Primary Prevention of Macroangiopathy in Patients With Short-Duration Type 2 Diabetes by Intensified Multifactorial Intervention

Abstract

OBJECTIVE
To explore whether intensified, multifactorial intervention could prevent macrovascular disease in patients with recently diagnosed type 2 diabetes.RESEARCH DESIGN AND METHODSA total of 150 type 2 diabetic patients, with disease duration of <1 year and without clinical arteriosclerotic disease or subclinical atherosclerotic signs confirmed by ultrasonographic scanning of three conducting arteries, were randomized into an intensive intervention group and a conventional intervention group. They then received intensive, multifactorial intervention or conventional intervention over 7 years of follow-up. The patients' common carotid intima-media thicknesses (CC-IMTs) were measured every year. The primary outcome was the time to the first occurrence of CC-IMTs ≥1.0 mm and/or development of atherosclerosis plaques in the carotid artery. The secondary outcome was clinical evidence of cardiovascular disease.RESULTSA total of 70 patients in the intensive group and 68 patients in the conventional group completed the 7-year follow-up. Subclinical macrovascular (primary) outcomes occurred in seven cases in the intensive group and 22 cases in the conventional group for a cumulative prevalence of 10.00 and 32.35%, respectively (P < 0.05). No significant differences between the two groups were observed regarding the secondary outcome.CONCLUSIONS
Primary prevention of macrovascular diseases can be achieved through intensified, multifactorial intervention in patients with short-duration type 2 diabetes. Type 2 diabetic patients should undergo intensive multifactorial interventions with individual targets for the prevention of macrovascular diseases.

Full text

Primary Prevention of Macroangiopathy
in Patients With Short-Duration Type 2
Diabetes by Intensified Multifactorial
Intervention
Seven-year follow-up of diabetes complications in Chinese
YUYANG,MD
1
JUN-JIE YAO,MD,PHD
1
JIAN-LING DU,MD,PHD
1
RAN BAI,MD,PHD
1
LI-PENG SUN,MD
2
GUO-HUA SUN,BS
3
GUI-RONG SONG,MD
4
SI-MING CAO,MD
1
CHUN-HONG SHI,MD,PHD
1
YING BA,MD
1
QIAN XING,MD,PHD
1
XUE-YANG ZHANG,MD,PHD
1
OBJECTIVEdTo explore whether intensified, multifactorial intervention could prevent
macrovascular disease in patients with recently diagnosed type 2 diabetes.
RESEARCH DESIGN AND METHODSdA total of 150 type 2 diabetic patients, with
disease duration of ,1 year and without clinical arteriosclerotic disease or subclinical athero-
sclerotic signs confirmed by ultrasonographic scanning of three conducting arteries, were ran-
domized into an intensive intervention group and a conventional intervention group. They then
received intensive, multifactorial intervention or conventional intervention over 7 years of
follow-up. The patients’common carotid intima-media thicknesses (CC-IMTs) were measured
every year. The primary outcome was the time to the first occurrence of CC-IMTs $1.0 mm and/
or development of atherosclerosis plaques in the carotid artery. The secondary outcome was
clinical evidence of cardiovascular disease.
RESULTSdA total of 70 patients in the intensive group and 68 patients in the conventional
group completed the 7-year follow-up. Subclinical macrovascular (primary) outcomes occurred
in seven cases in the intensive group and 22 cases in the conventional group for a cumulative
prevalence of 10.00 and 32.35%, respectively (P,0.05). No significant differences between the
two groups were observed regarding the secondary outcome.
CONCLUSIONSdPrimary prevention of macrovascular diseases can be achieved through
intensified, multifactorial intervention in patients with short-duration type 2 diabetes. Type 2
diabetic patient s should undergo intensive multif actorial interventions with indi vidual targets for
the prevention of macrovascular diseases.
Diabetes Care 36:978–984, 2013
The prevalence of diabetes, especially
type 2 diabetes, is increasing mark-
edly worldwide, including in China
(1,2). The chronic complications of dia-
betes seriously affect quality of life and
result in a significant decrease in life ex-
pectancy; they also impose a heavy eco-
nomic burden. Therefore, the prevention
and treatment of chronic diabetes compli-
cations have become a considerable
medical problem attracting worldwide at-
tention.
