Correlation of Non–High-Density Lipoprotein Cholesterol and Low-Density Lipoprotein Cholesterol With Apolipoprotein B During Simvastatin + Fenofibrate Therapy in Patients With Combined Hyperlipidemia (A Subanalysis of the SAFARI Trial)

Article Outline

• Abstract
• Methods
• Results
• Discussion
• Acknowledgment
• References
• Copyright

Guidelines have recommended non–high-density lipoprotein (non-HDL) cholesterol as a secondary target for therapy after the low-density lipoprotein (LDL) cholesterol goals have been met in patients with hypertriglyceridemia; non-HDL cholesterol is viewed as a surrogate for apolipoprotein (Apo)B, an alternate end point of treatment. The present analysis of the previously reported Simvastatin plus Fenofibrate for Combined Hyperlipidemia (SAFARI) trial assessed the associations of non-HDL cholesterol and LDL cholesterol with ApoB levels in patients with combined hyperlipidemia treated with combination simvastatin (20 mg) and fenofibrate (160 mg) or simvastatin monotherapy (20 mg). The correlations of these factors were analyzed in the overall modified intent-to-treat population (n = 594) and in patient subgroups stratified by triglyceride (TG) tertiles. Simvastatin plus fenofibrate and simvastatin alone significantly reduced LDL cholesterol, TG, non-HDL cholesterol and ApoB levels and non-HDL cholesterol/ApoB ratio (p ≤0.0004), regardless of the TG level. The greatest reductions occurred with combination treatment. The baseline levels of non-HDL cholesterol and LDL cholesterol correlated highly with ApoB and were stronger in the lower TG tertiles than in the higher TG tertiles. After 12 weeks, the correlations had changed little with simvastatin monotherapy but had increased substantially with combination therapy and were most improved at high TG levels. In conclusion, these results suggest that both non-HDL cholesterol and ApoB provide similar information in relation to treatment response in patients with combined hyperlipidemia and hypertriglyceridemia, and that non-HDL cholesterol is a good indicator of ApoB-containing lipoproteins, supporting its recommended use as a secondary therapeutic target in these patients.

Patients with high-risk coronary heart disease such as those with combined hyperlipidemia have elevated triglyceride (TG) and apolipoprotein (Apo)B-containing lipoprotein levels, including TG-rich lipoproteins (e.g., very-low-density lipoprotein, intermediate-density lipoprotein) and remnant lipoproteins. These lipoproteins confer additional atherogenic risk beyond that of low-density lipoprotein (LDL) cholesterol.¹, ², ³, ⁴, ⁵, ⁶, ⁷ In addition to LDL cholesterol, non–high-density lipoprotein (HDL) cholesterol and ApoB might be appropriate factors for guiding therapy in these patients.¹, ², ³, ⁸ Non-HDL cholesterol, the sum of cholesterol carried by very-low-density lipoprotein plus intermediate-density lipoprotein plus LDL, and ApoB, a measure of the number of atherogenic lipoprotein particles, are viewed as stronger predictors of coronary heart disease than LDL cholesterol in patients with hypertriglyceridemia.⁹, ¹⁰, ¹¹, ¹², ¹³, ¹⁴, ¹⁵, ¹⁶, ¹⁷, ¹⁸ Guidelines have recommended non-HDL cholesterol as a secondary target for therapy and ApoB as an alternative secondary goal in patients with elevated TGs ≥200 mg/dl.¹, ², ³, ⁴, ⁸ Among patients with metabolic risk, LDL cholesterol, non-HDL cholesterol, and ApoB have been suggested for assessment of those at high coronary heart disease risk.³ Baseline and on-treatment levels of non-HDL cholesterol and ApoB have been shown to correlate relatively strongly, although these associations have varied in the different populations studied.¹⁶, ¹⁷, ¹⁸, ¹⁹, ²⁰, ²¹ Non-HDL cholesterol can be readily calculated from a routine lipoprotein profile and has been proposed as a surrogate for ApoB measurement, which lags behind in standardization for risk assessments.⁷, ²² Thus, it is important to establish the relation of these factors during lipid therapy. The present post hoc analysis assessed the relation of non-HDL cholesterol and LDL cholesterol with ApoB levels in patients with combined hyperlipidemia who were treated with simvastatin plus fenofibrate combination therapy or simvastatin monotherapy in the previously reported SAFARI trial.²³

