Published online before print April 14, 2008, doi: 10.1161/CIRCULATIONAHA.107.746610
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(Circulation. 2008;117:2123-2130.)
© 2008 American Heart Association, Inc.
Vascular Medicine |
Increased High-Density Lipoprotein Cholesterol Predicts the Pioglitazone-Mediated Reduction of Carotid Intima-Media Thickness Progression in Patients With Type 2 Diabetes Mellitus
From the Pritzker School of Medicine (M.D.), The University of Chicago, Chicago, Ill; Department of Preventive Medicine (P.M.M., Z.C.) and Department of Medicine, Section of Cardiology (S.F.), Rush University Medical Center, Chicago, Ill; Department of Medicine, University of Texas Health Science Center (S.H.), San Antonio, Tex; Department of Mathematics (R.D.), Statistics and Consulting Unit, Boston University, Boston, Mass; Department of Medicine (T.M.) and Department of Medicine, Section of Cardiology (G.T.K.), University of Illinois College of Medicine, Chicago, Ill; and Takeda Global Research and Development, Ltd (A.P.), Deerfield, Ill.
Correspondence to Theodore Mazzone, MD, Section of Endocrinology, Diabetes and Metabolism (MC 797), University of Illinois at Chicago, 1819 W Polk St, Chicago, IL 60612. E-mail tmazzone{at}uic.edu
Received October 16, 2007; accepted February 20, 2008.
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Abstract |
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Background— Measurement of carotid intima-media thickness (CIMT) has been validated as a measure of atherosclerosis and as a predictor of future cardiovascular events. Compared with glimepiride, pioglitazone has been shown to slow the progression of atherosclerosis measured by CIMT in patients with type 2 diabetes mellitus.
Methods and Results— We evaluated individual cardiovascular risk factors as predictors of the change in CIMT produced by pioglitazone treatment by determining whether their addition to a baseline model resulted in loss of significance for the treatment effect on CIMT. Pioglitazone treatment led to improvement in levels of multiple cardiovascular risk markers, including high-sensitivity C-reactive protein, apolipoprotein B, apolipoprotein A1, high-density lipoprotein (HDL) cholesterol, triglyceride, insulin, and free fatty acid. At 24 weeks, there were significant differences in HDL cholesterol, triglyceride, total cholesterol, low-density lipoprotein cholesterol, insulin, body mass index, hip circumference, and high-sensitivity C-reactive protein between the pioglitazone and glimepiride treatment groups. After adjustment for 24-week on-treatment values of cardiovascular risk factors, only inclusion of the changes in HDL cholesterol and insulin significantly impacted the magnitude and significance of the treatment effect on CIMT. Furthermore, irrespective of treatment assignment, increased HDL cholesterol at 24 weeks was a significant predictor of reduced CIMT progression at 72 weeks.
Conclusions— The beneficial effect of pioglitazone on HDL cholesterol at 24 weeks predicted its beneficial effect for reducing CIMT progression at 72 weeks. Changes in HDL cholesterol at 24 weeks, irrespective of treatment, predicted less progression of CIMT at 72 weeks. These results suggest that suppression of atherosclerosis with pioglitazone therapy is linked to its ability to raise HDL cholesterol.
Key Words: atherosclerosis • lipoproteins • diabetes mellitus
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Introduction |
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Measurement of carotid intimal-medial thickness (CIMT) is a validated approach for monitoring atherosclerosis progression, and CIMT has been shown to be highly predictive of future cardiovascular events and cardiovascular death.1–4 Measurement of CIMT has also been shown to be useful for assessing the effect of therapeutic agents on atherosclerosis progression or regression. Statins and niacin, both established agents for reducing cardiovascular events, have also been shown to reduce progression of CIMT.5–7 There is currently a large increase in the prevalence of diabetes, and cardiovascular disease is the most important cause of morbidity and mortality in diabetes.8,9 It is therefore important to assess new approaches for reducing the risk of cardiovascular disease in subjects with diabetes.10,11 In the CHICAGO study (Carotid Intima-Media Thickness in Atherosclerosis Using Pioglitazone),12 the effect of pioglitazone versus glimepiride on CIMT in subjects with type 2 diabetes mellitus was assessed over a 72-week treatment period. The study was designed to test the hypothesis that pioglitazone would have a beneficial effect for reducing CIMT progression compared with glimepiride. This hypothesis was based on the established effects of thiazolidinediones in reducing atherosclerosis in animal models and favorably modifying cardiovascular risk factors in humans.13–19 For example, in patients with type 2 diabetes mellitus, treatment with pioglitazone has been shown not only to improve indices of glycemia but also to favorably modify levels of inflammatory factors, coagulation factors, lipid and apolipoprotein levels, and blood pressure.