The macrovascular complications of
diabetes, which can lead to cardiovascular
diseases, are the major cause of death in
patients with type 2 diabetes. A reduction
in all-cause mortality among individuals
with diabetes has occurred over time;
however, the mortality rate from cardio-
vascular causes among individuals with
diabetes remains approximately twofold
higher than the rate in those without
diabetes (3,4). In recent years, the results
of several large-scale clinical trials have
illustrated that interventions for the vari-
ous atherosclerosis (AS) risk factors in pa-
tients with type 2 diabetes can reduce the
risk of cardiovascular death by different
degrees, although it remains controversial
whether intensive glucose control can
help prevent cardiovascular events. The
Steno-2 study, which was conducted in
patients with type 2 diabetes and micro-
albuminuria of any duration, demon-
strated that target-driven, long-term,
intensified interventions aimed at multi-
ple risk factors can reduce the risk of car-
diovascular and microvascular events by
~50% (5,6).
Thickening of the common carotid
intima-media (CC-IMT) is considered a
surrogate marker of early AS and vascular
remodeling because it is correlated with
all of the traditional vascular risk factors
(7). Monitoring a combination of CC-IMT
thickening and plaque formation could
significantly improve the prediction of
cardiovascular events (8). Moreover,
these factors can be assessed quickly,
noninvasively, and inexpensively with
high-resolution ultrasound.
Thus, we designed a prospective study
in which patients with short-duration
type 2 diabetes without AS were assigned
to receive a combined intervention target-
ing multiple risk factors of AS, and their
CC-IMTs were measured to explore
whether intensified, multifactorial inter-
vention could prevent the occurrence of
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From the
1
Department of Endocrinology, First Affiliated Hospital of Dalian Medical University, Dalian, China;
the
2
Department of Ultrasonography, First Affiliated Hospital of Dalian Medical University, Dalian, China;
the
3
Department of Clinical Laboratory, First Affiliated Hospital of Dalian Medical University, Dalian,
China; and the
4
Department of Health Statistics, Dalian Medical University, Dalian, China.
Corresponding author: Jian-ling Du, yangyu@medmail.com.cn.
Received 2 February 2012 and accepted 16 September 2012.
DOI: 10.2337/dc12-0227. Clinical trial reg. no. ChiCTR-TRC-00000234, http://www.chictr.org.
This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/suppl/doi:10
.2337/dc12-0227/-/DC1.
Y.Y. and J.-j.Y. contributed equally to this study.
© 2013 by the American Diabetes Association. Readers may use this article as long as the work is properly
cited, the use is educa tional and not for profit, and the work is not alte red. See http://creativecommons.org/
licenses/by-nc-nd/3.0/ for details.
978 DIABETES CARE,VOLUME 36, APRIL 2013 care.diabetesjournals.org
Cardiovascular and Metabolic Risk
ORIGINAL ARTICLE

macrovascular disease over a 7-year
period.
RESEARCH DESIGN AND
METHODSdIn brief, 150 patients
with type 2 diabetes, diagnosed according
to the World Health Organization criteria
published in 1999, were recruited at the
First Affiliated Hospital of Dalian Medical
University. The enrollment took place
from 1 April 2002 to 31 December
2002. The design of our parallel con-
trolledstudyhaspreviouslybeende-
scribed (9).
The protocol for this study was
in accordance with the Declaration of
Helsinki and was approved by the ethics
committee of the First Affiliated Hospital
of Dalian Medical University. All of the
patients provided written informed con-
sent before enrollment and underwent a
7-year clinical follow-up.
The inclusion criteria were as follows:
1)age35–70 years; 2)diabetesduration
,1 year; 3) no previous histories or pres-
ent characteristics of cardiovascular dis-
eases, cerebral vascular diseases, or
peripheral artery disease as assessed by
thorough examinations before enroll-
ment; and 4) IMT values in the conduct-
ing arteries (common carotid artery,
femoral artery, and iliac artery) ,1.0
mm and no AS plaques detected by ultra-
sonography (10).
Ultrasonographic scanning of the
common carotid artery (between 5 cm
upstream and 5 cm downstream of the
carotid bulb), the femoral artery (within
10 cm upstream of the femoral artery
bifurcation), and the iliac artery (within
10 cm downstream of the abdominal
aorta bifurcation) was performed by des-
ignated physicians who were unaware of
the clinical characteristics of the subjects.
