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Differential Associations of Statin and Fibrate Treatment With Carotid Arterial Remodeling
AJH
2005; 18:1476 –1481
Differential Associations of Statin and Fibrate Treatment With Carotid Arterial Remodeling Gilles Chironi, Alain Simon, Jérôme Gariepy, Maria Balice, Muriel Del-Pino, and Jaime Levenson Background: The effects of statins on intima-media thickness (IMT) are well documented, whereas those of fibrates are unknown. Therefore we compared IMT under treatment with each class of drugs. Methods: We studied a cohort of consecutive dyslipidemic subjects treated with statin (n ⫽ 291) or fibrate (n ⫽ 82) drugs. Fibrate-treated subjects were matched with the same number of statin-treated subjects to obtain two subgroups of similar demographic and risk factors including LDL cholesterol. Common carotid far wall IMT and lumen diameter were measured by ultrasonography. Results: In the entire study population, IMT was greater in the fibrate group than in the statin group (P ⬍ .001), even after adjustment for LDL cholesterol and other covariates (P ⬍ .05). In the matched groups, IMT was greater in fibrate group than in the statin group (P ⬍ .01),
C
even after adjustment for LDL cholesterol and other covariates including treatment duration (P ⬍ .01). The IMT correlated positively with treatment duration in the fibrate group (P ⬍ 0.05) but not in the statin group. In addition, IMT correlated positively with carotid lumen diameter in both the fibrate and statin groups (P ⬍ .05, P ⬍ .01) but with a lower slope in the former (P ⬍ .05). Conclusions: In this study fibrate treatment was associated with greater IMT, steeper IMT–time relationship, and lower compensatory carotid enlargement than was statin treatment. These differences were not explained by differences in LDL cholesterol. Am J Hypertens 2005;18: 1476 –1481 © 2005 American Journal of Hypertension, Ltd. Key Words: Arterial remodeling, cardiovascular risk factors, carotid artery, fibrate derivatives, intima-media thickness, statins.
arotid intima-media thickness (IMT) is a surrogate endpoint for cardiovascular disease.1 Cross-sectional associations of IMT with cardiovascular risk factors and prevalent cardiovascular disease have been found, and prospective studies have shown that IMT predicted coronary artery disease and stroke.2 In hypercholesterolemia, HMG-CoA reductase inhibitors (statins), have been the subject of many clinical trials using IMT as an intermediate outcome.2 A retardation of IMT progression, or even a regression, has been shown under statin therapy, whatever the type of statin tested.3–11 This is consistent with the effectiveness of statins in reducing the incidence of the major atherosclerotic complications.12 By contrast, the effects of fibric acid derivatives (fibrates) have not been tested on IMT. This is surprising because whether fibrates reduce coronary risk in hyperlipemia is considered to be an important issue.13 The objective of this study was to assess carotid IMT in a cohort of
dyslipidemic patients treated with either statins or fibrates.
Received January 19, 2005. First decision May 16, 2005. Accepted May 20, 2005. From the Centre de Médecine Préventive Cardiovasculaire, Hôpital Broussais-Assistance Publique–Hôpitaux de Paris and Faculté de
Médecine Paris 5, Paris, France. Address correspondence and reprint requests to Prof. Alain Simon, Centre de Médecine Préventive Cardiovasculaire, Hôpital Broussais, 96 rue Didot, 75674, Paris, France; e-mail: [email protected]
0895-7061/05/$30.00 doi:10.1016/j.amjhyper.2005.05.019
Patients and Methods Study Population From March 2000 to June 2001, a total of 1895 consecutive men and women were referred to our clinic for 1-day hospitalization. Of them, 373 were selected because they fulfilled the following two conditions: 1) presence of lipid lowering treatment with either statin or fibrate for at least 3 months (Table 1); and 2) availability of carotid IMT and diameter data. These subjects constituted the entire study population (Table 2). Matched Groups Fibrate-treated subjects were matched with the same number of statin-treated subjects. The matching process was
© 2005 by the American Journal of Hypertension, Ltd. Published by Elsevier Inc.
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CAROTID REMODELING STATIN AND FIBRATE TREATMENT
Table 1. Distribution of lipid lowering treatments in the study overall population Drug class Statin Simvastatin Pravastatin Fluvastatin Atorvastatin Cerivastatin Fibrate Fenofibrate Bezafibrate Gemfibrozil Ciprofibrate
drug
Value 291 106 54 9 102 20 82 58 8 7 9
(78) (28) (15) (2) (28) (5) (22) (16) (2) (2) (2)
Values are number (%) of subjects.
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measured after overnight fast by enzymatic methods, and after precipitation of LDL and VLDL for HDL cholesterol. The LDL was calculated by the Friedewald formula: total cholesterol ⫺ HDL cholesterol ⫺ (triglycerides/2.2). Brachial blood pressure was measured at rest using a sphygmomanometer, and hypertension was defined as blood pressure (BP) ⱖ140 or ⱖ90 mmHg or the presence or antihypertensive therapy. Blood glucose was measured after an overnight fast; diabetes was defined as fasting glucose ⱖ7 mmol/L or the presence of antidiabetic treatment. Current smoking was defined as more than one cigarette per day for ⱖ3 months. Previous cardiovascular disease (CVD) was defined as the presence of current or past history of any cerebrovascular, coronary artery, or peripheral artery disease. Carotid Artery Geometry
performed one-to-one, by attributing to each fibratetreated patient a corresponding subject chosen among the 291 subjects of the statin group to obtain the same gender and closest values of age (⫾3 years) and other risk factors including LDL cholesterol (Table 2). The investigators responsible for the matching (AS, JL) were unaware of the subjects’ IMT. Risk Factors Risk factors were evaluated according to the guidelines of the National Education Cholesterol Program (Adult Treatment Panel III).13 Body mass index (BMI) was the ratio between weight and height squared. Blood lipids were
The imaging of IMT and lumen diameter of the distal segment of the right common carotid artery was performed according to a standardized procedure2,14,15 by means of high-resolution B-mode ultrasound imager (ATL 5000, Philips, Les Ulis, France). The IMT image, obtained in the far wall of the artery, consisted of two parallel echogenic lumen–intima and media–adventitia interfaces, free of any plaque visible on ⱖ1 cm of longitudinal length. Once the optimal quality of image of far wall IMT and diameter was obtained, it was frozen at end-diastole by electrocardiographic triggering (peak R wave), transferred to a computer equipped with digitization software, and analyzed by an automated edge-detection program (Iôtec, Iôdata, Paris,
Table 2. Characteristics of the entire study population and comparison between fibrate and statin groups
Parameter Number Age, (y) Men, n (%) Body mass index (kg/m2) Blood lipids, mmol/L Total cholesterol HDL cholesterol Triglycerides LDL cholesterol Duration of lipid-lowering therapy (mo) Blood pressure (mm Hg) Systolic Diastolic Hypertension, n (%) Antihypertensive therapy, n (%) Blood glucose (mmol/L) Diabetes, n (%) Current smoking, n (%) History of CVD, n (%)
Entire study population 373 56 ⫾ 10 285 (76) 26.9 ⫾ 4.0
Fibrate group 82 56 ⫾ 10 62 (76) 28.1 ⫾ 4.8
Statin group overall 291 56 ⫾ 9 223 (77) 26.6 ⫾ 3.8*
matched 82 56 ⫾ 10 62 (76) 27.4 ⫾ 3.9
5.34 1.33 1.46 3.34
⫾ 1.01 ⫾ 0.39 ⫾ 0.80 ⫾ 0.94 —
5.67 1.27 1.54 3.70 103
⫾ ⫾ ⫾ ⫾ ⫾
1.07 0.34 0.95 0.95 81
5.25 1.35 1.44 3.24
⫾ 0.98† ⫾ 0.40 ⫾ 0.76 ⫾ 0.92† —
5.50 1.33 1.46 3.50 77
⫾ ⫾ ⫾ ⫾ ⫾
139 84 251 188 5.91 52 64 34
⫾ 19 ⫾ 10 (67) (50) ⫾ 1.38 (14) (17) (9)
142 84 62 56 6.21 18 15 2
⫾ 21 ⫾ 10 (76) (68) ⫾ 1.77 (22) (18) (2)
138 84 189 132 5.83 34 49 32
⫾ 18 ⫾ 10 (65) (45)† ⫾ 1.24‡ (12)‡ (17) (11)
143 85 62 51 6.07 19 13 2
⫾ 20 ⫾ 12 (76) (62) ⫾ 1.47 (23) (16) (2)
1.04 0.34 0.76 1.02 63§
CVD ⫽ cardiovascular disease. Values are numbers, n (%) or means ⫾ SD. * P ⬍ .01, † P ⬍ .001, ‡ P ⬍ .05 when comparing overall statin group and fibrate group; § P ⬍ .05 when comparing matched statin and fibrate groups.
