Impact of acarbose on carotid intima-media thickness in patients with newly diagnosed impaired glucose tolerance or mild type 2 diabetes mellitus: A one-year, prospective, randomized, open-label, parallel-group study in Japanese adults with established coronary artery disease

Clinical Therapeutics/Volume 32, Number 9, 2010

Impact of Acarbose on Carotid Intima-Media Thickness in Patients With Newly Diagnosed Impaired Glucose Tolerance or Mild Type 2 Diabetes Mellitus: A One-Year, Prospective, Randomized, Open-Label, Parallel-Group Study in Japanese Adults With Established Coronary Artery Disease Masayoshi Koyasu, MD1,2; Hideki Ishii, MD, PhD1; Masato Watarai, MD, PhD2; Kenji Takemoto, MD, PhD2; Yasuya Inden, MD, PhD1; Kyosuke Takeshita, MD, PhD1; Tetsuya Amano, MD, PhD1; Daiji Yoshikawa, MD1; Tatsuaki Matsubara, MD, PhD3; and Toyoaki Murohara, MD, PhD1

'Department ofCardiology, Nagoya University Graduate School ofMedicine, Nagoya,Japan; 2Department ofCardiology, Anjyo Kosei Hospital, Anjyo,Japan; and 3Department ofInternal Medicine, School of Dentistry, Aichi-Gakuin University, Nagoya,Japan ABSTRACT Objective: This study examined the effect of acarbose therapy on carotid intima-media thickness (IMT)in patients with established coronary artery disease (CAD) who had been newly diagnosed with impaired glucose tolerance (IGT) or mild type 2 diabetes mellitus (T2DM). Methods: This was a I-year, prospective, randomized, open-label, parallel-group study in patients with established CAD (~50% stenosis on quantitative coronary angiography) who were newly diagnosed with IGT or mild T2DM. lGT was defined as 2-hour glucose concentrations of 140 to 199 mg/dL on the 75-g oral glucose tolerance test (OGTT). Mild T2DM was defined as a fasting plasma glucoseconcentration <126 mg/dL,2-hour plasma glucose concentration on OGrr >200 mg/dL, and glycosylatedhemoglobin (HbA1cl <6.5%. On the day after undergoing coronary angiography, patients were randomly allocated to receive either acarbose 150 mg/d or control (no treatment). Carotid IMT was measured by ultrasonography at baseline and at 12 months of follow-up. The changes in glucose profiles (75-g OGTT), HbA 1c' and lipid profiles were also compared between baseline and follow-up. At visits every 2 months, data on adverse events, drug adherence, and changes in medication were collected. Adverse events were recorded based on spontaneous reports and questioning by the investigator. Clinical follow-up data on outcomes of interest were obtained from patients' hospital charts or from telephone interviews; these outcomes were the incidence of mortality, nonfatal myocardial infarction,

1610

repeat percutaneous coronary intervention for a treated coronary artery, and stroke. Results: Ninety Japanese patients were enrolled in the study (45 in each group). Two patients in the acarbose group discontinued therapy due to drug-related diarrhea, and 1 patient in each group was discontinued because of a newly diagnosed malignancy.Three patients in the control group were discontinued because they initiated treatment with fibrates, and 2 patients in the control group were lost to follow-up. Thus, complete baseline and follow-up data were available for 42 patients in the acarbose group and 39 in the control group. These 81 patients were predominantly male (74 [91.4%]), with a mean (SD) age of 66.3 (9.0) years, mean body weight of 65.9 (10.5) kg, and mean HbA 1c of 5.57% (0.38%). Baseline characteristics appeared to be comparable between the 2 groups. In the acarbose group, IMT increased from a mean of 1.28 (0.53) rnm at baseline to 1.30 (0.52) mm at 12-month follow-up (mean change, 0.02 [0.29] mm; P = NS), whereas in the control group, it increased from a mean of 1.15 (0.37) mm to 1.32 (0.46) mm (mean change, 0.17 [0.25] mm; P < 0.001). The difference between groups was statistically significant (P =0.01). In addition, the acarbose group Accepted forpublicationJune25,2010. Express Track online publication July 22,2010. doi:l 0.1016/j.c1inthera.201 0.07.01 5 0149-2918/$ - see front matter © 2010 Excerpta Medica Inc. All rights reserved.

