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1304 Full
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O R I G I N A L
A R T I C L E
OBJECTIVEdThe two major classes of antidiabetic drugs, sulfonylureas and metformin, may
differentially affect macrovascular complications and mortality in diabetic patients. We compared the long-term effects of glipizide and metformin on the major cardiovascular events in type
2 diabetic patients who had a history of coronary artery disease (CAD).
RESEARCH DESIGN AND METHODSdThis study is a multicenter, randomized, doubleblind, placebo-controlled clinical trial. A total of 304 type 2 diabetic patients with CAD, mean age =
63.3 years (range, 3680 years), were enrolled. Participants were randomly assigned to receive either
glipizide (30 mg daily) or metformin (1.5 g daily) for 3 years. The primary end points were times to the
composite of recurrent cardiovascular events, including death from a cardiovascular cause, death
from any cause, nonfatal myocardial infarction, nonfatal stroke, or arterial revascularization.
RESULTSdAt the end of study drug administration, both groups achieved a signicant decrease in
the level of glycated hemoglobin (7.1% in the glipizide group and 7.0% in the metformin group). At a
median follow-up of 5.0 years, 91 participants had developed 103 primary end points. Intention-to-treat
analysis showed an adjusted hazard ratio (HR) of 0.54 (95% CI 0.300.90; P = 0.026) for the composites
of cardiovascular events among the patients that received metformin, compared with glipizide. The
secondary end points and adverse events were not signicantly different between the two groups.
CONCLUSIONSdTreatment with metformin for 3 years substantially reduced major cardiovascular events in a median follow-up of 5.0 years compared with glipizide. Our results indicated a
potential benet of metformin therapy on cardiovascular outcomes in high-risk patients.
Diabetes Care 36:13041311, 2013
c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c
From the 1Rui-jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; the 2Johns
Hopkins University School of Medicine, Baltimore, Maryland; the 3Xinhua Hospital, Shanghai Jiao Tong
University School of Medicine, Shanghai, China; 4The Second Xiangya Hospital of Central South University,
Changsha, China; the 5Shandong Provincial Hospital, Shandong University, Jinan, China; the 6Chang Hai
Hospital, Second Military Medical University, Shanghai, China; 7The First Afliated Hospital of Wenzhou
Medical College, Zhejiang Province, China; the 8Sir Run Run Shao Hospital, Zhejiang Province, China; the
9
Jiangsu Province Hospital, Jiangsu Province, China; the 10Shanghai Tens Peoples Hospital of Tongji University, Shanghai, China; the 11Nanfang Hospital, Guangdong Province, China; and the 12Nanjin Drum Tower
Hospital, Jiangsu Province, China.
Corresponding author: Guang Ning, [email protected].
Received 16 April 2012 and accepted 4 October 2012.
DOI: 10.2337/dc12-0719. Clinical trial reg. no. NCT00513630, clinicaltrials.gov.
This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/suppl/doi:10
.2337/dc12-0719/-/DC1.
J.H. and Y.Z. contributed equally to this study.
*A complete list of the investigators of SPREAD-DIMCAD can be found in the APPENDIX.
2013 by the American Diabetes Association. Readers may use this article as long as the work is properly
cited, the use is educational and not for prot, and the work is not altered. See http://creativecommons.org/
licenses/by-nc-nd/3.0/ for details.
1304
infarction, nonfatal stroke or arterial revascularization by percutaneous transluminal coronary angioplasty (PTCA) or
by coronary artery bypass graft, death
from a cardiovascular cause, and death
from any cause. The end points were
obtained and conrmed by the medical
records and death certicates that were
kept in each center. The secondary cardiovascular end points included new or
worsening angina, new or worsening
heart failure, new critical cardiac arrhythmia, and new peripheral vascular
events. Other adverse events, including
hypoglycemia (severe hypoglycemia in
which the subject required assistance
and/or a plasma glucose level ,56 mg/dL
[3.1 mmol/L] was recorded as a hypoglycemic attack and would be reported
in this manuscript) and microvascular
complications, were also monitored.
Randomization and study medication
After a 2-week run-in period, the eligible
study participants were required to withdraw from all antidiabetic agents and
were randomly assigned in double-blind
to receive either glipizide plus metformin
placebo or metformin plus glipizide placebo for 3 years. The baseline metabolic
values were obtained immediately after
the withdrawal of previous antidiabetic
therapy. The randomization codes were
generated by the studys biostatistician at
Shanghai Jiao Tong University School of
Medicine. Study sites did not have access
to the codes.
