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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2004-1685
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 4 1986-1991
Copyright © 2005 by The Endocrine Society

Effect of Thiazolidinedione Treatment on Progression of Subclinical Atherosclerosis in Premenopausal Women at High Risk for Type 2 Diabetes

Anny H. Xiang, Ruth K. Peters, Siri L. Kjos, Cesar Ochoa, Aura Marroquin, Jose Goico, Sylvia Tan, Chengwei Wang, Stanley P. Azen, Chao-ran Liu, Ci-hua Liu, Howard N. Hodis and Thomas A. Buchanan

Departments of Preventive Medicine (A.H.X., R.K.P., S.T., C.W., S.P.A., H.N.H.), Obstetrics and Gynecology (S.L.K., T.A.B.), and Medicine (C.O., A.M., J.G., C.-r.L., C.-h.L., H.N.H., T.A.B.), University of Southern California Keck School of Medicine, Los Angeles, California 90089-9317

Address all correspondence and requests for reprints to: Thomas A. Buchanan, M.D., University of Southern California Keck School of Medicine, Room 6602 GNH, 1200 North State Street, Los Angeles, California 90089-9317. E-mail: buchanan{at}usc.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
We tested the effects of treatment with a thiazolidinedione drug on rates of progression of carotid intima-media thickness (CIMT) and some putative determinants of CIMT in young women at high risk for type 2 diabetes. A total of 266 nondiabetic, Hispanic women with recent gestational diabetes were randomized to placebo or troglitazone. CIMT measurements were made at baseline, annually, and at study end, together with measurements of obesity, serum lipids, and glucose and insulin levels during oral glucose tolerance tests. Insulin sensitivity (minimal model analysis) was measured at baseline and 3 months later. Data were analyzed to compare CIMT progression rates between treatment groups and investigate potential determinants of differences in CIMT progression.

One hundred ninety-two women had a CIMT measurement at baseline and at least one follow-up visit. The mean rate of CIMT change was 31% lower in women assigned to troglitazone (P = 0.048). This intergroup difference was not explained by baseline or on-trial differences in obesity, lipids, glucose, or insulin. The reduction in CIMT progression developed gradually, occurred only in women who had an increase in insulin sensitivity, and was unrelated to the presence of the metabolic syndrome at baseline.

Troglitazone reduced the progression of subclinical atherosclerosis via a mechanism that involved unmeasured mediators of atherosclerosis, either in the circulation or directly in the arterial wall.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
CLINICAL COMPLICATIONS OF atherosclerosis are the leading cause of death and a major cause of morbidity in people with diabetes mellitus. The atherosclerosis that leads to these events is a chronic process that begins many years before clinical events occur. Modification of the primary atherosclerotic process can reduce morbidity and mortality, as evidenced by trials in which putative etiologic factors for atherosclerosis such as hypercholesterolemia and hypertension have been modified to lower risks of clinical events.

Peroxisomal proliferator-activated receptor (PPAR)-{gamma} agonists of the thiazolidinedione class have many characteristics that make them attractive as treatments for atherosclerosis in people who have type 2 diabetes or are at risk for the disease. The drugs ameliorate insulin resistance (1, 2, 3, 4, 5, 6) and, to different degrees, also ameliorate the dyslipidemia that often accompanies insulin resistance and type 2 diabetes (7, 8, 9). They lower circulating levels of glucose (1, 2, 3, 5, 7, 8, 9), insulin (3, 4, 6), and inflammatory (10, 11, 12) and antifibrinolytic (13, 14) markers that are often increased with insulin resistance and obesity. Thiazolidinediones also have beneficial effects on vascular function in vivo (15, 16), limit development of atherosclerosis in animal models (17, 18, 19, 20), and have direct antiproliferative effects on vascular cells in vitro (21). To date, two 6-month studies revealed a reduction in one preclinical measure of atherosclerosis, carotid artery intima-media thickness (CIMT), in Japanese patients with type 2 diabetes during treatment with troglitazone (22) or pioglitazone (23). A separate 48-wk study of rosiglitazone in nondiabetic people with clinically stable coronary artery disease revealed stability of CIMT in treated patients (24). In all three studies, CIMT increased in placebo-treated patients. Long-term effects of thiazolidinedione treatment on CIMT and its possible regulators have not been reported.

