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Effect of Pioglitazone Compared With
Glimepiride on Carotid Intima-Media
Thickness in Type 2 Diabetes
A Randomized Trial
Context Carotid artery intima-media thickness (CIMT) is a marker of coronary ath-
erosclerosis and independently predicts cardiovascular events, which are increased in type 2 diabetes mellitus (DM). While studies of relatively short duration have sug-gested that thiazolidinediones such as pioglitazone might reduce progression of CIMT in persons with diabetes, the results of longer studies have been less clear.
Objective To evaluate the effect of pioglitazone vs glimepiride on changes in CIMT
of the common carotid artery in patients with type 2 DM.
Design, Setting, and Participants Randomized, double-blind, comparator-
controlled, multicenter trial in patients with type 2 DM conducted at 28 clinical sites in
the multiracial/ethnic Chicago metropolitan area between October 2003 and May 2006.
The treatment period was 72 weeks (1-week follow-up). CIMT images were capturedby a single ultrasonographer at 1 center and read by a single treatment-blinded reader PATIENTSWITHTYPE2DIABETES usingautomatededge-detectiontechnology.Participantswere462adults(meanage, 60 [SD, 8.1] years; mean body mass index, 32 [SD, 5.1]) with type 2 DM (mean du- ration, 7.7 [SD, 7.2] years; mean glycosylated hemoglobin [HbA1c] value, 7.4% [SD,1.0%]), either newly diagnosed or currently treated with diet and exercise, sulfonyl- urea, metformin, insulin, or a combination thereof.
stantially worse prognosis after MI com-pared with patients without diabetes.1-3 Interventions Pioglitazone hydrochloride (15-45 mg/d) or glimepiride (1-4 mg/d)
as an active comparator.
In recent years, it has become appar-ent that optimal control of blood pres- Main Outcome Measure Absolute change from baseline to final visit in mean pos-
terior-wall CIMT of the left and right common carotid arteries.
Results Mean change in CIMT was less with pioglitazone vs glimepiride at all time
points (weeks 24, 48, 72). At week 72, the primary end point of progression of mean CIMT was less with pioglitazone vs glimepiride (−0.001 mm vs ϩ0.012 mm, respec- with optimal control of these potent car- tively; difference, −0.013 mm; 95% confidence interval, −0.024 to −0.002; P=.02).
Pioglitazone also slowed progression of maximum CIMT compared with glimepiride (0.002 mm vs 0.026 mm, respectively, at 72 weeks; difference, −0.024 mm; 95% con- fidence interval, −0.042 to −0.006; P=.008). The beneficial effect of pioglitazone on mean CIMT was similar across prespecified subgroups based on age, sex, systolic blood pressure, duration of DM, body mass index, HbA1c value, and statin use.
Conclusion Over an 18-month treatment period in patients with type 2 DM, pi-
oglitazone slowed progression of CIMT compared with glimepiride.
Trial Registration clinicaltrials.gov Identifier: NCT00225264
JAMA. 2006;296:(doi:10.1001/jama.296.21.joc60158) zolidinediones could be useful for re-ducing cardiovascular risk. In isolatedvessel-wall cells, troglitazone, piogli- Author Affiliations are listed at the end of this
article.
Corresponding Author: Theodore Mazzone, MD, Uni-
versity of Illinois College of Medicine, Section of En- lipoprotein profile, and endothelial cell docrinology, Diabetes and Metabolism, 1819 W PolkSt, 612 CMW MC 797, Chicago, IL 60612 (tmazzone function.9-12 Some of these beneficial ef- 2006 American Medical Association. All rights reserved.
