂ activity. The highest proportion of Caucasian participants was in the Q4 LpPLA₂ quartile, whereas Asian, African-Americans, and Hispanics had higher percentages in the lowest LpPLA₂ quartile. The proportion of patients with diabetes mellitus was highest in the lowest quartile of Lp-PLA₂ activity (44.6% in Q1, 26.3% in Q4, P < .001). There was no significant difference in Lp-PLA₂ quartile distribution in patients with or without metabolic syndrome, history of prior MI, percutaneous coronary intervention, stroke or cerebrovascular disease, or peripheral arterial disease. Among patients with coronary artery bypass grafting, there was a higher proportion in higher quartiles of LpPLA₂ activity. There was no significant difference based on statin therapy duration between quartiles of Lp-PLA₂ activity. The proportion that used ezetimibe was higher in Q1 of Lp-PLA₂ activity. Mean LDL-C, TG, and non-HDL cholesterol levels were higher with increasing Lp-PLA₂ quartile. HDL-C and HDL2-C levels were highest in Q1 and lowest in Q4.

Table 1.

Baseline Characteristics by Quartile of Baseline LpPLA2 Activity Level.

		Q1, N = 773	Q2, N = 771	Q3, N = 772	Q4, N = 772	P Value
Age	N	773	771	772	772	.443
	Mean (SD)	64.2 (8.5)	63.5 (8.7)	63.7 (8.8)	64.0 (8.9)
	Median	64.0	64.0	64.0	64.0
	25, 75%tile	58.0, 70.0	57.0, 70.0	58.0, 70.0	58.0, 71.0
	Age <65	399 (51.6%)	415 (53.8%)	415 (53.8%)	408 (52.8%)	.804
	Age ≥65	374 (48.4%)	356 (46.2%)	357 (46.2%)	364 (47.2%)
Gender	Female	235 (30.4%)	110 (14.3%)	70 (9.1%)	44 (5.7%)	<.001
	Male	538 (69.6%)	661 (85.7%)	702 (90.9%)	728 (94.3%)
Race	American Indian/Alaska Native/Aboriginal Canadian	4 (0.5%)	3 (0.4%)	7 (0.9%)	7 (0.9%)	<.001
	Asian	20 (2.6%)	7 (0.9%)	9 (1.2%)	4 (0.5%)
	Black/African American	49 (6.3%)	25 (3.2%)	12 (1.6%)	13 (1.7%)
	Native Hawaiian or other Pacific Islander	3 (0.4%)	3 (0.4%)	3 (0.4%)	3 (0.4%)
	White	674 (87.2%)	721 (93.5%)	722 (93.5%)	734 (95.1%)
	Mutiracial or other	23 (3.0%)	12 (1.6%)	19 (2.5%)	11 (1.4%)
Ethnicity	Not Hispanic or Latino	722 (93.4%)	753 (97.7%)	741 (96.0%)	747 (96.8%)	<.001
	Hispanic or Latino	51 (6.6%)	17 (2.2%)	31 (4.0%)	25 (3.2%)
BMI	N	772	768	772	772
	Mean (SD)	31.7 (5.7)	31.3 (5.5)	31.0 (5.3)	30.8 (5.0)
	Median	31.0	30.0	30.0	30.0
	25, 75%tile	28.0, 35.0	27.0, 34.0	27.0, 34.0	27.0, 34.0
Risk factors
History of diabetes		345 (44.6%)	278 (36.1%)	241 (31.2%)	203 (26.3%)	<.001
Metabolic syndrome	3 criteria	148 (19.1%)	161 (20.9%)	157 (20.3%)	149 (19.3%)	.345
	4 criteria	624 (80.7%)	608 (78.9%)	610 (79.0%)	621 (80.4%)
	5 criteria	0 (0.0%)	2 (0.3%)	5 (0.6%)	2 (0.3%)
Concomitant medications
Receiving statin at entry		773 (100.0%)	771 (100.0%)	772 (100.0%)	772 (100.0%)
Statin duration	Not reported	26 (3.4%)	28 (3.6%)	25 (3.2%)	25 (3.2%)	.406