Volume 32 Number 9

M. Koyasu et al.

had significant reductions from baseline in 2-hour glucose concentrations on the 75-g OGTT (mean change, -24.8 [45.2] mg!dL; P =0.001), fasting total cholesterol (mean change, -11.26 [26.1] mg!dL; P = 0.009), and fasting triglyceride concentrations (mean change, -30.4 [62.7] mg!dL; P = 0.003), whereas the corresponding changes were not significant in the control group (mean change,-8.5 [39.4],-6.22 [26.7], and-LOS [74.2] mgt dL, respectively). Cardiovascular events requiring hospitalization occurred in 4 patients (9.5 %) in the acarbose group and 4 patients (10.3%) in the control group. No deaths, nonfatal myocardial infarctions, or strokes occurred in either group over the follow-up period. Conclusion: In this small, open-label study in patients with established CAD who were newly diagnosed with IGT or mild T2DM, 12 months of treatment with acarbose was associated with a beneficial effect in terms of preventing the progression of carotid IMT compared with control, although it was not associated with a significant decrease in IMT from baseline. UMIN (University Hospital Medical Information Network) Clinical Trials Registry identifier: UMIN000000544. (Clin Ther. 2010;32:1610-1617) © 2010 Excerpta Medica Inc. Key words: acarbose, impaired glucose tolerance, type 2 diabetes mellitus, carotid intima-media thickness.

INTRODUCTION The association between diabetes mellitus (DM) and increased cardiovascular morbidity is well recognized.l>' Patients with DM also are at increased risk for both cardiovascular mortality and all-cause mortality compared with those without DM. Furthermore, an association has been reported between elevated glucose concentrations and the development of ischemic heart disease and adverse clinical outcomes in patients with DM.4,5 In the UK Prospective Diabetes Study, higher glycosylated hemoglobin (HbA1cl values predicted development of coronary artery disease (CAD) and fatal myocardial infarction.f Patients who have mild type 2 DM (T2DM) or impaired glucose tolerance (IGT) have a poorer prognosis compared with those who have normal glucose tolerance or impaired fasting glucose.V Use of a-glucosidase inhibitors such as acarbose has been reported to modify postprandial plasma glucose concentrations, reducing the risk for cardiovascular disease and hypertension in patients with IGT.9,10 In addition, these agents have been found to prevent increases in carotid intima-media thickness (IMT) in

August 2010

patients with IGT and T2DM. In a subgroup analysis of patients with IGT in the Study to Prevent NonInsulin-Dependent Diabetes Mellitus, acarbose was associated with less progression of IMT compared with placebo (P = 0.027).11 A prospective, randomized, open-label study in 101 patients with DM found that voglibose treatment was associated with significantly less progression of IMT compared with no voglibose (P < 0.001),12 Absolute IMT values and changes in IMT over time have been reported to be highly associated with the risk of future cardiovascular events. 13- 15 However, few studies have examined the effects of acarbose on slowing the progression of IMT in patients with CAD and IGT or mild T2DM. Prevention of future cardiovascular events is an important goal in this patient population. The present study examined the effect of acarbose therapy on carotid IMT in patients with established CAD who had been newly diagnosed with IGT or mild T2DM.