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Table 3. Comparison of arterial parameters between fibrate and statin groups Entire study population
Matched groups
Parameter
Fibrate (n ⴝ 82)
Statin (n ⴝ 291)
P value
Fibrate (n ⴝ 82)
Statin (n ⴝ 82)
P value
Carotid IMT (mm) Unadjusted Adjusted Carotid diameter (mm) Unadjusted Adjusted
0.63 ⫾ 0.12 0.65 ⫾ 0.02 (n ⫽ 80) 6.12 ⫾ 0.91 6.04 ⫾ 0.14
0.58 ⫾ 0.10 0.61 ⫾ 0.01 (n ⫽ 268) 6.08 ⫾ 1.11 6.10 ⫾ 0.10
⬍.01 ⬍.01
0.63 ⫾ 0.12 0.70 ⫾ 0.03 (n ⫽ 80) 6.12 ⫾ 0.91 5.85 ⫾ 0.23
0.57 ⫾ 0.08 0.65 ⫾ 0.03 (n ⫽ 77) 6.06 ⫾ 0.88 5.79 ⫾ 0.23
⬍.01 ⬍.01
NS NS
NS NS
IMT ⫽ intima-media thickness. Data are for comparison of arterial parameters between fibrate and statin groups; within the entire population and in matched groups, before and after adjustment for age, gender, body mass index, LDL cholesterol, systolic pressure, antihypertensive therapy, diabetes, history of cardiovascular disease and treatment duration only in matched groups. Unadjusted values are given as means ⫾ SD; adjusted values are given as means ⫾ SE.
France). Average IMT was the mean value of ⱖ100 successive local measures between the lumen–intima and media–adventitia interfaces every 10 m. Average lumen diameter was the mean value of ⱖ100 successive measures between the near wall and far wall lumen–intima interfaces. Variation coefficients of IMT and diameter measurements with this method were previously found to be 3.6% and 2.4%, respectively.14,15
other. The slopes of the relationships of IMT and diameter were compared between treatment groups by multivariate analysis of diameter on IMT, group category, and [IMT*group category] product. Statistical significance was set at P ⬍ .05.
Results Overall Study Population
Statistical Analysis Univariate comparisons were performed using the Student t test for quantitative parameters and the 2 test for qualitative variables. Univariate correlations were performed by the least-squares method. Multivariate analyses were performed by standard least-squares model by entering all of the independent parameters previously mentioned. These independent parameters were chosen for their clinical relevance as risk factors likely to affect IMT or diameter or both and also to avoid collinearity among each
Higher BMI (P ⬍ .01), total and LDL cholesterol (P ⬍ .001), and blood glucose (P ⬍ .05), as well as more frequent antihypertensive therapy (P ⬍ .001) and diabetes (P ⬍ .05), were found in the fibrate group than in the statin group (Table 2). The IMT was greater in the fibrate than in the statin group, both before and after adjustment for age, gender, BMI, LDL cholesterol, systolic BP, antihypertensive therapy, diabetes, and history of CVD (P ⱕ .01) (Table 3). Carotid diameter did not differ between groups (Table 3). Multivariate analysis of IMT showed indepen-
Table 4. Multivariate analysis of carotid intima-media thickness (IMT) in the entire study population and in matched groups Entire study population (n ⴝ 373) Independent variable Age (y) Gender (male ⫽ 1; female ⫽ 0) Lipid-lowering drug class (statin ⫽ 1; fibrate ⫽ 0) Body mass index (kg/m2) LDL cholesterol (mmol/L) Systolic pressure (mm Hg) Antihypertensive therapy (yes ⫽ 1; no ⫽ 0) Diabetes (yes ⫽ 1; no ⫽ 0) History of CVD (yes ⫽ 1; no ⫽ 0) Treatment duration (mo) R2 CVD ⫽ cardiovascular disease. Data are  estimates (SE) with P values.
 (SE) 0.004 0.001 0.019 0.003 0.007 0.002 0.002 0.002 0.037
(0.001) (0.007) (0.007) (0.001) (0.006) (0.001) (0.006) (0.008) (0.010) — 0.21
P value .0001 .9331 .0054 .0155 .2560 .0666 .7225 .7743 .0001 —
Matched groups (n ⴝ 164)
 (SE) 0.003 0.005 0.025 0.004 0.007 0.001 0.009 ⫺0.011 0.074 0.001
(0.001) (0.010) (0.008) (0.002) (0.009) (0.000) (0.010) (0.010) (0.025) (0.009) 0.27
P value .0032 .5881 .0020 .0425 .4201 .0158 .3672 .2718 .0036 .9606
CAROTID REMODELING STATIN AND FIBRATE TREATMENT
dent associations with age (P ⱕ .001), lipid treatment (P ⱕ .01), BMI (P ⱕ .05), and previous CVD (P ⱕ .001) (Table 4). No interaction existed between lipid-lowering drug class and other independent variables. Multivariate analysis of carotid diameter on the same variables was not statistically significant.