The Troglitazone in Prevention of Diabetes (TRIPOD) study was a randomized, double-blind, placebo-controlled study designed to determine the effects of treatment with troglitazone in premenopausal Hispanic women at high risk for type 2 diabetes by virtue of a recent history of gestational diabetes mellitus (GDM). Main outcomes were diabetes incidence rates, pancreatic ß-cell function, and progression of CIMT. The design of the trial (25) and results relevant to prevention (26) and early treatment (27) of type 2 diabetes and preservation of pancreatic ß-cell function (26, 27) have been published. The present report describes the effects of treatment on CIMT and some of its putative determinants.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects and design

Between August 1995 and May 1998, 266 nondiabetic premenopausal women of Mexican or Central American descent who were18 yr old or older; had a history of GDM in the prior 4 yr; had a current sum of five glucose values on a 2-h, 75-g oral glucose tolerance test (OGTT) that was above the median for women with GDM (28); had no evidence of chronic diseases other than obesity and mild hyperglycemia; and were willing to use effective contraception were randomly assigned to receive placebo or 400 mg troglitazone daily in a double-blind fashion. Intravenous glucose tolerance tests (IVGTTs) for measurement of insulin resistance and pancreatic ß-cell function were conducted at baseline and 3 months later to determine responsiveness to troglitazone. Fasting plasma glucose was measured at baseline and every 3 months, and 75-g OGTTs were performed annually to test for diabetes. Height, weight, sitting blood pressure, fasting serum lipids, and CIMT were performed at the times of OGTTs. Women continued on their assigned medication until they developed diabetes (29), dropped out of the trial, or reached the end of the trial. Women who developed diabetes at any visit had a final OGTT, CIMT, and related measurements. The study was designed to end in August 2000. Troglitazone was withdrawn from clinical use in March 2000. Subjects active in the trial at that time were asked to return for a final on-trial OGTT, CIMT and associated blood pressure, and lipid and morphometric measurements. All participants gave written informed consent for participation in the institutional review board-approved study. Institutional review board approval and informed consent were updated during the study as information about potentially serious hepatotoxicity of troglitazone became available. No serious hepatotoxicity was observed during the TRIPOD study. A summary of the frequency of reversible transaminase elevations is available in the description of the blinded trial (26).

Clinical testing protocols

High-resolution B-mode carotid artery ultrasounds for the purpose of measuring the intima-media thickness (IMT) were obtained using an SSH 140A ultrasound system (Toshiba Corp., Tokyo, Japan) with a linear array 7.5-MHz probe as described previously (30, 31). In brief, the common carotid artery (CCA) was first imaged in cross-section with the jugular vein juxtaposed above the carotid artery. The scan head was then rotated 90° around the central image line, maintaining the jugular vein stacked above the CCA while obtaining a longitudinal view of both vessels. The proximal portion of the carotid bulb was included in all images as an anatomical reference point for standardization of IMT measurements. The electrocardiogram signal and ultrasound images were simultaneously recorded on SVHS videotape. Minimum gain necessary for clear visualization of structures was used, and all initial instrumentation settings were recorded and used in subsequent scans. Each individual’s baseline image was used as an on-line guide for follow-up examinations on a spilt-screen system designed for repeat-image acquisition for longitudinal studies (patent pending) as part of the standardization protocol. Ultrasound examinations and image processing were conducted blinded to treatment randomization. The computer system and software program (Prowin, patent pending) used to measure CIMT used automated boundary detection to locate the lumen-intima and media-adventitia echo boundaries at subpixel resolution (32, 33). The IMT measurement consisted of an average of 70–100 individual measurements made along a 1-cm distance in the far wall of the right distal CCA. The coefficient of variation for CIMT was 2.5% within and between operators.

Height was measured with a stadiometer. Weight was measured on a standardized beam balance. Waist circumference was measured with a tape measure. Blood pressure was measured in triplicate by Dinamap (Critikon, Inc., Tampa, FL) after subjects had been sitting with legs dangling for longer than 5 min. Width of the blood pressure cuff was at least 80% of the arm circumference in each subject. OGTTs and IVGTTs were initiated between 0700 and 0900 h, after an 8- to 12-h overnight fast. For OGTTs, subjects drank 75 g dextrose. Venous blood was sampled from an indwelling catheter before and 30, 60, 90, and 120 min after the dextrose ingestion. For IVGTTs, dextrose (300 mg/kg body weight) was injected into an antecubital vein. Tolbutamide (125 mg/m2 body surface area) was injected 20 min later. Twenty-two arterialized venous blood samples were drawn and placed on ice before and up to 240 min after the dextrose injection. Plasma was separated within 20 min and stored at –80 C.