(Reprinted) JAMA, Published online November 13, 2006 PIOGLITAZONE VS GLIMEPIRIDE AND CIMT IN TYPE 2 DIABETES tant question regarding the effect of thia- zolidinediones on CIMT in type 2 DM.
comparator-controlled clinical trial con- heart failure; or significant cardiac val- v e r s e p o p u l a t i o n o f a l a r g e U S for estimating future risk of such events effect of pioglitazone with that of glime- ethically justified in terms of maintain- dition, glimepiride represents a class of value.18,19 Statins, established agents for Study Design and Participants
“other” category were Asian and so were pooled into an Oriental/Asian group.
a baseline systolic blood pressure of ap- if the cohort generally reflected the ra- level, statin use was less than 20% at the start of the study. Hodis et al24 recently tees, and all participants provided writ- related to small cohort size, short dura- piride (1-4 mg/d). The initial study drug E2 JAMA, Published online November 13, 2006 (Reprinted)
2006 American Medical Association. All rights reserved.
PIOGLITAZONE VS GLIMEPIRIDE AND CIMT IN TYPE 2 DIABETES for at least 1 second along with the elec- diastolic image identification. After the terim data analyses, but a data and safety start of the study.26,27 Participants re- Laboratory Measurements
4, 8, 16, 24, 32, 40, 48, 60, and 72 weeks Measurement of Carotid
Intima-Media Thickness
values at all visits after week 8, and lipid ated as described for the sonographer.
Statistical Analysis
2 readings was 0.002 (SD, 0.058) mm.
of the study, with an SD of 0.224 for in- to obtain longitudinal scans of the right a 2-sided, 2-sample t test at a .05 signifi- steering committee decided to include all on the posterior wall of the artery. Once index, HbA1c value, and use of statins.
2006 American Medical Association. All rights reserved.
(Reprinted) JAMA, Published online November 13, 2006 PIOGLITAZONE VS GLIMEPIRIDE AND CIMT IN TYPE 2 DIABETES Figure 1. Participant Disposition
Of the 1346 patients screened for eli-gibility, 462 (34%) were randomly as- signed to treatment (FIGURE 1). The
study was completed by 68% of the pi-
glimepiride-treated patients. The rea-sons for study discontinuation were generally similar between treatmentgroups. Within the intention-to-treat baseline CIMT image were included inthe CIMT analysis (CIMT popula- treated and 186 glimepiride-treated pa-tients met the criteria for inclusion for clinical characteristics (TABLE 1). More
CIMT indicates carotid intima-media thickness; ITT, intention-to-treat.
aspirin or diuretics. The majority of pa-tients entering the study were taking an ciples. Three sites had fewer than 6 par- analysis of covariance analyses were used differences. All treated participants were fects of site and CIMT baseline values.
14 days after the last dose of study drug treatment effects was assessed using F to-treat population with respect to base- in the statistical analysis plan, with sig- nificance set at .05 (2-sided). A sensitiv- FIGURE 2A shows the mean change
zyme inhibitors, ␤-blockers, angiotensin baseline at final visit (the prespecified site, using 2-way analysis of variance for E4 JAMA, Published online November 13, 2006 (Reprinted)
2006 American Medical Association. All rights reserved.
PIOGLITAZONE VS GLIMEPIRIDE AND CIMT IN TYPE 2 DIABETES tively. At the end of the study, triglyc- from baseline in the pioglitazone com-pared with the glimepiride group was Table 1. Baseline Demographics and Clinical Characteristics*
ITT Population
CIMT Population
[CI], −0.024 to −0.002; P = .02). As analternative to last observation carried Pioglitazone Glimepiride Pioglitazone Glimepiride
mm (95% CI, −0.024 to −0.001; P=.03).
w a s a s e c o n d a r y e n d p o i n t i n t h e g l i m e p i r i d e g r o u p . T h e History of antidiabetes treatment, No. (%) −0.006; P = .008). Changes in maxi- (FIGURE 3), including statin users
of the study are shown in FIGURE 4. In
els, there was a significant increase with Abbreviations: CIMT, carotid intima-media thickness; HbA1c, glycosylated hemoglobin; ITT, intent-to-treat.