	<1 year	97 (12.5%)	93 (12.1%)	89 (11.5%)	80 (10.4%)
	1 to 5 years	310 (40.1%)	278 (36.1%)	308 (39.9%)	268 (34.7%)
	>5 years	298 (38.6%)	328 (42.5%)	314 (40.7%)	340 (44.0%)
History of hypertension		570 (73.7%)	540 (70.0%)	538 (69.7%)	553 (71.6%)	.277
Presenting history or diagnosis
History of MI		431 (55.8%)	427 (55.4%)	467 (60.5%)	444 (57.5%)	.162
CABG		259 (33.5%)	263 (34.1%)	277 (35.9%)	329 (42.6%)	<.001
PCI		488 (63.1%)	497 (64.5%)	485 (62.8%)	448 (58.0%)	.051
Stroke or cerebrovascular disease		166 (21.5%)	150 (19.5%)	169 (21.9%)	173 (22.4%)	.511
PVD		117 (15.1%)	87 (11.3%)	87 (11.3%)	110 (14.2%)	.041
Use of niacin within the past month		119 (15.4%)	162 (21.0%)	143 (18.5%)	166 (21.5%)	.008
Use of bile acid sequestrants within the past month		2 (0.3%)	5 (0.6%)	4 (0.5%)	2 (0.3%)	.553
Use of nicotinic acid other than niacin within the past month		4 (0.5%)	3 (0.4%)	3 (0.4%)	4 (0.5%)	.963
Use of fibric acids within the past month		3 (0.4%)	4 (0.5%)	3 (0.4%)	1 (0.1%)	.629
Use of cholesterol absorption inhibitors within the past month		50 (6.5%)	41 (5.3%)	24 (3.1%)	16 (2.1%)	<.001
Use of other lipid modifying agents within the past month		19 (2.5%)	9 (1.2%)	14 (1.8%)	8 (1.0%)	.101
Baseline lipid profile
LDL-C (mg/dL)	N	773	771	772	772	<.001
	Mean (SD)	61.6 (17.1)	69.1 (16.6)	73.7 (16.9)	79.8 (16.7)
	Median	61.0	69.0	74.0	80.0
	25, 75%tile	49.0, 73.0	58.0, 81.0	62.0, 85.0	70.0, 91.0
Triglycerides (mg/dL)	N	773	771	772	772	<.001
	Mean (SD)	172 (63.2)	179 (65.7)	182 (64.3)	187 (68.7)
	Median	154	160	167	167
	25, 75%tile	126, 200	130, 209	131, 218	131, 226
Non-HDL cholestrol (mg/dL)	N	773	771	772	772	<.001
	Mean (SD)	95.8 (20.2)	105 (19.1)	110 (19.6)	117 (19.6)
	Median	94.0	104	108	116
	25, 75%tile	82.0, 108	92.0, 116	97.0, 122	104, 131
HDL-C (mg/dL)	N	773	771	772	772	<.001
	Mean (SD)	36.7 (6.2)	35.2 (5.5)	34.3 (5.3)	33.4 (4.9)
	Median	37.0	36.0	35.0	33.0
	25, 75%tile	33.0, 41.0	32.0, 39.0	31.0, 38.0	30.0, 37.0
LpPLA2 Activity
LpPLA2 activity at baseline (nmol/min/mL)	N	773	771	772	772	<.001
	Mean (SD)	132 (18.1)	167 (7.20)	193 (8.33)	240 (33.1)
	Median	136	168	192	230
	25, 75%tile	122, 146	161, 173	186, 200	218, 249
LpPLA2 activity at year 1 (nmol/min/mL)	N	658	670	666	652	<.001
	Mean (SD)	135 (28.1)	162 (26.9)	178 (28.2)	208 (40.4)
	Median	134	161	176	204
	25, 75%tile	117, 151	143, 179	159, 195	183, 229
Absolute change in LpPLA2 activity from baseline to year 1 (nmol/min/mL)	N	658	670	666	652	<.001
	Mean (SD)	2.83 (26.1)	−5.6 (26.4)	−15 (27.3)	−31 (35.9)
	Median	1.35	−6.9	−17	−31
	25, 75%tile	−15, 16.0	−24, 10.7	−33, 1.30	−55, −11
Percent change in LpPLA2 activity from baseline to year 1 (%)	N	658	670	666	652	<.001
	Mean (SD)	4.67 (61.1)	−3.3 (15.7)	−8.0 (14.1)	−13 (14.1)
	Median	1.01	−4.0	−8.6	−13
	25, 75%tile	−11, 12.1	−14, 6.48	−17, 0.63	−23, −4.7