The exclusion criteria included the
following: 1) type 1 diabetes or other spe-
cial type of diabetes; 2) acute diabetes
complications within the previous 6
months, including diabetic ketoacidosis,
hyperglycemic hyperosmolar status, lac-
tic acidosis, and hypoglycemic coma; 3)
renal failure (serum creatinine .106
mmol/L) or hepatic dysfunction (serum
alanine aminotransferase .80 units/L);
4) diagnosis of coronary heart disease, ce-
rebral vascular stroke, and/or peripheral
artery disease; and 5) a conducting artery
IMT $1.0 mm or AS plaques detected by
ultrasonography.
Sex, age, BMI, waist-to-hip ratio,
systolic blood pressure (SBP), diastolic
blood pressure (DBP), and resting 12-lead
electrocardiogram were recorded upon
enrollment in the clinical trial. Fasting
serum total cholesterol, triglyceride, HDL
cholesterol (HDL-C), LDL cholesterol
(LDL-C), creatinine, and alanine amino-
transferase levels, along with plasma
glucose, were measured by routine labo-
ratory techniques. HbA
1c
was measured
by high-performance liquid chromatog-
raphy.
A total of 268 patients underwent
screening, and 150 patients met the in-
clusion criteria. The 150 patients were
randomized into an intensive, multifacto-
rial intervention group or a conventional
intervention group as shown in Fig. 1. The
total duration of the follow-up was 7 years.
Intensive treatment protocol
Physical examination and plasma glucose
(fasting plasma glucose [FPG] and 2-h
plasma glucose [2hPG]) measurements
were conducted monthly. HbA
1c
, blood
lipid, serum creatinine, and alanine
aminotransferase levels were measured
every 6 months. CC-IMTs and electrocar-
diograms were analyzed yearly. During
the consultations, a healthy lifestyle
(e.g., at least three 30-min sessions of
light to moderate exercise per week) and
diet (e.g., obtain 60–70% of daily caloric
intake from carbohydrates from whole
grains, fruits, and vegetables, together
with monounsaturated fat) were recom-
mended using one-to-one teaching or
group counseling supplemented with au-
diovisual and printed materials monthly.
Hypoglycemic strategy
Overweight patients (BMI .24 kg/m
2
)re-
ceived metformin (starting at 0.25 g three
times daily; maximum 0.5 g three times
daily); nonoverweight patients received
glipizide (starting at 2.5 mg three times
daily; maximum 10 mg three times daily).
At the next follow-up, if FPG was .7.0
mmol/L, 2hPG was .10.0 mmol/L, and/
or HbA
1c
was .7.0%, metformin was
Figure 1dEnrollment and outcomes.
care.diabetesjournals.org DIABETE S CARE,VOLUME 36, APRIL 2013 979
Yang and Associates

prescribed to the nonoverweight patients
and glipizide to the overweight patients.
Acarbose was prescribed to only those pa-
tients with 2hPG still .10.0 mmol/L after
any type of hypoglycemic administra-
tion. Insulin supplementation was rec-
ommended for patients whose HbA
1c
remained .7.0% on maximal doses of
oral agents or drug combinations and in
patients who had intolerable adverse reac-
tions to oral drugs. Premixed, combined hu-
man insulin (30% short-acting insulin and
70% neutral protamine Hagedorn insulin)
was the first choice.
Antihypertensive strategy
Patients primarily received ACE inhibitor
and/or calcium channel blockers; if
unsuccessful, a diuretic and/or b-blocker
was added as a supplemental therapy. The
blood pressure target was 130/85 mmHg.
Lipid-lowering strategy
Statins or a Chinese herb complex called
Xue-Zhi-Kang was recommended to pa-
tients with hypercholesterolemia and/or
high levels of serum LDL-C, and fenofibrate
was prescribed to patients with hyper-
triglyceridemia. Total cholesterol within
4.66 mmol/L, triglyceride within 1.7
mmol/L, and LDL-C within 2.6 mmol/L
were considered controlled. Low-dose
acetylsalicylic acid (100 mg/day) was also
recommended to all of the patients who
did not exhibit contraindications.
The dosages of the drugs were mod-
ulated every month based on the levels of
FPG, HbA
1c
, blood pressure, and blood
lipid until target values were achieved.
The patients were treated under the guid-
ance of specialists, and all of the examina-
tions and some of the drugs were freely
provided.
Conventional treatment protocol
In the conventional group, loose outpa-
tient management was performed with-
out intensive intervention targets, and the
drugs were not provided freely. These
patients could go to any hospital at any
frequency that they chose. The same re-
search indices as those measured in the
intensive group were measured each year
free of charge in our center.