Discussion This work is the first to compare IMT under statin and fibrate therapy in a cohort of asymptomatic dyslipidemic subjects. Fibrate-treated subjects had a greater IMT, a steeper relationship between IMT and treatment duration (which may reflect IMT progression), and a weaker relationship between diameter and IMT (which may reflect compensatory carotid enlargement) than did the statintreated subjects. These differences were unexplained by difference in LDL cholesterol. The IMT difference between fibrate and statin treatment
Fibrate Group n=82 r=0.02 p=NS
Carotid IMT, mm
1.0
1.0 0.9
0.8
0.8
0.7
0.7
0.6
0.6
0.5
n=82 r=0.25 p<0.05
1.1
0.9
0.5
0.4
0.4 7
20
60
150
260
7
20
60
n=80 r=0.24 p<0.05
9
8
8
7
7
6
6
5
5 4 0.5
0.6
0.7
0.8
0.9
0.4
0.5
0.6
0.7
0.8
0.9
1.0
1.1
Carotid IMT, mm
Clinical and biological characteristics did not differ between groups except in duration of lipid-lowering therapy, with higher values in the fibrate than in the statin group (P ⬍ .05) (Table 2). The IMT was greater in the fibrate than in the statin group (P ⬍ .01), both before and after adjustment for age, gender, BMI, LDL cholesterol, systolic BP, antihypertensive therapy, diabetes, history of CVD and lipid-lowering therapy duration, whereas diameter was similar (Table 3). The IMT was positively correlated with treatment duration in the fibrate group (P ⬍ .05) but not in the statin group (Fig. 1). The IMT was positively correlated with diameter in statin and fibrate groups (P ⬍ .001, P ⬍ .05) (Fig. 2) with a lower slope in the latter (P ⬍ .05) ; this slope difference remained close to the level of significance after adjustment for LDL cholesterol (P ⫽ .08) and after adjustment for LDL cholesterol, age, gender, BMI, systolic BP, antihypertensive therapy, diabetes, smoking, previous CVD, and treatment duration (P ⫽ .06). Multivariate analysis of IMT showed independent associations with age (P ⱕ .01), lipid-lowering drug class (P ⱕ .01), BMI (P ⱕ .05), systolic BP (P ⱕ .05), and previous CVD (P ⱕ .01), but not with treatment duration (Table 4).
Statin Group
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Fibrate Group n=77 r=0.42 p<0.001
9
4 0.4
Matched Fibrate and Statin Groups
1.1
Statin Group
Carotid diameter, mm
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150
260
Lipid-lowering therapy duration, months (log-scale)
FIG. 1. Correlations of carotid artery intima-media thickness (IMT) with duration of lipid lowering therapy in matched groups of statins and fibrates treatment.
FIG. 2. Correlations of carotid artery diameter with intima-media thickness (IMT) in matched groups of statins and fibrates treatment.
groups is newly recognized and is relevant, as IMT predicts cardiovascular complications.1,2 The longer duration of fibrate treatment compared with statin treatment might have participated in such an IMT difference. First, the treatment duration may be a simple marker for the duration of dyslipidemia, so that IMT might be lower in the statin group because of a shorter disease duration. This is unlikely because the association between IMT and lipidlowering drug class persists after adjustment for treatment duration. On the other hand, assuming a similar effect of statin and fibrate on IMT, longer fibrate treatment should have induced a lower IMT and not the greater IMT that was observed. Thus the IMT difference between fibrate and statin treatments probably results from different effects of both classes of drugs on IMT progression. Longitudinal placebo-controlled trials have demonstrated that statin treatment reduced IMT progression3–9 and even induced IMT regression when statins were given at the highest dose.10,11 Studies of fibrates on IMT progression are scarce, but it has been shown that fibrates may prevent the increase in IMT.16 It has also been reported that 3 years of fenofibrate treatment reduced the progression of coronary atherosclerosis in diabetic patients.17 Nonetheless, in our study, the fact that a positive correlation existed between IMT and treatment duration in the fibrate group but not in the statin group suggests that fibrates are less likely to retard IMT progression than are statins. However, we cannot draw a conclusion as to whether fibrates provided less reduction of IMT progression than did statins, or whether they failed to block IMT progression. Moreover, both groups were constituted on the basis of current therapy at study entry, which does not exclude the possibility that certain fibrate-treated patients could previously have been treated with statins and vice versa. To clarify this issue, further longitudinal placebo-controlled trials with fibrates and using IMT as outcome are needed. In this study the greater IMT of fibrate-treated subjects was not explained by a lower reduction in LDL cholesterol. In the entire study population, the IMT difference between drugs remained significant after adjustment for LDL cholesterol. In matched groups, in which LDL cholesterol was similar, IMT was greater in the fibrate group than in the statin group. The lack of influence of LDL cholesterol on IMT difference between groups agrees with
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data in the literature showing that IMT progression did not correlate with LDL cholesterol changes under statin.8 Although other confounding factors are likely to modulate IMT,18 our multivariate analyses showed that they did not abolish the difference in IMT between both groups. Other lipoprotein-related mechanisms may have contributed to the IMT difference between statin and fibrate treatment, such as differences in triglycerides or HDL cholesterol8,10 However, these particles did not differ between statins and fibrates in the entire study population, probably because both treatments were prescribed for lowering LDL cholesterol irrespective of the presence of triglyceride and HDL cholesterol abnormalities. Currently the indication of using fibrates as an LDL-lowering drug treatment is no longer accepted,13 but at the time that the study subjects were assigned to treatment, the European guidelines for hypercholesterolemia19 indicated that the single drug treatment considered for persistent LDL cholesterol elevation could be bile acid sequestrant of either nicotin or fibrate derivatives (or both) or HMG-CoA reductase inhibitor. Finally, the pleiotropic effects of statins,20 such as inhibition of smooth-muscle cell proliferation,21 modification of the rate of lipid deposit in macrophages,22 and improvement of endothelial function23 may have contributed to decrease IMT to a greater extent in statin-treated than in fibrate-treated subjects, although such mechanisms could not be assessed in our study. A last interesting result was that the positive relationship between diameter and IMT was observed in both matched groups. This relationship may reflect carotid enlargement in response to early wall thickening.24,25 Nevertheless, the slope of the diameter– IMT relationship was lower in the fibrate group than in the statin group, even after adjustment for LDL cholesterol and other confounding factors. This suggests that other factors, such as statin-related improvement of endothelial function,23 may be involved in these distinct carotid enlargement slopes between drug types. Nonetheless it is unclear whether a lower carotid enlargement is actually detrimental or beneficial.24 By contrast, the 0.06-mm IMT difference between treatment groups has an important clinical significance. Indeed, in patients with established coronary disease, the Cholesterol Lowering Athersosclerosis Study (CLAS) showed that the risk for any coronary event was multiplied by three for each 0.03 mm increase per year of IMT.2,26 There are several notable limitations to this study. First, the fibrate and statin groups were constituted according to the current therapy at the time of subjects’ selection. This does not exclude that certain fibratetreated patients may have previously been treated with statin and vice versa. Unfortunately, precise information on lipid-lowering drug history for each patient was lacking. However this lack does not confound the IMT difference between the statin-treated and fibrate-treated groups. In the statin group, a previous switch from fibrate to statin may have contributed to increase IMT and so to blunt the IMT difference between groups. In
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the fibrate group, a previous switch from statin to fibrate is unlikely because of the current use of statin as firstline drug for treating hypercholesterolemia. In addition, we are unaware of the characteristics of each patient before treatment. Initial LDL cholesterol and cardiovascular risk may have been greater in the statin group than in the fibrate group, in agreement with cholesterol treatment guidelines. Nonetheless this suspected difference of initial risk level could not confound our results. Indeed, if the statin group really had a higher initial risk and therefore greater initial IMT, this difference should have prevented IMT from becoming lower under statin than under fibrate therapy. Furthermore, our cross-sectional study did not allow the follow-up of the time change in IMT, diameter, and other covariates. Therefore, further prospective studies comparing the effects of statins and fibrates on IMT are clearly needed. Finally, we focused our measures on the common carotid segment, which does not allow extrapolation to other carotid segments. However, the greatest precision and reproducibility are obtained in common carotid artery. In conclusion, the different influence of fibrate and statin treatment on carotid artery structure and remodeling suggested by the present findings questions the antiatherosclerotic effect of fibrate treatment, which needs to be assessed by longitudinal IMT trial.
