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J Am Coll Cardiol, 2007; 49:2003-2009, doi:10.1016/j.jacc.2007.01.083 (Published online 3 May 2007).
© 2007 by the American College of Cardiology Foundation
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CLINICAL RESEARCH: CORONARY ARTERY DISEASE

Low-Density Lipoprotein-Dependent and -Independent Effects of Cholesterol-Lowering Therapies on C-Reactive Protein

A Meta-Analysis

Scott Kinlay, MBBS, PhD, FRACP, FACC*,1

Veteran’s Affairs Boston Healthcare System, West Roxbury Campus, Brigham and Women’s Hospital, and Harvard Medical School, Boston, Massachusetts.

Manuscript received January 19, 2006; revised manuscript received December 19, 2006, accepted January 3, 2007.

* Reprint requests and correspondence: Dr. Scott Kinlay, Cardiovascular Division, VA Boston Healthcare System, 1400 VFW Parkway, West Roxbury, Massachusetts 02132. (Email: skinlay{at}partners.org).


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 Conclusions
 References
 
Objectives: This study sought to assess the contribution of low-density lipoprotein (LDL)–dependent and LDL–independent effects of LDL-lowering therapies to changes in C-reactive protein (CRP) in healthy or stable subjects.

Background: Correlations of change in LDL and CRP in individuals are lowered by their measurement variability. By using average changes in LDL and CRP in study groups, meta-analysis reduces this variability to better assess their correlation.

Methods: A systematic search for randomized placebo-controlled trials reporting change in LDL and CRP with LDL-lowering interventions retrieved 23 studies with 57 groups treated with a variety of statins, nonstatin drugs, or other regimens. Meta-analysis techniques assessed the relationships between average mean differences (placebo – treatment) in change in CRP and LDL.

Results: The overall reduction in CRP was 28% (95% confidence interval 26% to 30%). Significantly greater CRP reduction occurred in statin and statin-ezetimibe interventions, interventions using 80 mg/day of statins, and with greater LDL lowering. Meta-regression analysis showed a strong correlation between the change in LDL and CRP (r = 0.80, p < 0.001). Statin therapies had no significant effect on CRP after adjusting for the change in LDL. In a multivariate model applied to a range of LDL reduction typically seen with statins (20% to 60%), 89% to 98% of CRP change was related to LDL lowering and 2% to 11% was related to non-LDL effects of statins.

Conclusions: In clinical practice, most of the anti-inflammatory effect of LDL-lowering therapies is related to the magnitude of change in LDL. The potential non-LDL effects of statins on inflammation are much smaller in magnitude.

Abbreviations and Acronyms
  CRP = C-reactive protein
  LDL = low-density lipoprotein
  RCT = randomized controlled trial

Inflammation plays a central role in the progression and destabilization of atherosclerosis that herald cardiovascular events (1,2). Modest elevations of plasma markers of inflammation, such as C-reactive protein (CRP), are associated with future risk of cardiovascular disease (3–6) and are thought to reflect inflammation in atherosclerosis.

The 5-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) lower cardiovascular risk (7–13) and have potent anti-inflammatory effects on atherosclerosis (2). Statins can diminish inflammation by decreasing plasma low-density lipoprotein (LDL) cholesterol and removing pro-inflammatory modified LDL from the artery wall. However, in vitro studies suggest that statins may have non-LDL anti-inflammatory effects. For example, statins also decrease cholesterol-independent isoprenoids and prevent activation of the proinflammatory rho kinase (14,15).

In clinical studies, it is difficult to tease the known lipid effects of statins from their potential nonlipid effects. Although the correlations between changes in LDL and CRP are small among individuals within any single study, the intraindividual variation in the measurement of these variables can cloud any true relationships. This variation can be reduced by examining the relationships of average changes among different groups of individuals.

In this study, a novel use of meta-analysis techniques assessed the relationship between group changes in LDL cholesterol and CRP from a variety of statin and nonstatin interventions designed to lower LDL cholesterol. Meta-analysis is usually used to assess clinical outcomes, however, in this study the techniques are used to explore mechanisms of disease to provide insights into the clinical importance of lipid and nonlipid effects of statin therapy.


   Methods
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 Abstract
 Methods
Results
 Discussion
 Conclusions
 References
 
Literature search.   Studies evaluating LDL and high-sensitivity CRP reduction were drawn from a systematic review of the English literature in Medline and other systematic reviews (16) up until August 2005. The search terms were: "crp" or "c-reactive protein" or "c reactive protein," and "statins" or "ezetimibe" or "fish oil" or "resin" or "fibrate" or "diet" or "apheresis" or "diet and cholesterol." Studies also were identified through searching the references of articles.

