Effect of atorvastatin on C-reactive protein and benefits for cardiovascular disease in patients with type 2 diabetes: analyses from the Collaborative Atorvastatin Diabetes Trial
Soedamah-Muthu, S.S. ; Livingstone, S.J. ; Charlton-Menys, V. ; Betteridge, D.J. ; Hitman, G.A. ; Neil, H.A.W. ; Bao, W. ; DeMicco, D.A. ; Preston, G.M. ; Fuller, J.H. ; Stehouwer, C.D.A. ; Schalkwijk, C.G. ; Durrington, P.N. ; Colhoun, H.M. - \ 2015
Diabetologia 58 (2015)7. - ISSN 0012-186X - p. 1494 - 1502.
placebo-controlled trial - acute coronary syndromes - cardiac outcomes trial - statin therapy - myocardial-infarction - on-treatment - follow-up - cholesterol - mortality - heart
Aims/hypothesis We investigated whether atorvastatin 10 mg daily lowered C-reactive protein (CRP) and whether the effects of atorvastatin on cardiovascular disease (CVD) varied by achieved levels of CRP and LDL-cholesterol. Methods CRP levels were measured at baseline and 1 year after randomisation to atorvastatin in 2,322 patients with type 2 diabetes (40–75 years, 69% males) in a secondary analysis of the Collaborative Atorvastatin Diabetes Study, a randomised placebo-controlled trial. We used Cox regression models to test the effects on subsequent CVD events (n¿=¿147) of CRP and LDL-cholesterol lowering at 1 year. Results After 1 year, the atorvastatin arm showed a net CRP lowering of 32% (95% CI -40%, -22%) compared with placebo. The CRP response was highly variable, with 45% of those on atorvastatin having no decrease in CRP (median [interquartile range, IQR] per cent change -9.8% [-57%, 115%]). The LDL-cholesterol response was less variable, with a median (IQR) within-person per cent change of -41% (-51%, -31%). Baseline CRP did not predict CVD over 3.8 years of follow-up (HRper SD log 0.89 [95% CI 0.75, 1.06]), whereas baseline LDL-cholesterol predicted CVD (HRper SD 1.21 [95% CI 1.02, 1.44]), as did on-treatment LDL-cholesterol. There was no significant difference in the reduction in CVD by atorvastatin, with above median (HR 0.57) or below median (HR 0.52) change in CRP or change in LDL-cholesterol (HR 0.61 vs 0.50). Conclusions/interpretation CRP was not a strong predictor of CVD. Statin efficacy did not vary with achieved CRP despite considerable variability in CRP response. The use of CRP as an indicator of efficacy of statin therapy on CVD risk in patients with type 2 diabetes is not supported by these data.
Predicting individual responses to pravastatin using a physiologically based kinetic model for plasma cholesterol levels
Pas, N.C.A. van de; Rullmann, J. ; Woutersen, R.A. ; Ommen, B. van; Rietjens, I. ; Graaf, A.A. de - \ 2014
Journal of Pharmacokinetics and Pharmacodynamics 41 (2014)4. - ISSN 1567-567X - p. 351 - 362.
coa reductase inhibitors - statin therapy - lowering-therapy - ldl cholesterol - hepg2 cells - atorvastatin - simvastatin - absorption - metabolism - trial
We used a previously developed physiologically based kinetic (PBK) model to analyze the effect of individual variations in metabolism and transport of cholesterol on pravastatin response. The PBK model is based on kinetic expressions for 21 reactions that interconnect eight different body cholesterol pools including plasma HDL and non-HDL cholesterol. A pravastatin pharmacokinetic model was constructed and the simulated hepatic pravastatin concentration was used to modulate the reaction rate constant of hepatic free cholesterol synthesis in the PBK model. The integrated model was then used to predict plasma cholesterol concentrations as a function of pravastatin dose. Predicted versus observed values at 40 mg/d pravastatin were 15 versus 22 % reduction of total plasma cholesterol, and 10 versus 5.6 % increase of HDL cholesterol. A population of 7,609 virtual subjects was generated using a Monte Carlo approach, and the response to a 40 mg/d pravastatin dose was simulated for each subject. Linear regression analysis of the pravastatin response in this virtual population showed that hepatic and peripheral cholesterol synthesis had the largest regression coefficients for the non-HDL-C response. However, the modeling also showed that these processes alone did not suffice to predict non-HDL-C response to pravastatin, contradicting the hypothesis that people with high cholesterol synthesis rates are good statin responders. In conclusion, we have developed a PBK model that is able to accurately describe the effect of pravastatin treatment on plasma cholesterol concentrations and can be used to provide insight in the mechanisms behind individual variation in statin response.
C-Reactive Protein, fibrinogen and cardiovascular disease prediction
Kromhout, D. - \ 2012
New England Journal of Medicine 367 (2012). - ISSN 0028-4793 - p. 1310 - 1320.
coronary-heart-disease - nonvascular mortality - practice guidelines - primary prevention - cost-effectiveness - statin therapy - risk profile - association - inflammation - metaanalysis
Background There is debate about the value of assessing levels of C-reactive protein (CRP) and other biomarkers of inflammation for the prediction of first cardiovascular events. Full Text of Background... Methods We analyzed data from 52 prospective studies that included 246,669 participants without a history of cardiovascular disease to investigate the value of adding CRP or fibrinogen levels to conventional risk factors for the prediction of cardiovascular risk. We calculated measures of discrimination and reclassification during follow-up and modeled the clinical implications of initiation of statin therapy after the assessment of CRP or fibrinogen. Results The addition of information on high-density lipoprotein cholesterol to a prognostic model for cardiovascular disease that included age, sex, smoking status, blood pressure, history of diabetes, and total cholesterol level increased the C-index, a measure of risk discrimination, by 0.0050. The further addition to this model of information on CRP or fibrinogen increased the C-index by 0.0039 and 0.0027, respectively (P
The potential influence of genetic variants in genes along bile acid and bile metabolic pathway on blood cholesterol levels in the population
Lu, Y. ; Feskens, E.J.M. ; Boer, J.M.A. ; Müller, M.R. - \ 2010
Atherosclerosis 210 (2010)1. - ISSN 0021-9150 - p. 14 - 27.
x-receptor-alpha - apolipoprotein b-100 kinetics - ldl-lowering response - 7-alpha-hydroxylase gene - lipid-levels - dietary-cholesterol - nuclear receptor - statin therapy - transcriptional regulation - promoter polymorphism
The liver is currently known to be the major organ to eliminate excess cholesterol from our body. It accomplishes this function in two ways: conversion of cholesterol molecules into bile acids (BAs) and secretion of unesterified cholesterol molecules into bile. BAs are synthesized in the hepatocytes, secreted into bile and delivered to the lumen of the small intestine where they act as detergents to facilitate absorption of fats and fat-soluble vitamins. About 95% of BAs are recovered in the ileum during each cycle of the enterohepatic circulation. Five percent are lost and replaced by newly synthesized BAs, which amounts to 500 mg/day in adult humans. In contrast to the efficiency of the BAs’ enterohepatic circulation, 50% of the 1000 mg of cholesterol secreted daily into bile is lost in feces. It is known that rare human mutations in certain genes in bile acid and bile metabolic pathway influence blood cholesterol levels. With the recent success of genome-wide association studies, we are convinced that common genetic variants also play a role in the genetic architecture of plasma lipid traits. In this review, we summarized the current state of knowledge about genetic variations in bile acid and bile metabolic pathway, and assessed their impact on blood cholesterol levels and cholesterol metabolic kinetics in the population