References 1.
2.
3.
4.
5.
6.
7.
Hodis HN, Mack WJ, Barth J: Carotid intima-media thickness as a surrogate end point for coronary artery disease. Circulation 1996; 94:2311–2312. Simon A, Gariepy J, Chironi G, Megnien JL, Levenson J: Intimamedia thickness: a new tool for diagnosis and treatment of cardiovascular risk. J Hypertens 2002;20:159 –169. Blankenhorn DH, Selzer RH, Crawford DW, Barth JD, Liu CR, Liu CH, Mack WJ, Alaupovic P: Beneficial effects of colestipol-niacin therapy on the common carotid artery. Two- and four–year reduction of intima-media thickness measured by ultrasound. Circulation 1993;88:20 –28. Furberg CD, Adams HP Jr, Applegate WB, Byington RP, Espeland MA, Hartwell T, Hunninghake DB, Lefkowitz DS, Probstfield J, Riley WA: Effect of lovastatin on early carotid atherosclerosis and cardiovascular events. Asymptomatic Carotid Artery Progression Study (ACAPS) Research Group. Circulation 1994;90:1679 –1687. Salonen R, Nyyssonen K, Porkkala E, Rummukainen J, Belder R, Park JS, Salonen JT: Kuopio Atherosclerosis Prevention Study (KAPS). A population-based primary preventive trial of the effect of LDL lowering on atherosclerotic progression in carotid and femoral arteries. Circulation 1995;92:1758 –1764. Hodis HN, Mack WJ, LaBree L, Selzer RH, Liu C, Liu C, Alaupovic P, Kwong-Fu H, Azen SP: Reduction in carotid arterial wall thickness using lovastatin and dietary therapy: a randomized controlled clinical trial. Ann Intern Med 1996;124:548 –556. MacMahon S, Sharpe N, Gamble G, Hart H, Scott J, Simes J, White H: Effects of lowering average of below-average cholesterol levels on the progression of carotid atherosclerosis: results of the LIPID Atherosclerosis Substudy. LIPID Trial Research Group. Circulation 1998; 97:1784 –1790.
AJH–November 2005–VOL. 18, NO. 11
8.
9.
10.
11.
12. 13.
14.
15.
16.
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Baldassarre D, Veglia F, Gobbi C, Gallus G, Ventura A, Crepaldi G, Fisicaro M, Rimondi S, Ricci G, Mancini M, Bong MG, Collatina S, Sirtori CR: Intima-media thickness after pravastatin stabilizes also in patients with moderate to no reduction in LDL-cholesterol levels: the carotid atherosclerosis Italian ultrasound study. Atherosclerosis 2000;151:575–583. De Groot E, Jukema JW, Montauban van Swijndregt AD, Zwinderman AH, Ackerstaff RG, van der Steen AF, Bom N, Lie KI, Bruschke AV: B-mode ultrasound assessment of pravastatin treatment effect on carotid and femoral artery walls and its correlations with coronary arteriographic findings: a report of the Regression Growth Evaluation Statin Study (REGRESS). J Am Coll Cardiol 1998;31:1561–1567. Smilde TJ, van Wissen S, Wollersheim H, Trip MD, Kastelein JJ, Stalenhoef AF: Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolaemia (ASAP): a prospective, randomised, double blind trial. Lancet 2001;357:577–581. Taylor AJ, Kent SM, Flaherty PJ, Coyle LC, Markwood TT, Vernalis MN: ARBITER: Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol: a randomized trial comparing the effects of atorvastatin and pravastatin on carotid intima medial thickness. Circulation 2002;106:2055–2060. Topol EJ: Intensive statin therapy—a sea change in cardiovascular prevention. N Engl J Med 2004;350:1562-1564. National Education Cholesterol Program. Detection, Evaluation, and Treatment of High blood cholesterol in Adults (Adults Treatment Panel III). Circulation 2002;106:3143–3421. Graf S, Gariepy J, Massonneau M, Armentano RL, Mansour S, Barra JG, Simon A, Levenson J: Experimental and clinical validation of arterial diameter waveform and intimal media thickness obtained from B-mode ultrasound image processing. Ultrasound Med Biol 1999;25:1353–1363. Simon A, Gariepy J, Moyse D, Levenson J: Differential effects of nifedipine and co-amilozide on the progression of early carotid wall changes. Circulation 2001;103:2949 –2954. Mikgdalis IN, Gerolimou B, Kozanidou G, Voudouris G, Hatzigakis SM, Petroupoulos A: Effect of gemfibrozil on early carotid ather-
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
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sosclerosis in diabetic patients with hyperlipidaemia. Int Angiol 1997;16:258 –261. [No authors listed] Effect of fenofibrate on progression of coronaryartery disease in type 2 diabetes: the Diabetes Atherosclerosis Intervention Study, a randomized study. Lancet 2001;357:905–10. Gariepy J, Salomon J, Denarie N, Laskri F, Megnien JL, Levenson J, Simon A: Sex and topographic differences in associations between large-artery wall thickness and coronary risk profile in a French working cohort: the AXA Study. Arterioscler Thromb Vasc Biol 1998;18:584 –590. [No authors listed] The recognition and management of hyperlipidaemia in adults: a policy statement of the European Atherosclerosis Society. Eur Heart J 1988;9:571– 600. Rosenson RS, Tangney CC: Antiatherothrombotic properties of statins: implications for cardiovascular event reduction. J Am Med Assoc 1998;279:1643–1650. Corsini A, Mazzotti M, Raiteri M, Soma MR, Gabbiani G, Fumagalli R, Paoletti R: Relationship between mevalonate pathway and arterial myocyte proliferation: in vitro studies with inhibitors of HMG-CoA reductase. Atherosclerosis 1993;101:117–125. Keidar S, Aviram M, Maor I, Oiknine J, Brook JG: Pravastatin inhibits cellular cholesterol synthesis and increases low density lipoprotein receptor activity in macrophages: in vitro and in vivo studies. Br J Clin Pharmacol 1994;38:513–519. O’Driscoll G, Green D, Taylor RR: Simvastatin, an HMG-coenzyme A reductase inhibitor, improves endothelial function within 1 month. Circulation 1997;95:1126 –1131. Chironi G, Gariepy J, Denarie N, Balice M, Megnien JL, Levenson J, Simon A: Influence of hypertension on early carotid artery remodeling. Arterioscler Thromb Vasc Biol 2003;23:1460 –1484. Crouse JR, Goldbourt U, Evans G, Pinsky J, Sharrett AR, Sorlie P, Riley W, Heiss G: Arterial enlargement in the Atherosclerosis Risk in Communities (ARIC) cohort. In vivo quantification of carotid arterial enlargement. The ARIC Investigators. Stroke 1994;25:1354 –1359. Hodis HN, Mack WJ, LaBree L, Selzer RH, Liu CR, Liu CH, Azen SP: The role of carotid arterial intima-media thickness in predicting clinical coronary events. Ann Intern Med 1998;128:262–269.
