Cholesterol-lowering therapies and C-reactive protein

Coronary and other vascular events are often a result of plaque progression or destabilization that is strongly related to inflammation in atherosclerosis. Plasma markers of inflammation, such as C-reactive protein (CRP), are associated with future cardiovascular events and are thought to reflect this inflammation.¹ 5-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) decrease cardiovascular events and reduce inflammation in atherosclerosis,¹ potentially by removing modified low-density lipoprotein (LDL) cholesterol from the artery wall or by non-LDL cholesterol effects, such as decreasing isoprenoids.²

It is not easy to separate the known lipid effects of statins from their potential nonlipid effects in clinical studies because of the variability in measuring inflammation (eg, by CRP levels) and LDL cholesterol. This inconsistency can be decreased by using a novel application of meta-analysis to examine the associations between average changes in LDL cholesterol and CRP levels in various groups of individuals. This technique was used to assess the relationship between changes in LDL cholesterol and CRP levels from a variety of statin and nonstatin interventions designed to lower LDL cholesterol.

Subjects and methods

MEDLINE and other sources were searched for original randomized, placebo-controlled studies that assessed the effects of cholesterol-lowering interventions on LDL cholesterol and high-sensitivity CRP in clinically stable or healthy adults.³ Studies of subjects with acute coronary syndromes were excluded because of the highly elevated CRP levels related to these conditions. Interventions included therapy with statins, nonstatin drug therapy (fibrates, fish oils, resins, cholesterol absorbers), and nondrug therapies (cholesterol-lowering diets or apheresis).

The average change in LDL cholesterol and CRP (placebo — treatment values) was ascertained for each study group. The decrease in CRP level was determined for heterogeneity and by subgroups of various explanatory variables using meta-analysis techniques. The correlation coefficient between changes in CRP and LDL cholesterol was calculated using analytical weights. The relationship between average LDL cholesterol change and average CRP change, with and without adjustment for different types of treatment and study characteristics, was determined using a regression model of the average mean differences in CRP and LDL cholesterol. Finally, the relationship between change in LDL cholesterol and change in CRP level was assessed in the more recent randomized trials comparing 2 or more statins.³

Results

Of the 738 reports identified by the literature search, 47 studies were randomized controlled trials. The studies were further narrowed down to 23 studies that were randomized placebo-controlled trials including 57 treatment groups Table.³ Fifty-eight percent of the studies (n = 33) used statin-only treatment; 23% (n = 13) used a statin along with ezetimibe (Zetia); 10% (n = 6) used other treatments (niacin, n = 2; fish oil, n = 2; fibrate, n = 1; diet, n = 1); and 9% (n = 5) used ezetimibe only.

Table. Description of the 57 interventions among the 23 randomized placebo-controlled

trials included in the meta-analysis.

LDL indicates low-density lipoprotein; CRP, C-reactive protein. (Reprinted with permission

from Kinlay S. Low-density lipoprotein-dependent and -independent effects of cholesterol-

lowering therapies on C-reactive protein. J Am Coll Cardiol. 2007;49[20]:2003-2009.)

The average reduction in CRP among all groups was 28% (95% confidence interval [CI], 26%-30%; P < .001). However, significant heterogeneity in the change in CRP level among studies existed (P < .001). Therefore, the change in CRP was examined by subgroups (Figure 1). Statin drugs alone as well as combination therapy with a statin drug and ezetimibe showed markedly greater decreases in CRP levels compared with other LDL cholesterol-lowering therapies. In addition, significant decreases in CRP levels were seen with studies in which 80 mg/day of statins were compared with lower doses. A dose—response relationship with greater LDL cholesterol reduction also existed.³

The average net change in C-reactive protein level (placebo — treatment) and 95%

confidence intervals by potential explanatory and methodological characteristics of the studies.

(Reprinted with permission from Kinlay S. Low-density lipoprotein-dependent and -independent

effects of cholesterol-lowering therapies on C-reactive protein. J Am Coll Cardiol. 2007;49[20]:

2003-2009.)

Figure 1.

As shown in Figure 2, there was a strong correlation between the change in LDL cholesterol and change in CRP level (r = 0.80, P < .001). After adjustment for change in LDL cholesterol level, no significant effect on CRP level was shown by statin or any other therapy (change in LDL cholesterol, P < .001; statin monotherapy, P = .7; statin/ezetimibe combination therapy, P = .7; ezetimibe monotherapy, P = .9).

