Strong decrease of high sensitivity C-reactive protein with high-dose atorvastatin in patients with type 2 diabetes mellitus
Introduction
Inflammation is thought to play an important role in the progression and complications of atherosclerosis. Hence, several markers of inflammation have been evaluated in the previous years. C-reactive protein (CRP), a non-specific marker of inflammation, has been proven to be one of the strongest predictors of the risk of cardiovascular events in patients with cardiovascular disease, [1] as well as in patients without cardiovascular disease [2], [3], [4]. This prediction is equally strong for men and women and is independent of the predictive value of serum lipids [2], [3]. The importance of CRP is thought to be related to the fact that it is one of the most sensitive markers of inflammation. Furthermore, CRP may aggravate the atherothrombotic process since the protein has a function in activation of complement and monocytes/macrophages, the latter of which involves the induction of tissue factor production and uptake of modified LDL [5], [6]. These CRP induced processes ultimately may result in accelerated atherosclerosis and larger areas of trauma and infarction. The specific relation between CRP and atherothrombosis or acute coronary syndromes is supported by the fact that no association has been found between CRP levels and previous bacterial or viral infections [4].
In patients with type 2 diabetes, accelerated atherosclerosis is common and the risk of acute coronary syndromes is increased. In these patients CRP levels have also been shown to predict future cardiovascular events [7].
Treatment with statins reduced CRP levels in patients with overt cardiovascular disease, [8], [9], [10] as well as in patients without cardiovascular disease [11], [12]. In the CARE study, the effect of pravastatin was particularly strong for the group with elevated CRP at baseline [13]. Thus CRP is a marker of increased risk for cardiovascular disease and the beneficial effects of statins are especially found in patients with high CRP levels at baseline. At present, no dose-dependent effects of statins on CRP levels have been reported.
In a placebo controlled, double-blind randomized study we evaluated the effects of a low and a high dose of atorvastatin during a 30-week treatment period on the CRP level in type 2 diabetes. We observed a strong and dose-dependent reduction of CRP with atorvastatin.
Section snippets
Methods
The design, methodology and other practical aspects of the DALI study have been described in detail previously [14]. In short, the patients with type 2 diabetes participating in this placebo controlled double-blind randomized prospective trial, had plasma triglycerides between 1.5 and 6.0 mmol/l at inclusion. Total cholesterol levels were between 4.0 and 8.0 mmol/l. Patients had no manifest coronary artery disease or prior history of MI or angina. Special attention was paid to the exclusion of
Statistics
Continuous variables are presented as mean values with the standard deviation when distribution is normal and as median and interquartile range (IQR) when distribution is not normal. Differences at baseline were tested for significance using the Student's t-test for continuous variables and using the Mann–Whitney U-test for the not normally distributed CRP levels and the χ2 test for dichotomic variables. Stepwise linear regression was used to evaluate the influence of potential determinants for
Results
The baseline characteristics of the 186 patients are shown in Table 1. No statistical differences between the groups were present in the baseline characteristics. There was a trend towards a lower BMI and a larger proportion of males in the atorvastatin 10 mg group.
Baseline plasma lipid levels are shown in Table 1. Significant dose-dependent reductions in LDL-c were achieved using atorvastatin, being −3.4±18.9, −41±11.9 and −54±22.9% for placebo, atorvastatin 10 mg and atorvastatin 80 mg,
CRP changes
A significant and specifically strong reduction in CRP levels was observed during treatment with high dose atorvastatin (P<0.001), (Table 2). In both the placebo treated patients and the patients treated with atorvastatin 10 mg the CRP levels varied non-significantly between pre-treatment and 30 weeks treatment showing an increase of 0.22±2.21 mg/l (median +6.6%, IQR −22.0 to +44.6%) in the placebo group and a decrease in the atorvastatin 10 mg group of 0.22±2.40 mg/l (median −14.6%, IQR −48.1
IL-6
Median baseline levels of IL-6 were 2.59 (IQR 1.73–3.74) ng/l. No differences were found in baseline IL-6 levels between the groups (Table 2). Levels did not change significantly with atorvastatin, and no significant difference between 10 and 80 mg was found. At baseline IL-6 associated for 15.9% with the CRP level (N=186, r2=0.159 P<0.001). The variation in CRP was associated for 21% with the variation in IL-6, P<0.001.