Primary and secondary outcomes
The primary outcome (subclinical AS)
was the time to the first occurrence of
CC-IMT $1.0 mm and/or development
of AS plaques in the carotid artery.
The secondary outcome (clinical AS)
was clinical evidence of cardiovascular
Table 1dHbA
1c
, FPG, SBP, DBP, LDL-C, HDL-C, triglyceride, and total cholesterol of the two groups at baseline and at every follow-up year
Baseline Year 1 Year 2 Year 3
Conventional
group
Intensive
group
Conventional
group
Intensive
group
Conventional
group
Intensive
group
Conventional
group
Intensive
group
HbA
1c
(%) 8.69 61.74 8.86 61.66 7.81 60.65 5.44 60.56*†7.92 60.81 5.66 60.79*†7.53 61.61* 6.11 60.97*†
FPG (mmol/L) 9.95 60.74 9.98 62.81 6.95 61.03* 6.86 61.43* 7.25 62.03* 6.80 63.88*†8.22 62.97 6.94 64.56*†
SBP (mmHg) 128.80 611.30 129.10 615.20 123.45 612.42 121.58 614.21* 125.38 612.77 120.67 613.99* 127.35 613.62 123.28 613.18
DBP (mmHg) 76.90 66.40 79.80 611.80 78.91 67.3 78.73 69.74 79.43 69.07 77.85 69.05 80.30 610.13 78.47 69.53
LDL-C (mmol/L) 3.00 60.52 2.99 60.61 2.62 60.61 2.56 60.55 2.74 60.56 2.57 60.46 3.02 60.63 2.59 60.44
HDL-C (mmol/L) 1.01 60.29 0.94 60.72 1.14 60.25 1.08 60.33 1.04 60.30 1.06 60.48 1.19 60.36 1.03 60.39
TG (mmol/L) 2.28 60.54 3.05 61.46 1.62 61.12* 1.55 61.29* 1.61 61.54* 1.54 61.26* 1.75 61.45* 1.85 64.28
TC (mmol/L) 5.95 61.15 5.92 61.04 5.01 61.15 4.42 60.73*†5.43 61.09 4.49 60.81*†5.13 60.98 4.49 60.71*†
Year 4 Year 5 Year 6 Year 7
Conventional
group
Intensive
group
Conventional
group
Intensive
group
Conventional
group
Intensive
group
Conventional
group
Intensive
group
HbA
1c
(%) 6.43 61.64* 5.96 61.48*†7.14 61.06* 6.46 61.15* 7.03 61.72* 6.75 61.08* 7.98 61.95 7.13 61.22*†
FPG (mmol/L) 7.64 61.95 7.0 61.76* 7.26 60.64* 6.54 61.81* 8.09 61.79 7.35 61.83* 8.33 61.23 7.36 61.37*†
SBP (mmHg) 128.16 612.76 126.05 611.66 121.40 611.10* 120.50 68.70* 128.57 612.31 120.69 69.09*†127.78 612.13 120.72 69.61*†
DBP (mmHg) 79.48 69.40 78.34 67.44 73.90 65.90 76.10 67.10 78.08 65.76 75.80 65.72†79.44 68.47 76.20 64.43
LDL-C (mmol/L) 3.04 60.66 2.74 60.43 2.42 60.72 2.63 60.63 3.10 60.28 2.70 60.55 3.03 60.19 2.75 60.43
HDL-C (mmol/L) 1.12 60.59 1.05 60.34 1.01 60.14 0.99 60.15 1.09 60.28 1.11 60.26 1.10 60.37 1.02 60.20
TG (mmol/L) 1.51 60.78* 1.91 61.62* 1.98 60.73* 1.68 61.05* 1.40 60.55* 1.70 61.36* 1.83 61.06* 1.7 61.23*
TC (mmol/L) 5.15 61.12 4.61 60.84*†4.83 60.56 4.50 60.75* 5.19 60.77 4.68 60.93*†5.10 61.21 4.57 60.84*†
TC, total cholesterol; TG, triglyceride. *P,0.05, compared with baseline. †P,0.05, compared with the conventional group.
980 DIABETES CARE,VOLUME 36, APRIL 2013 care.diabetesjournals.org
Multifactorial intervention in macroangiopathy

diseases, such as asymptomatic myocar-
dial ischemia (ST segment depression
and/or T wave inversion on electrocardio-
gram), angina pectoris, myocardial infarc-
tion, transient ischemic attack, stroke,
intermittent claudication, or critical limb
ischemia.