Plot of the average net change in low-density lipoprotein (LDL) cholesterol (placebo —

treatment) by the average net change in C-reactive protein (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. (Reprinted with permission from Kinlay S. Low-density lipoprotein-dependent and

-independent effects of cholesterol-lowering therapies on C-reactive protein. J Am Coll Cardiol.

2007;49[20]:2003-2009.)

Figure 2.

The potential contribution of LDL cholesterol-dependent and LDL cholesterol-independent effects of statins on change in CRP level was assessed over various dosages of statin therapy commonly used in clinical practice (LDL cholesterol reduction of 20%-60%). LDL cholesterol reduction was related to 89% to 98% of the decrease in CRP level in this model, and statin effects independent of LDL cholesterol reduction were related to 2% to 11% of CRP change.³ A similar high correlation between change in CRP and change in LDL cholesterol (r = 0.84; P = .002) was shown in a separate analysis of 11 of the 47 randomized controlled trials that compared 14 statin regimens with control subjects taking different or lower-dose statins.

Discussion

This meta-analysis showed a significant correlation between change in LDL cholesterol level and change in CRP level. Because the treatment effect on change in LDL cholesterol and CRP was subtracted from the placebo effect, the correlations lack spurious temporal changes, such as regression to the mean. The average change in CRP was greater for statin and statin/ezetimibe therapies compared with other therapies and with high-dose statin therapy. The dose—response relationship between change in LDL cholesterol and change in CRP level, and the high correlation between changes in LDL cholesterol and CRP level (r = 0.80) strongly indicate that there is a causal link between changes in LDL cholesterol and the arterial inflammation present in atherosclerosis. Results of our study concur with findings from histopathologic studies of animals and humans that used statin and nonstatin therapies, in which LDL cholesterol-lowering significantly decreased oxidized LDL cholesterol, inflammatory cell density, and activity in atherosclerotic plaque.^4-7

Despite the fact that statin drugs have been shown to have non-LDL cholesterol effects that decrease inflammatory pathways in cell culture and animal studies, drug concentrations much higher than those achieved in clinical practice are required. There was no significant non-LDL cholesterol effect of statins on CRP in our study, and only 10% or less of the change in CRP could potentially be associated with the non-LDL effects of statins. In contrast, 90% or more of the change in CRP was related to a decrease in LDL cholesterol.

These findings are similar to results from a previous meta-analysis of clinical outcomes in which nearly all of the reduction in cardiovascular risk was attributable to the degree of decrease in LDL cholesterol.⁸ Collectively, these studies indicate that LDL cholesterol lowering and inflammation are not unrelated elements, but that LDL cholesterol lowering is probably a chief reason for the decrease in inflammation that is a factor in lower cardiovascular risk.

For a reduction in LDL cholesterol and CRP to occur reliably in individual patients, the change in these markers with therapy should be greater than their biological variability. Prior to the development of statin drugs, LDL cholesterol lowering was modest, usually from 5% to 15%, and change was difficult to identify because it was similar to the biological variability of LDL cholesterol. As stronger LDL cholesterol-lowering treatments able to decrease LDL cholesterol by 50% to 60% were developed, a reliable response to treatment was seen. The equivalent was not true for CRP, however, because the variability of CRP⁹ is comparable in magnitude to the moderate change in CRP, even with intensive LDL cholesterol-lowering treatment. Thus, 27% to 46% of subjects in clinical studies seem to have increased CRP.^10-12 These subjects may be individuals in whom measurement variability has masked the signal of a real change in CRP and may not necessarily be "nonresponders."

Conclusions

The extent of LDL cholesterol reduction is related to the antiinflammatory effect of statins and other LDL cholesterol-lowering interventions. The findings from this study support the use of intensive LDL cholesterol-lowering therapy to achieve maximum reductions in inflammation to stabilize atherosclerotic plaque. They also suggest, somewhat paradoxically, that LDL cholesterol reduction may be a more consistent measure of a decrease in inflammation in individual patients receiving LDL cholesterol-lowering therapies. Low-density lipoprotein cholesterol, therefore, is not just a key target for the prevention of cardiovascular disease, it should continue to be the chief gauge of the effectiveness of statin and nonstatin LDL cholesterol-lowering therapies.

Grant support was provided by Pfizer. Dr Kinlay has served as a speaker or consultant for Pfizer, Merck, and Schering-Plough.

Disclosure