Clinical Perspective p 2130
In the CHICAGO study, pioglitazone significantly reduced progression of mean CIMT in the posterior wall of the common carotid arteries compared with glimepiride.12 Pioglitazone also reduced progression of maximum CIMT at this site. In addition to measuring treatment-related changes on CIMT in the CHICAGO trial, the investigators also measured the treatment effect on parameters implicated as cardiovascular risk factors in diabetes. The availability of these measures provides an important opportunity for analyzing the relationship of these factors to a validated measure of atherosclerosis progression in diabetes. The importance of this analysis is emphasized by recent reports that large increases in high-density lipoprotein (HDL) cholesterol, a well-validated protective factor against atherosclerosis and cardiovascular disease events in observational studies, did not have a beneficial effect on atherosclerosis progression in subjects treated with torcetrapib, an inhibitor of cholesterol ester transfer protein.20–22 Examination of the relationship of treatment-related changes in cardiovascular risk factors to changes in atherosclerosis could also provide insight into a potential mechanism for the beneficial effect of pioglitazone on atherosclerosis.
Here, we present detailed results concerning the effects of pioglitazone and glimepiride on cardiovascular risk factors in diabetes. We further evaluate the relationship of baseline and on-treatment changes in cardiovascular risk factors to treatment-related changes in CIMT over the course of the study.
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Methods |
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Study Design and Participants
CHICAGO was a prospective, randomized, double-blind, comparator-controlled, multicenter study conducted between October 2003 and May 2006 in a multiracial and multiethnic population at 28 clinical sites in the Chicago, Ill, metropolitan area. Eligible subjects were men and women 45 to 85 years of age with type 2 diabetes mellitus (by American Diabetes Association criteria) who were newly diagnosed; had their diabetes controlled by diet or by taking sulfonylurea or metformin monotherapy, sulfonylurea/metformin combination therapy, or insulin; and were asymptomatic for coronary artery disease. The complete trial design has been reported previously.12
Randomized treatment consisted of pioglitazone hydrochloride (15 to 45 mg/d) or glimepiride (1 to 4 mg/d). The use of metformin or insulin was allowed in either group to reach glycemic goals. The study protocol specified adherence to American Diabetes Association guidelines for lipid and blood pressure control that were current at the start of the study.23,24 The primary end point of the study was absolute change from baseline to final visit in mean posterior-wall CIMT in the right and left common carotid arteries. Absolute change in maximal CIMT from baseline to final visit was included as a secondary end point.
The study protocol was approved by central or local institutional review board committees, and all participants provided written informed consent.
Laboratory Measurements
The following parameters were measured at a central laboratory (Clinical Reference Laboratory; Lenexa, Kan): triglyceride, total cholesterol, and plasma glucose levels from fasting blood samples, measured by standard enzymatic methods (Roche Diagnostics, Indianapolis, Ind); HDL and low-density lipoprotein (LDL) cholesterol, measured by direct methods,12 and hemoglobin A1c values, measured by high-performance liquid chromatography (Bio-Rad, Hercules, Calif); free fatty acid, measured by the Wako enzymatic method (Wako Chemicals, Richmond, Va); apolipoprotein (apo)-B and apo-A1, measured by immunoturbidimetry (Hitachi/Roche Diagnostics, Basel, Switzerland); human insulin, measured by ELISA (Linco, St. Charles, Mo); and high-sensitivity C-reactive protein (hs-CRP), measured by immunoturbidimetry (Roche Diagnostics). Methods for CIMT measurements have been described in detail previously.12
Statistical Analysis
Means, SDs, medians, and quartiles were used to summarize baseline values and changes in values of the various measures at 24 and 72 weeks. The average percent of missing values was small at baseline and at 24 weeks (1.3% at baseline, 4.6% at 24 weeks, and 19.1% at 72 weeks). Consistent with the primary outcome report,12 we used the last observation carried forward for CIMT at 72 weeks to include data from subjects who participated in the study but did not complete the entire study. Statistical tests were used to compare 24- and 72-week observed values with baseline. Lipids, fasting plasma glucose, and insulin were log-transformed before tests were performed because of skewed distributions. With the exception of hs-CRP, probability values from paired t tests were used as indicators of whether changes over time within treatment groups were significant. We tested for differences in hs-CRP using paired Wilcoxon tests.
We estimated and tested for treatment group differences for each cardiovascular risk predictor in terms of baseline and 24-week changes using observed values. Baseline and 24-week differences were tested with ANCOVA models. Baseline models adjusted for site and treatment group, whereas models for 24-week change also included baseline values as a covariate. Lipids, fasting plasma glucose, and insulin were log-transformed because of skewed distributions. There were 
25 models fit for each time category, so we determined significance using a Bonferroni adjusted cutoff of 0.05/25=0.002.