SI conversion factor: To convert fasting plasma glucose values to mmol/L, multiply by 0.0555.
*No statistically significant differences were identified comparing the pioglitazone and glimepiride groups in either the ITT or CIMT population except where indicated.
†Calculated as weight in kilograms divided by height in meters squared.
‡PϽ.05.
§PϽ.01.
2006 American Medical Association. All rights reserved.
(Reprinted) JAMA, Published online November 13, 2006 PIOGLITAZONE VS GLIMEPIRIDE AND CIMT IN TYPE 2 DIABETES Figure 2. Change From Baseline to Week 72 in Mean and Maximum CIMT of the Common Carotid Artery
Values presented are least-square (LS) means using last observation carried forward. Error bars indicate SEs. A, Baseline LS mean, 0.771 (SE, 0.008) mm for pioglitazoneand 0.779 (SE, 0.008) mm for glimepiride. Treatment-group difference (pioglitazone−glimepiride) at final visit, −0.013 (95% confidence interval, −0.024 to −0.002;P = .02). B, Baseline LS mean, 1.038 (SE, 0.0100) mm for pioglitazone and 1.042 (SE, 0.0100) mm for glimepiride. Treatment-group difference at final visit, −0.024(95% confidence interval, −0.042 to −0.006; P=.008). CIMT indicates carotid intima-media thickness.
Figure 3. Absolute Change from Baseline to Week 72 in Least-Squares Mean Posterior Wall
Common Carotid Artery CIMT, by Prespecified Subgroups spectively (P = .12). At the end of the in systolic blood pressure in the piogli- TABLE2presentsthenumberofpatients
fied clinical end points. Overall, few pa- tients had a clinical event. No cardiovas- cular deaths were reported, and there was atic carcinoma in an 80-year-old woman.
A numerically higher incidence for clini- cal end points was observed in the glime- Difference in Mean Change in Posterior Wall CIMT, mm Analysis shows the point estimate of the treatment-group difference (pioglitazone−glimepiride) for the pri- cated event (a coronary revascularization mary end point for each prespecified subgroup. Error bars indicate 95% confidence intervals; vertical line in- dicates no difference. For this subgroup analysis, statin use was defined as “yes” if statins were taken within7 days of the first dose of study drug. BMI indicates body mass index (calculated as weight in kilograms di- patients with a history of MI at baseline.
vided by height in meters squared); CIMT, carotid intima-media thickness; DM, diabetes mellitus; HbA1c, gly- cosylated hemoglobin; SBP, systolic blood pressure.
pioglitazone-treated patient. A single sec-ond event (a coronary revascularization performed 1 year after the initial event) PϽ.001). Mean baseline LDL-C levels E6 JAMA, Published online November 13, 2006 (Reprinted)
2006 American Medical Association. All rights reserved.
PIOGLITAZONE VS GLIMEPIRIDE AND CIMT IN TYPE 2 DIABETES Figure 4. Absolute Change Over Time in Levels of HbA1c and HDL-C
Values indicate absolute change (least-squares [LS] means using last observation carried forward). Error bars indicate SEs. A, Baseline LS mean glycosylated hemoglobin(HbA1c) values, 7.36% (SE, 0.07%) for glimepiride (n=206) and 7.42% (SE, 0.07%) for pioglitazone (n=203). Treatment-group difference (pioglitazone−glimepiride)at final visit, −0.32% (95% confidence interval, −0.52% to −0.12%; P=.002). P=.04 and P=.01 for treatment-group differences at 48 and 60 weeks, respectively.
B, Baseline LS mean high-density lipoprotein cholesterol (HDL-C) values, 47.6 (SE, 0.9) mg/dL for glimepiride (n=206) and 47.1 (0.9) mg/dL for pioglitazone (n=201).