For both groups, the targeted glycated hemoglobin level was ,7.0%, the
fasting blood glucose concentration was
,7 mmol/L, and the postload 2-h blood
glucose concentration was ,10 mmol/L.
The study drugs and the matched placebo
were prepared in indistinguishable tablets. For the glipizide group, the initial
dose was 15 mg daily (5 mg per one
pill, three times daily) and titrated to 30
mg (10 mg per two pills, three times
daily) within 3 months, if not to target.
The mean daily dose of glipizide was
28.3 6 3.9 mg. For the metformin group,
the initial dose was 0.75 g daily (0.25 g
per one pill, three times daily), and titrated to 1.5 g (0.5 g per two pills, three
times daily) within 3 months, if not to
target. The mean daily dose of metformin
was 1.4 6 0.2 g. After 3 months, insulin
was added for patients with the maximum dose of study drug administration
in either group who did not achieve targeted glucose control level (see Supplementary Data). Lifestyle intervention and
1305
End of follow-up
Glipizide
(n = 148)
Metformin
(n = 156)
Glipizide
(n = 97)
Metformin
(n = 111)
P value*
P valuex
63.8 6 9.4
62.8 6 8.5
114 (77.0%)
34 (23.0%)
122 (78.2%)
34 (21.8%)
5.6 6 4.9
3.0 6 5.1
5.6 6 5.3
2.9 6 4.8
0.947
0.837
94 (63.5%)
84 (53.8%)
0.103
95 (64.2%)
13 (9.0%)
106 (71.6%)
53 (35.8%)
19 (12.8%)
68.7 6 10.6
25.1 6 2.9
90 6 9
98 (62.8%)
18 (11.5%)
105 (67.3%)
61 (39.1%)
36 (23.1%)
69.6 6 10.1
25.2 6 3.0
91 6 9
0.813
0.428
0.408
0.726
0.068
0.465
0.675
0.317
69.6 6 11.0
25.7 6 2.9
92 6 9
68.6 6 10.4
24.7 6 2.8
90 6 9
0.554
0.026
0.118
0.002
,0.001
0.001
7.6 6 1.7
7.3
6.58.4
7.6 6 1.7
7.3
6.68.4
0.847
7.1 6 1.1
7.0
6.37.8
7.0 6 1.3
6.8
6.27.4
0.662
0.419
7.77 6 2.22
7.4
6.48.4
8.21 6 2.28
7.8
6.69.0
0.075
6.91 6 1.52
7.0
6.07.7
7.21 6 2.24
6.8
6.27.7
0.297
0.405
12.56 6 4.20
12.0
9.615.1
13.61 6 4.05
13.0
10.516.3
0.014
11.34 6 3.58
10.5
8.813.0
10.84 6 3.41
10.3
8.512.7
0.370
0.207
129.1 6 18.4
78.3 6 9.7
130.1 6 17.6
78.4 6 10.0
0.667
0.921
128.6 6 15.1
75.8 6 9.8
128.0 6 15.5
75.9 6 8.3
0.804
0.933
0.737
0.950
4.55 6 1.32
2.73 6 0.90
1.16 6 0.32
2.07 6 1.65
86.7 6 18.9
4.93 6 3.00
2.79 6 0.89
1.15 6 0.32
2.44 6 1.96
83.8 6 17.6
0.159
0.544
0.748
0.080
0.165
4.36 6 1.30
2.40 6 0.83
1.28 6 0.38
2.10 6 2.49
86.3 6 22.0
4.52 6 1.23
2.60 6 0.83
1.23 6 0.33
2.10 6 1.71
83.3 6 25.2
0.442
0.132
0.339
1.000
0.433
0.667
0.248
0.958
0.537
0.302
80 (54.1%)
81 (54.7%)
3 (2.0%)
30 (20.3%)
4 (2.7%)
15 (10.1%)
24 (16.2%)
76 (48.7%)
74 (47.4%)
3 (1.9%)
37 (23.7%)
5 (3.2%)
13 (8.3%)
37 (23.7%)
0.349
0.201
0.948
0.469
0.797
0.586
0.103
25 (26.3%)
30 (27.0%)
0.908
0.259
122 (82.4%)
76 (51.4%)
132 (84.6%)
79 (50.6%)
0.703
0.893
77 (81.1%)
53 (55.8%)
99 (89.2%)
54 (48.6%)
0.067
0.338
0.287
0.492
P value*
0.302
0.805
Continued on p. 1308
care.diabetesjournals.org
1307
End of follow-up
Glipizide
(n = 148)
Metformin
(n = 156)
P value*
Glipizide
(n = 97)
Metformin
(n = 111)
P value*
11 (7.4%)
80 (54.1%)
47 (31.8%)
22 (14.9%)
97 (65.5%)
17 (10.9%)
90 (57.7%)
48 (30.8%)
16 (10.3%)
97 (62.2%)
0.297
0.524
0.910
0.223
0.582
5 (5.3%)
60 (63.2%)
34 (35.8%)
11 (11.6%)
70 (73.7%)
10 (9.0%)
73 (65.8%)
35 (31.5%)
10 (9.0%)
66 (59.5%)
0.294
0.632
0.580
0.558
0.039
P valuex
0.456
0.625
0.901
0.726
0.013
Data are means 6 SD for data normally distributed, n (%), or median and IQR for data not normally distributed. Statistical signicances were determined using
a Student t test (for data normally distributed) or a Mann-Whitney U test (for data not normally distributed) and x2 test (for categorical variable data). *P values are for
the difference between the groups at baseline or at the end of follow-up. xP value refers to comparison between the glipizide and the metformin groups after treatment
using the ANCOVA analysis.