Primary interest of the present study focused on identifying predictors and potential mediators of the treatment effect. To identify these, we added change (measured at 24 weeks) to an ANCOVA model for 72-week change in CIMT that already included baseline CIMT (consistent with the International Conference on Harmonisation E9 guidelines25), site, and treatment group. The percentage change in the treatment effect estimate relative to a model that did not include the new predictor was calculated, as was the probability value for the treatment effect in the new model. Those predictors that resulted in the treatment effect becoming nonsignificant were identified as predictors, and therefore potential mediators, of the treatment effect. We next added these to ANCOVA models that included only baseline CIMT and site, to evaluate their relationship to CIMT before adjustment for treatment effect (ie, irrespective of treatment).
We examined Cook’s distance (to determine whether conclusions rested only on a few influential values) for observations in models that included HDL cholesterol and insulin and repeated fits after the exclusion of observations with the largest values of Cook’s distance. Because results were similar to the results utilizing the full sample, results for the reduced sample are not shown. We used a bootstrap analysis to test whether the impact of HDL cholesterol on the treatment effect estimate was sensitive to small changes in sample composition. Using 10 000 ordinary replicates, we constructed bias-corrected and adjusted CIs for the treatment effect and compared these with the model-based CI. Because the only missing values in the model for change in CIMT that included HDL cholesterol were 7 missing HDL cholesterol values (<2%), we did not pursue multiple imputation or other missing data techniques, consistent with the advice of Harrell26 that missing data techniques are unlikely to alter results when the proportion of missing data is small. Analyses were performed in R version 2.3.027 (including the bootstrap functions of Canty) and confirmed with SAS/STAT software version 9.1.3.
The authors had full access to the data and take full responsibility for its integrity. All authors have read and agree to the manuscript as written.
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Results |
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Table 1 presents descriptive statistics for personal characteristics, blood pressure, lipid, glycemic, anthropometric, and inflammatory measures at baseline and for changes at 24 and 72 weeks by treatment group. Both treatment groups demonstrated significant increases in weight and body mass index, as well as in apoA1. Both treatment groups also demonstrated decreases in free fatty acid level, glycohemoglobin, and fasting plasma glucose levels. In the pioglitazone-treatment group, there were significant increases in LDL cholesterol at 24 weeks and in HDL cholesterol at 24 and 72 weeks. Also in this treatment group, triglyceride levels fell significantly at 24 and 72 weeks, as did apoB and fasting insulin levels. Waist circumference was increased significantly at 72 weeks and hip circumference was increased significantly at 24 and 72 weeks in the pioglitazone-treatment group. hs-CRP levels were decreased in the pioglitazone-treatment group at 24 and 72 weeks and in the glimepiride-treatment group at 72 weeks.
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We next wanted to evaluate whether differences in these parameters, which have previously been associated with risk for cardiovascular disease or atherosclerosis, were related to the treatment effect on CIMT. We evaluated differences between the treatment groups in these parameters at baseline and in terms of 24-week change and examined the relationship of baseline and 24-week differences to treatment effects on CIMT at 72 weeks. In Table 2, statistics for treatment-group differences at baseline and change at 24 weeks are presented. For most parameters, differences were evaluated on a log scale and are calculated as the value for the pioglitazone-treatment group minus that for the glimepiride-treatment group. Positive numbers, therefore, indicate higher values in the pioglitazone group. None of the parameters presented in Table 2 significantly differed by treatment group at baseline. HDL cholesterol, total cholesterol, LDL cholesterol, and hip circumference were increased significantly in the pioglitazone group compared with the glimepiride group at 24 weeks. Total triglyceride level, insulin level, and hs-CRP were decreased significantly at 24 weeks in the pioglitazone-treatment group compared with the glimepiride group. Weight and body mass index were almost significantly different between the treatment groups, being higher for pioglitazone.
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We next focused on identifying potential mediators of the pioglitazone-treatment effect on CIMT. The parameters shown in Table 2 were added to an ANCOVA model for 72-week change in CIMT that already included baseline CIMT, study site, and treatment group. There was no effect of any of the baseline parameters on treatment-mediated changes in CIMT at 72 weeks (not shown). Although there were numerous measures with a pattern of change that differed between the treatment groups at 24 weeks (Table 2), there were only 2 for which inclusion in a model predicting 72-week change in mean CIMT resulted in a loss of significance for the treatment effect: 
log HDL cholesterol and log fasting insulin (calculated as log week 24 minus log baseline value; Table 3). None of the other parameters shown in Table 2 impacted the treatment effect of pioglitazone on mean CIMT, and several of these are also included in Table 3. The addition of log HDL cholesterol resulted in a 30.7% decrease in the estimated treatment effect, whereas the addition of log insulin resulted in a 19.8% decrease; the addition of both was almost additive in attenuating the treatment effect by 46.2%, which suggests they were associated with somewhat independent aspects of the treatment effect. A bootstrap CI for treatment effect with the inclusion of log HDL was similar to the model-based CI. A similar analysis was done for treatment effect on maximal CIMT. The addition of log HDL cholesterol level resulted in a 25.6% decrease in estimated treatment effect, with a subsequent loss of significance for treatment effect on maximal CIMT (Table 4). The addition of log insulin resulted in a 4.8% decrease. The addition of both together attenuated the treatment effect by 33.3%.