PATIENTS AND METHODS

Patients Participants were recruited from patients admitted to the Department of Cardiology of Anjyo Kosei Hospital (Anjyo, Japan) for elective coronary angiography between October 2006 and October 2008. For inclusion in the study, patients had to have stable angina pectoris and CAD (<::50% stenosis on quantitative coronary angiography), as well as newly diagnosed IGT or mild T2DM. IGTwas defined as a fasting plasma glucose concentration <126 mg!dL and a 2-hour plasma glucose concentration on the 75-g oral glucose tolerance test (OGIT) of 140 to 199 mg/dL.16 MildT2DM was defined as a fasting plasma glucose concentration <126 mg/dL, a 2-hour plasma glucose concentration on OGIT >200 mg/dL, and HbA l c <6.5%. Exclusion criteria were age> 70 years, active inflammatory disease, previous treatment with antidiabetic agents, a previous diagnosis ofDM, HbA l c <::6.5%, previous cerebrovascular disease, acute coronary syndrome, renal dysfunction (serum creatinine >1.5 mg/dl.), and history or presence of cancer.

Study Design This 1-year, prospective, randomized, open-label, parallel-group trial was approved by the hospital ethics committee. All candidates who met the initial inclusion criteria underwent a 75-g OGTT on the day before coronary angiography. If coronary stenosis was con-

1611

Clinical Therapeutics

firmed on angiography, informed consent was obtained the following day. Patients were then randomly allocated to either the acarbose 150-mg/d group or the control group (no treatment). Randomization was performed using a simple sealed-envelope method. Doses of antiangina, antihypertensive, and lipidlowering drugs were not to be altered during the study period. If a dose of one of these medications was changed, the patient was discontinued from the study. Patients were also discontinued in the case of a newly diagnosed malignancy. Patients visited the hospital every 2 months for assessment of adverse events, drug adherence, and changes in medications. Adverse events were recorded based on spontaneous reports and questioning by the investigator. Blood pressure was measured with the patient in a sitting position after 5 minutes' rest in a supine position. Patients were encouraged to exercise, stop smoking, restrict fat intake, increase dietary fiber intake, and reduce between-meal snacks. Clinical follow-up data were obtained from patients' hospital charts or from telephone interviews with patients conducted by a single trained interviewer who was blinded to patient characteristics and treatment assignment. The data of interest included the incidence of death, nonfatal myocardial infarction, repeat percutaneous coronary intervention for a treated coronary artery, and stroke. The primary end point was the absolute change from baseline to 12 months in the largest measured IMT value in the right and left common carotid arteries. Secondary end points included the change from baseline to 12 months in glucose profiles (OGTT), HbA Ic ' and lipid profiles. The primary and secondary end points were evaluated by blinded evaluators.

Laboratory Tests At baseline, venous blood samples for determination of plasma glucose, HbA I c' serum insulin, serum lipids (total cholesterol, LDL-C, HDL-C, and triglycerides), and the homeostasis model assessment of insulin resistance (HOMA-IR) were obtained between 7:00 and 8:00 AM on the day of the 75-g OGTT. On the day of carotid IMT ultrasonography at 12-month follow-up, the 75-g OGTT was repeated, and fasting blood samples were obtained for repeat laboratory testing. Plasma glucose concentrations were measured using the glucose oxidase method, and HbA l c was determined by HPLC (Hi-AUTOA l c HA-8150, Arkray Inc., Kyoto, japan).

1612

Serum insulin concentrations were measured using a radioimmunoassay (Insulin-RIA bead II, Abbott, Tokyo, japan). Serum lipids were measured by enzymatic methods using a chemical autoanalyzer (Hitachi Ltd., Tokyo.japan). These tests were performed in the hospital laboratory immediately after blood sampling. HOMAIR was calculated as follows: (fasting immunoreactive insulin concentration [ul.l/rnl.] x fasting glucose level [mg/dL]/405)Y