Statistical analyses
SPSS 13.0 was used for the statistical
analysis. Normally distributed data are
presented as means 6SD. An indepen-
dent ttest was adopted for group compar-
isons, and a pair bond ttest was adopted
for intergroup comparisons. Numerical
data are presented as absolute frequency
or percentage, and the x
2
test was used for
comparison between groups. Statistical
significance was accepted at P,0.05.
RESULTSdA total of 268 patients who
had type 2 diabetes for ,1yearandno
clinical AS underwent the screening, and
101 (37.69%) were found to have sub-
clinical AS. One hundred and fifty pa-
tients who showed no signs of AS on
ultrasound were randomly divided into
an intensive group and a conventional
group, with 75 cases in each group. Sev-
enty patients in the intensive group and
68 patients in the conventional group fin-
ished the 7-year follow-up (6.67 and
9.33% lost to follow-up, respectively).
The biochemical characteristics of the
patients at baseline have previously been
described (9). The data at every follow-up
year and at the end of the follow-up pe-
riod (7 years) are shown in Table 1 and
Supplementary Fig. 1. The two study
groups were similar at baseline but dif-
fered significantly at the end of the inter-
vention period, indicating that intensive
therapy was superior to conventional
therapy in controlling the level of FPG,
SBP, HbA
1c
, and fasting serum total cho-
lesterol.
After 7 years of follow-up, among the
68 patients in the conventional group,
IMTs $1.0 mm and/or AS plaques in the
carotid artery were observed in 22 pa-
tients; 1 patient developed myocardial in-
farction, 4 patients suffered from angina
pectoris, 1 patient developed silent myo-
cardial ischemia (electrocardiogram showed
that the ST segment was descended, and
the T wave was low and calm in contrast
to baseline), 2 patients had a transient
ischemic attack, and 1 patient developed
Table 2dCumulative macrovascular end points at every follow-up year
Baseline Year 1 Year 2 Year 3
Conventional
group
Intensive
group
Conventional
group
Intensive
group
Conventional
group
Intensive
group
Conventional
group
Intensive
group
Follow-up events (n) 7575757574757374
Thickened IMT/AS plaques (n)00215272
Subclinical macrovascular
outcomes 0 0 2.67 1.33 6.76 2.67 9.59 2.70
Anginapectoris 00202030
Myocardial infarction 0 0 0 0 0 0 0 0
Silent myocardial ischemia 0 0 0 0 0 0 1 0
Transientischemicattack 00000000
Intermittent claudication 0 0 0 0 0 0 0 0
Suddendeath 00000001
Total clinical macrovascular
end events (n) 00202041
Final clinical macrovascular
events 0 0 2.67 0 2.70 0 5.48 1.35
Year 4 Year 5 Year 6 Year 7
Conventional
group
Intensive
group
Conventional
group
Intensive
group
Conventional
group
Intensive
group
Conventional
group
Intensive
group
Follow-up events (n) 7173 68 71 6870 6870
Thickened IMT/AS plaques (n)9 2 9 4 13 5 22 7
Final subclinical macrovascular
outcomes 12.68 2.74* 13.24 5.63 19.12 7.14* 32.35 10.00*
Anginapectoris 31 3141 42
Myocardial infarction 0 0 1 0 1 0 1 1
Silent myocardial ischemia 1 0 1 0 1 1 1 1
Transient ischemic attack 0 0 0 0 1 0 2 0
Intermittent claudication 0 0 0 0 0 0 1 0
Suddendeath 01 0101 01
Total clinical macrovascular
end events (n) 42 5273 95
Final clinical macrovascular
events 5.63 2.74 7.35 2.82 10.29 4.29 13.24 7.14
Data are percent unless otherwise indicated. *P,0.05, compared with the conventional group.
care.diabetesjournals.org DIABETE S CARE,VOLUME 36, APRIL 2013 981
Yang and Associates

intermittent claudication. Thus, clinical
macrovascular events occurred in nine
cases. Five of the nine patients who de-
veloped clinical macrovascular events
also had increased CC-IMTs and/or AS
plaques in the common carotid arteries.
However, among the 70 patients in the
intensive group, IMTs $1.0 mm and/or
AS plaques in the carotid arteries were
observed in only 7 patients. One patient
developed myocardial infarction in addi-
tion to increased CC-IMT, two patients
suffered from angina pectoris, and one
of these patients also had increased CC-
IMT. One patient had silent myocardial
ischemia, and one patient died suddenly.