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As an additional means of examining the importance of change in HDL cholesterol or insulin at 24 weeks for change in CIMT at 72 weeks, we next evaluated whether change in either parameter at 24 weeks was significantly related to change in mean or maximal CIMT at 72 weeks in the entire cohort. These results are shown in Table 5. An increase in HDL cholesterol level at 24 weeks significantly predicted less progression of both mean and maximal CIMT. The predictive value of increased HDL cholesterol at 24 weeks for CIMT benefit at 72 weeks was similar in statin users and nonusers (P=0.82 for interaction). In addition, there was no impact of either race or gender on the relationship between change in HDL and change in CIMT shown in Table 5 (P values for interaction were 0.10 for race and 0.62 for gender). Twenty-four-week change in insulin did not significantly predict change in either mean or maximal CIMT at 72 weeks (Table 5). Quartiles of log HDL cholesterol change at 24 weeks were also significantly related to change in CIMT at 72 weeks. Compared with the first quartile (used as the referent group), subjects in the second quartile had a reduction of CIMT of 0.013±0.008 mm, those in the third quartile had a 0.016±0.008-mm reduction, and those in the fourth quartile had a 0.024±0.008-mm reduction (P=0.02 for trend). An increase in HDL cholesterol of 5% to 16% (which corresponded to the third quartile of log HDL cholesterol change) at 24 weeks predicted a significant benefit for CIMT at 72 weeks.
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Discussion |
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The results of the present report demonstrate that pioglitazone treatment produces a substantial benefit in multiple parameters that have been proposed as putative risk factors for atherosclerosis and/or cardiovascular events in patients with diabetes mellitus. Treatment with pioglitazone produced improvement in hs-CRP, systolic blood pressure, free fatty acid levels, apolipoproteins, and lipid levels, including a 14% increase in HDL cholesterol. Treatment with pioglitazone was also associated with increased LDL cholesterol and borderline increases in weight and body mass index. The increase in the latter measures may have been predominantly related to subcutaneous fat accumulation in the hips, which has been associated with reduced atherosclerosis.28 Of all on-treatment changes evaluated at 24 weeks, however, only changes in HDL cholesterol and insulin predicted a pioglitazone-related benefit on CIMT at 72 weeks. Changes in other lipid parameters, measures of glycemia, hs-CRP, or anthropometric measures did not predict improvement in CIMT with pioglitazone treatment. The present study included an active comparator to minimize glycemic differences between treatment groups and was not designed to assess the effect of glycemic control on CIMT. The present analysis indicates that pioglitazone produces benefit for CIMT independent of its glycemic effect. This is consistent with conclusions of shorter-term studies that compared the effect of glimepiride and pioglitazone on CIMT.29 The role of a reduced insulin level as a predictor of benefit suggests improved insulin sensitivity may play a role in atheroprotection. Change in HDL predicted benefit in both mean and maximal CIMT progression, and irrespective of treatment-group assignment, only an increased HDL cholesterol level at 24 weeks was a significant predictor of reduced CIMT progression. The significance of the 24-week change in HDL cholesterol for predicting improvement in CIMT at 72 weeks was not different in subjects using statins compared with those not using statins during the trial. Therefore, even in patients treated with statins, who were already benefiting from the increased HDL cholesterol level associated with this treatment,30 further increases in HDL cholesterol related to pioglitazone treatment predicted less progression of atherosclerosis on CIMT.