CONCLUSIONSdSPREAD-DIMCAD
was the rst double-blind, randomized,
controlled trial to compare the different
effects of glipizide and metformin on the
major cardiovascular events among patients with type 2 diabetes and CAD.
After a median of 5.0 years of follow-up,
treatment with metformin showed a significant reduction of the recurrence of composite cardiovascular events compared
with glipizide, which indicated a protective
effect of metformin on cardiovascular
events in high-risk patients. Such a protective effect of metformin may also be
present in a later stage of type 2 diabetes
during insulin therapy (19).
Cardiovascular disease is the most
common complication and the leading
cause of mortality in patients with type 2
diabetes (20,21). Sulfonylureas and metformin have been the cornerstone of drug
therapy for type 2 diabetes, either alone or
in combination, for a quarter of a century
(22). Experimental studies have shown
different effects of these two kinds of antidiabetic drugs on cardiovascular disease
besides their glucose-lowering effect (23
29). However, studies comparing these
two classes of medications on cardiovascular risk in humans generated highly inconsistent results (714). Several reasons
may account for the discrepancies among
these studies. First, most of the previous
studies are retrospective and observational in design. The patients included
in different studies varied in the severity
of diabetes and cardiovascular disorders
as well as other characteristics, such as
BMI and glucose levels, which might inuence drug choice. Second, the uses of
cardiovascular medications were not well
controlled in some studies and might also
contribute to the diverse associations with
cardiovascular events. Moreover, few previous studies directly compared the
Figure 2dChanges of major clinical and biochemical characteristics at baseline and during follow-up in different groups. HbA1c (A), fasting
plasma glucose (B), BMI (C), triglycerides (D), total cholesterol (E), LDL cholesterol (F), HDL cholesterol (G), and estimated glomerular ltration
rate (eGFR) (H). Data displayed as means 6 SD. P value refers to comparison between the groups.
care.diabetesjournals.org
1309
AcknowledgmentsdThis study was supported by grants from the 863 Project (2006
AA 02A409), the National Natural Science
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APPENDIX
SPREAD-DIMCAD CLINICAL
SITES
The investigators and coordinators of this
study are as follows: Guang Ning, MD,
PHD; Jie Hong, PHD; Yifei Zhang, PHD;
Weiqing Wang, MD, PHD; Minghui Gui,
PHD; Ying Chen, MD; Zhenni Chi, MD;
Qun Yan, MD; Ying Zhai, MD (Shanghai
Clinical Center for Endocrine and Metabolic Diseases, Ruijin Hospital); Weifeng
Shen, MD, PHD; Ankang Lv, MD; Ruiyan
Zhang, MD, PHD (Department of Cardiology, Ruijin Hospital); Jialin Yang, PHD;
Yu Zhang, MD; Xiaofang Fan, MD (Department of Endocrinology, Min Hang
Center Hospital, Shanghai, China); Dadong Zhang, MD, PHD (Department of
Cardiology, Min Hang Center Hospital);
Qing Su, PHD; Yan Dong, PHD; Huili
Xing, MD (Department of Endocrinology,
Xinhua Hospital); Zhiguang Zhou, MD,
PHD; Xing Li, MD; Weili Tang, PHD
5.
6.
7.
8.
9.
10.
11.
12.
13.
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16.
17.
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19.
20.
21.
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