Abbreviations: BMI, body mass index; ERN, extended-release niacin; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; LpPLA2, lipoprotein-associated phospholipase A₂; MI, myocardial infarction; CABG, coronary artery bypass graft surgery; PCI, percutaneous coronary intervention; PVD, peripheral vascular disease.

Effect of Treatment Group Assignment on Lp-PLA₂ Activity

Among participants who had Lp-PLA₂ activity levels measured at both baseline and 1 year (1338 in the placebo group and 1308 in the ERN group), the effect of blinded treatment on Lp-PLA₂ activity levels was more pronounced in the ERN group, where a significant decrease in Lp-PLA₂ activity was observed, as compared with the placebo-treated patients, with an average absolute change of −18 nmol/min/mL versus −6.4 nmol/min/mL, and mean percent changes of −8.9% versus −0.84%, respectively, P < .001 (Table 2). This differential ERN treatment effect on Lp-PLA₂ remained significant after adjusting for diabetes mellitus, sex, change in baseline to year 1 LDL-C and baseline Lp-PLA₂ activity, −20.44 nmol/min/mL for ERN group versus −11.43 nmol/min/mL for placebo, P < .001.

Table 2.

LpPLA2 Activity by Randomized Treatment Group

		Placebo, n = 1601	ERN, n = 1595	Overall, N = 3196	P Value
Baseline LpPLA2 activity (nmol/min/mL)	N	1556	1532	3088	.750
	Mean (SD)	183 (45.6)	183 (42.0)	183 (43.9)
	Median	179	179	179
	25, 75%tile	154, 208	154, 208	154, 208
Year 1 LpPLA2 activity (nmol/min/mL)	N	1340	1310	2650	<.001
	Mean (SD)	176 (41.0)	165 (40.2)	171 (41.0)
	Median	173	162	167
	25, 75%tile	148, 200	137, 187	143, 194
Absolute change in LpPLA2 activity from baseline (nmol/min/mL)	N	1338	1308	2646	<.001
	Mean (SD)	−6.4 (31.1)	−18 (31.4)	−12 (31.8)
	Median	−5.0	−18	−12
	25, 75%tile	−24, 11.6	−38, 1.30	−31, 7.50
Percent change in LpPLA2 activity from baseline (%)	N	1338	1308	2646	<.001
	Mean (SD)	−.84 (44.0)	−8.9 (16.7)	−4.8 (33.6)
	Median	−2.9	−11	−6.8
	25, 75%tile	−13, 7.63	−20, 0.82	−17, 4.61

Abbreviations: ERN, extended-release niacin; LpPLA2, lipoprotein-associated phospholipase A₂.

Relationship Between Baseline Lp-PLA₂ Activity and the Primary End point

In the placebo group, the highest Lp-PLA₂ quartile had a statistically significantly lower 4-year event-free survival probability as compared to the combined 3 lower quartiles, log-rank P = .032. By contrast, for the ERN group, the event rate in the highest Lp-PLA₂ quartile was not significantly different from that in the combined 3 lower quartiles, log rank P = .718. (Figures 1 and 2) The primary end point event rates by Lp-PLA₂ actvity level quartiles are depicted in Table 3.