Laboratory methods

Glucose was measured by glucose oxidase (Beckman Glucose Analyzer II; Beckman Instruments, Brea, CA). Insulin was measured by a RIA (Linco Research, St. Charles, MO) that provided less than 0.2% cross-reactivity with proinsulin. Plasma total cholesterol, total triglyceride (TG), and high-density lipoprotein (HDL)-cholesterol concentrations were determined by enzymatic assays and standardized to the Centers for Disease and Control and Prevention using the Lipid Research Clinic protocol (34). HDL-cholesterol levels were measured after apolipoprotein B-containing lipoproteins were precipitated in whole plasma with heparin manganese chloride. Low-density lipoprotein (LDL)-cholesterol levels were estimated using the Friedewald equation (35).

Data analysis

Whole-body insulin sensitivity (SI) was calculated from the IVGTTs using the Bergman minimal model (36). Glucose disappearance during the IVGTTs was calculated as 100 x the fractional glucose disappearance rate between 10 and 40 min after the glucose injection. Areas under glucose and insulin curves were calculated using the trapezoid rule.

Baseline characteristics were compared between groups using two-group t tests for continuous variables and {chi}2 or Fisher’s exact tests for categorical variables. For nonnormally distributed variables, such as TGs, insulin, insulin area, SI, and first-phase insulin response, natural log transformation was used before t tests. Means and SD values are presented in their original measurement scales.

Comparison of CIMT progression rates was performed by intention to treat using all CIMT values from all women who had a baseline CIMT measurement and at least one annual follow-up measurement. No missing data were imputed. Linear mixed-effects models with random coefficients corresponding to individual subjects were used to estimate and test for group differences in the average rate of change in CIMT. Group differences in CIMT rates were tested by examining the interaction between group and follow-up time variables in the mixed-effects model. Baseline variables that were found to be different (P < 0.05) between treatment groups were included as covariates in the multivariate adjusted analysis. Both cross-sectional and longitudinal correlations between baseline covariates and CIMT were considered in the adjusted analysis.

When we observed a difference in CIMT progression rates between placebo and troglitazone groups, we conducted exploratory analyses to examine potential mediators of the observed differences in CIMT progression. Variables that were tested included body weight; systolic and diastolic blood pressure; total, LDL-, and HDL-cholesterol; total TGs; and total areas under insulin and glucose curves during OGTTs. Changes from baseline in these variables were compared between treatment groups by linear mixed-effects models to compare average rates of change and two-group t tests to compare change of mean on-trial values from baseline. The two approaches provided consistent results and results comparing the change of mean on-trial values from baseline are presented. A multivariate linear mixed-effects model analysis was used to compare CIMT differences while adjusting for on-trial differences in the nine putative mediators of CIMT differences between treatment groups. An analogous approach was used to compare CIMT rates adjusting for the presence or absence of the metabolic syndrome, as defined by National Cholesterol Education Program criteria (37), at baseline and the presence or absence of an increase in SI during the first 3 months of treatment, as defined in the description of the primary TRIPOD trial (26).

For mixed-effects models, the restricted maximum likelihood procedure was used to estimate and test hypotheses about the parameters. SAS (SAS, Inc., Cary, NC) was used to perform all the analyses, and PROC MIXED was used to perform the mixed-effects model analyses. All statistical tests were two sided, and statistical significance was set at P = 0.05.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Of the 266 women randomized to the study, 257 agreed to participate in the CIMT portion and had baseline CIMT measurements. One hundred ninety-two women, 99 in the placebo group and 93 in the troglitazone group, had at least one CIMT measurement after the baseline measurement. These 192 women provided data on changes in CIMT. At baseline, they had lower body mass index (BMI; 29.9 ± 5.2 vs. 32.8 ± 6.9 kg/m2, P = 0.002), higher SI [2.57 ± 1.79 vs. 1.84 ± 1.34 x 10–4 min–1/µU·ml, P = 0.004 (4.28 ± 2.98 vs. 3.07 ± 2.23 x 10–3 min–1/pmol·liter)], and lower OGTT total insulin area [9,812 ± 5,779 vs. 12,226 ± 7,439 µU/ml x min (58,872 ± 34,674 vs. 73,356 ± 44,634 pmol/ml x min), P = 0.01], compared with women who did not provide follow-up CIMT data. Baseline CIMT (0.58 ± 0.08 vs. 0.59 ± 0.08 mm, P = 0.7) and all of the other characteristics listed in Table 1Go were similar (P > 0.2) in women who did and did not have follow-up CIMT measurements (data not shown).