In evaluating the clinical implications of the present study, an important limitation is that we measured atherosclerosis progression using CIMT, which may not relate directly to any beneficial effect of HDL cholesterol elevation by pioglitazone on cardiovascular disease events. In the PROactive trial (PROspective pioglitAzone Clinical Trial In macroVascular Events), treatment with pioglitazone did not significantly reduce the risk of a composite primary end point (which included death due to any cause, nonfatal myocardial infarction, stroke, acute coronary syndrome, leg amputation, coronary revascularization, or leg revascularization).31 Pioglitazone treatment did, however, significantly reduce (by 16%) the relative risk of the main secondary end point (a composite of all-cause mortality, myocardial infarction, or stroke). A recent meta-analysis of clinical trials of pioglitazone demonstrated an association between pioglitazone treatment and a lower risk of death, myocardial infarction, and stroke.32 The use of rosiglitazone, the other commercially available thiazolidinedione, was not associated with a reduction in cardiovascular disease events in a similar meta-analysis.33 The impact of rosiglitazone on CIMT in patients with diabetes has also not been firmly established in large, long-term studies. In a trial that reported results for 447 subjects (165 with type 2 diabetes mellitus), there was no significant effect of rosiglitazone on the primary CIMT end point in the entire cohort or in the subgroup of diabetic subjects at 12 months.34 There was benefit for a secondary CIMT end point. In a 24-week study that included 92 subjects with type 2 diabetes mellitus, rosiglitazone produced a significant benefit on CIMT as a secondary end point.35 It is of interest that in a head-to-head trial, rosiglitazone was less effective than pioglitazone for increasing HDL cholesterol level in subjects with diabetes.17 The results of the present analysis support the contention that a potential benefit of pioglitazone compared with rosiglitazone for reducing CVD events is based on an atheroprotective effect related to its incremental raising of HDL cholesterol.
In animal models, raising HDL by expression of human apoA1 markedly attenuates atherosclerosis.36 In humans, there is a strong epidemiological inverse relationship between HDL cholesterol and cardiovascular morbidity and mortality.37,38 Low HDL is also associated with measures of increased atherosclerosis progression measured by multiple techniques.39–42 Pharmacological therapies that raise HDL, such as niacin and statins, have also been associated with reduced progression of atherosclerosis and reduced cardiovascular mortality.5–7,43 Although statins have their most profound effect on atherosclerosis by lowering LDL cholesterol, a recent analysis concluded that part of the beneficial effect of statins in reducing atherosclerosis progression measured by intravascular ultrasound of the coronary arteries can be ascribed to increased HDL cholesterol.30 Furthermore, in a post hoc analysis of the Treating to New Targets Study, HDL cholesterol levels predicted major cardiovascular events in patients taking statins.44 Fibrates are another class of drugs that increase HDL cholesterol and reduce atherosclerosis disease progression; however, HDL elevations have not been observed in all studies.45–48 In the Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT), there was a significant 5% increase in HDL cholesterol with gemfibrozil treatment compared with placebo. Concentrations of HDL cholesterol achieved with gemfibrozil treatment in that trial predicted a significant reduction in coronary heart disease events in patients with low HDL cholesterol. In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial, there was a smaller and unsustained change in HDL cholesterol and no significant reduction in the primary outcome of coronary events.
Not all therapies that raise HDL cholesterol are associated with improved measures of atherosclerosis or reduced cardiovascular mortality. In a recently completed series of trials, torcetrapib, a cholesterol ester transfer protein inhibitor that can increase HDL cholesterol levels by >60%, was associated with increased mortality in a clinical end-point trial49 and no improvement in, or a trend toward worsening of, atherosclerosis in intravascular ultrasound and CIMT trials.20–22 This emphasizes the need to evaluate not only the level of HDL cholesterol but also its in vivo functionality for suppressing atherosclerosis progression or reducing cardiovascular events.
In the CHICAGO trial, pioglitazone treatment produced multiple benefits on cardiovascular risk factors, including an increase of 14% in HDL cholesterol. HDL cholesterol is an established and potent inverse risk factor for cardiovascular disease in humans, and increasing HDL cholesterol in animals and humans suppresses progression of atherosclerosis. The present analysis, the first to evaluate the relationship between thiazolidinedione-related changes in multiple cardiovascular risk factors and atherosclerosis progression in a large cohort of well-characterized subjects with diabetes, therefore suggests that the beneficial effect of pioglitazone for reducing atherosclerosis progression is derived in part from pioglitazone-related increases in HDL cholesterol. These results contrast with those of the torcetrapib trials in which increases in HDL cholesterol produced by treatment with cholesterol ester transfer protein inhibitors did not reduce atherosclerosis progression. The results in the present report support the importance of addressing low HDL cholesterol levels for suppressing atherosclerosis progression in patients with diabetes.43,50
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Acknowledgments |
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Sources of Funding
The study was sponsored and funded by Takeda Global Research & Development, Inc, Lincolnshire, Ill. Work on this report also was supported by National Heart, Lung, and Blood Institute grant No. K25 HL68139-01A1 to Dr Meyer.