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Methods 

This was a post hoc analysis of data obtained from the previously reported SAFARI study of patients (21 to 68 years old) with combined hyperlipidemia, defined as a fasting TG level of ≥150 but ≤500 mg/dl and an LDL cholesterol level of >130 mg/dl.²³ Eligible patients received 12 weeks of daily treatment with either simvastatin (20 mg) and fenofibrate (160 mg) or simvastatin 20 mg and placebo to match the fenofibrate. Randomization was stratified by baseline TG level (≥150 to <300 and ≥300 to ≤500 mg/dl), and HDL cholesterol level (men: <40 or ≥40 mg/dl; women: <50 or ≥50 mg/dl). As previously described,²³ the primary efficacy end point was the percentage of change from baseline in the fasting TG level, and the secondary efficacy measures included the percentage of change from baseline for total cholesterol, LDL cholesterol, HDL cholesterol, non-HDL cholesterol, and ApoB after 12 weeks of treatment.

Fasting plasma samples were analyzed by the Medical Research Laboratories International (Highland Heights, Kentucky), a National Heart, Lung, and Blood Institute and Centers for Disease Control-certified laboratory. Total cholesterol and TG levels were quantified using the cholesterol oxidase assay and glycerokinase enzymatic assay, respectively, on Hitachi 747 analyzers (Roche Diagnostics, Indianapolis, Indiana). HDL cholesterol was quantified using the cholesterol oxidase colorimetric assay of the supernatant from the precipitation of non-HDL lipoproteins with heparin and manganese chloride. LDL cholesterol levels were calculated using the Friedewald equation (LDL cholesterol = total cholesterol − [HDL cholesterol + TG/5]) for patients with TGs <400 mg/dl. Direct LDL cholesterol measurements were used for patients with TGs ≥400 mg/dl. Plasma ApoB was measured using fixed-rate immunonephelometry.²⁴, ²⁵

Efficacy was assessed in the modified intent-to-treat (mITT) population, which included all randomized and treated patients with a baseline and ≥1 valid on-treatment measurement, as previously described.²³ A nonparametric analysis of variance model that included terms for treatment, baseline TG level, and baseline HDL cholesterol level was used to compare the treatment effect on the percentage of change from baseline to week 12 in TGs. The p value was based on the nonparametric results, and the between-treatment difference was estimated on Hodges-Lehmann location shift. The distribution-free 95% confidence interval for the difference was determined using Wilcoxon's rank sum test statistics. For the other efficacy parameters, a parametric analysis of variance model, similar to that described above, was used for treatment comparisons. The p values and 95% confidence intervals for the within- and between-treatment differences were calculated using the model-based least squares means and the associated standard errors. A comparison of the mean values for efficacy parameters between the 2 treatment regimens, monotherapy with simvastatin 20 mg/day versus the combination of simvastatin 20 mg/day plus fenofibrate 160 mg/day, was done nonparametrically, using the Mann-Whitney U test. Descriptive statistics for the baseline and week 12 measurements for TGs, non-HDL cholesterol, and ApoB, and all other lipid parameters are reported as the mean ± SD. Pearson's correlation (r) coefficients were estimated between non-HDL cholesterol and ApoB, and for LDL cholesterol and ApoB for the overall mITT population and the TG subgroups.

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Results 

The efficacy and safety of the combination of simvastatin 20 mg plus fenofibrate 160 mg versus simvastatin 20 mg alone was previously reported for 600 patients with combined hyperlipidemia (mITT population).²³ Of these, 398 patients in the simvastatin plus fenofibrate group (mean age 52.3 ± 8.8 years; body mass index 31.6 ± 6.5 kg/m²) and 196 patients in the simvastatin group (mean age 53.4 ± 8.7 years; body mass index 31.2 ± 6.4 kg/m²) were included in the present analysis of the correlation of non-HDL cholesterol and ApoB and LDL cholesterol and ApoB levels.

The patient baseline characteristics were generally well-balanced among the treatment groups in the mITT population. Approximately 30% of patients had coronary heart disease or coronary heart disease risk equivalents, metabolic syndrome, or categorical obesity (body mass index ≥30 kg/m²) and ∼ 20% had diabetes. The mean baseline levels were 165 mg/dl for LDL cholesterol, 213 mg/dl for non-HDL cholesterol, 166 mg/dl for ApoB, and 252 mg/dl for TGs. The baseline LDL cholesterol, non-HDL cholesterol, ApoB, and TG levels were also comparable across the TG tertiles of patients in both treatment groups (Table 1). With increasing TG tertile, the baseline levels of LDL cholesterol decreased and non-HDL cholesterol and non-HDL cholesterol/ApoB levels increased slightly.