CRP target levels
Patients with baseline CRP levels above the arbitrary target level of 3.0 mg/l (see Section 2) and consequently at increased risk for cardiovascular disease were selected and separately evaluated for the effects of atorvastatin. In these patients we evaluated the number of individuals who reached the treatment goal of <3.0 mg/l at the end of the study (Table 2). A significantly larger proportion of patients reached the arbitrary treatment goal in those treated with atorvastatin 80 mg (56%),
Discussion
In this prospective, randomized study we have for the first time demonstrated a strong effect on plasma CRP levels after 30 weeks of treatment with a high dose statin, much stronger than with a low-dose, and also showing the strongest reduction reported until now. Atorvastatin 80 mg showed a 47% reduction in CRP levels, which was significantly larger than the reduction with atorvastatin 10 mg (−14.6%). This strong reduction of CRP by atorvastatin 80 mg was comparable in magnitude but
Conclusions
Several conclusions can be drawn from the present data. First, the results show that high dose therapy with atorvastatin is able to induce a significant reduction of CRP levels in addition to and independently of its beneficial effects on lipids in type 2 diabetes. Atorvastatin 80 mg markedly reduced CRP levels by 47%. This lipid independent effect is in our view strongly suggestive of a non-lipid, anti-inflammatory effect of statins. Whether this profound CRP lowering of atorvastatin is
Acknowledgements
The results of this study were presented in part in abstract form on the ADA conference, Philadelphia, June 2001. This study was supported by an unconditional research grant from Pfizer the Netherlands.
References (31)
- et al.
Statins and C-reactive protein
Lancet
(1999) - et al.
Serum neopterin in acute coronary syndromes
Lancet
(1997) - et al.
Lipophilic HMG-CoA reductase inhibitor has an anti-inflammatory effect: reduction of MRNA levels for interleukin-1beta, interleukin-6, cyclooxygenase-2, and p22phox by regulation of peroxisome proliferator-activated receptor alpha (PPARalpha) in primary endothelial cells
Life Sci.
(2000) - et al.
Peroxisome proliferator-activated receptor alpha negatively regulates the vascular inflammatory gene response by negative cross-talk with transcription factors NF-kappaB and AP-1
J. Biol. Chem.
(1999) - et al.
Production of C-reactive protein and risk of coronary events in stable and unstable angina
Lancet
(1997) - et al.
C-reactive protein adds to the predictive value of total and HDL cholesterol in determining risk of first myocardial infarction
Circulation
(1998) - et al.
C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women
New Engl. J. Med.
(2000) - et al.
Low grade inflammation and coronary heart disease: prospective study and updated meta-analyses
Br. Med. J.
(2000) - et al.
C-reactive protein in the arterial intima: role of C-reactive protein receptor-dependent monocyte recruitment in atherogenesis
Arterioscler. Thromb. Vasc. Biol.
(2000) - et al.
C-reactive protein-mediated low density lipoprotein uptake by macrophages: implications for atherosclerosis
Circulation
(2001)
von Willebrand factor, C-reactive protein, and 5-year mortality in diabetic and nondiabetic subjects
Arterioscler. Thromb. Vasc. Biol.
Long-term effects of pravastatin on plasma concentration of C-reactive protein
Circulation
Associations between change in C-reactive protein and serum lipids during statin treatment
Ann. Med.
Effects of fluvastatin and bezafibrate combination on plasma fibrinogen, t-plasminogen activator inhibitor and C reactive protein levels in coronary artery disease patients with mixed hyperlipidaemia (FACT study). Fluvastatin alone and in combination treatment
Thromb. Haemost.
Rapid reduction in C-reactive protein with cerivastatin among 785 patients with primary hypercholesterolemia
Circulation
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Department of Internal Medicine, Erasmus Medical Centre Rotterdam, (I. Berk-Planken, N. Hoogerbrugge); Department of Biochemistry, Erasmus University Rotterdam, (H. Jansen); Gaubius Laboratory TNO-PG, Leiden (H.M.G. Princen); Leiden University Medical Centre (M.V. Huisman, M.A. van de Ree); University Medical Centre Utrecht, Julius Centre for General Practice and Patient Oriented Research (R.P. Stolk, F.V. van Venrooij); Division of Internal Medicine, University Medical Centre Utrecht, (J.D. Banga, G. Dallinga-Thie, F.V. van Venrooij).