Disclosures
Dr Mazzone is a consultant for Takeda, Merck, Amylin, and Novartis; received grants/research support from Takeda; and received honoraria from Merck, Pfizer, Takeda, and Novartis. Dr Meyer is a consultant for Takeda. Dr Kondos is a consultant for Takeda; received grants/research support from Takeda; and received honoraria from Takeda. Dr Davidson is a consultant for Abbott, AstraZeneca, Merck, Merck/Schering-Plough, Pfizer, Novartis, Reliant, Roche, Sankyo, Sumitomo, and Takeda; is on the speaker’s bureau for Abbott, AstraZeneca, Kos, Merck, Merck/Schering-Plough, Pfizer, Reliant, Sankyo, and Takeda; and has received grants/research support from Abbott, AstraZeneca, Bristol-Myers Squibb, Kos, Merck, Merck/Schering-Plough, Pfizer, Novartis, Reliant, Roche, Sankyo, and Takeda. Dr Feinstein is a consultant for Takeda. Dr D’Agostino is a consultant for Takeda, Pfizer, Bayer, and Sanofi. Dr Perez is employed by Takeda Global Research & Development. Dr Haffner is a consultant for GlaxoSmithKline, Pfizer, AstraZeneca, Merck Sharpe & Dohme Ltd, and Takeda and has received grants/research support from Pfizer, GlaxoSmithKline, and Novartis. Z. Chen reports no conflicts.
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References |
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1. O’Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson SK. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults: Cardiovascular Health Study Collaborative Research Group. N Engl J Med. 1999; 340: 14–22.
2. Chambless LE, Heiss G, Folsom AR, Rosemond W, Szklo M, Sharrett AR, Clegg LX. Association of coronary heart disease incidence with carotid arterial wall thickness and major risk factors: the Atherosclerosis Risk in Communities (ARIC) Study, 1987–1993. Am J Epidemiol. 1997; 146: 483–494.
3. 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.
4. Greenland P, Smith SC, Grundy SM. Improving coronary heart disease risk assessment in asymptomatic people: role of traditional risk factors and noninvasive cardiovascular tests. Circulation. 2001; 104: 1863–1867.
5. Furberg CD, Adams HP, Applegate WB, Byington RP, Espeland MA, Hartwell T, Hunninghake DB, Lefkowitz DS, Probstfield J, Riley WA; Asymptomatic Carotid Artery Progression Study (ACAPS) Research Group. Effect of lovastatin on early carotid atherosclerosis and cardiovascular events. Circulation. 1994; 90: 1679–1687.
6. 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.[CrossRef][Medline] [Order article via Infotrieve]
7. Taylor AJ, Sullenberger LE, Lee HJ, Lee JK, Grace KA. Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins. Circulation. 2004; 110: 3512–3517.
8. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care. 2004; 27: 1047–1053.
9. Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998; 339: 229–234.
10. Mazzone T. Reducing cardiovascular disease in patients with diabetes mellitus. Curr Opin Cardiol. 2005; 20: 245–249.[CrossRef][Medline] [Order article via Infotrieve]
11. Mazzone T. Strategies in ongoing clinical trials to reduce cardiovascular disease in patients with diabetes mellitus and insulin resistance. Am J Cardiol. 2004; 93: 27C–31C.[CrossRef][Medline] [Order article via Infotrieve]
12. Mazzone T, Meyer P, Feinstein SB, Davidson MH, Kondos GT, D’Agostino RB, Perez A, Provost JC, Haffner SM. Effect of pioglitazone compared with glimepiride on carotid intima-media thickness in type 2 diabetes: a randomized trial. JAMA. 2006; 296: 2572–2581.
13. Li AC, Brown KK, Silvestre MJ, Willson TM, Palinski W, Glass CK. Peroxisome proliferator–activated receptor ligands inhibit development of atherosclerosis in LDL receptor–deficient mice. J Clin Invest. 2000; 106: 523–531.[Medline] [Order article via Infotrieve]
14. Levi Z, Shaish A, Yacov N, Levkovitz H, Trestman S, Gerber Y, Cohen H, Dvir A, Rhachmani R, Ravid M, Harats D. Rosiglitazone (PPARgamma-agonist) attenuates atherogenesis with no effect on hyperglycaemia in a combined diabetes-atherosclerosis mouse model. Diabetes Obes Metab. 2003; 5: 45–50.[CrossRef][Medline] [Order article via Infotrieve]
15. Chen Z, Ishibashi S, Perrey S, Osuga JI, Gotoda T, Kitamine T, Tamura Y, Okazaki H, Yahagi N, Iizuka Y, Shionoiri F, Ohashi K, Harada K, Shimano H, Nagai R, Yamada N. Troglitazone inhibits atherosclerosis in apolipoprotein E-knockout mice: pleiotropic effects on CD36 expression and HDL. Arterioscler Thromb Vasc Biol. 2001; 21: 372–377.
16. Szapary PO, Bloedon LT, Samaha FF, Duffy D, Wolfe ML, Soffer D, Reilly MP, Chittams J, Rader DJ. Effects of pioglitazone on lipoproteins, inflammatory markers, and adipokines in nondiabetic patients with metabolic syndrome. Arterioscler Thromb Vasc Biol. 2006; 26: 182–188.