Measurement of Carotid Intima-Media Thickness Carotid IMT (defined as the distance from the edge of the lumen-intima interface to the edge of the collagencontaining upper layer of the adventitia) was measured usinghigh-resolutionB-modeultrasonography (LOGIQ 7, GE Healthcare, Bedford, United Kingdom). All ultrasound images were obtained by a single technician. The scans were stored, and measurements were obtained from the stored images by a separate individual who was blinded to patient characteristics and treatment status. Baseline measurement of IMT was performed just after the OGTT. At 12 months, follow-up ultrasonography was performed and evaluated by the same individuals as at baseline. For evaluation of reproducibility (intraobserver variability), the baseline images of 30 randomly selected patients were analyzed at least 1 month apart. The IMT measurements were found to be well correlated (mean [SO] difference, 0.047 [0.065] mm; r =0.96; P < 0.001). Statistical Analysis No sample-size calculation was performed. The study results are expressed as mean (SO) or frequency (%). Differences between groups at baseline were evaluated by the t test for continuous variables and the x2 test for categorical variables.lf Differences in the change from baseline to 12-month follow-up in the 2 groups were evaluated using the paired t test for continuous variables. P < 0.05 was considered statistically significant in all analyses. Statistical analysis was performed using SPSS software (SPSS Inc., Chicago, Illinois). RESULTS The study enrolled 90 japanese patients, 45 in each group. Two patients in the acarbose group discontinued treatment due to drug-related diarrhea. One patient in each group was excluded because of a newly diagnosed malignancy. Three patients in the control group were

Volume 32 Number 9

M. Koyasu et al.

discontinued for initiating treatment with fibrates, and 2 patients in the control group were lost to follow-up. Thus, 42 patients in the acarbose group and 39 patients in the control group had both baseline and follow-up data and were included in the study analyses. The baseline characteristics of the patients with complete follow-up data are summarized in Table I. There were no significant differences between groups in terms of age, sex, coronary risk factors, glycemic profiles, lipid profiles, blood pressure, echocardiographic findings, or use of oral medications. After 12 months, there was no significant change from baseline in laboratory or ultrasonography findings in either group (Table II). In the acarbose group, IMT increased from a mean (SD) of 1.28 (0.53) mm to 1.30 (0.52) mm (mean change, 0.02 [0.29] mm; P =NS), whereas in the control group, it increased from a mean of 1.15 (0.37) mm to 1.32 (0046) mm (mean change, 0.17 [0.25] mm; P < 0.001). The difference between the acarbose and control groups was statistically significant (P =0.01) (Figure). After 12 months, only the acarbose group had significant reductions from baseline in mean (SD) 2-hour glucose concentrations on the 75-g OGTT (from 192.8 [35.9] to 168.6 [51.0] mg/dL; mean change,-24.8 [45.2] mg/dL; P =0.001), fasting total cholesterol (from 178.0 [28.3] to 165.5 [22.9] mg/dL; mean change, -11.26 [26.1] mg/dL; P = 0.009), and triglycerides (from 146.8 [79.5] to 112.8 [55.7] mg/dL; meanchange,-30A [62.7] mg/dL; P = 0.003) (Table II). Only the control group had significant increases in fasting immunoreactive insulin (from 7.17 [5.18] to 8.58 [6.70] IlU/mL; mean change, 1.30 [3.70] IlU/mL; P =0.02) and HOMA-IR (from 2.02 [1.67] to 2040 [1.95]; mean change, 0.35 [1.23]; P =0.012). During the 12-month follow-up period, 4 patients (9.5%) in the acarbose group and 4 patients (10.3%) in the control group required hospitalization due to cardiovascular events (P = NS). In the acarbose group, the cardiovasculareventswere congestive heart failurein 1 patient, angina pectoris in 2, and lacunar infarction in 1. In the control group, the cardiovascular events were congestive heart failure in 1 patient and angina pectoris in 3. No other adverseeventsof interest (death, nonfatal myocardial infarction, and stroke) occurred in either group. DISCUSSION DM is well recognized as a major cardiovascular risk faeroe!" Because of the poor prognosis of cardiovascular