Inclusion criteria.   Studies were included if they reported original randomized placebo-controlled data on the effects of cholesterol-lowering interventions on LDL and CRP in healthy or clinically stable subjects. Groups were treated with statin therapy, nonstatin drug therapy (fibrates, fish oils, resins, cholesterol absorbers), and nondrug therapies (cholesterol-lowering diets or apheresis).

Studies were excluded if they were review articles, nonhuman studies, prognostic (risk factor) or cross-sectional studies, histopathological studies, non–LDL-lowering therapies or diets (e.g., weight loss diets), studies in subjects with conditions known to markedly elevate inflammation processes (e.g., vasculitis, infection, acute coronary syndromes), duplicate publications, acute studies (single-dose treatments or therapies lasting <2 weeks), herbal treatments, studies in which change in LDL or CRP were not reported or could not be estimated, or studies using low-sensitivity CRP assays (lower limits of assay >0.5 mg/l). The corresponding author and companies that made the CRP assay kits were contacted if there was any doubt about the assay or other aspects of the study.

Study quality and data extraction.   A standardized data form was used to record the study type (e.g., randomized controlled study, parallel or crossover design), blinding, intention-to-treat analysis, completeness of follow-up (attrition rate), type of intervention, number of subjects, weeks of treatment, baseline LDL and CRP, and follow-up or changes in LDL and CRP. For each intervention within a study, the average changes in LDL and CRP over the study period as a percent of baseline were those reported or were values estimated from the final and baseline LDL and CRP.

Statistical analysis.   The average mean differences (placebo – treatment) change in LDL and CRP were calculated for each study group. The variance for the change in CRP within each treatment group (change variance) was estimated as described previously (17) from 25 treatment groups in 16 studies that reported the standard deviations or standard errors of change in CRP (18–20), or by inverting the exact p values for change in CRP (20–33). It was assumed that there was a common change variance ({sigma}{Delta} 2), estimated by the weighted average of the 25 change variances above (17). The treatment – placebo effect variance for the average mean difference in CRP of treatment (t) and placebo (p) was estimated as {sigma}{Delta} 2/(1/nt + 1/np) for parallel studies and {sigma}{Delta} 2/n for crossover studies (17).

The pooled estimate for CRP reduction was assessed with the random-effects and fixed-effects estimators and heterogeneity tested using the meta command in Stata (Stata Corp., College Station, Texas). Because significant heterogeneity existed, the average mean differences in CRP change (and 95% confidence intervals [CIs]) were assessed for subgroups of different explanatory variables. Publication bias was assessed with a funnel plot and the Begg and Egger tests of bias. The correlation coefficient between changes in CRP and LDL was estimated using analytical weights based on the inverse of the effect variance of change in CRP. A meta-regression model of the average mean differences in CRP and LDL assessed the relationship of average LDL change to average CRP change, with and without adjustment of different types of treatment (statin only, ezetimibe only, combination statin and ezetimibe, or other LDL-lowering therapies), and study characteristics. The coefficients from a model including change in LDL and any statin therapy were used to quantify the lipid and nonlipid effects of statin therapy on CRP reduction using a range of LDL reduction (20% to 60% reduction) typically observed with statin therapy in humans. Because recent randomized trials comparing 2 or more statins have suggested no relationship between change in LDL and CRP, their relationship was assessed in a separate analysis of the statin-versus-statin randomized controlled trials (RCTs). A p value of <0.05 was considered significant, and all analyses used Stata statistical software.


   Results
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 Methods
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Discussion
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The search yielded 738 reports, of which 656 were rejected (183 [25%] review articles, 109 [15%] nonlipid lowering interventions, 92 [13%] subjects with nonatherosclerotic inflammatory diseases, 76 [10%] cross-sectional studies, 36 [5%] with either change in CRP or LDL not reported or not calculable, 34 [5%] prognostic studies, 24 [3%] nonhuman studies, 20 [3%] histopathological studies, 18 [2%] patients with acute coronary syndromes, 16 [2%] duplicate publications, 13 [2%] low-sensitive CRP assays, 13 [2%] herbal treatments, 10 [1%] acute [<2 weeks] treatment duration, 10 [1%] studies of methodology or economic analysis, 2 [0.3%] number of subjects not reported). Of the remaining 82 studies, 47 studies were RCTs (placebo or active comparison), and 35 studies were nonrandomized longitudinal studies. Of the 47 randomized trials, 23 studies that form the basis of this report were randomized placebo controlled trials with 57 treatment groups (18,19,21,23,26,30,34–50).

The characteristics of the 57 intervention groups are shown in Table 1. Most studies used a parallel design, with the average duration of therapy being 12 weeks. Most interventions were statin-only therapies (58%) or combinations of statin-ezetimibe (23%), with 5 (9%) testing ezetimibe-only interventions and 6 (10%) using other interventions (2 fish oil, 1 fibrate, 2 niacin, 1 diet).