Table 1. Efficacy of therapies on plasma lipids and lipoproteins (modified intent-to-treat [mITT] population)

Parameter	Simvastatin 20 mg (n = 196)⁎		Simvastatin 20 mg Plus Fenofibrate 160 mg (n = 398)†
	Baseline	Treatment	Baseline	Treatment
TGs (mg/dl)	252±89	207±80‡	252±94	142±59‡§
LDL cholesterol (mg/dl)	163±35	121±29‡	166±31	115±27‡§
Non-HDL cholesterol (mg/dl)	213±37	156±34‡	213±35	137±32‡§
ApoB (mg/dl)	165±26	126±25‡	166±26	110±26‡§
Total cholesterol (mg/dl)	256±39	203±36‡	257±36	188±30‡§
HDL cholesterol (mg/dl)	43±9	47±10‡	44±10	51±12‡§
Non-HDL cholesterol/ApoB (ratio)	1.30±0.16	1.25±0.16‡	1.30±0.13	1.20±0.12‡§

Data are presented as mean ± SD.

Treatment with simvastatin monotherapy and combination simvastatin plus fenofibrate for 12 weeks significantly reduced the baseline levels of all parameters assessed in the overall mITT population (Table 1) and in each TG tertile (Table 2; p <0.0001). The overall improvements in TG, LDL cholesterol, non-HDL cholesterol, and ApoB levels were considerably greater with the combination treatment than with the monotherapy in the mITT population and in all TG tertiles. The changes in the non-HDL cholesterol/ApoB ratios were greater with combination treatment than with monotherapy in the mITT population and were similar in the lower TG tertile for both treatments. However, they were lower in the middle tertile and slightly greater in the highest tertile for the combination treatment.

Table 2. Efficacy of therapies on plasma lipids and lipoproteins by TG tertiles

Parameter	Simvastatin 20 mg (n = 189)⁎		Simvastatin 20 mg Plus Fenofibrate 160 mg (n = 388)†
	Baseline	Treatment	Baseline	Treatment
Lowest TG tertile	n = 63		n = 130
TGs (mg/dl)	175±23	167±60‡	163±28	113±39‡
LDL cholesterol (mg/dl)	170±33	117±31‡	168±29	112±26‡
Non-HDL cholesterol (mg/dl)	202±32	146±35‡	197±30	130±31‡
ApoB (mg/dl)	161±24	120±26‡	155±23	104±24‡
Non-HDL cholesterol/ApoB (ratio)	1.26±0.08	1.22±0.10§	1.28±0.10	1.24±0.08‡
Middle TG tertile	n = 63		n = 129
TGs (mg/dl)	231±19	194±59‡	236±21	141±49‡
LDL cholesterol (mg/dl)	167±35	121±29‡	167±31	114±27‡
Non-HDL cholesterol (mg/dl)	210±34	152±31‡	211±32	137±32‡
ApoB (mg/dl)	165±24	125±24‡	165±24	110±25‡
Non-HDL cholesterol/ApoB (ratio)	1.28±0.08	1.22±0.09‡	1.28±0.09	1.25±0.11¶
Highest TG tertile	n = 63		n = 129
TGs (mg/dl)	349±87	260±90‡	353±82	172±68‡
LDL cholesterol (mg/dl)	154±35	124±28‡	162±33	117±27‡
Non-HDL cholesterol (mg/dl)	227±41	170±33‡	231±36	144±33‡
ApoB (mg/dl)	168±28	132±24‡	177±27	117±27‡
Non-HDL cholesterol/ApoB (ratio)	1.36±0.25	1.30±0.25‡	1.32±0.19	1.24±0.11‡

Data are presented as mean ± SD.

With increasing baseline TG levels, the magnitude of the reductions in LDL cholesterol decreased and that of TGs increased with both treatments. At higher TG concentrations, the reductions in non-HDL cholesterol levels decreased slightly after simvastatin and increased slightly with simvastatin plus fenofibrate. The reductions in ApoB were slightly smaller at higher TG levels for simvastatin monotherapy and were generally unchanged for combination therapy at all TG levels. In the higher TG tertiles, reductions in the non-HDL cholesterol/ApoB ratio increased slightly with both treatments compared with changes in the lower tertile.