2005; 18:1476 –1481
Differential Associations of Statin and Fibrate Treatment With Carotid Arterial Remodeling Gilles Chironi, Alain Simon, Jérôme Gariepy, Maria Balice, Muriel Del-Pino, and Jaime Levenson Background: The effects of statins on intima-media thickness (IMT) are well documented, whereas those of fibrates are unknown. Therefore we compared IMT under treatment with each class of drugs. Methods: We studied a cohort of consecutive dyslipidemic subjects treated with statin (n ⫽ 291) or fibrate (n ⫽ 82) drugs. Fibrate-treated subjects were matched with the same number of statin-treated subjects to obtain two subgroups of similar demographic and risk factors including LDL cholesterol. Common carotid far wall IMT and lumen diameter were measured by ultrasonography. Results: In the entire study population, IMT was greater in the fibrate group than in the statin group (P ⬍ .001), even after adjustment for LDL cholesterol and other covariates (P ⬍ .05). In the matched groups, IMT was greater in fibrate group than in the statin group (P ⬍ .01),
C
even after adjustment for LDL cholesterol and other covariates including treatment duration (P ⬍ .01). The IMT correlated positively with treatment duration in the fibrate group (P ⬍ 0.05) but not in the statin group. In addition, IMT correlated positively with carotid lumen diameter in both the fibrate and statin groups (P ⬍ .05, P ⬍ .01) but with a lower slope in the former (P ⬍ .05). Conclusions: In this study fibrate treatment was associated with greater IMT, steeper IMT–time relationship, and lower compensatory carotid enlargement than was statin treatment. These differences were not explained by differences in LDL cholesterol. Am J Hypertens 2005;18: 1476 –1481 © 2005 American Journal of Hypertension, Ltd. Key Words: Arterial remodeling, cardiovascular risk factors, carotid artery, fibrate derivatives, intima-media thickness, statins.
arotid intima-media thickness (IMT) is a surrogate endpoint for cardiovascular disease.1 Cross-sectional associations of IMT with cardiovascular risk factors and prevalent cardiovascular disease have been found, and prospective studies have shown that IMT predicted coronary artery disease and stroke.2 In hypercholesterolemia, HMG-CoA reductase inhibitors (statins), have been the subject of many clinical trials using IMT as an intermediate outcome.2 A retardation of IMT progression, or even a regression, has been shown under statin therapy, whatever the type of statin tested.3–11 This is consistent with the effectiveness of statins in reducing the incidence of the major atherosclerotic complications.12 By contrast, the effects of fibric acid derivatives (fibrates) have not been tested on IMT. This is surprising because whether fibrates reduce coronary risk in hyperlipemia is considered to be an important issue.13 The objective of this study was to assess carotid IMT in a cohort of
dyslipidemic patients treated with either statins or fibrates.
Received January 19, 2005. First decision May 16, 2005. Accepted May 20, 2005. From the Centre de Médecine Préventive Cardiovasculaire, Hôpital Broussais-Assistance Publique–Hôpitaux de Paris and Faculté de
Médecine Paris 5, Paris, France. Address correspondence and reprint requests to Prof. Alain Simon, Centre de Médecine Préventive Cardiovasculaire, Hôpital Broussais, 96 rue Didot, 75674, Paris, France; e-mail: [email protected]
0895-7061/05/$30.00 doi:10.1016/j.amjhyper.2005.05.019
Patients and Methods Study Population From March 2000 to June 2001, a total of 1895 consecutive men and women were referred to our clinic for 1-day hospitalization. Of them, 373 were selected because they fulfilled the following two conditions: 1) presence of lipid lowering treatment with either statin or fibrate for at least 3 months (Table 1); and 2) availability of carotid IMT and diameter data. These subjects constituted the entire study population (Table 2). Matched Groups Fibrate-treated subjects were matched with the same number of statin-treated subjects. The matching process was
© 2005 by the American Journal of Hypertension, Ltd. Published by Elsevier Inc.
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CAROTID REMODELING STATIN AND FIBRATE TREATMENT
Table 1. Distribution of lipid lowering treatments in the study overall population Drug class Statin Simvastatin Pravastatin Fluvastatin Atorvastatin Cerivastatin Fibrate Fenofibrate Bezafibrate Gemfibrozil Ciprofibrate
drug
Value 291 106 54 9 102 20 82 58 8 7 9
(78) (28) (15) (2) (28) (5) (22) (16) (2) (2) (2)
Values are number (%) of subjects.
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measured after overnight fast by enzymatic methods, and after precipitation of LDL and VLDL for HDL cholesterol. The LDL was calculated by the Friedewald formula: total cholesterol ⫺ HDL cholesterol ⫺ (triglycerides/2.2). Brachial blood pressure was measured at rest using a sphygmomanometer, and hypertension was defined as blood pressure (BP) ⱖ140 or ⱖ90 mmHg or the presence or antihypertensive therapy. Blood glucose was measured after an overnight fast; diabetes was defined as fasting glucose ⱖ7 mmol/L or the presence of antidiabetic treatment. Current smoking was defined as more than one cigarette per day for ⱖ3 months. Previous cardiovascular disease (CVD) was defined as the presence of current or past history of any cerebrovascular, coronary artery, or peripheral artery disease. Carotid Artery Geometry
performed one-to-one, by attributing to each fibratetreated patient a corresponding subject chosen among the 291 subjects of the statin group to obtain the same gender and closest values of age (⫾3 years) and other risk factors including LDL cholesterol (Table 2). The investigators responsible for the matching (AS, JL) were unaware of the subjects’ IMT. Risk Factors Risk factors were evaluated according to the guidelines of the National Education Cholesterol Program (Adult Treatment Panel III).13 Body mass index (BMI) was the ratio between weight and height squared. Blood lipids were
The imaging of IMT and lumen diameter of the distal segment of the right common carotid artery was performed according to a standardized procedure2,14,15 by means of high-resolution B-mode ultrasound imager (ATL 5000, Philips, Les Ulis, France). The IMT image, obtained in the far wall of the artery, consisted of two parallel echogenic lumen–intima and media–adventitia interfaces, free of any plaque visible on ⱖ1 cm of longitudinal length. Once the optimal quality of image of far wall IMT and diameter was obtained, it was frozen at end-diastole by electrocardiographic triggering (peak R wave), transferred to a computer equipped with digitization software, and analyzed by an automated edge-detection program (Iôtec, Iôdata, Paris,
Table 2. Characteristics of the entire study population and comparison between fibrate and statin groups
Parameter Number Age, (y) Men, n (%) Body mass index (kg/m2) Blood lipids, mmol/L Total cholesterol HDL cholesterol Triglycerides LDL cholesterol Duration of lipid-lowering therapy (mo) Blood pressure (mm Hg) Systolic Diastolic Hypertension, n (%) Antihypertensive therapy, n (%) Blood glucose (mmol/L) Diabetes, n (%) Current smoking, n (%) History of CVD, n (%)
Entire study population 373 56 ⫾ 10 285 (76) 26.9 ⫾ 4.0
Fibrate group 82 56 ⫾ 10 62 (76) 28.1 ⫾ 4.8
Statin group overall 291 56 ⫾ 9 223 (77) 26.6 ⫾ 3.8*
matched 82 56 ⫾ 10 62 (76) 27.4 ⫾ 3.9
5.34 1.33 1.46 3.34
⫾ 1.01 ⫾ 0.39 ⫾ 0.80 ⫾ 0.94 —
5.67 1.27 1.54 3.70 103
⫾ ⫾ ⫾ ⫾ ⫾
1.07 0.34 0.95 0.95 81
5.25 1.35 1.44 3.24
⫾ 0.98† ⫾ 0.40 ⫾ 0.76 ⫾ 0.92† —
5.50 1.33 1.46 3.50 77
⫾ ⫾ ⫾ ⫾ ⫾
139 84 251 188 5.91 52 64 34
⫾ 19 ⫾ 10 (67) (50) ⫾ 1.38 (14) (17) (9)
142 84 62 56 6.21 18 15 2
⫾ 21 ⫾ 10 (76) (68) ⫾ 1.77 (22) (18) (2)
138 84 189 132 5.83 34 49 32
⫾ 18 ⫾ 10 (65) (45)† ⫾ 1.24‡ (12)‡ (17) (11)
143 85 62 51 6.07 19 13 2
⫾ 20 ⫾ 12 (76) (62) ⫾ 1.47 (23) (16) (2)
1.04 0.34 0.76 1.02 63§
CVD ⫽ cardiovascular disease. Values are numbers, n (%) or means ⫾ SD. * P ⬍ .01, † P ⬍ .001, ‡ P ⬍ .05 when comparing overall statin group and fibrate group; § P ⬍ .05 when comparing matched statin and fibrate groups.
