Pooled Analyses of Effects on C-Reactive Protein and Low Density Lipoprotein Cholesterol in Placebo-Controlled Trials of Ezetimibe Monotherapy or Ezetimibe Added to Baseline Statin Therapy

ArticleinThe American journal of cardiology 103(3):369-74 · February 2009with8 Reads
DOI: 10.1016/j.amjcard.2008.09.090 · Source: PubMed
Inflammation is associated with coronary artery disease (CAD), and statins reduce the inflammatory marker C-reactive protein (CRP). The effects of ezetimibe, alone or in combination with statins, on CRP and low-density lipoprotein (LDL) cholesterol were examined in 2 pooled analyses of randomized, placebo-controlled trials of ezetimibe 10 mg/day in patients with hypercholesterolemia: 6 12-week trials as monotherapy (n = 1,372) and 7 6- to 8-week trials as add-on to baseline statin therapy (n = 3,899). Mean percentage changes from baseline in CRP and LDL cholesterol were examined using analysis of variance in patients with CRP ≤10 mg/L. Effects within subgroups (age, gender, race, body mass index, diabetes mellitus, metabolic syndrome, CAD, baseline CRP or lipids, and statin potency) and correlations between CRP and LDL cholesterol were also examined. Reduction in CRP by ezetimibe monotherapy was numerically greater than with placebo (treatment difference 6%, p = 0.09). Added to statin therapy, ezetimibe was associated with a significant additional reduction in CRP (treatment difference 10%, p <0.001). Treatment effects were generally consistent across subgroups for the 2 analyses. With monotherapy and add-on to statin therapy, LDL cholesterol reduction with ezetimibe was significantly greater than with placebo (treatment differences -19% and -23%, respectively, p <0.001). Spearman's correlation coefficients among baseline values and percentage changes from baseline in CRP and LDL cholesterol ranged from -0.007% to 0.13%. In conclusion, the addition of ezetimibe to statin treatment provides significantly enhanced CRP reductions over and above those achieved with statin monotherapy. Correlations between changes in CRP and changes in LDL cholesterol were weakly positive and significant only when ezetimibe was added to statin treatment. The effects of ezetimibe monotherapy are not well defined. The effects of ezetimibe on CRP were consistent across patient subgroups.
    • "Ricans. The therapeutic effect of LLA use, especially statins, on the reduction of hs-CRP levels has been established for more than a decade by large clinical trials such as JUPITER, PRINCE, and other pooled data analyses from similar trials (Ridker et al., 2008) (Albert et al., 2001, Pearson et al., 2009), and was corroborated by our findings. Most recently, the LOOK AHEAD trial found a substantial additive anti-inflammatory effect of LLAs with intensive lifestyle intervention on reduction of CRP-levels among overweight/obese diabetic patients (Belalcazar et "
    [Show abstract] [Hide abstract] ABSTRACT: Objective: To assess the association of LLA use with high-sensitivity C-reactive protein (hs-CRP) and oral inflammation. Design: Cross-sectional analysis using baseline data from 1,300 overweight/obese participants aged 40-65 years, recruited for the ongoing San Juan Overweight Adults Longitudinal Study. Serum hs-CRP was measured by ELISA, gingival/periodontal inflammation was evaluated as bleeding upon probing (BOP), and LLA was self-reported. Separate logistic models were performed for systemic and oral inflammation. Results: 24% participants reported history of dyslipidemia, of which, 50.3% self-reported LLA use. Sixty percent of the participants had elevated hs-CRP (>3 mg/dL) and 50% had high BOP (defined as at or above the median: 21%). After adjusting for age, gender, smoking, HDL-C, physical activity, diabetes, blood pressure medications, and percent body fat composition, LLA users had significantly lower odds of elevated hs-CRP compared to LLA non-users (OR=0.55; 95% CI: 0.38-0.81). After adjusting for age, gender, smoking status, educational level, and mean plaque index, LLA users had significantly lower odds of high BOP compared to LLA non-users (OR= 0.62; 95% CI: 0.42-0.91). Conclusions: Lipid-lowering agents may reduce both systemic and oral inflammatory responses. This article is protected by copyright. All rights reserved.