17. Goldberg RB, Kendall DM, Deeg MA, Buse JB, Zagar AJ, Pinaire JA, Tan MH, Khan MA, Perez AT, Jacober SJ. A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia. Diabetes Care. 2005; 28: 1547–1554.
18. Satoh N, Ogawa Y, Usui T, Tagami T, Kono S, Uesugi H, Sugiyama H, Sagawara A, Yamada K, Shimatsu A, Kuzuya H, Nakao K. Antiatherogenic effect of pioglitazone in type 2 diabetic patients irrespective of the responsiveness to its antidiabetic effect. Diabetes Care. 2003; 26: 2493–2499.
19. Hodis HN, Mack WJ, Zheng L, Li Y, Torres M, Scvilla D, Stewart Y, Hollen B, Garcia K, Alaupovic P, Buchanan TA. Effect of peroxisome proliferator-activated receptor gamma agonists treatment on subclinical atherosclerosis in patients with insulin-requiring type 2 diabetes. Diabetes Care. 2006; 29: 1545–1553.
20. Kastelein JJ, Van Leuven SI, Evans GW, Riley WAA, Revkin JH, Shear CL, Bots ML. Designs of RADIANCE 1 and 2: carotid ultrasound studies comparing the effects of torcetrapib/atorvastatin with atorvastatin alone on atherosclerosis. Curr Med Res Opin. 2007; 23: 885–894.[CrossRef][Medline] [Order article via Infotrieve]
21. Bots ML, Visseren FL, Evans GW, Riley WA, Revkin JH, Tegeler CH, Shear CL, Duggan WT, Vicari RM, Grobbee DE, Kastelein JJ. Torcetrapib and carotid intima-media thickness in mixed dyslipidaemia (RADIANCE 2 study): a randomised, double-blind trial. Lancet. 2007; 370: 153–160.[CrossRef][Medline] [Order article via Infotrieve]
22. Nissen SE, Tardif J-C, Nicholls SJ, Revkin JH, Shear CL, Duggan WT, Ruzyllo W, Bachinsky WB, Lasala GP, Tuzou EM. Effect of torcetrapib on the progression of coronary atherosclerosis. N Engl J Med. 2007; 356: 1304–1316.
23. American Diabetes Association. Treatment of hypertension in adults with diabetes. Diabetes Care. 2002; 25: S71–S73.[CrossRef]
24. American Diabetes Association. Management of dyslipidemia in adults with diabetes. Diabetes Care. 2002; 25: S74–S77.[CrossRef]
25. International Conference on Harmonisation E9 Expert Working Group. ICH Harmonised Tripartite Guideline: statistical principals for clinical trials. Stat Med. 1999; 18: 1905–1942.[Medline] [Order article via Infotrieve]
26. Harrell FE. Regression Modeling Strategies: With Applications to Linear Models, Logistic Regression, and Survival Analysis. New York, NY: Springer; 2001.
27. R Development Core Team. A Language and Environment for Statistical Computing. Vienna, Austria: R Foundation for Statistical Computing; 2006.
28. Fantuzzi G, Mazzone T. Adipose tissue and atherosclerosis: exploring the connection. Arterioscler Thromb Vasc Biol. 2007; 27: 996–1003.
29. Langenfeld MR, Forst T, Hohberg C, Kann P, Lubben G, Konrad T, Fullert SD, Sachara C, Pfutzner A. Pioglitazone decreases carotid intima-media thickness, independently of glycemic control in patients with type 2 diabetes mellitus. Circulation. 2005; 111: 2525–2531.
30. Nicholls SJ, Tuzcu EM, Sipahi I, Grasso AW, Schoenhagen P, Hu T, Wolski K, Crowe T, Desai MY, Hazen SL, Kapadia SR, Nissen SE. Statins, high-density lipoprotein cholesterol, and regression of coronary atherosclerosis. JAMA. 2007; 297: 499–508.
31. Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Bernedetti M, Moules IK, Skene AM, Tan MH, Lefebvre PJ, Murray GD, Standl E, Wilcox RG, Wilhelmsen L, Betteridge J, Birkeland K, Golay A, Heine RJ, Koranyi L, Laakso M, Mokan M, Norkus A, Pirags V, Podar T, Scheen A, Scherbaum W, Schemthaner G, Schmitz O, Skrha J, Smith U, Taton J. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005; 366: 1279–1289.[CrossRef][Medline] [Order article via Infotrieve]
32. Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA. 2007; 298: 1180–1188.
33. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007; 356: 2457–2471.