Across the simvastatin and simvastatin plus fenofibrate treatment groups, the baseline correlations between non-HDL cholesterol and ApoB and those of LDL cholesterol and ApoB in the mITT patients were similar (Figure 1 and Table 3). Individual values were more dispersed for non-HDL cholesterol and ApoB than for LDL cholesterol and ApoB owing to the presence of outlier values corresponding to higher levels of non-HDL cholesterol at baseline relative to ApoB. After 12 weeks of treatment with simvastatin, the correlations between non-HDL cholesterol and ApoB and between LDL cholesterol and ApoB had increased slightly from baseline levels in these patients, with little improvement in the outlier values. In contrast, the correlations and variation in distribution were substantially improved with combination therapy (Figure 1 and Table 3).

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• Figure 1. 

  Correlations between non-HDL cholesterol and ApoB and LDL cholesterol and ApoB in mITT population. Correlations in simvastatin 20-mg treatment group for non-HDL cholesterol and ApoB at baseline (A) and after 12 weeks of treatment (B) and for LDL cholesterol and ApoB at baseline (C) and after 12 weeks of treatment (D). Correlations in simvastatin 20-mg plus fenofibrate 160-mg treatment group for non-HDL cholesterol and ApoB at baseline (E) and after 12 weeks of treatment (F) for LDL cholesterol and ApoB at baseline (G) and after 12 weeks of treatment (H).

Table 3. Baseline and treatment correlations for non–high-density lipoprotein cholesterol and apolipoprotein B and low-density lipoprotein cholesterol and apolipoprotein B by baseline triglyceride tertiles

TG Tertile	Baseline⁎	Treatment⁎
Monotherapy
Non-HDL cholesterol vs. ApoB
Low TG	0.93	0.95
Middle TG	0.93	0.93
High TG	0.69	0.65
LDL cholesterol vs. ApoB
Low TG	0.92	0.91
Middle TG	0.95	0.90
High TG	0.86	0.86
Combination therapy
Non-HDL cholesterol vs. ApoB
Low TG	0.93	0.96
Middle TG	0.91	0.93
High TG	0.69	0.94
LDL cholesterol vs. ApoB
Low TG	0.91	0.95
Middle TG	0.91	0.93
High TG	0.86	0.91

The baseline correlations between non-HDL cholesterol and ApoB and between LDL cholesterol and ApoB were similar in the low and middle TG tertiles and were weaker in the highest TG tertile (Table 3). The lowest correlations were observed for non-HDL cholesterol and ApoB in the highest TG tertile. The data points clustered at greater values with increasing TG tertiles for non-HDL cholesterol and ApoB levels, and the distributions for LDL cholesterol and ApoB levels were generally unchanged in all tertiles (plots not shown). For both the non-HDL cholesterol and LDL cholesterol with ApoB relations, the individual values were more scattered in the highest baseline TG tertile group and the distributions were more linear in the lower TG tertiles (plots not shown).

After 12 weeks of simvastatin treatment, little change was seen in the correlations between non-HDL cholesterol and ApoB and those for LDL cholesterol and ApoB in the low, middle, and high TG tertile groups (Table 3). After 12 weeks of treatment with simvastatin plus fenofibrate, the correlations between non-HDL cholesterol and ApoB and between LDL cholesterol and ApoB had increased, regardless of the baseline TG levels (Table 3), with the greatest improvements in the highest TG tertile, particularly for non-HDL cholesterol and ApoB. Combination therapy reduced the number of outliers, resulting in a more linear distribution of values in all groups and was most evident in the highest TG tertile (Table 3; plots not shown).

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Discussion 

The present analysis has demonstrated associations between non-HDL cholesterol and ApoB, and between LDL cholesterol and ApoB on the basis of TG stratification in patients with combined hyperlipidemia and hypertriglyceridemia, after treatment with simvastatin 20 mg or the combination of simvastatin 20 mg plus fenofibrate 160 mg. In the absence of therapy, the baseline levels of non-HDL cholesterol and LDL cholesterol correlated with ApoB levels; these associations were greatest among patients with lower TG levels. Combination simvastatin plus fenofibrate therapy improved these correlations in all patients, particularly in patients with high TG levels, although little change was observed for simvastatin monotherapy.