Treatment-group difference at final visit, 6.4 mg/dL (95% confidence interval, 5.0 to 7.9 mg/dL; PϽ.001). PϽ.001 for treatment-group differences at both 24 and 48weeks. To convert HDL-C values to mmol/L, multiply by 0.02586.
TABLE 3 shows the reporting rates for
Table 2. Number of Patients With an Adjudicated First Event in the Composite Clinical Event
End Points (ITT Population)
Pioglitazone
Glimepiride
Cardiovascular Event or Event Category*
Cardiovascular mortality, nonfatal MI, and nonfatal stroke Cardiovascular mortality, nonfatal MI, nonfatal stroke, coronary revascularization, carotid endarterectomy/ stenting, hospitalization for unstable angina, the final visit, mean weight gain was 3.2 Abbreviations: CHF, congestive heart failure; ITT, intention-to-treat; MI, myocardial infarction.
*Component events within the composite clinical end points were adjudicated by the independent clinical events com- (SD, 3.7) kg for glimepiride (PϽ.001).
mittee in a treatment-blinded manner. Analysis includes the first event within either composite end point. Only a singlesecond event within either composite event was recorded. A single patient (receiving glimepiride) had a second eventof percutaneous coronary revascularization 1 year after the first adjudicated event, which was also percutaneous †Pancreatic cancer in an 80-year-old woman.
In this randomized trial of 462 pa-tients with type 2 DM, we found that,compared with glimepiride, pioglita- ments in each carotid artery segment.
2006 American Medical Association. All rights reserved.
(Reprinted) JAMA, Published online November 13, 2006 PIOGLITAZONE VS GLIMEPIRIDE AND CIMT IN TYPE 2 DIABETES e a s e r i s k c o m p a r e d w i t h t h e Table 3. Summary of Adverse Events (Intention-to-Treat Population)
Pioglitazone
Glimepiride
Any adverse event causing discontinuation from study* Adverse events Ն5% incidence rate in either group control of cardiovascular risk factors.
*Twenty-six pioglitazone-treated participants discontinued study-drug dosing because of an adverse event; however, adverse-event documentation was available for only 25 of these participants. Adverse events are listed in order ofdecreasing frequency in the pioglitazone group.
rovascular Events) study.37 This trialrandomized more than 5000 patientswith type 2 DM who had evidence of erally reflects the diversity of the type 2 DM population in the United States.
treatment in a cohort with a better level factors (ie, a higher rate of statin use, considered for a beneficial effect of pi- systolic blood pressure, duration of type strate beneficial effects of pioglitazone function.9-12,38,39 Thiazolidinedione treat- els.9-12 In the current study, blood pres- E8 JAMA, Published online November 13, 2006 (Reprinted)
2006 American Medical Association. All rights reserved.
PIOGLITAZONE VS GLIMEPIRIDE AND CIMT IN TYPE 2 DIABETES Financial Disclosures: Dr Mazzone reports serving as
a consultant for Amylin, Merck, Novartis, Pfizer, and
Takeda and receiving speaking honoraria from Merck, Novartis, Pfizer, and Takeda. Dr Meyer reports serv- ing as a consultant for Takeda. Dr Feinstein reportsserving as a consultant for Kos and Takeda. Dr David- son reports serving as a consultant for Abbott, Astra- Zeneca, Kos, Merck, Merck/Schering-Plough, Novar-tis, Pfizer, Reliant, Roche, Sankyo, Sumitomo, and Takeda; serving on the speaker’s bureau for Abbott, AstraZeneca, Kos, Merck, Merck/Schering-Plough, Pfizer, Reliant, Sankyo, and Takeda; and receivinggrants/research support from Abbott, AstraZeneca, Bristol-Myers Squibb, Kos, Merck, Merck/Schering- Plough, Novartis, Pfizer, Reliant, Roche, Sankyo, andTakeda. Dr Kondos reports serving as a consultant for, and receiving grants/research support and honoraria from, Takeda. Dr D’Agostino reports serving as a con-sultant for Bayer, Pfizer, Sanofi, and Takeda. Dr Perez triglycerides levels.12 Both of these ef- results demonstrate, in a relatively large reports that he is a employed by Takeda Global Re- search and Development. Dr Provost reports that he is employed by Synarc. Dr Haffner reports serving asa consultant for AstraZeneca, GlaxoSmithKline, Merck Sharpe & Dohme Ltd, Pfizer, and Takeda and receiv- efit was measured in participants with ex- ing grants/research support from Novartis and Pfizer.