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Table 3. Comparison of arterial parameters between fibrate and statin groups Entire study population
Matched groups
Parameter
Fibrate (n ⴝ 82)
Statin (n ⴝ 291)
P value
Fibrate (n ⴝ 82)
Statin (n ⴝ 82)
P value
Carotid IMT (mm) Unadjusted Adjusted Carotid diameter (mm) Unadjusted Adjusted
0.63 ⫾ 0.12 0.65 ⫾ 0.02 (n ⫽ 80) 6.12 ⫾ 0.91 6.04 ⫾ 0.14
0.58 ⫾ 0.10 0.61 ⫾ 0.01 (n ⫽ 268) 6.08 ⫾ 1.11 6.10 ⫾ 0.10
⬍.01 ⬍.01
0.63 ⫾ 0.12 0.70 ⫾ 0.03 (n ⫽ 80) 6.12 ⫾ 0.91 5.85 ⫾ 0.23
0.57 ⫾ 0.08 0.65 ⫾ 0.03 (n ⫽ 77) 6.06 ⫾ 0.88 5.79 ⫾ 0.23
⬍.01 ⬍.01
NS NS
NS NS
IMT ⫽ intima-media thickness. Data are for comparison of arterial parameters between fibrate and statin groups; within the entire population and in matched groups, before and after adjustment for age, gender, body mass index, LDL cholesterol, systolic pressure, antihypertensive therapy, diabetes, history of cardiovascular disease and treatment duration only in matched groups. Unadjusted values are given as means ⫾ SD; adjusted values are given as means ⫾ SE.
France). Average IMT was the mean value of ⱖ100 successive local measures between the lumen–intima and media–adventitia interfaces every 10 m. Average lumen diameter was the mean value of ⱖ100 successive measures between the near wall and far wall lumen–intima interfaces. Variation coefficients of IMT and diameter measurements with this method were previously found to be 3.6% and 2.4%, respectively.14,15
other. The slopes of the relationships of IMT and diameter were compared between treatment groups by multivariate analysis of diameter on IMT, group category, and [IMT*group category] product. Statistical significance was set at P ⬍ .05.
Results Overall Study Population
Statistical Analysis Univariate comparisons were performed using the Student t test for quantitative parameters and the 2 test for qualitative variables. Univariate correlations were performed by the least-squares method. Multivariate analyses were performed by standard least-squares model by entering all of the independent parameters previously mentioned. These independent parameters were chosen for their clinical relevance as risk factors likely to affect IMT or diameter or both and also to avoid collinearity among each
Higher BMI (P ⬍ .01), total and LDL cholesterol (P ⬍ .001), and blood glucose (P ⬍ .05), as well as more frequent antihypertensive therapy (P ⬍ .001) and diabetes (P ⬍ .05), were found in the fibrate group than in the statin group (Table 2). The IMT was greater in the fibrate than in the statin group, both before and after adjustment for age, gender, BMI, LDL cholesterol, systolic BP, antihypertensive therapy, diabetes, and history of CVD (P ⱕ .01) (Table 3). Carotid diameter did not differ between groups (Table 3). Multivariate analysis of IMT showed indepen-
Table 4. Multivariate analysis of carotid intima-media thickness (IMT) in the entire study population and in matched groups Entire study population (n ⴝ 373) Independent variable Age (y) Gender (male ⫽ 1; female ⫽ 0) Lipid-lowering drug class (statin ⫽ 1; fibrate ⫽ 0) Body mass index (kg/m2) LDL cholesterol (mmol/L) Systolic pressure (mm Hg) Antihypertensive therapy (yes ⫽ 1; no ⫽ 0) Diabetes (yes ⫽ 1; no ⫽ 0) History of CVD (yes ⫽ 1; no ⫽ 0) Treatment duration (mo) R2 CVD ⫽ cardiovascular disease. Data are  estimates (SE) with P values.
 (SE) 0.004 0.001 0.019 0.003 0.007 0.002 0.002 0.002 0.037
(0.001) (0.007) (0.007) (0.001) (0.006) (0.001) (0.006) (0.008) (0.010) — 0.21
P value .0001 .9331 .0054 .0155 .2560 .0666 .7225 .7743 .0001 —
Matched groups (n ⴝ 164)
 (SE) 0.003 0.005 0.025 0.004 0.007 0.001 0.009 ⫺0.011 0.074 0.001
(0.001) (0.010) (0.008) (0.002) (0.009) (0.000) (0.010) (0.010) (0.025) (0.009) 0.27
P value .0032 .5881 .0020 .0425 .4201 .0158 .3672 .2718 .0036 .9606
CAROTID REMODELING STATIN AND FIBRATE TREATMENT
dent associations with age (P ⱕ .001), lipid treatment (P ⱕ .01), BMI (P ⱕ .05), and previous CVD (P ⱕ .001) (Table 4). No interaction existed between lipid-lowering drug class and other independent variables. Multivariate analysis of carotid diameter on the same variables was not statistically significant.
