original article
T h e
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2560
Intensive Blood Glucose Control and Vascular
Outcomes in Patients with Type 2 Diabetes
The ADVANCE Collaborative Group*
The members of the Writing Committee
of the Action in Diabetes and Vascular Dis-
ease: Preterax and Diamicron Modified
Release Controlled Evaluation (ADVANCE)
Collaborative Group are listed in the Ap-
pendix. Address reprint requests to Dr.
Anushka Patel at the Cardiovascular Divi-
sion, George Institute for International
Health, University of Sydney, P.O. Box
M201, Missenden Rd., Sydney, NSW 2050,
Australia, or at apatel@george.org.au.
*Members of the ADVANCE Collabora-
tive Group are listed in the Supplemen-
tary Appendix (available with the full text
of this article at www.nejm.org).
This article (10.1056/NEJMoa0802987) was
published at www.nejm.org on June 6,
2008.
N Engl J Med 2008;358:2560-72.
Copyright © 2008 Massachusetts Medical Society.
A b s t r a c t
Background
In patients with type 2 diabetes, the effects of intensive glucose control on vascular
outcomes remain uncertain.
Methods
We randomly assigned 11,140 patients with type 2 diabetes to undergo either stan-
dard glucose control or intensive glucose control, defined as the use of gliclazide
(modified release) plus other drugs as required to achieve a glycated hemoglobin
value of 6.5% or less. Primary end points were composites of major macrovascular
events (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal
stroke) and major microvascular events (new or worsening nephropathy or retinopa-
thy), assessed both jointly and separately.
Results
After a median of 5 years of follow-up, the mean glycated hemoglobin level was
lower in the intensive-control group (6.5%) than in the standard-control group (7.3%).
Intensive control reduced the incidence of combined major macrovascular and micro-
vascular events (18.1%, vs. 20.0% with standard control; hazard ratio, 0.90; 95%
confidence interval [CI], 0.82 to 0.98; P = 0.01), as well as that of major microvascular
events (9.4% vs. 10.9%; hazard ratio, 0.86; 95% CI, 0.77 to 0.97; P = 0.01), primarily
because of a reduction in the incidence of nephropathy (4.1% vs. 5.2%; hazard ratio,
0.79; 95% CI, 0.66 to 0.93; P = 0.006), with no significant effect on retinopathy
(P = 0.50). There were no significant effects of the type of glucose control on major
macrovascular events (hazard ratio with intensive control, 0.94; 95% CI, 0.84 to 1.06;
P = 0.32), death from cardiovascular causes (hazard ratio with intensive control, 0.88;
95% CI, 0.74 to 1.04; P = 0.12), or death from any cause (hazard ratio with intensive
control, 0.93; 95% CI, 0.83 to 1.06; P = 0.28). Severe hypoglycemia, although uncom-
mon, was more common in the intensive-control group (2.7%, vs. 1.5% in the
standard-control group; hazard ratio, 1.86; 95% CI, 1.42 to 2.40; P<0.001).
Conclusions
A strategy of intensive glucose control, involving gliclazide (modified release) and
other drugs as required, that lowered the glycated hemoglobin value to 6.5% yielded
a 10% relative reduction in the combined outcome of major macrovascular and
microvascular events, primarily as a consequence of a 21% relative reduction in
nephropathy. (ClinicalTrials.gov number, NCT00145925.)
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2561
T
he prevalence of diabetes is increas-
ing worldwide, and most people with dia-
betes will die or be disabled as a conse-
quence of vascular complications.
1,2
Prospective
studies have shown continuous associations of
blood glucose and glycated hemoglobin levels
with the risks of major vascular events.
3,4
How-
ever, previous randomized trials evaluating the
effects of glycemic control in patients with dia-
betes have provided inconsistent evidence of ef-
fects on vascular disease.
5-11
Nevertheless, current
guidelines recommend a target glycated hemo-
globin level of 7.0% or less for most patients with
diabetes.
12-14
The Action in Diabetes and Vascular Disease:
Preterax and Diamicron Modified Release Con-
trolled Evaluation (ADVANCE) trial was designed
to assess the effects on major vascular outcomes
of lowering the glycated hemoglobin value to a
target of 6.5% or less in a broad cross-section of
patients with type 2 diabetes. The part of the
study that evaluated the lowering of blood pres-
sure with the use of perindopril and indapamide,
completed in June 2007, showed a reduction in the
risks of major vascular events and death, regard-
less of the initial blood pressure.
15
Here we re-
port the main results from the comparison of the
blood-glucose-lowering strategies, completed in
January 2008, which evaluated an intensive glu-
cose-control strategy based on gliclazide (modi-
fied release) and other drugs as required to achieve
the target glycated hemoglobin level.