(No autopsy was performed; the cause of
death was unknown and was considered
relevant to diabetic macroangiopathy.) In
total, final clinical macrovascular events
occurred in five cases in the intensive
group. Two of the five patients who de-
veloped clinical macrovascular events
also had increased CC-IMTs and/or AS
plaques in the common carotid arteries.
The difference in the frequency of sub-
clinical macrovascular outcomes be-
tween the two groups was significant
(P= 0.002); however, no significant dif-
ference in the frequency of clinical mac-
rovascular events was observed between
the two groups (P= 0.271) (Table 2 and
Fig. 2).
CONCLUSIONSdType 2 diabetes is
usually accompanied by a number of
cardiovascular risk factors, including hy-
pertension, dyslipidemia, and platelet
dysfunction. Trials of intensified inter-
ventions for single risk factors in patients
with type 2 diabetes, including the UK
Prospective Diabetes Study (UKPDS),
Collaborative Atorvastatin Diabetes Study
(CARDS), Microalbuminuria Cardiovas-
cular Renal Outcomes–Heart Outcomes
Prevention Evaluation (MICRO-HOPE)
study, and Veterans Affairs Diabetes Trial
(VADT), have demonstrated efficacy in
reducing the development and progres-
sion of both micro- and macrovascular
complications (11–14), although studies
on intensive glucose control alone in pa-
tients with type 2 diabetes have reached
conflicting conclusions regarding the in-
cidence of major cardiovascular events or
death (15–17). However, only a delayed
effect in reducing the incidence of cardio-
vascular events was observed in UKPDS
(18), suggesting that long-term observa-
tion might be necessary for the study of
macroangiopathy in recent-onset type 2
diabetes and that cardiovascular events
or death cannot be taken as indicators if
the investigators want to draw conclu-
sions about diabetes in the short term.
In our study, we implemented a multifac-
torial intervention aimed at primary pre-
vention for patients with type 2 diabetes
without any manifestation of AS that used
macrovascular end points, including sub-
clinical AS lesions, as the evaluation in-
dex. We measured the preventive
efficacy after 4–7 years of intervention,
expanding upon the results of UKPDS
and the STENO-2 trial and strengthening
their conclusions. Our approach achieved
the primary prevention of diabetic macro-
vascular complications, implying that in-
tensive, multifactorial intervention
should be administered to type 2 diabetic
patients as soon as possible to provide the
most benefits.
Recent results from UKPDS suggested
that the effects of blood pressure–and
glucose-lowering interventions might be
additive; there was a trend toward a
greater benefit with a combination of
intensive blood pressure–and glucose-
lowering interventions. Because only a
small subset of hypertensive subjects re-
ceived both interventions, UKPDS had in-
sufficient power to determine conclusively
whether the effects of the treatments were
additive in this group or in the broader
population with type 2 diabetes (19). The
new results of the Action in Diabetes and
Vascular Disease (ADVANCE) trial demon-
strated that a combined approach of rou-
tine blood pressure–lowering interventions
and intensive glucose control resulted in
substantial reductions in major renal events
and all-cause deaths, supporting and
strengthening the results of the UKPDS
trial and providing further evidence
for thebenefits of a multifactorial treat-
ment approach in patients with type 2
diabetes (20). However, ADVANCE em-
phasized the control of only two risk fac-
tors for diabetic macroangiopathy. As
demonstrated by the STENO-2 study, a
target-driven, long-term, intensified inter-
vention aimed at multiple risk factors in
patients with type 2 diabetes and micro-
albuminuria can reduce the risk of cardio-
vascular and microvascular events by
~50%; furthermore, the benefits were
maintained over the long term even after
the randomized treatment period (5,6).
However, the STENO-2 subjects were dif-
ferent from ours in that the statuses of
their arterial intima were uncertain at
baseline.