Figure 1.

Time to primary end point comparing highest quartile of baseline Lp-PLA₂ activity to lower three quartiles (statin + placebo). Kaplan-Meier curves depicting time to primary end point between the highest quartile (Q4) of Lp-PLA₂ activity and lower quartiles (Q1-Q3) in participants assigned to placebo group. Q1 indicates lowest LpPLA₂ activity quartile; Q4, highest Lp-PLA₂ activity quartile.

Figure 2.

Time to primary end point comparing highest quartile of baseline Lp-PLA₂ activity to lower three quartiles (statin + ERN). Kaplan-Meier curves depicting time to primary end point between the highest quartile (Q4) of Lp-PLA₂ activity and lower quartiles (Q1-Q3) in participants assigned to extended-release niacin (ERN). Q1 indicates lowest LpPLA₂ activity quartil; Q4, highest Lp-PLA₂ activity quartile.

Table 3.

End Points by Quartile of LpPLA2 Activity Level.

		Q1, N = 773	Q2, N = 771	Q3, N = 772	Q4, N = 772	P Value
Number of primary end point events	Overall	107 (13.8%)	127 (16.5%)	128 (16.6%)	146 (18.9%)	.065
	Placebo	53 (6.9%)	54 (7.0%)	66 (8.5%)	79 (10.2%)	.044
	ERN	54 (7.0%)	73 (9.5%)	62 (8.0%)	67 (8.7%)	.385

Abbreviation: ERN, extended-release niacin.

To further evaluate the association between Lp-PLA₂ activity level and the risk of developing an event, the hazard ratio (HR) for events among Lp-PLA₂ activity level quartiles was computed separately in the placebo and ERN groups. In the placebo group, there was a higher event rate in the highest Lp-PLA₂ quartile compared to the lower 3 quartiles in unadjusted analysis, (HR 1.34, 95% confidence interval [CI] 1.02-1.74, P = .033), which became non-significant on multivariable analysis (HR 1.26, 95% CI 0.94-1.68, P = .119). There was no significant difference in outcomes between the highest and lower 3 Lp-PLA₂ activity quartiles in the ERN group (unadjusted HR 1.05, 95% CI 0.8-1.39, P = .718; adjusted HR 1.05, 95% CI 0.78-1.42, P = .736).

Discussion

Our study revealed a number of important findings. The analysis of baseline characteristics demonstrated that female sex and the presence of diabetes mellitus were associated with lower Lp-PLA₂ activity levels. Race distribution was skewed with the highest proportion of Caucasians in the highest Lp-PLA₂ activity quartile. The addition of ERN to statin therapy resulted in a significantly greater decrease in Lp-PLA₂ activity from the baseline value to one year, almost a 3-fold greater absolute change compared to statin only therapy (18 nmol/min/mL versus −6.4 nmol/min/mL). In the placebo group, event-free survival was the lowest in the quartile with the highest Lp-PLA₂ activity compared to the other 3 quartiles. By contrast, within the ERN-treated group, there was no significant difference in event-free survival between Lp-PLA₂ activity quartiles. Similarly, the highest Lp-PLA₂ quartile in the placebo group had a higher risk for the composite primary end point than the other 3 quartiles, on univariate analysis (HR 1.34, P = .033), but not on multivariable analysis (HR 1.26, P = .119). There was no significant difference in outcomes between the Q4 Lp-PLA₂ activity versus Q1-3 in the ERN group on both univariate and multivariable analysis (unadjusted HR 1.05, P = .718, adjusted HR 1.05, P = .736).