M e t h o d s
The ADVANCE trial is a factorial randomized,
controlled trial conducted at 215 collaborating
centers in 20 countries from Asia, Australasia, Eu-
rope, and North America (see the Supplementary
Appendix, available with the full text of this ar-
ticle at www.nejm.org). Approval to conduct the
trial was obtained from the ethics committee of
each study center, and all participants provided
written informed consent. Detailed study methods
have been published previously.
16
The ADVANCE trial was an investigator-initiat-
ed trial that was designed, conducted, analyzed,
and had data interpreted independently of both
sponsors. Study data were collected and retained
by the investigators and were not made available
to the study sponsors. The writing committee and
the management committee, whose membership
did not include any sponsor representatives, had
final responsibility for the manuscript prepara-
tion and the decision to submit for publication.
The first five authors vouch for the validity and
completeness of the reported data.
Participant s
Eligibility criteria, as detailed previously,
16
were a
diagnosis of type 2 diabetes mellitus at 30 years
of age or older, an age of at least 55 years at the
time of study entry, and a history of major macro-
vascular or microvascular disease or at least one
other risk factor for vascular disease. There were no
inclusion or exclusion criteria related to glycated
hemoglobin. Exclusion criteria included a definite
indication for, or contraindication to, any of the
study treatments or a definite indication for long-
term insulin therapy at the time of study entry.
Study Treatment
Potentially eligible participants entered a 6-week
run-in period, during which they continued their
usual methods of glucose control and received a
fixed combination of perindopril and indapamide.
Those who tolerated and were compliant with the
treatment during the run-in period were randomly
assigned, according to a factorial design, to re-
ceive continued therapy with either perindopril
and indapamide or matching placebo and to un-
dergo either a strategy of intensive blood glucose
control (target glycated hemoglobin value, ≤6.5%)
or a strategy of standard glucose control (with tar-
get glycated hemoglobin levels defined on the ba-
sis of local guidelines). Central, computer-based
randomization was stratified according to several
factors,
16
including study center and presence or
absence of a history of major vascular disease.
Patients who were randomly assigned to under-
go intensive glucose control were given gliclazide
(modified release, 30 to 120 mg daily) and were
required to discontinue any other sulfonylurea.
Although the timing, selection, and doses of all
other treatments were at the discretion of the
treating physician, a treatment protocol was sug-
gested (see the Supplementary Appendix). On the
basis of the glycated hemoglobin level at each
visit, this protocol initially advised increasing
the dose of gliclazide (modified release), with
the sequential addition or increase in dose of
metformin, thiazolidinediones, acarbose, or in-
sulin (advising the initial use of basal insulin,
with the addition of short-acting insulin at meals
for patients in whom the target glycated hemo-
globin level was not achieved, despite acceptable
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T h e
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2562
fasting blood glucose levels). Patients in the
standard-control group who were using glicla-
zide (modified release) when they entered the
study were required to substitute this drug with
another sulfonylurea, if continued therapy was
required.
Follow-up Schedule
Patients in the intensive-control group were seen
at week 2 after randomization; then at months 1,
2, 3, 4, and 6; and every 3 months thereafter.
These patients were also encouraged to attend
other, unscheduled visits to improve the monitor-
ing and intensification of glucose control. Partici-
pants assigned to undergo standard control were
seen at 3, 4, and 6 months after randomization
and every 6 months thereafter. At study visits
common to both groups, information was col-
lected on blood glucose, glycated hemoglobin,
blood pressure, and lipids, as well as adherence
to, and tolerability of, study treatments and occur-
rence of study outcomes. At the 2-year, 4-year,
and final visits, the ratio of urinary albumin to
creatinine was measured and a retinal examina-
tion, the Mini–Mental State Examination, and
quality-of-life assessment were also performed. At
study visits for patients in the intensive-control
group only, the information collected was limited
to blood glucose, glycated hemoglobin, and glu-
cose-lowering treatments.
Laboratory Mea surements
All measurements were performed in local labora-
tories, and each glycated hemoglobin measure-
ment was standardized (see the Supplementary
Appendix).
17
Blood glucose measurements were
performed on samples of venous or capillary
blood, depending on local practice.