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  		Table 1 Description of the 57 Interventions Among the 23 Randomized Placebo Controlled Trials Included in the Meta-Analysis
 
The pooled estimate across all interventions was a 28% (95% CI 26% to 30%) reduction in CRP (p < 0.0001) (Fig. 1). However, there was significant heterogeneity in the change in CRP between studies (p < 0.0001). To assess potential explanations for the heterogeneity, the change in CRP was assessed in a number of subgroups based on characteristics of the individual studies (Fig. 2). Significantly greater reductions in CRP occurred for combination statin-ezetimibe and statin-alone interventions versus other LDL-lowering therapies, studies using 80 mg/day of statins versus lower doses of statins, and a dose-response relationship with greater LDL reduction. The overall estimate of change in CRP was less with the fixed effects model compared to the random effects model, consistent with a heterogenous pattern of CRP change across studies.


Figure 1
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  		Figure 1 Average Net Change in CRP (Placebo – Treatment) for Each of the 57 Treatment Groups in 23 RCTs

The treatment and daily dose for drugs is listed next to the year and author. Dotted line indicates the weighted overall random-effects estimate of C-reactive protein (CRP) reduction. A = atorvastatin; C = cerivastatin; Ez = ezetimibe 10 mg/day; FF = fenofibrate; FO = fish oil; L = lovastatin; N = niacin; P = pravastatin; R = rosuvastatin; RCT = randomized controlled trial; S = simvastatin.

 

Figure 2
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  		Figure 2 Average Change in CRP by Study Characteristics

Average net change in C-reactive protein (CRP) (placebo – treatment) and 95% confidence intervals show significantly greater CRP reduction for statin or statin-ezitimibe interventions, 80 mg per day statin regimins, and therapies that offered greater low-density lipoprotein (LDL) reduction.

 
A funnel plot and Begg analysis for publication bias showed a significant bias in CRP reduction (Begg p = 0.03, Egger p < 0.001) (Fig. 3A). However, when stratified by the median reduction in LDL (–40%) across the 57 interventions (Figs. 3B and 3C), there was no evidence of publication bias, suggesting the overall result was related to differences in LDL reduction across studies rather than publication bias.


Figure 3
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  		Figure 3 Funnel Plots to Assess Publication Bias

The dashed line is the fixed-effects estimate of change in CRP across interventions, and the dotted lines are pseudo-95% confidence intervals for the standard error of change in CRP, assuming no heterogeneity between studies. Bias is suspected if the plots are asymmetric (i.e., the point estimates tend to fall to one side of the dashed line). (A) Significant bias in all interventions (Egger p < 0.001). However, stratification by the median change in LDL showed no evidence of bias. (B) LDL >40% (Egger p = 0.5). (C) LDL ≤40% (Egger p = 0.7). Abbreviations as in Figure 2.

 
Meta-regression analysis was used to assess the relationship of average LDL change and the use of statin therapy to average change in CRP. On univariate analysis, there was a highly significant correlation between change in LDL and change in CRP (regression coefficient or slope for change in LDL = 0.89, 95% CI 0.70 to 1.09, p < 0.001). The variance adjusted correlation between change in LDL and change in CRP was r = 0.80 (p < 0.001) (Fig. 4). On multivariate analysis, there was no significant effect of statin therapy, or any other therapy, on change on CRP after accounting for change in LDL (coefficient for LDL = 1.03, p < 0.001; statin alone therapy = 0.075, p = 0.7; statin-ezetimibe combination = 0.09, p = 0.7; ezetimibe alone = 0.02, p = 0.9).


Figure 4
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  		Figure 4 Plot of Change in CRP by Change in LDL

The plot shows average net change in LDL (placebo – treatment) by the average net change in CRP (placebo – treatment) for the 57 interventions. The size of each circle is proportional to the inverse of the variance of change in CRP, and the dotted line indicates the regression line estimated from the meta-regression analysis. Abbreviations as in Figure 2.

 
The coefficients for a model of change in CRP as a function of change in LDL, and any statin therapy ({Delta} CRP = 0.93 · {Delta} LDL – 0.01 · statin + 0.105) were used to estimate the proportion of CRP change related to LDL change and non-LDL statin effects across a range of intensity of statin therapy (LDL reduction of 20% to 60%). In this model, 98% to 89% of the CRP reduction was related to LDL reduction and 2% to 11% of CRP change was related to statin effects independent of LDL reduction.

The relationship of change in LDL and change in CRP was also assessed in 11 of the 47 RCTs that compared 14 statin regimens to controls receiving different or lower-dose statins (28,31,51–59). The variance adjusted correlation coefficient of change in CRP to change in LDL was r = 0.84 (p = 0.0002).