Discussion This work is the first to compare IMT under statin and fibrate therapy in a cohort of asymptomatic dyslipidemic subjects. Fibrate-treated subjects had a greater IMT, a steeper relationship between IMT and treatment duration (which may reflect IMT progression), and a weaker relationship between diameter and IMT (which may reflect compensatory carotid enlargement) than did the statintreated subjects. These differences were unexplained by difference in LDL cholesterol. The IMT difference between fibrate and statin treatment
Fibrate Group n=82 r=0.02 p=NS
Carotid IMT, mm
1.0
1.0 0.9
0.8
0.8
0.7
0.7
0.6
0.6
0.5
n=82 r=0.25 p<0.05
1.1
0.9
0.5
0.4
0.4 7
20
60
150
260
7
20
60
n=80 r=0.24 p<0.05
9
8
8
7
7
6
6
5
5 4 0.5
0.6
0.7
0.8
0.9
0.4
0.5
0.6
0.7
0.8
0.9
1.0
1.1
Carotid IMT, mm
Clinical and biological characteristics did not differ between groups except in duration of lipid-lowering therapy, with higher values in the fibrate than in the statin group (P ⬍ .05) (Table 2). The IMT was greater in the fibrate than in the statin group (P ⬍ .01), both before and after adjustment for age, gender, BMI, LDL cholesterol, systolic BP, antihypertensive therapy, diabetes, history of CVD and lipid-lowering therapy duration, whereas diameter was similar (Table 3). The IMT was positively correlated with treatment duration in the fibrate group (P ⬍ .05) but not in the statin group (Fig. 1). The IMT was positively correlated with diameter in statin and fibrate groups (P ⬍ .001, P ⬍ .05) (Fig. 2) with a lower slope in the latter (P ⬍ .05) ; this slope difference remained close to the level of significance after adjustment for LDL cholesterol (P ⫽ .08) and after adjustment for LDL cholesterol, age, gender, BMI, systolic BP, antihypertensive therapy, diabetes, smoking, previous CVD, and treatment duration (P ⫽ .06). Multivariate analysis of IMT showed independent associations with age (P ⱕ .01), lipid-lowering drug class (P ⱕ .01), BMI (P ⱕ .05), systolic BP (P ⱕ .05), and previous CVD (P ⱕ .01), but not with treatment duration (Table 4).
Statin Group
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Fibrate Group n=77 r=0.42 p<0.001
9
4 0.4
Matched Fibrate and Statin Groups
1.1
Statin Group
Carotid diameter, mm
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150
260
Lipid-lowering therapy duration, months (log-scale)
FIG. 1. Correlations of carotid artery intima-media thickness (IMT) with duration of lipid lowering therapy in matched groups of statins and fibrates treatment.
FIG. 2. Correlations of carotid artery diameter with intima-media thickness (IMT) in matched groups of statins and fibrates treatment.
groups is newly recognized and is relevant, as IMT predicts cardiovascular complications.1,2 The longer duration of fibrate treatment compared with statin treatment might have participated in such an IMT difference. First, the treatment duration may be a simple marker for the duration of dyslipidemia, so that IMT might be lower in the statin group because of a shorter disease duration. This is unlikely because the association between IMT and lipidlowering drug class persists after adjustment for treatment duration. On the other hand, assuming a similar effect of statin and fibrate on IMT, longer fibrate treatment should have induced a lower IMT and not the greater IMT that was observed. Thus the IMT difference between fibrate and statin treatments probably results from different effects of both classes of drugs on IMT progression. Longitudinal placebo-controlled trials have demonstrated that statin treatment reduced IMT progression3–9 and even induced IMT regression when statins were given at the highest dose.10,11 Studies of fibrates on IMT progression are scarce, but it has been shown that fibrates may prevent the increase in IMT.16 It has also been reported that 3 years of fenofibrate treatment reduced the progression of coronary atherosclerosis in diabetic patients.17 Nonetheless, in our study, the fact that a positive correlation existed between IMT and treatment duration in the fibrate group but not in the statin group suggests that fibrates are less likely to retard IMT progression than are statins. However, we cannot draw a conclusion as to whether fibrates provided less reduction of IMT progression than did statins, or whether they failed to block IMT progression. Moreover, both groups were constituted on the basis of current therapy at study entry, which does not exclude the possibility that certain fibrate-treated patients could previously have been treated with statins and vice versa. To clarify this issue, further longitudinal placebo-controlled trials with fibrates and using IMT as outcome are needed. In this study the greater IMT of fibrate-treated subjects was not explained by a lower reduction in LDL cholesterol. In the entire study population, the IMT difference between drugs remained significant after adjustment for LDL cholesterol. In matched groups, in which LDL cholesterol was similar, IMT was greater in the fibrate group than in the statin group. The lack of influence of LDL cholesterol on IMT difference between groups agrees with
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data in the literature showing that IMT progression did not correlate with LDL cholesterol changes under statin.8 Although other confounding factors are likely to modulate IMT,18 our multivariate analyses showed that they did not abolish the difference in IMT between both groups. Other lipoprotein-related mechanisms may have contributed to the IMT difference between statin and fibrate treatment, such as differences in triglycerides or HDL cholesterol8,10 However, these particles did not differ between statins and fibrates in the entire study population, probably because both treatments were prescribed for lowering LDL cholesterol irrespective of the presence of triglyceride and HDL cholesterol abnormalities. Currently the indication of using fibrates as an LDL-lowering drug treatment is no longer accepted,13 but at the time that the study subjects were assigned to treatment, the European guidelines for hypercholesterolemia19 indicated that the single drug treatment considered for persistent LDL cholesterol elevation could be bile acid sequestrant of either nicotin or fibrate derivatives (or both) or HMG-CoA reductase inhibitor. Finally, the pleiotropic effects of statins,20 such as inhibition of smooth-muscle cell proliferation,21 modification of the rate of lipid deposit in macrophages,22 and improvement of endothelial function23 may have contributed to decrease IMT to a greater extent in statin-treated than in fibrate-treated subjects, although such mechanisms could not be assessed in our study. A last interesting result was that the positive relationship between diameter and IMT was observed in both matched groups. This relationship may reflect carotid enlargement in response to early wall thickening.24,25 Nevertheless, the slope of the diameter– IMT relationship was lower in the fibrate group than in the statin group, even after adjustment for LDL cholesterol and other confounding factors. This suggests that other factors, such as statin-related improvement of endothelial function,23 may be involved in these distinct carotid enlargement slopes between drug types. Nonetheless it is unclear whether a lower carotid enlargement is actually detrimental or beneficial.24 By contrast, the 0.06-mm IMT difference between treatment groups has an important clinical significance. Indeed, in patients with established coronary disease, the Cholesterol Lowering Athersosclerosis Study (CLAS) showed that the risk for any coronary event was multiplied by three for each 0.03 mm increase per year of IMT.2,26 There are several notable limitations to this study. First, the fibrate and statin groups were constituted according to the current therapy at the time of subjects’ selection. This does not exclude that certain fibratetreated patients may have previously been treated with statin and vice versa. Unfortunately, precise information on lipid-lowering drug history for each patient was lacking. However this lack does not confound the IMT difference between the statin-treated and fibrate-treated groups. In the statin group, a previous switch from fibrate to statin may have contributed to increase IMT and so to blunt the IMT difference between groups. In
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the fibrate group, a previous switch from statin to fibrate is unlikely because of the current use of statin as firstline drug for treating hypercholesterolemia. In addition, we are unaware of the characteristics of each patient before treatment. Initial LDL cholesterol and cardiovascular risk may have been greater in the statin group than in the fibrate group, in agreement with cholesterol treatment guidelines. Nonetheless this suspected difference of initial risk level could not confound our results. Indeed, if the statin group really had a higher initial risk and therefore greater initial IMT, this difference should have prevented IMT from becoming lower under statin than under fibrate therapy. Furthermore, our cross-sectional study did not allow the follow-up of the time change in IMT, diameter, and other covariates. Therefore, further prospective studies comparing the effects of statins and fibrates on IMT are clearly needed. Finally, we focused our measures on the common carotid segment, which does not allow extrapolation to other carotid segments. However, the greatest precision and reproducibility are obtained in common carotid artery. In conclusion, the different influence of fibrate and statin treatment on carotid artery structure and remodeling suggested by the present findings questions the antiatherosclerotic effect of fibrate treatment, which needs to be assessed by longitudinal IMT trial.