The results of the present study have corroborated those of several studies that have demonstrated that non-HDL cholesterol and ApoB levels and LDL cholesterol and ApoB levels are highly correlative, although the TG levels in patients with combined hyperlipidemia and hypertriglyceridemia can affect the concordance of these associations.¹⁷, ¹⁸, ¹⁹, ²⁰, ²¹, ²⁶, ²⁷ In particular, elevated baseline TG concentrations indicative of atherogenic lipoproteins can reduce the strength of these correlations.¹⁹, ²⁰, ²¹, ²⁷ Similarly, in the present study, the baseline correlations of non-HDL cholesterol and LDL cholesterol with ApoB levels were reduced in the highest TG tertile (baseline mean 350 mg/dl), as evidenced by the increased variation and outlier values. This effect, attributed mainly to disproportionately lower levels of LDL cholesterol and elevated levels of non-HDL cholesterol compared with ApoB levels, indicated the presence of complex lipoprotein profiles (e.g., small dense LDL, lipoprotein remnants) in these patients³, ⁴, ⁷ and was most pronounced for the non-HDL cholesterol and ApoB relation at high TG levels. The presence of high levels of large very-low-density lipoprotein particles associated with hypertriglyceridemia in these patients might have resulted in an underestimation of the ApoB lipoprotein levels by the immunonepholometry technique used to measure ApoB in this study,⁶, ²⁸, ²⁹, ³⁰ contributing to the reduced ApoB and non-HDL cholesterol correlation.

Treatment with combination simvastatin plus fenofibrate improved the correlations of non-HDL cholesterol and LDL cholesterol with ApoB levels at all TG levels and was most effective at the highest TG levels, but simvastatin monotherapy had little effect at any TG level. The substantial improvements in correlations with combination therapy may be attributed to the greater reductions in TG, very-low-density lipoprotein cholesterol, and intermediate-density lipoprotein cholesterol levels, and a shift to larger, buoyant, less atherogenic particles achieved by the addition of fenofibrate to simvastatin compared with simvastatin alone, as reported in the original study.²³ A reduction of the complexity of the lipoprotein profile likely led to improvements in the measurement of ApoB lipoprotein particles⁶, ²⁸, ²⁹, ³⁰ and its correlation with non-HDL cholesterol.

Baseline triglyceride concentrations modified the treatment response of LDL cholesterol but had little effect on those of non-HDL cholesterol and ApoB. The magnitude of LDL cholesterol lowering progressively decreased with increasing TG concentrations for both treatments, and reductions from baseline in non-HDL cholesterol and ApoB and the non-HDL cholesterol/ApoB ratio were only slightly modified at greater TG levels. These results are consistent with those of other studies, which showed that a reduction of non-HDL cholesterol by statins is less influenced by the baseline TG levels¹⁹, ²¹ and indicate that non-HDL cholesterol and ApoB measurements could better assess the lipid abnormalities present at greater TG levels than LDL cholesterol, which becomes less accurate as the TG levels increase.², ¹⁹, ²¹

Non-HDL cholesterol and ApoB have been reported to carry as much or more predictive power for cardiovascular events as LDL cholesterol, and it has been suggested that these factors can replace LDL cholesterol as targets of therapy in all persons.⁹, ¹¹, ²⁰, ²², ²⁷ Both are reliable measurements, although limitations exist to the general acceptance and use of ApoB in risk assessment, and thus ApoB has not replaced non-HDL cholesterol in clinical practice.

The marked improvement in non-HDL cholesterol and ApoB correlations after combination therapy that substantially reduced the TG levels and improved the overall lipid profile in this study support that either measure can be used to monitor treatment efficacies in patients with combined hyperlipidemia and hypertriglyceridemia. Although these results support the use of non-HDL cholesterol as an indicator of ApoB-containing atherogenic lipoproteins, the potential future role of ApoB in assessing patients at high coronary heart disease risk should not be excluded. Additional studies are needed to further characterize the importance of non-HDL cholesterol and ApoB in coronary heart disease risk management.

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Acknowledgment 

Merck and Company, Incorporated, Whitehouse Station, New Jersey, facilitated the design and conduct of the study and the collection and analysis of the study data.

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