End Points
The primary study outcomes were a composite of
macrovascular events and a composite of micro-
vascular events, considered both jointly and sepa-
rately. Macrovascular events were defined as death
from cardiovascular causes, nonfatal myocardial
infarction, or nonfatal stroke. Microvascular events
were defined as new or worsening nephropathy
(i.e., development of macroalbuminuria, defined as
a urinary albumin:creatinine ratio of more than
300 μg of albumin per milligram of creatinine
[33.9 mg per millimole], or doubling of the serum
creatinine level to at least 200 μmol per liter
[2.26 mg per deciliter], the need for renal-replace-
ment therapy, or death due to renal disease) or reti-
nopathy (i.e., development of proliferative retinop-
athy, macular edema or diabetes-related blindness
or the use of retinal photocoagulation therapy).
Prespecified secondary outcomes were death
from any cause, death from cardiovascular caus-
es, major coronary events (death due to coronary
heart disease [including sudden death] or non-
fatal myocardial infarction), total coronary events
(major coronary events, silent myocardial infarc-
tion, coronary revascularization, or hospital ad-
mission for unstable angina), major cerebrovascu-
lar events (death due to cerebrovascular disease
or nonfatal stroke), total cerebrovascular events
(major cerebrovascular events, transient ischemic
attack, or subarachnoid hemorrhage), heart fail-
ure (death due to heart failure, hospitalization for
heart failure, or worsening New York Heart As-
sociation class), peripheral vascular events, all
cardiovascular events, new or worsening nephrop-
athy, new or worsening retinopathy, development
of microalbuminuria (urinary albumin:creatinine
ratio, 30 to 300 μg per milligram [0.34 to 33.9 mg
per millimole]), visual deterioration, new or wors-
ening neuropathy, decline in cognitive function
(reduction in the Mini–Mental State Examination
score by at least 3 points, as compared with the
baseline score), dementia (satisfying the criteria
in the Diagnostic and Statistical Manual of Mental Dis-
orders, 4th Edition), and hospitalization for 24 hours
or more. Hypoglycemia was defined as a blood
glucose level of less than 2.8 mmol per liter (50 mg
per deciliter) or the presence of typical symptoms
and signs of hypoglycemia without other apparent
cause. Patients with transient dysfunction of the
central nervous system who were unable to treat
themselves (requiring help from another person)
were considered to have severe hypoglycemia.
An independent End Point Adjudication Com-
mittee, unaware of the group assignments, re-
viewed source documentation for all suspected
primary end points and deaths. An independent
data and safety monitoring committee reviewed
the unblinded data at regular intervals.
Statistic al Analysis
The ADVANCE trial was originally designed to
have a statistical power of 90% to detect a rela-
tive risk reduction of 16% or more for intensive
control, as compared with standard control, for
each of the primary outcomes, with the use of a
two-tailed test with an alpha level of 5%. After a
mean of approximately 3 years of follow-up, it be-
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Intensive Blood Glucose Control and Vascular Out comes in T y pe 2 Diabetes
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2563
came apparent that the event rates (in the two
groups combined) were lower than expected. Thus,
in a manner blinded to any results of the effects
of intervention, two changes were made to the
protocol to increase the power of the study: joint
(as well as separate) analysis of the primary out-
comes was prespecified, and the period of treat-
ment and follow-up was extended by 12 months
for the part of the study that evaluated the lower-
ing of blood pressure and by 18 months for the
part that evaluated the control of blood glucose.
All analyses were conducted according to the
intention-to-treat principle. Effects of treatment
on study end points were estimated with the use
of unadjusted Cox proportional-hazard models,
involving survival time to the first relevant end
point in any individual patient. Data for patients
were censored at their date of death, date of last
visit (for those still alive at the end of the follow-
up period), or date when last known to be alive
(for those with unknown vital status). Differences
in continuous variables between the two study
groups during the follow-up period were estimat-
ed with the use of linear mixed models. The num-
bers needed to treat were calculated as recipro-
cals of the absolute differences in risk with their
normally approximated 95% confidence inter-
vals.
18
All P values were two-sided, and P values
less than 0.05 were considered to indicate statis-
tical significance. No adjustment for multiple
statistical testing was made.