References 1.
2.
3.
4.
5.
6.
7.
Hodis HN, Mack WJ, Barth J: Carotid intima-media thickness as a surrogate end point for coronary artery disease. Circulation 1996; 94:2311–2312. Simon A, Gariepy J, Chironi G, Megnien JL, Levenson J: Intimamedia thickness: a new tool for diagnosis and treatment of cardiovascular risk. J Hypertens 2002;20:159 –169. Blankenhorn DH, Selzer RH, Crawford DW, Barth JD, Liu CR, Liu CH, Mack WJ, Alaupovic P: Beneficial effects of colestipol-niacin therapy on the common carotid artery. Two- and four–year reduction of intima-media thickness measured by ultrasound. Circulation 1993;88:20 –28. Furberg CD, Adams HP Jr, Applegate WB, Byington RP, Espeland MA, Hartwell T, Hunninghake DB, Lefkowitz DS, Probstfield J, Riley WA: Effect of lovastatin on early carotid atherosclerosis and cardiovascular events. Asymptomatic Carotid Artery Progression Study (ACAPS) Research Group. Circulation 1994;90:1679 –1687. Salonen R, Nyyssonen K, Porkkala E, Rummukainen J, Belder R, Park JS, Salonen JT: Kuopio Atherosclerosis Prevention Study (KAPS). A population-based primary preventive trial of the effect of LDL lowering on atherosclerotic progression in carotid and femoral arteries. Circulation 1995;92:1758 –1764. Hodis HN, Mack WJ, LaBree L, Selzer RH, Liu C, Liu C, Alaupovic P, Kwong-Fu H, Azen SP: Reduction in carotid arterial wall thickness using lovastatin and dietary therapy: a randomized controlled clinical trial. Ann Intern Med 1996;124:548 –556. MacMahon S, Sharpe N, Gamble G, Hart H, Scott J, Simes J, White H: Effects of lowering average of below-average cholesterol levels on the progression of carotid atherosclerosis: results of the LIPID Atherosclerosis Substudy. LIPID Trial Research Group. Circulation 1998; 97:1784 –1790.
AJH–November 2005–VOL. 18, NO. 11
8.
9.
10.
11.
12. 13.
14.
15.
16.
CAROTID REMODELING STATIN AND FIBRATE TREATMENT
Baldassarre D, Veglia F, Gobbi C, Gallus G, Ventura A, Crepaldi G, Fisicaro M, Rimondi S, Ricci G, Mancini M, Bong MG, Collatina S, Sirtori CR: Intima-media thickness after pravastatin stabilizes also in patients with moderate to no reduction in LDL-cholesterol levels: the carotid atherosclerosis Italian ultrasound study. Atherosclerosis 2000;151:575–583. De Groot E, Jukema JW, Montauban van Swijndregt AD, Zwinderman AH, Ackerstaff RG, van der Steen AF, Bom N, Lie KI, Bruschke AV: B-mode ultrasound assessment of pravastatin treatment effect on carotid and femoral artery walls and its correlations with coronary arteriographic findings: a report of the Regression Growth Evaluation Statin Study (REGRESS). J Am Coll Cardiol 1998;31:1561–1567. Smilde TJ, van Wissen S, Wollersheim H, Trip MD, Kastelein JJ, Stalenhoef AF: Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolaemia (ASAP): a prospective, randomised, double blind trial. Lancet 2001;357:577–581. Taylor AJ, Kent SM, Flaherty PJ, Coyle LC, Markwood TT, Vernalis MN: ARBITER: Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol: a randomized trial comparing the effects of atorvastatin and pravastatin on carotid intima medial thickness. Circulation 2002;106:2055–2060. Topol EJ: Intensive statin therapy—a sea change in cardiovascular prevention. N Engl J Med 2004;350:1562-1564. National Education Cholesterol Program. Detection, Evaluation, and Treatment of High blood cholesterol in Adults (Adults Treatment Panel III). Circulation 2002;106:3143–3421. Graf S, Gariepy J, Massonneau M, Armentano RL, Mansour S, Barra JG, Simon A, Levenson J: Experimental and clinical validation of arterial diameter waveform and intimal media thickness obtained from B-mode ultrasound image processing. Ultrasound Med Biol 1999;25:1353–1363. Simon A, Gariepy J, Moyse D, Levenson J: Differential effects of nifedipine and co-amilozide on the progression of early carotid wall changes. Circulation 2001;103:2949 –2954. Mikgdalis IN, Gerolimou B, Kozanidou G, Voudouris G, Hatzigakis SM, Petroupoulos A: Effect of gemfibrozil on early carotid ather-
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
1481
sosclerosis in diabetic patients with hyperlipidaemia. Int Angiol 1997;16:258 –261. [No authors listed] Effect of fenofibrate on progression of coronaryartery disease in type 2 diabetes: the Diabetes Atherosclerosis Intervention Study, a randomized study. Lancet 2001;357:905–10. Gariepy J, Salomon J, Denarie N, Laskri F, Megnien JL, Levenson J, Simon A: Sex and topographic differences in associations between large-artery wall thickness and coronary risk profile in a French working cohort: the AXA Study. Arterioscler Thromb Vasc Biol 1998;18:584 –590. [No authors listed] The recognition and management of hyperlipidaemia in adults: a policy statement of the European Atherosclerosis Society. Eur Heart J 1988;9:571– 600. Rosenson RS, Tangney CC: Antiatherothrombotic properties of statins: implications for cardiovascular event reduction. J Am Med Assoc 1998;279:1643–1650. Corsini A, Mazzotti M, Raiteri M, Soma MR, Gabbiani G, Fumagalli R, Paoletti R: Relationship between mevalonate pathway and arterial myocyte proliferation: in vitro studies with inhibitors of HMG-CoA reductase. Atherosclerosis 1993;101:117–125. Keidar S, Aviram M, Maor I, Oiknine J, Brook JG: Pravastatin inhibits cellular cholesterol synthesis and increases low density lipoprotein receptor activity in macrophages: in vitro and in vivo studies. Br J Clin Pharmacol 1994;38:513–519. O’Driscoll G, Green D, Taylor RR: Simvastatin, an HMG-coenzyme A reductase inhibitor, improves endothelial function within 1 month. Circulation 1997;95:1126 –1131. Chironi G, Gariepy J, Denarie N, Balice M, Megnien JL, Levenson J, Simon A: Influence of hypertension on early carotid artery remodeling. Arterioscler Thromb Vasc Biol 2003;23:1460 –1484. Crouse JR, Goldbourt U, Evans G, Pinsky J, Sharrett AR, Sorlie P, Riley W, Heiss G: Arterial enlargement in the Atherosclerosis Risk in Communities (ARIC) cohort. In vivo quantification of carotid arterial enlargement. The ARIC Investigators. Stroke 1994;25:1354 –1359. Hodis HN, Mack WJ, LaBree L, Selzer RH, Liu CR, Liu CH, Azen SP: The role of carotid arterial intima-media thickness in predicting clinical coronary events. Ann Intern Med 1998;128:262–269.