August 2010

disease in patients with DM, effective medication is essential.lt has been reported that acarbose, an a-glucosidase inhibitor, slows the progression of carotid IMT in patients with IGT and DM.ll,12 This study examined the effect of acarbose on the progression of carotid IMT in patients with established CAD who had IGT or mild T2DM. The main mechanism of action of a-glucosidase inhibitors involves delaying the release of glucose from disaccharides and complex carbohydrates in the proximal small intestine, resulting in smaller postprandial glucose excursions.I'' Postprandial hyperglycemia (but not impairment of fasting glucose) has an adverse influence on future cardiovascular events." In addition, postprandial hyperglycemia has a stronger impact on the development of cardiovascular disease than does total exposure to hyperglycernia.f There is evidence that reducing postprandial hyperglycemia has several beneficial effects on the vessel walls, including reduction of oxidative stress, increased flow-mediated vasodilatation, and increased endothelial nitric oxide release. 21,22 The present study found a significant reduction from baseline in 2-hour glucose concentrations on the 75-g OGTT in the acarbose group (P = 0.001), although HbA l c did not differ significantly between the acarbose and control groups. Acarbose treatment was also associated with a significant reduction in triglycerides (P = 0.003), consistent with the results of a previous study.23 Thus, in this study, acarbose may have had a beneficial effect on the progression of carotid IMT through the above-mentioned mechanisms. Absolute carotid artery IMT has been reported to be a good surrogate marker for coronary atherosclerosis and an independent predictor of both stroke and cardiovascular disease.Pv" Measurement of IMT has also be used to monitor the effectiveness of oral antidiabetic agents in the prevention of atherosclerosis. 11,12,24 Therefore, it is thought that any detectable change in the carotid arteries induced by improved glycemic control may reflect similar changes elsewhere in the arterial tree, including the coronary and cerebral arteries. Metformin has been reported to significantly attenuate the progression of carotid IMT compared with placebo (P < 0.01).25 Pioglitazone has been found to slow the progression of IMT in patients with T2DM compared with glimepiride, with significant reduction of IMT from baseline to 72 weeks in patients treated with pioglitazone (P =0.02).24 Further studies will be needed to detect differences in efficacy against IMT thickening between antidiabetic agents.

1613

Clinical Therapeutics

Table I. Baseline demographic and clinical characteristics of the study population. Values are mean (SD), unless otherwise specified.

Characteristic

Acarbose (n = 42)

Control (n = 39)

p

Age, y

66.1 (8.6)

66.5 (8.0)

0.769

Sex, no. (%) Male Female

1.000 38 (90.5) 4 (9.5)

Height, cm

163.0 (8.6)

Weight, kg

36 (92.3) 3 (7.7) 161.7 (8.6)

0.471

66.5 (10.1)

64.1 (10.9)

0.318

kg/m 2

24.9 (2.7)

24.5 (3.3)

0.486

Waist circumference, cm

88.2 (8.7)

87.4 (10.1)

0.704

Body mass index,

Hypertension, no. (%)

40 (95.2)

36 (92.3)

0.668

Previous percutaneous coronary intervention, no. (%)

33 (78.6)

27 (69.2)

0.481

Previous myocardial infarction, no. (%)

18 (42.9)

20(51.3)

0.509

3 (7.1)

2 (5.1)

0.459

Current smoker, no. (%) eGFR, mL/min/l.73

m2

76.5 (22.8)

73.4 (15.1)

0.451

(59.5) (97.6) (95.2) (59.5) (31.0) (7.1)

25 (64.1) 35 (89.7) 38 (97.4) 19 (48.7) 17 (43.6) 5 (12.8)

0.845 0.191 1.000 0.198 0.229 0.213

107.3 (10.5) 192.8 (35.9)

108.6 (17.8) 187.3 (50.0)

0.719 0.193

HbA1c ' %

5.55 (0.38)

5.59 (0.39)

0.682

Immunoreactive insulin, IlU/mL

7.14 (3.86)

7.17 (5.18)

0.700

HOMA-IR

1.90 (1.09)

2.02 (1.67)

0.870

(28.3) (79.5) (37.8) (13.5)

171.6 (24.5) 137.0 (88.2) 92.9 (34.3) 46.5 (12.0)

0.276 0.467 0.851 0.587

Intima-media thickness, mm

1.28 (0.53)

1.15 (0.37)

0.359

Echocardiographic parameters Septal wall thickness, mm LVEF, % Left ventricular diastolic diameter, mm