   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
Conclusions
 References
 
This analysis clearly revealed a strong relationship between the change in LDL cholesterol and change in CRP, a marker of inflammation in atherosclerosis. The principal reason that single studies rarely show a correlation between change in LDL and CRP among individual subjects is that any correlation is obscured by measurement error that is largely related to the intraindividual variation in LDL and CRP. In contrast, assessing the relationship between the average change in CRP and LDL across many studies diminishes the diluting effect of intraindividual variation to reveal a strong relationship.

Heterogeneity of net CRP change across studies.   The change in CRP was very heterogenous across studies. Average CRP change was greater for statin and statin-ezetimibe therapies versus other therapies and with high-dose statin therapy. However, the dose-response relationship between change in LDL and change in CRP suggests that it is the greater reduction in LDL with statin and high-dose regimens that account for the treatment differences. The study type, the duration of intervention, or the sample size of the studies had no impact on the change in CRP after adjusting for change in LDL.

Similarly, the bias in the funnel plot of CRP change (Fig. 3) was no longer present in plots stratified by intensity of LDL change—a more likely explanation for the overall pattern than publication bias.

LDL and non-LDL effects of statins on inflammation.   In this study, the change in LDL was the predominant factor related to change in CRP. The high correlation between changes in LDL and CRP (r = 0.80) strongly support a causal link between changes in LDL and arterial inflammation in atherosclerosis, and complements histopathological studies in animals and humans using a variety of statin and nonstatin therapies. In these studies, LDL lowering dramatically reduces the content of oxidized LDL in plaque and inflammatory cell density and activity (60–64).

Although statins do have non-LDL effects that reduce inflammatory pathways in cell culture and animal experiments (2,14), in many studies these require high concentrations of statins that are several log concentrations higher than those achieved with their therapeutic use in humans (2). If these LDL-independent effects were clinically important (for example, the rho pathway), then statins should decrease CRP more than nonstatin therapies for a similar change in LDL. However, in this study, the effects of statin therapies and other LDL-lowering therapies were minimal and not statistically significant after accounting for the LDL-lowering effect. The potential magnitude of nonlipid effects of statins on inflammation was explored with a multivariate model using change in LDL and any statin use as independent variables. Across a range of LDL reduction typically seen with statin therapy (20% to 60%), 90% or more of the change in CRP was related to LDL reduction and 10% or less was related to non-LDL effects of statins.

This study provides mechanistic insights into the conclusions from an earlier meta-analysis of clinical outcomes in lipid-lowering trials, in which virtually all of the decrease in cardiovascular risk was attributable to the degree of LDL reduction (65). The lack of any substantial LDL-independent effect of statins on cardiovascular outcomes (65) reflects similar findings on CRP reduction in this study. These results, along with animal and pathology studies, suggest that LDL lowering and inflammation are not separate entities. Rather, LDL lowering is likely a primary driver for the reduction in inflammation that contributes to lower cardiovascular risk.

Measuring change in inflammation in individuals.   To consistently observe a change in LDL or CRP in individual patients, the change in these markers needs to be greater than the intraindividual variability. Before statins, LDL lowering was modest in the range of 5% to 15%, and often was obscured in individual patients by measurement variability. With the development of more powerful therapies, with which LDL is lowered by 50% to 60%, a response to therapy is consistently observed. The same cannot be said for CRP. The interindividual variability of CRP (66,67) is similar in magnitude to the modest change in CRP, even with intensive LDL-lowering therapy. Thus, in clinical studies of statins, 27% to 46% of patients seem to increase their CRP (31,68,69). These are not necessarily nonresponders, but merely patients in whom the whims of variability have obscured the signal of a real change in CRP.

Although the ongoing JUPITER (Randomized Trial of Rosuvastatin in the Primary Prevention of Cardiovascular Events Among Individuals with Low Levels of LDL-C and Elevated levels of CRP) study (70) is incorporating CRP as an independent focus of lipid-lowering therapy, this meta-analysis suggests somewhat paradoxically that LDL reduction may be a more consistent measure of a decrease in inflammation in individual patients receiving LDL-lowering therapies.


   Conclusions
Top
 Abstract
 Methods
 Results
 Discussion
 Conclusions
References
 
This study employed a novel use of meta-analysis to explore the relationship between change in LDL and CRP across a number of LDL-lowering interventions. Most of the anti-inflammatory effect of statins and other LDL-lowering interventions was related to the magnitude of LDL reduction. This study supports the concept of intensive LDL lowering to achieve maximum reductions in inflammation to stabilize atherosclerotic plaque. Thus, LDL cholesterol is not only a primary target for prevention of cardiovascular disease, it also should remain the primary measure of the efficacy of statin and nonstatin LDL-lowering therapies.


   Footnotes
 
1 Dr. Kinlay is a speaker or consultant with Pfizer, Merck, and Schering-Plough. Back


   References
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 Methods
 Results
 Discussion
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 References
 

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