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  		TABLE 1. Baseline characteristics of women who had a baseline CIMT and at least one follow-up CIMT measurement1

 
Among women who provided baseline and follow-up CIMT measurements, baseline characteristics were similar in the two treatment groups (Table 1Go). Only baseline SI differed statistically between groups, and the difference was small, compared with the overall marked insulin resistance in both groups.

Follow-up CIMT measurements were made 1, 2, 3, and 4 yr after randomization in 94, 67, 55, and 28 women in the placebo group and 89, 71, 57, and 36 women in the troglitazone group. Some of the reductions in group sizes in yr 3 and 4 were due to the fact that enrollment occurred over a 22-month period, and the study was terminated 5 months early due to withdrawal of troglitazone, so not all subjects reached their 3- and 4-yr anniversaries during the study. The remaining reductions were due to women who reached the study end point, diabetes, and women who were lost to follow-up. The annual rates of loss to follow-up were 12.2 and 13.1% in placebo and troglitazone groups, respectively (P = 0.8). Baseline characteristics were similar for drop-outs in the placebo and troglitazone groups (all P > 0.10, data not shown).

Median follow-up was similar in placebo and troglitazone groups (2.8 vs. 3.0 yr), as were minimum (0.8 vs. 0.5 yr) and maximum (4.6 vs. 4.6 yr) follow-up. Compliance rates with study medications, assessed by pill counts at each visit, were 86 and 88%, respectively (P = 0.5). Both treatment groups gained weight, but the rate of weight gain was slightly higher in the troglitazone group, resulting in a higher change of mean BMI from baseline (Table 2Go). Differences between baseline and mean on-trial values for blood pressure and LDL- and HDL-cholesterol levels were similar in the two treatment groups (Table 2Go). Assignment to troglitazone was associated with on-trial reductions in TGs, glucose, and insulin and a smaller rise in hemoglobin A1C, compared with placebo (Table 2Go).


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  		TABLE 2. Difference between mean on-trail values and baseline values for variables relevant to CIMT1

 
The mean rate of change of CIMT was 31% lower in the troglitazone group (6.5 x 10–3 vs. 9.4 x 10–3 mm/yr; Fig. 1Go, left panel). Adjustment for differences at baseline in the characteristics listed in Table 1Go (Fig. 1Go, middle panel) and on-trial differences in the characteristics listed in Table 2Go (Fig. 1Go, right panel) did not reduce the intergroup difference in the CIMT progression rates. A plot of CIMT change revealed a relatively linear increase in women assigned to placebo (Fig. 2Go). The pattern of CIMT change was similar during the first year of treatment with troglitazone but slowed thereafter. There were no clinical cardiovascular events during the study.



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  		FIG. 1. Annual CIMT progression rates in women assigned to placebo or troglitazone. Adjustments refer to statistical adjustment for effects of baseline characteristics listed in Table 1Go and on-trial characteristics listed in Table 2Go.

 


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  		FIG. 2. Longitudinal changes in CIMT. Data are expressed as percent above basal to eliminate variability due to inclusion of patients with different baseline CIMT values at different follow-up times. Data at 0, 1, 2, 3, and 4 yr are from 99, 94, 67, 55, and 28 women in the placebo group and 93, 89, 71, 57, and 36 women in the troglitazone group.

 
As reported previously, (26), approximately one third of women who received troglitazone in TRIPOD failed to increase their SI during the first 3 months of treatment. They were designated nonresponders to the primary insulin-sensitizing effects of the drug. Of the 93 women who contributed baseline and follow-up CIMT values in the troglitazone group, 89 had IVGTTs 3 months after enrollment; 29 (33%) were nonresponders. The reduction in CIMT progression rate in the troglitazone group was limited to the 60 women who increased their SI when placed on the drug (Fig. 3Go). The average rate of CIMT progression in those 60 women was 45% lower than the average rate in the placebo group (5.2 x 10–3 vs. 9.4 x 10–3 mm/yr, P = 0.02).