9.36 (1.48) 62.0 (10.9) 51.7

9.38 (1.77) 61.0 (12.0) 51.4

0.671 0.558 0.315

Medications, no. (%) ACE inhibitors/ARBs Aspirin Statins CCBs ~-Blockers

Diuretics Plasma glucose, mg/dL Fasting 2-Hour concentration on 75-g OGTT

Lipids, mg/dL Total cholesterol Triglycerides LDL-C HDL-C

25 41 40 25 13 3

178.0 146.8 89.9 48.1

eGFR = estimated glomerular filtration rate; ACE = p.ngiotensin-converting enzyme; ARBs = angiotensin ll-receptor blockers; CCBs = calcium channel blockers; OGTT = oral glucose tolerance test; HbA1c = glycosylated hemoglobin; HOMA-IR = homeostasis model assessment of insulin resistance; LVEF ~ left ventricular ejection fraction.

1614

Volume 32 Number 9

>

VI

0\

......

~

o o

N

rot

III

~C

-- .-----~ -- -~-·~·-~---- - ---- ··----·- -----~-- .-- --- ------- -- --

..--.--- - -..-..- ---.- - - -----.-

131.3 (19.6) 69 .7 (12.9) 71.8 (22 .8)

eGFR , mL/min/l.73 m 2

.

.__ ._ ~: ~_~ J~ . 5~ .....

(26 .1) (62.7) (21.6) (6.76)

0.009 0.003 0.43 1.00

..o.:.~.~i~· 2~)_~ ......

- 11.26 - 3 0.4 0 - 5.47 0.30

0.76

0.53

0.12

0.35 0.001

0.57

0.31 0.18

0.65

0.75

39)

-6.22 -1.05 - 6.70 0.85

(26 .7) (74 .2) (25.1) (8 .66)

0.35 (1.2 3)

1.30 (3 .70)

- 0.02 (0. 24)

2.10 (11.9) -8.5 (39.4)

- 3.36 (12.8 )

-7.69 (23 .2) - 1.12 (13 .1)

0.15 (0.75)

0.4 (1.97)

Change

=

t _.._O. 1 7_ (~:~S.)