34. Hedblad B, Zambanini A, Nilsson P, Janzon L, Berglaund G. Rosiglitazone and carotid IMT progression rate in a mixed cohort of patients with type 2 diabetes and the insulin resistance syndrome: main results from the Rosiglitazone Atherosclerosis Study. J Intern Med. 2007; 261: 293–305.[CrossRef][Medline] [Order article via Infotrieve]
35. Stocker DJ, Taylor AJ, Langley RW, Jezior MR, Vigersky RA. A randomized trial of the effects of rosiglitazone and metformin on inflammation and subclinical atherosclerosis in patients with type 2 diabetes. Am Heart J. 2007; 153: 445.e1–445.e6.
36. Tangirala RK, Tsukamoto K, Chun SH, Usher D, Pure E, Rader DJ. Regression of atherosclerosis induced by liver-directed gene transfer of apolipoprotein A-I in mice. Circulation. 1999; 100: 1816–1822.
37. Gordon DJ, Probstfield JL, Garrison RJ, Neaton JD, Castelli WP, Knoke JD, Jacobs DR, Bangdiwala S, Tyroler HA. High-density lipoprotein cholesterol and cardiovascular disease: four prospective American studies. Circulation. 1989; 79: 8–15.
38. Boden WE. High-density lipoprotein cholesterol as an independent risk factor in cardiovascular disease: assessing the data from Framingham to the Veterans Affairs High-Density Lipoprotein Intervention Trial. Am J Cardiol. 2000; 86: 19L–22L.[Medline] [Order article via Infotrieve]
39. Raitakari OT, Juonala M, Kähönen M, Taittonen L, Laitinen T, Maki-Torkko N, Jarvisalo MJ, Uhari M, Jokinen E, Ronnemaa T, Akerblom HK, Viikari JS. Cardiovascular risk factors in childhood and carotid artery intima-media thickness in adulthood: the Cardiovascular Risk in Young Finns Study. JAMA. 2003; 290: 2277–2283.
40. Yeh ST, Morton DJ, Barrett-Connor E. Lower extremity arterial disease in older women: the Rancho Bernardo Study. J Womens Health Gend Based Med. 2000; 9: 373–380.[CrossRef][Medline] [Order article via Infotrieve]
41. Wong ND, Kawakubo M, LaBree L, Azen SP, Xiang M, Detrano R. Relation of coronary calcium progression and control of lipids according to National Cholesterol Education Program guidelines. Am J Cardiol. 2004; 94: 431–436.[CrossRef][Medline] [Order article via Infotrieve]
42. Ashen MD, Blumenthal RS. Low HDL cholesterol levels. N Engl J Med. 2005; 353: 1252–1260.
43. Canner PL, Berge KG, Wenger NK, Stamler J, Friedman L, Prineas RJ, Friedewald W. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol. 1986; 8: 1245–1255.[Abstract]
44. Barter P, Gotto AM, LaRosa JC, Maroni J, Szarek M, Grundy SM, Kastelein JJ, Bittner V, Fruchart JC. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med. 2007; 357: 1301–1310.
45. Diabetes Atherosclerosis Intervention Study Investigators. Effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes: the Diabetes Atherosclerosis Intervention Study, a randomised study. Lancet. 2001; 357: 905–910.[CrossRef][Medline] [Order article via Infotrieve]
46. Keech A, Simes RJ, Barter P, Best J, Scott R, Taskinen MR, Forder P, Pillai A, Davis T, Glasziou P, Drury P, Kesaniemi YA, Sullivan D, Hunt D, Colman P, d’Emden M, Whiting M, Ehnholm C, Laakso M. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet. 2005; 366: 1849–1861.[CrossRef][Medline] [Order article via Infotrieve]
47. Robins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, Faas FH, Linares E, Schaefer EJ, Schectman G, Wilt TJ, Wittes J; Veterans Affairs High-Density Lipoprotein Intervention Trial Study Group. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med. 1999; 341: 410–418.
48. Robins SJ, Collins D, Wittes JT, Papademetriou V, Deedwania PC, Schaefer EJ, McNamara JR, Kashyap ML, Hershman JM, Wexler LF, Rubins HB. Relation of gemfibrozil treatment and lipid levels with major coronary events: VA-HIT: a randomized controlled trial. JAMA. 2001; 285: 1585–1591.
49. Barter PJ, Caulfield M, Eriksson M, Grundy SM, Kastelein JJ, Komajda M, Lopez-Sendon J, Mosca L, Tardif JC, Waters DD, Shear CL, Revkin JH, Buhr KA, Fisher MR, Tall AR, Brewer B. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med. 2007; 357: 2109–2122.
50. Mazzone T. HDL cholesterol and atherosclerosis. Lancet. 2007; 370: 107–108.[CrossRef][Medline] [Order article via Infotrieve]
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Footnotes |
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Guest Editor for this article was William R. Hyatt, MD.
Clinical trial registration information—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00225264.
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Circulation 2008 117: 2041.
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