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  		FIG. 3. CIMT progression rates in women assigned to placebo and troglitazone, divided according to whether they did not (nonresponders) or did (responders) exhibit an increase in SI during the first 3 months of troglitazone treatment, as defined in the text.

 
Fractions of women who met National Cholesterol Education Program criteria for the metabolic syndrome [three or more of the following at baseline: waist circumference > 35 in.; total TGs > 150 mg/dl (1.7 mmol/liter); HDL-cholesterol < 50 mg/dl (1.3 mmol/liter); blood pressure ≥ 130/85 mm Hg; fasting plasma glucose ≥ 110 mg/dl (6.1 mmol/liter)] (37) were similar in placebo and troglitazone subjects who provided follow-up CIMT data (32 vs. 24%, respectively; P = 0.18). Women without and with the metabolic syndrome had similar CIMT progression rates in each treatment group (9.5 x 10–3 vs. 9.0 x 10–3 mm/yr, respectively, in the placebo group; 6.4 x 10–3 vs. 6.1 x 10–3 mm/yr in the troglitazone group). Mixed-effects modeling revealed no impact of baseline metabolic syndrome status on the rate of CIMT progression (P = 0.83) and no evidence of an interaction between baseline metabolic syndrome status and treatment group (P = 0.73).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
There are three main findings in this report. First, assignment to troglitazone as compared with placebo was associated with a 31% reduction in the CIMT progression rate in young premenopausal Hispanic women who were insulin resistant and at high risk for type 2 diabetes. Second, although there were significant differences between the placebo and troglitazone groups in on-trial weight gain and circulating levels of glucose, insulin, and total TGs, those differences did not account for the intergroup differences in CIMT progression. Neither did the presence or absence of the metabolic syndrome at entry into the trial. Third, the reduction in CIMT progression in women assigned to troglitazone was limited to women who manifested an increase in SI soon after being placed on the drug. Thus, we observed a mitigating effect on the development of subclinical atherosclerosis that was closely linked to amelioration of insulin resistance, but that was not explained by amelioration of the components of the insulin resistance syndrome that we measured.

There are two general mechanisms that could explain the reduction in CIMT progression that was observed in the troglitazone group. The first is indirect, i.e. a change in some circulating factor or factors that modify atherosclerosis and were not measured in this study. Examples include increased LDL particle size (38) and/or adiponectin levels (39) and reduction in levels of inflammatory markers (10, 11, 12) and plasminogen activator inhibitor-1 (14). The second general mechanism involves direct effects of PPAR{gamma} activation in the arterial wall. PPAR{gamma} agonists are known to directly inhibit vascular smooth muscle cell growth and migration, production of vascular adhesion molecules by endothelial cells, and migration of monocytes (21, 40). These actions should reduce atherosclerosis over time. Failure of PPAR{gamma} activation, in either nonvascular tissues in the case of insulin sensitization and related indirect vascular effects or vascular tissues in the case of direct effects, would explain the lack of an effect on CIMT progression in women who did not experience insulin sensitization from troglitazone. The mechanisms underlying failed PPAR{gamma} activation are not known. We have shown the failure of insulin sensitization to be dose dependent (6) and unrelated to the Pro12Ala variant of the PPAR{gamma} gene (41). Whether these or other mechanisms explain the lack of an antiatherosclerotic effect from a PPAR{gamma} agonist in some people remains to be determined.

The pattern of effect on CIMT progression that we observed is different from the patterns that have been reported by others. Minamikawa et al. (22) reported a significant decrease in CIMT values within 3 months after initiation of treatment with troglitazone at a dose of 400 mg/d, the same dose employed in the present study. The CIMT reduction persisted after 6 months of treatment and was unrelated to changes in circulating glucose or total TG levels. Reporting for the same group, Koshiyama et al. (23) described a similar reduction in CIMT in type 2 diabetic patients during 3–6 months of treatment with pioglitazone. Sidhu et al. (24) reported stable CIMT measurements during 48 wk of treatment in nondiabetic patients with coronary artery disease. In all three studies, CIMT increased in placebo-treated patients. We observed a similar increase in IMT in placebo and troglitazone groups the first year of treatment but a substantially lower rate of progression thereafter. Rates of change in CIMT approached zero by the third and fourth years of treatment. The explanation for these interstudy differences is not clear but could include differences in the ethnicity of study subjects, the degree of atherosclerosis present at the beginning of treatment, and the degree of metabolic decompensation present at entry and its improvement during treatment.