19
The homogeneity of treatment effects across
subgroups (none of which were prespecified) was
tested by adding interaction terms to the relevant
Cox models. Interaction between the blood-pres-
sure intervention and the blood-glucose interven-
tion in the ADVANCE trial was assessed with the
use of the database locked at the end of the period
33p9
11,140 Underwent randomization
12,877 Patients were registered
1737 (13.5%) Were withdrawn during run-in phase
394 (3.1%) Were ineligible
391 (3.0%) Chose to withdraw consent
269 (2.1%) Had poor compliance
238 (1.8%) Had cough
99 (0.8%) Had dizziness or hypotension
133 (1.0%) Had other suspected intolerance
186 (1.4%) Had other reasons
27 (0.2%) Had serious adverse events
5571 Were assigned to undergo
intensive glucose control
5569 Were assigned to undergo
standard glucose control
7 Were lost to follow-up
10 Were lost to follow-up
At scheduled end of follow-up:
7 (0.1%) Had unknown vital
status
498 (8.9%) Died
5066 (90.9%) Lived
4828 (86.7%) Were assessed
at final visit
4209 (75.6%) Had adherence
to gliclazide (modified
release)
At scheduled end of follow-up:
10 (0.2%) Had unknown vital
status
533 (9.6%) Died
5026 (90.2%) Lived
4741 (85.1%) Were assessed
at final visit
AUTHOR:
FIGURE:
JOB: ISSUE:
4-C
H/T
RETAKE
SIZE
ICM
CASE
EMail
Line
H/T
Combo
Revised
AUTHOR, PLEASE NOTE:
Figure has been redrawn and type has been reset.
Please check carefully.
REG F
Enon
1st
2nd
3rd
Patel
1 of 5
6-12-08
ARTIST: ts
35824
Figure 1. Enrollment, Randomization, and Follow-up of Study Participants.
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2564
Table 1. Characteristics of Participants at Baseline and at the End of the Follow-up Period.*
Characteristic Baseline End of Follow-up
Intensive Control
(N = 5571)
Standard Control
(N = 5569)
Intensive Control
(N = 4828)
Standard Control
(N = 4741)
Age — yr 66±6 66±6
Female sex — no. (%) 2376 (42.6) 2357 (42.3)
Age when diabetes first diagnosed — yr 58±9 58±9
Duration of diabetes — yr 7.9±6.3 8.0±6.4
Region — no. (%)
Australia and New Zealand 744 (13.4) 741 (13.3)
Asia 2069 (37.1) 2067 (37.1)
Europe 2538 (45.6) 2545 (45.7)
North America 220 (4.0) 216 (3.9)
Previous vascular disease
History of major macrovascular disease — no. (%) 1794 (32.2) 1796 (32.3)
Myocardial infarction 668 (12.0) 666 (12.0)
Stroke 515 (9.2) 508 (9.1)
Other 683 (12.3) 678 (12.2)
History of major microvascular disease — no. (%) 571 (10.3) 584 (10.5)
Macroalbuminuria† 189 (3.4) 215 (3.9)
Microvascular eye disease‡
403 (7.2) 392 (7.0)
History of microalbuminuria — no. (%) 1434 (27.0) 1423 (26.7)
Blood-glucose control
Glycated hemoglobin, nonstandardized level — %
Mean ±SD 7.51±1.57 7.52±1.54 6.53±0.91 7.30±1.26
Median 7.2 7.2 6.4 7.0
Interquartile range 6.5–8.2 6.5–8.2 6.0–6.8 6.5–7.9
Glycated hemoglobin, standardized level — %
Mean ±SD 7.48±1.65 7.48±1.63 6.49±0.99 7.24±1.38
Median 7.2 7.2 6.3 7.0
Interquartile range 6.4–8.2 6.4–8.2 5.9–6.9 6.4–7.9
Fasting blood glucose — mmol/liter
Mean ±SD 8.51±2.78 8.48±2.76 6.56±1.88 7.75±2.34
Median 7.9 7.9 6.2 7.3
Interquartile range 6.6–9.7 6.6–9.7 5.4–7.3 6.2–8.7
Other major risk factors
Blood pressure — mm Hg
Systolic 145.0±21.7 145.0±21.4 135.5±17.6 137.9±18.4
Diastolic 80.8±11.0 80.5±10.8 73.5±9.8 74.3±9.9
Serum cholesterol — mmol/liter
Low-density lipoprotein 3.12±1.04 3.11±1.02 2.64±0.97 2.65±1.06
High-density lipoprotein 1.26±0.35 1.25±0.35 1.24±0.35 1.25±0.35
Serum triglycerides — mmol/liter
Median 1.60 1.64 1.45 1.59
Interquartile range 1.20–2.30 1.20–2.30 1.03–2.03 1.10–2.20
Serum triglycerides — μmol/liter 1.95±1.29 1.96±1.29 1.70±1.06 1.82±1.15
Serum creatinine — μmol/liter 86±24 87±27 94±37 93±41
Weight — kg 78.2±16.8 78.0±16.8 78.1±17.5 77.0±16.7
Body-mass index§ 28±5 28±5 28±5 28±5
Waist circumference — cm 99±13 98±13 99±14 98±13
Current smoking — no. (%) 793 (14.2) 757 (13.6) 385 (8.3) 350 (7.8)
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