    Full-text · Article · Sep 2015
    • "The co-administration of ezetimibe and statin produces an incremental reduction of LDL-C in the range of 12% to 15% compared to single statin therapy.1)2)3)4) As shown above, LDL-C was reduced by 25-27% when ezetimibe was added to an on-going statin therapy.8)9)10)14) This difference may be caused by the method used for calculating the change in cholesterol levels. "
    [Show abstract] [Hide abstract] ABSTRACT: Background and Objectives The inhibition of cholesterol absorption by ezetimibe increases cholesterol synthesis. The effect of inhibition of cholesterol synthesis on cholesterol absorption is controversial. The influence of these interactions on cholesterol levels is unknown. We investigated on the extent to which cholesterol levels were affected by the reaction of one pathway to the inhibition of the other pathway. Subjects and Methods This case-controlled study enrolled 198 patients who needed cholesterol-lowering drugs. Ezetimibe (10 mg) was administered to the patients with (n=58) and without on-going statin therapy (n=58). Simvastatin (20 mg) was administered to the patients treated with (n=41) and without ezetimibe (n=41). Results Ezetimibe without statin lowered the total cholesterol by 13.3±8.8% (p<0.001) and the low density lipoprotein-cholesterol (LDL-C) by 18.7±15.3% (p<0.001). Ezetimibe added to statin decreased the total cholesterol by 21.1±7.7% (p<0.001) and the LDL-C by 29.9±12.6% (p<0.001). The total cholesterol and LDL-C were reduced more by ezetimibe in patients with statin therapy than in those without statin therapy (p<0.001 and p<0.001, respectively). The differences in the effect of simvastatin on total cholesterol and LDL-C between the patients with and without ezetimibe showed borderline significance (p=0.10 and p=0.055, respectively). Conclusion A prior inhibition of cholesterol synthesis by statin enhanced the effect of ezetimibe on total cholesterol and LDL-C by 7.8% and 11.2%, respectively. This finding suggests that ezetimibe increased cholesterol synthesis, resulting in a significant elevation of cholesterol levels.
    Full-text · Article · Jul 2014
    • "On the other hand, cholesterol absorption in hypercholesterolemic patients is often blocked using statins in combination with ezetimibe, which is a cholesterol transporter Niemann-Pick C1-Like 1 protein inhibitor. Several investigators have reported that ezetimibe also has both anti-inflammatory [13] and pleiotropic effects [14] . However , only a few studies have specifically examined the effects of ezetimibe, whereas statins have been investigated in detail. "
    [Show abstract] [Hide abstract] ABSTRACT: Statins are frequently administered to reduce low-density lipoprotein cholesterol (LDL-C) and vascular inflammation, because LDL-C and high sensitive C-reactive protein (hs-CRP) are associated with high risk for cardiovascular events. When statins do not reduce LDL-C to desired levels in high-risk patients with coronary artery disease (CAD), ezetimibe can be added or the statin dose can be increased. However, which strategy is more effective for treating patients with CAD has not been established. The present study compares anti-inflammatory effects and lipid profiles in patients with CAD and similar LDL-C levels who were treated by increasing the statin dose or by adding ezetimibe to the original rosuvastatin dose to determine the optimal treatment for such patients. 46 patients with high-risk CAD and LDL-C and hs-CRP levels of >70 mg/dL and >1.0 mg/L, respectively, that were not improved by 4 weeks of rosuvastatin (2.5 mg/day) were randomly assigned to receive 10 mg (R10, n = 24) of rosuvastatin or 2.5 mg/day of rosuvastatin combined with 10 mg/day of ezetimibe (R2.5/E10, n = 22) for 12 weeks. The primary endpoint was a change in hs-CRP. Baseline characteristics did not significantly differ between the groups. At 12 weeks, LDL-C and inflammatory markers (hs-CRP, interleukin-6, tumour necrosis factor-alpha and pentraxin 3) also did not significantly differ between the two groups (LDL-C: R10 vs. R2.5/E10: -19.4 ± 14.2 vs. -22.4 ± 14.3 mg/dL). However, high-density lipoprotein cholesterol (HDL-C) was significantly improved in the R10, compared with R2.5/E10 group (4.6 ± 5.9 vs. 0.0 ± 6.7 mg/dL; p < 0.05). Both enhanced therapies exerted similar anti-inflammatory effects under an equal LDL-C reduction in patients with high-risk CAD despite 2.5 mg/day of rosuvastatin. However, R10 elevated HDL-C more effectively than R2.5/E10. Trial registration
    Full-text · Article · Feb 2013
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