Funding/Support: Takeda Pharmaceuticals North
cellent blood pressure control, statin use America Inc, Lincolnshire, Ill, sponsored and funded this study and provided the study drugs. Work on this study also was supported by National Heart, Lung, andBlood Institute (NHLBI) grant K25 HL68139-01A1 to First, it was not powered to detect a dif- needed to determine the clinical signifi- Role of the Sponsors: Takeda Global Research & De-
velopment Inc, Lincolnshire, Ill, participated in proto-
col development and in the development and review of the manuscript and also oversaw participant re- cruitment, study conduct, collection of study data. TheNHLBI had no role in the design and conduct of the end points in patients with type 2 DM.
study; the collection, analysis, and interpretation of the data; or the preparation, review, or approval ofthe manuscript.
Published Online: November 13, 2006 (doi:10.1001
CHICAGO Steering Committee: Theodore Mazzone
(Principal Investigator), George Kondos (University ofIllinois at Chicago); Peter Meyer (Rush Presbyte- Author Affiliations: Department of Medicine, Sec-
tion of Endocrinology, Diabetes and Metabolism (Dr
rian-St Luke’s Medical Center, Chicago, Ill); Steven Mazzone) and Section of Cardiology (Dr Kondos), Uni- Feinstein, Michael Davidson (Rush University Medi- versity of Illinois College of Medicine, Chicago; De- cal Center, Chicago); Ralph D’Agostino, Sr (Boston Uni- partments of Preventive Medicine (Dr Meyer) and versity, Boston, Mass); Alfonso Perez (Takeda Global Medicine, Section of Cardiology (Drs Feinstein and Research & Development, Lincolnshire, Ill); and Steven Davidson), Rush University Medical Center, Chi- Haffner (University of Texas Health Science Center at cago; Department of Mathematics, Statistics and Con- result of an effect of pioglitazone to sup- sulting Unit, Boston University, Boston, Mass (Dr CHICAGO Site Investigators: Dennis C. Abella, DO
press or delay the progression of CIMT.
D’Agostino); Takeda Global Research and Develop- (Radiant Research Alexian Brothers, Elk Grove Vil- ment Inc, Lincolnshire, Ill (Dr Perez); Synarc, Paris, lage, Ill); Frank O. Apantaku, MD (Illinois Center France (Dr Provost); and Department of Medicine, Uni- for Clinical Research, Chicago); Leon Fogelfeld, MD versity of Texas Health Science Center at San Anto- (Cook County Hospital, Division of Endocrinology, C h i c a g o ) ; M i c h a e l D a v i d s o n , M D ( R a d i a n t Author Contributions: Dr Meyer had full access to all
Research, Chicago); Richard A. Margolin, MD of the data in the study and takes responsibility for (Midwest Physicians Group, Homewood, Ill, and the integrity of the data and the accuracy of the data Accelovance, Crestwood, Ill); Bernard J. Mizock, analysis. Dr Meyer performed an independent statis- MD (Peryam and Kroll Healthcare Research, Chi- tical analysis, and all of the results shown in this ar- cago); Gary P. Plundo, DO (Accelovance, Orland intention-to-treat population (Table 1).
Park, Ill); Jeffrey G. Shanes, MD (Consultants in In addition, an analysis of baseline char- Study concept and design: Mazzone, Meyer, Feinstein, Cardiovascular Medicine, Melrose Park, Ill); Waldo Kondos, D’Agostino, Perez, Provost, Haffner.