Ultrasonography to measure CC-IMT
is a noninvasive test that can be used
to determine the presence of coronary
AS. IMT is an independent predictor of
future cardiovascular events, and it is
often used in research trials as a surrogate
for the presence of cardiovascular disease
(21–23). The 150 patients with a diabetes
duration of ,1 year included in our study
had initial IMTs of ,1.0 mm in the three
conducting arteries (common carotid ar-
tery, femoral artery, and iliac artery) and
no atherosclerotic plaques detected by ul-
trasonography in addition to an absence
of clinical manifestations or history of
macrovascular diseases; these patients
were considered not to have AS. They
then underwent intensified or conven-
tional treatment. The reduced incidence
of subclinical outcomes in the intensive
group indicates that these interventions re-
duced the incidence of macroangiopathy,
which suggests that this intensified,
multifactorial intervention can produce
Figure 2dComparison of the prevalence of macrovascular end events in every follow-up year.
A: Comparison of the prevalence of final subclinical macrovascular end points. B: Comparison of
the prevalence of final clinical macrovascular events. CG, conventional group; IG, intensive
group. *Compared with the conventional group, P,0.05.
982 DIABETES CARE,VOLUME 36, APRIL 2013 care.diabetesjournals.org
Multifactorial intervention in macroangiopathy

a marked effect on the primary prevention
of macrovascular disease in patients with
type 2 diabetes. No significant differences
between the two groups were observed if
only the secondary outcome was consid-
ered, irrespective of the primary outcome.
Benefits emerged only after a relatively
short period when IMTs and/or the occur-
rence of AS plaques were regarded as end
points, implying that evidence of early-
stage AS might be more important. These
data also suggest that as a chronic progres-
sive disease, subclinical AS might be con-
sidered an important index in the study of
diabetic macroangiopathy.
In contrast to the uncertain follow-up
frequency of those in the conventional
group, the subjects in the intensive group
were followed up every month. These
monthly visits may themselves represent
an intervention and may have partially
contributed to the final outcomes.
In addition, incidence of macroangiopathy
in our study decreased significantly when
the HbA
1c
target of 7.0% was reached.
However, during the 7-year follow-up,
the mean HbA
1c
in the intensive group
was actually ~6.5%; furthermore, no se-
vere hypoglycemic events occurred, indi-
cating that an HbA
1c
of 6.5%, rather than
7%, might be desirable in patients with
short-duration type 2 diabetes without
macroangiopathy who are younger than
60 years old. The HbA
1c
target in the Ac-
tion to Control Cardiovascular Risk in Di-
abetes (ACCORD) trial was ,6.0%, and
the all-cause mortality and cardiovascular
fatality rates in the intensive blood glucose
therapy group were both significantly
higher than those in the control group
(24). Therefore, it might be reasonable to
consider an HbA
1c
of 7.0% as the target for
intensive blood glucose control in patients
with relatively long durations of type 2
diabetes.
Because this study was performed in a
small group of type 2 diabetic patients,
there was insufficient information for a
stratified analysis of the correlation be-
tween each hypoglycemic regimen and
macrovascular end points. Additionally,
the period of observation was only 7
years, and total clinical macrovascular
events occurred in only 14 cases. We
expect to observe the correlation between
subclinical AS and clinical atherosclerotic
disease, followed by increased clinical
macrovascular events, as time progresses.
In conclusion, the primary preven-
tion of macrovascular disease could be
achieved through intensified, multifacto-
rial intervention in patients with type 2
diabetes. Patients with short-duration
type 2 diabetes should receive an inten-
sive multifactorial intervention approach
with individual targets for the prevention
of macrovascular diseases.
AcknowledgmentsdThis research was sup-
ported by funds from the National Key Re-
search Project for the Tenth Five-Year Plan
(2001BA702B01), the National Key Research
Project for the Eleventh Five-Year Plan
(2006BAI02B08), and the Key Research Pro-
ject of Liaoning Province Bureau of Science
and Technology (2002225003-6).
No potential conflicts of interest relevant to
this article were reported.
Y.Y. and J.-j.Y. collected data and wrote the
manuscript. J.-l.D. designed the research, di-
rected the entire study, and revised the
manuscript. R.B. collected data. L.-p.S. con-
tributed to the ultrasound examination of the
three conducting arteries. G.-h.S. collected
data from laboratory examinations. G.-r.S.
contribut ed to the statistical a nalyses. S.-m.C.,
C.-h.S., Y.B., Q.X., and X.-y.Z. collected data.
J.-l.D. is the guarantor of this work and,
as such, had full access to all the data in the
study and takes responsibility for the integ-
rity of the data and the accuracy of the data
analysis.
The authors thank Changchen Li, De-
partment of Endocrinology of the First Affili-
ated Hospital of Dalian Medical University
(Dalian, China), for providing many construc-
tive suggestions for the manuscript.
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