Because troglitazone is no longer available for use in humans, our results cannot be translated directly into clinical care. However, as cited above, other thiazolidinedione drugs that are clinically available appear to have important effects on CIMT. In several studies, CIMT and its rate of change have been directly associated with the risk of myocardial infarction and stroke (42, 43). Interventions that reduce clinical events have also been reported to slow CIMT progression (44). Only larger studies conducted either in higher-risk individuals or for longer periods of time and with clinical cardiovascular events as primary outcomes can determine the true role of thiazolidinediones in the prevention of clinically important atherosclerosis.

Three factors limit the extent to which our results can be generalized. First, our patients were all Hispanic Americans of Mexican or Central American descent. Second, they were all premenopausal women with prior gestational diabetes. The studies cited above suggest that important CIMT effects will occur in other ethnic groups and both genders, but the patterns of the effects may differ from the pattern we observed. Third, whereas the entire cohort tended to be obese, insulin resistant, and hyperinsulinemic at baseline, women who returned for follow-up CIMT measurements were less so than women who had only baseline tests. We have no explanation for this participation bias. We have observed that response to the insulin-sensitizing effects of troglitazone was not determined by baseline obesity, insulin resistance, or insulin levels (26). Nonetheless, we cannot offer proof that our results would apply to the most obese and insulin-resistant women.

In summary, we observed a 31% reduction in the mean rate of CIMT progression in insulin-resistant, premenopausal Hispanic women at high risk for type 2 diabetes who were treated with troglitazone. The protective effect occurred gradually over time because control subjects manifested a continuous increase in CIMT, but treated subjects manifested a progressive reduction in their rate of increase in CIMT. The reduction in CIMT progression was not explained by treatment-associated reductions in glucose, insulin, or TG levels. It occurred equally in women with and without the metabolic syndrome. Nonetheless, the reduction was limited to women who had amelioration of insulin resistance, suggesting a close link to either circulating mediators of atherosclerosis that change with insulin resistance or a direct, PPAR{gamma}-mediated effect on several tissues, including the arterial wall. Given the association between CIMT progression and clinical cardiovascular events, our results demonstrate the potential importance of thiazolidinedione drugs in reducing insulin resistance and subclinical atherosclerosis in one group of individuals at high risk for type 2 diabetes. Additional studies are needed to test for analogous effects in other high-risk groups.


   Acknowledgments
 
The authors thank Susie Nakao, Carmen Martinez, and the staff of the General Clinical Research Center for assistance with metabolic studies; the TRIPOD Data Safety Monitoring Committee for their guidance in the conduct of the study; and Lilit Zeberians, Mike Salce, and Jay Sisam for performance of assays.


   Footnotes
 
This work was supported by Parke-Davis Pharmaceutical Research Grant PD-991-053, Grant M01-RR-43 from the General Clinical Research Branch, National Center for Research Resources, National Institutes of Health; a Clinical Research Award from the American Diabetes Association; and Grant R01-DK-46374 from the National Institute of Diabetes and Digestive and Kidney Diseases (National Institutes of Health).

First Published Online December 28, 2004

Abbreviations: BMI, Body mass index; CCA, common carotid artery; CIMT, carotid intima-media thickness; GDM, gestational diabetes mellitus; HDL, high-density lipoprotein; IMT, intima-media thickness; IVGTT, iv glucose tolerance test; LDL, low-density lipoprotein; OGTT, oral glucose tolerance test; PPAR, peroxisomal proliferator-activated receptor; SI, insulin sensitivity; TG, triglyceride; TRIPOD, Troglitazone in Prevention of Diabetes study.

Received August 23, 2004.

Accepted December 20, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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H. N. Hodis, W. J. Mack, L. Zheng, Y. Li, M. Torres, D. Sevilla, Y. Stewart, B. Hollen, K. Garcia, P. Alaupovic, et al.
Effect of Peroxisome Proliferator-Activated Receptor {gamma} Agonist Treatment on Subclinical Atherosclerosis in Patients With Insulin-Requiring Type 2 Diabetes
Diabetes Care, July 1, 2006; 29(7): 1545 - 1553.
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