Harvey, Jr, MD (ICCT Research International Inc, Acquisition of data: Mazzone, Perez, Provost.
Chicago); Azazuddin A. Ahmed, MD (American Analysis and interpretation of data: Mazzone, Meyer, Medical Research Inc, Chicago); Richard Berten- Davidson, D’Agostino, Perez, Provost, Haffner.
shaw, Jr, MD (LaGrange, Ill); Judy A. Carter, MD with those who remained in the study.
Drafting of the manuscript: Mazzone, Kondos, (Oak Park Hospital, Oak Park, Ill); Lee S. Freedman, MD (Highland Park, Ill); Daniel H. Litoff, MD (Har- Critical revision of the manuscript for important in- bor Medical Group, Chicago); Shishir Jain, MD tellectual content: Mazzone, Meyer, Feinstein, (Personal Physicians, Cicero, Ill); Neil B. Perlman, Davidson, D’Agostino, Perez, Provost, Haffner.
MD (Westlake Medical Associates, Vernon Hills, Ill); Statistical analysis: Mazzone, Meyer, Feinstein, Alan D. Kogan, MD (Evanston, Ill, and North Sub- Davidson, D’Agostino, Provost, Haffner.
urban Cardiology Group Ltd, Arlington Heights, Ill); Obtained funding: Mazzone, Perez.
Betul A. Hatipoglu, MD (University of Illinois at Administrative, technical, or material support: Chicago); Thomas L. Pitts, MD (Chicago, Ill); Aud- isho B. Khoshaba, MD (ABK Medical Center Ltd, Study supervision: Mazzone, Kondos, Perez, Provost.
Chicago); Reuben T. Nichols, MD (Midlake Medical 2006 American Medical Association. All rights reserved.
(Reprinted) JAMA, Published online November 13, 2006 PIOGLITAZONE VS GLIMEPIRIDE AND CIMT IN TYPE 2 DIABETES Corporation, Chicago); Steven M. Malkin, MD Members of the Clinical Events Committee: William
School of Public Health, Houston); and Spencer King, (Medical Care Group Ltd, Arlington Heights, Ill); Gaasch, MD (Lahey Clinic, Burlington, Mass); I. K. Jang, Danny Sugimoto, MD (Cedar-Crosse Research MD (Massachusetts General Hospital, Boston); Ajit B.
Imaging Core Laboratory: Laure Arnaud, Arnaud Mar-
Center, Chicago); Santosh Gill, MD (Fox Valley Raisinghani, MD, Ori Ben-Yehuda, MD (UCSD Medi- morat, Armelle Merle, PhD, Jean-Claude Provost, MD, Clinical Research Center, Aurora, Ill); Antonio Bara- cal Center, San Diego, Calif ); Theo Meyer, MD (Uni- and Laurence Torcel (Synarc, Paris, France); Ales Lin- jas, MD (Family Practice, Chicago); Arnold F.
versity of Massachusetts Medical Center, Worcester).
hart, MD (sonographer training) (Charles University, Turner, MD (Prairie Medical Associates Ltd, Chi- Members of the Data and Safety Monitoring Board: Ed-
cago); James G. Cunnar, MD (DuPage Family ward Horton, MD (Boston, Mass): George Bakris, MD Acknowledgment: The authors thank Stephanie
Medicine, Naperville, Ill); and Albert Reynolds, MD (Rush-Presbyterian-St Luke’s Medical Center, Chi- Thompson, University of Illinois, for manuscript prepa- (South Suburban Health Professional Group, Floss- cago, Ill); Sidney Goldstein, MD (Henry Ford Hospital, ration. Ms Thompson received no compensation for Detroit, Mich); Barry Davis, MD, PhD (University of Texas REFERENCES
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2006 American Medical Association. All rights reserved.

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