We observed a prominent decrease in Lp-PLA₂ activity of about 9% with the addition of ERN to statin therapy. Kuvin et al have previously reported a 20% reduction of Lp-PLA₂ levels with the addition of niacin to medical therapy, which included statins, in patients with coronary heart disease followed for 3 months (28). The authors, however, did not specify whether mass or activity of Lp-PLA₂ was measured. It is unclear whether ERN causes an additional decrease of the Lp-PLA₂ amount (ie, concentration) or a decrease in its function (ie, activity), or possibly both. Ganji et al demonstrated inhibition of vascular oxidative stress and reduction of LDL-C oxidation by 60% with niacin in cultured aortic endothelial cells.²⁴ In addition, HDL-C has been shown to decrease oxidation of lipoproteins.²⁵ Overall, the AIM-HIGH trial demonstrated a significant 25% increase in HDL-C in the ERN group at 1 year of treatment versus placebo.²³ These observations suggest that niacin decreases oxidized lipoproteins, the main substrate for Lp-PLA₂, which may explain the observed reduction of Lp-PLA₂ activity by ERN.

Our analysis demonstrated that, in the statin only group, there was significantly lower event-free survival in the quartile with the highest Lp-PLA₂ activity as compared with the other quartiles, a novel finding. Treatment with statins still leaves a significant proportion of patients vulnerable to recurrent CV events despite a reduction of LDL-C to optimal levels (ie, <70 mg/dL), as shown in the AIM-HIGH trial, where the event rate over 36 months follow-up was 16%.²³ Identifying patients with elevated Lp-PLA₂ in the setting of optimal LDL-C levels can be potentially an important tool to identify those patients at higher residual risk for CV events who may require additional therapeutic agents that can potentially further reduce this risk.

We observed that in the ERN group, the Kaplan-Meier curves for event free survival in all Lp-PLA₂ quartiles did not separate significantly. Possibly, the presence of high Lp-PLA₂ activity levels identifies a higher risk subgroup that may benefit from ERN. It is interesting to note that the Q4 subgroup for Lp-PLA₂ activity had the lowest mean HDL-C (33 mg/dL), and the highest mean TG (186 mg/dL). As described previously, participants with both very low HDL-C (<32 mg/dL) and high TG (>200 mg/dL) levels, showed incremental benefit with ERN.²⁶ Whether Lp-PLA₂ could be a supplementary marker to high TG/low HDL-C combination to identify patients who may benefit with ERN is uncertain.

Recent trials with Lp-PLA₂ inhibitors have not shown event reduction although these trials did not preselect patients with high Lp-PLA₂ activity.^20,21 This could be the potential reason why those trials did not show clinical benefit. The subgroup analysis in SOLID-TIMI 52 trial did not show any difference in outcomes between tertiles of Lp-PLA₂ activity.²¹ Unlike our patient population with stable CHD, the SOLID-TIMI 52 trial investigated patients within 30 days of ACS. As previously reported by Khuseyinova et al, Lp-PLA₂ levels are suppressed after ACS and do not return to baseline for up to 3 months, a possible explanation for the lack of difference in outcomes between the Lp-PLA₂ groups.²⁷

Analysis of baseline characteristics has shown an interesting and counter-intuitive observation, namely that the presence of diabetes mellitus was associated with lower Lp-PLA₂ activity levels. By contrast, the prior study of patients with newly-diagnosed diabetes mellitus without a history of CV disease demonstrated higher levels of Lp-PLA₂ activity compared to healthy controls.²⁸ The potential explanation of the difference in findings could be due to dissimilarity between cohorts, as our study includes participants with atherosclerotic CV disease who were treated with statins while the former studied patients with newly diagnosed diabetes before initiation of any therapy. Further prospective studies would be helpful to better clarify the association of Lp-PLA₂ activity levels with diabetes.

Prior Consensus Panel recommendations stated that very-high-risk patients already on statins with LDL-C levels at goal, but with an elevated Lp-PLA₂ level >200 ng/mL, should be considered for combination dyslipidemic therapies that modify HDL-C and TG.¹ However, an expert panel of lipid specialists did not recommend measurement of Lp-PLA₂ for on-treatment risk management decisions in those with CVD.¹⁷ As well, recommendations to include Lp-PLA₂ in formulating treatment decisions were not incorporated into the latest guidelines on lipid management.²⁹ A prospective clinical trial to assess the effect of the addition of ERN to guideline-directed medical therapy in patients with CHD and very high levels of Lp-PLA₂ may be warranted.

