Niacin Increases Atherogenic Proteins in High-Density Lipoprotein of Statin-Treated Subjects

Abstract

OBJECTIVE: Niacin therapy fails to reduce cardiovascular events in statin-treated subjects even though it increases plasma HDL-C (HDL [high-density lipoprotein] cholesterol) and decreases LDL-C (LDL [low-density lipoprotein] cholesterol) and triglyceride levels. To investigate potential mechanisms for this lack of cardioprotection, we quantified the HDL proteome of subjects in 2 niacin clinical trials: the CPC study (Carotid Plaque Composition) and the HDL Proteomics substudy of the AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides). APPROACH AND RESULTS: Using targeted proteomics, we quantified levels of 31 HDL proteins from 124 CPC subjects and 120 AIM-HIGH subjects. The samples were obtained at baseline and after 1 year of statin monotherapy or niacin-statin combination therapy. Compared with statin monotherapy, niacin-statin combination therapy did not reduce HDL-associated apolipoproteins APOC1, APOC2, APOC3, and APOC4, despite significantly lowering triglycerides. In contrast, niacin markedly elevated HDL-associated PLTP (phospholipid transfer protein), CLU (clusterin), and HP/HPR (haptoglobin/haptoglobinrelated proteins; P≤0.0001 for each) in both the CPC and AIM-HIGH cohorts. CONCLUSIONS: The addition of niacin to statin therapy resulted in elevated levels of multiple HDL proteins linked to increased atherosclerotic risk, which might have compromised the cardioprotective effects associated with higher HDL-C levels and lower levels of LDL-C and triglycerides. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00715273; NCT00880178; NCT00120289.

Keywords: atherosclerosis; cardioprotection; clusterin; high-density lipoprotein metabolism; lipid metabolism.

Figures

Figure 1.

Workflow.

Figure 2.. Effects of lipid-altering therapies on the HDL proteome in the CPC study.

All CPC subjects were off all lipid-lowering drugs when they entered the study. HDL proteins were quantified by parallel reaction monitoring before and after 1 year on statin or niacin-statin therapy. For each protein, the P value from the Wilcoxon signed rank test is plotted against the log2 fold median change between 1-year on therapy and baseline. Proteins overexpressed after 1 year on therapy are displayed to the right of the value 0 on the x-axis, while underexpressed proteins are to the left. After we controlled for multiple comparison testing, only proteins situated above the P value of 0.004 for statin treatment and 0.009 for combination therapy (niacin plus statin) on the y-axis were considered significantly different between 1-year on therapy and baseline. The dashed (red) horizontal line shows the corrected critical P value threshold (P=0.004) for statin treatment. The solid horizontal line shows the corrected overall critical P value threshold (P=0.009) for statin plus niacin treatment. The dotted (black) horizontal line shows the uncorrected overall critical P value of 0.05.

Figure 3.. Changes in HDL protein amounts after 1-year on statin or niacin-statin therapy for CPC study subjects.

The differences in the changes between the therapies were compared using the Wilcoxon rank-sum test. P values were corrected for multiple comparisons using the method of Benjamini and Hochberg. P values of proteins with significant changes between therapies are shown. Proteins with P ≤0.0001 are in bold.

Figure 4.. Effect of niacin therapy on the HDL proteome in the AIM-HIGH study.

All subjects were on statin monotherapy on entry into the study. HDL proteins were quantified by selected reaction monitoring before and after 1 year on statin or niacin-statin therapies. For each protein, the P value from the Wilcoxon signed rank test is plotted against the log2 fold median change between 1-year on therapy and baseline. Proteins overexpressed after one year on therapy are displayed to the right of the value 0 on the x-axis, while underexpressed proteins are to the left. After we controlled for multiple comparison testing, only proteins situated above the P value of 0.004 for statin treatment and 0.009 for combination therapy (niacin plus statin) on the y-axis were considered significantly different between 1-year on therapy and baseline. The dashed (red) horizontal line shows the corrected critical P value threshold (P= 0.008) for statin treatment. The solid horizontal line shows the corrected overall critical P value threshold (P= 0.033) for statin plus niacin treatment. The dotted (black) horizontal line shows the uncorrected overall critical P value of 0.05.

Figure 5.. Changes in HDL protein amounts after 1-year on niacin therapy for AIM-HIGH study subjects.

The differences in change between treatments (maintenance of statin monotherapy or addition of niacin to statin therapy) were compared using the Wilcoxon rank-sum test. P values were corrected for multiple comparisons using the method of Benjamini and Hochberg. P values of proteins with significant changes between therapies are shown. Proteins with P ≤0.0003 are in bold.