(24.5) (74 .6) (31.7) (11.4)

~~~_~ .~0 .4 6

165 .0 135 .9 83.9 47.4

2.40 (1.95)

8.58 (6 .70)

5.57 (0 .3 9)

110.8 (12.9) 178.7 (47.8)

70 .1 (15.1)

129 .0 (19.5 ) 71.1 (10 .3)

24 .3 (3 .3)

63.7 (10 .9)

End Point

Control (n

:~' 00 1

0.14 0 .93 0.56 0.53

0.012

0.02

0.65

0.27 0.17

0.19

0.51 0.14

0.49

0 .91

~:_O'~

0.43 0.05 0.82 0.61

0.116

0 .043

0.46

0.93 0.097

0.45

0.66 0.15

0 .53

0 .11

__

Acarbose vs Control

P,

_ . h

t_ ._.

•

" • ••

M

~.

•

..

•

•

•_

_ •• • _ .

._ • •

•• h

••• ,.

•••

~

-- ---------~-_.

eGFR ~ est imat ed glomerular f ilt rat io n rate; OGn = oral glucose tol erance test; HbA1c = glycosylated hemoglobin ; HOMA -IR = hom eostasis model assessment of insulin resistance.

~tL".:_~_~.~~~~c: t:~_i_ck".:.s.~~.~...._

(22 .9) (55.7 ) (35.0) (12 .5)

1.85 (1.00)

HOMA-IR 165 .5 112.8 84.4 48.4

-0.32 (3.47)

6.76 (3.42)

Immunoreactive insulin , J.lU/mL

Lipids, mg /dL Total cholesterol Triglycerides LDL-C HDL-C

- 0.06 (0.23)

5.50 (0.34)

HbA,c' % - 0 .04 8 (1.04)

1.74 (12.7) - 24 .8 (45 .2)

109 .2 (13.6) 168 .6 (51.0)

4.67 (14.4)

11.20 (23.5) 4 .05 (12 .5)

0.69 (1.05)

- 1.8 (2 .54)

P

-- - - - - - -

42)

Change

=

Plasma glucose, mg /dL Fasting 2-Hour concentrations on 75-g OGTT

Body mass index,

Blood pressure, mm Hg Systolic Diastolic

Weight, kg 24.2 (2.7)

64 .7 (10.1)

Parameter

kg/m 2

End Point

Acarbose (n

P

-.----.----~.,-- --------.-.--,---

Table II. Changes in outcomes from baseline to 12-month follow-up . Values are mean (SO), unless otherwise specified.

r-- -- - - - .

I

!.

III rot

ie

6'

~

Clinical Therapeutics carotid IMT. However, acarbose treatment was not associated with a significant decrease in carotid IMT from baseline.

0.6-

P = 0.01

'""' E E 0.4'-'

f-

~

c

II

Q)

eo c

til

.c U

0.2-

--

--

REFERENCES 1. Brun E, Nelson RG, Bennett PH, et ai, for the Verona Dia-

O+-----'--L----,----..JI---'------, I Acarbose

ACKNOWLEDGMENTS Dr. Ishii was supported by a grant-in-aid for scientific research (22-790699) from the Japanese Ministry of Education, Culture, Sports, Science and Technology and the Japanese Society for the Promotion of Science. The authors have indicated that they have no other conflicts of interest regarding the content of this article.

Control

Figure. Change in mean (SO) intima-media thickness (IMT) from baseline to 12-month follow-up in the acarbose and control groups.

betes Study. Diabetes duration and cause-specific mortality in the Verona Diabetes Study. Diabetes Care. 2000;

23:1119-1123. 2. Hu FB, Stampfer Mj, Solomon CG, et al. The impact of diabetes mellitus on mortality from all causes and coronary heart disease in women: 20 Years of follow-up. Arch Intern Med. 2001 ;161 :1717-1723.

3. Fox CS, Sullivan L, D'Agostino RB Sr, Wilson PW, for the

This study had several limitations, including its small sample size, open-label design, and low statistical power. There was a possibility of selection bias, as well as possible recall bias in adverse-event reporting. Furthermore, the study was performed at a single center. The inclusion and exclusion criteria limit the ability to extrapolate the results to the general population. Data on major adverse events (eg, cardiovascular events) will need to be monitored systematically in future studies. In this study, there were no significant differences in clinical data (death, nonfatal myocardial infarction, repeat percutaneous coronary intervention for a treated coronary artery, and stroke) at 12-month follow-up; it is possible that longer follow-up periods are needed before differences in the occurrence of such events become apparent. Finally, although concomitant agents were not changed during this study, such therapies may have effects on IMT and subsequent cardiovascular events. There is a need for further studies with larger sample sizes and/or longer durations.