Limitations

This is a post hoc analysis, which has inherent limitations. A number of participants from the AIM-HIGH cohort were excluded from the analysis as not all the participants had LpPLA₂ activity measured at baseline and, of those participants with baseline measurements, not all patients had LpPLA₂ activity levels measured at 1 year. Additionally, the present analysis represents a patient population with CHD, low HDL-C, and elevated TG, so our findings may not be generalizable to patients who have CHD without atherogenic dyslipidemia.

Conclusion

In AIM-HIGH participants, all of whom had atherosclerotic CV disease and atherogenic dyslipidemia, the addition of ERN to statin therapy resulted in a significant decrease in LpPLA₂ activity levels. Elevated Lp-PLA₂ activity in statin-treated individuals with CV disease who were not receiving ERN was associated with worse CV outcomes compared to those with lower Lp-PLA₂ activity. However, the addition of ERN appeared to mitigate the difference in CV events between the high and low Lp-PLA₂ activity groups. These findings in the placebo group were attenuated with multivariable adjustment, which suggests that Lp-PLA₂ does not improve risk assessment beyond the traditional risk factors.

Footnotes

Author Contributions

Dr Lyubarova, as first author, drafted and revised the manuscript and led the effort in these analyses. Ms Yao was the lead statistician for the manuscript, assisted by Ms McBride, Co-Director for the Data Coordinating Center for AIM-HIGH. Drs Fleg and Desvigne-Nickens were project officers from NHLBI for AIM-HIGH, members of the Executive Committee and provided scientific input to the manuscript. Drs Albers, Marcovina, Topliceanu, Anderson, Kashyap, McGovern, and Fleg provided scientific input on the content of the manuscript, reviewed and provided suggested revisions to the approach for the analyses. Dr Boden and Ms McBride assisted Dr Lyubarova in writing and revising the manuscript. The manuscript was reviewed and approved by each of the co-authors and by the AIM-HIGH Publications Committee. The content of this manuscript is solely the responsibility of the authors and does not necessarily reflect the views of the National Heart, Lung, and Blood Institute, National Institutes of Health, or the United States Department of Health and Human Services.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: AIM-HIGH was supported by the National Heart, Lung, and Blood Institute (U01 HL081616 and U01HL081649) and by an unrestricted grant from AbbVie, Inc. AbbVie donated the extended-release niacin,the matching placebo, and the ezetimibe; Merck donated the simvastatin. Diadexus provided thelaboratory kits for analysis of Lp-PLA₂. Neither of these companies had any role in the oversight ordesign of the study or in the analysis or interpretation of the data.

ORCID iD

Radmila Lyubarova

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Effects of Extended-Release Niacin on Quartile Lp-PLA 2 Levels and Clinical Outcomes in Statin-treated Patients with Established Cardiovascular Disease and Low Baseline Levels of HDL-Cholesterol: Post Hoc Analysis of the AIM HIGH Trial

Abstract

Background:

Objective:

Methods:

Results:

Conclusion:

Keywords

Introduction

Methods

Study Population and Trial Design

Laboratory Measurements and Stratification

Statistical Analyses

Results

Baseline Characteristics by Treatment Group

Baseline Characteristics by Quartile of Lp-PLA2 Activity

Effect of Treatment Group Assignment on Lp-PLA2 Activity

Relationship Between Baseline Lp-PLA2 Activity and the Primary End point

Discussion

Limitations

Conclusion

Footnotes

Author Contributions

Declaration of Conflicting Interests

Funding

ORCID iD

References

Baseline Characteristics by Quartile of Lp-PLA₂ Activity

Effect of Treatment Group Assignment on Lp-PLA₂ Activity

Relationship Between Baseline Lp-PLA₂ Activity and the Primary End point