Framingham Heart Study Group. The significant effect of diabetes duration on coronary heart disease mortality: The Framingham Heart Study. Diabetes Care. 2004;27:704-708. 4. Burchfiel CM, Reed DM, Marcus EB, et al. Association of diabetes mellitus with coronary atherosclerosis and myocardial lesions. An autopsy study from the Honolulu Heart Program. Am} Epidemial. 1993;137:1328-1340. 5. Cho E, Rimm EB, Stampfer Mj, et al. The impact of diabetes mellitus and prior myocardial infarction on mortality from all causes and from coronary heart disease in men.} Am CallCardiel. 2002;40:954-960. 6. Turner RC, Millns H, Neil HA, et al. Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS: 23). 8M). 1998;316:823-828. 7. Tominaga M, Eguchi H, Manaka H, et al. Impaired glucose tolerance is a risk factor for cardiovascular disease, but not impaired fasting glucose. The Funagata Diabetes Study. Diabetes Care. 1999;22:920-924. 8. Bonora E, Muggeo M. Postprandial blood glucose as a risk factor for cardiovascular disease in Type II diabetes: The epidemiological evidence. Diabetalagia. 2001 ;44:2107-2114. 9. Hulin B. New hypoglycaemic agents. Prog Med Chem. 1994;

CONCLUSIONS In this small study in patients with established CAD who had newly diagnosed IGT or mild T2DM, 12 months of acarbose treatment had a beneficial effect compared with control in terms of preventing the progression of

1616

31:1-58. 10. Chiasson jL, jesse RG, Gomis R, et al, for the STOPNIDDM Trial Research Group. Acarbose for prevention of type 2 diabetes mellitus: The STOP-NIDDM randomised trial. Lancet. 2002;359:2072-2077.

Volume 32 Number 9

M. Koyasu et al.

11 . Hanefeld M, Chiasson JL, Koehler C, et al. Acarbose slows progression of intima-media thickness ofthe carotid arteries in subjects with impaired glucose tolerance. Stroke. 2004 ;35 : 1073 -1078. 12 . Yamasaki Y, Katakarn i N, Haya ishiOkano R, et al. Alpha -glucosidase inh ibitor reduces the progression of carotid intima-media thickness.

Diabetes Res Clin Prado2005 ;67 :204210 . 13 . O 'Leary DH, PolakJF, Kronmal RA, et ai, for the Cardiovascular Health Study Collaborative Research Group. Ca rotid-artery intima and media th ickness as a risk factor for myoca rdial infarction and stroke in older adults . N Engl J Med. 1999;340: 14-22. 14 . Chambless LE, Folsom AR, Clegg LX, et al. Carotid wall thickness is pred ictive of incident clinical stroke: The Atherosclerosis Risk in Communities (ARIC) study. Am J Epidemiol. 2000;151 :478-487. 15 . Hod is HN, Mack WJ, laBree L, et al. The role of carotid arterial intimamed ia thickness in predicting clinical coronary events. Ann Intern Med. 1998;128:262-269 .

ment of diabetes. Clin Invest Med. 1995;18 :303 -311 . 21 . Ceriello A, Taboga C, Tonutti L, et al. Post-meal coagulation activation in diabetes mellitus: The effect of acarbose . Diabetologia. 1996;39:469-473 . 22 . Kawano H, Motoyama T, Hirashima 0 , et al. Hyperglycemia rapidly suppresses flow-mediated endotheliumdependent vasodilation of brachial artery. J Am Coli Cardiol. 1999 ;34 : 146-154. 23. Hanefeld M, Cagatay M, Petrowitsch T, et al. Acarbose reduces the risk for myocardial infa rctio n in type 2

diabetic patients: Meta-analysis of seven long-term studies. Eur Heart). 2004;25 :10-16. 24 . Mazzone T, Meyer PM, Feinstein SB, et al. Effect of pioglitazone compared with glimepiride on carotid intima-med ia thickness in type 2 diabetes: A randomized trial.JAMA. 2006;296:2572-2581 . 25 . Matsumoto K, Sera Y, Abe Y, et al. Metformin attenuates progression of carotid arterial wall thickness in patients with type 2 diabetes.

Diabetes ResClin Prado 2004;64:225228.

16 . Treatment Guide for Diabetes 2007 (in

English). Tokyo, Japan : Japan Diabetes Society; 2007. 17. Matthews DR, Hosker JP, Rudenski AS, et al. Homeostasis model assessment: Insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man . Diabetoloyja. 1985;28:412-419. 18 . Armitage P, Berry G, Matthews IN . Statistical Methods in Medical Research. 4th ed. Oxford , UK: Blackwell Scientific Publications; 2002. 19 . Haffner SM, Lehto S, Ronnernaa T, et al. Mortality from coronary heart disease in subjects with type 2 d iabet es and in nondiabetic subjects with and without prior myocard ial infa rctio n. N Engl J Med. 1998;339: 229 -234. 20 . BischoffH. The mechanism of alphaglucosidase inhibition in the manage-

August 2010

Address correspondence to: Hideki Ishii, MD, PhD, Department of Cardiology, Nagoya University Graduate School of Medicine, 65, Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan. E-mail: hkishii@ med.nagoya-u.ac.jp

1617