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original article
T h e
n e w e n g l a n d j o u r n a l
o f
m e d ici n e
n engl j med 363;15 nejm.org october 7, 2010
1410
Severe Hypoglycemia and Risks of Vascular
Events and Death
Sophia Zoungas, M.D., Ph.D., Anushka Patel, M.D., Ph.D.,
John Chalmers, M.D., Ph.D., Bastiaan E. de Galan, M.D., Ph.D.,
Qiang Li, M.Biostat., Laurent Billot, M.Sc., Mark Woodward, Ph.D.,
Toshiharu Ninomiya, M.D., Ph.D., Bruce Neal, M.D., Ph.D.,
Stephen MacMahon, D.Sc., Ph.D., Diederick E. Grobbee, M.D., Ph.D.,
Andre Pascal Kengne, M.D., Ph.D., Michel Marre, M.D., Ph.D.,
and Simon Heller, M.D., for the ADVANCE Collaborative Group
From the George Institute for Interna-
tional Health, University of Sydney, Syd-
ney (S.Z., A.P., J.C., B.E.G., Q.L.M., L.B.,
M.W., T.N., B.N., S.M., A.P.K.); the School
of Public Health, Monash University, Mel-
bourne, Australia (S.Z.); the Department
of General Internal Medicine, Radboud
University Nijmegen Medical Center, Nij-
megen (B.E.G.), and the Julius Center for
Health Sciences and Primary Care, Uni-
versity Medical Center Utrecht, Utrecht
(D.E.G.) — both in the Netherlands;
Mount Sinai School of Medicine, New
York (M.W.); Hôpital Bichat–Claude Ber-
nard and Université Paris, Paris (M.M.);
and the University of Sheffield and Shef-
field Teaching Hospitals National Health
Service Foundation Trust, Sheffield, United
Kingdom (S.H.). Address reprint requests
to Dr. Zoungas at the George Institute for
International Health, University of Sydney,
P.O. Box M201, Missenden Rd., Sydney,
NSW 2050, Australia, or at szoungas@
george.org.au.
N Engl J Med 2010;363:1410-8.
Copyright © 2010 Massachusetts Medical Society.
A b s t r ac t
Background
Severe hypoglycemia may increase the risk of a poor outcome in patients with type 2
diabetes assigned to an intensive glucose-lowering intervention. We analyzed data
from a large study of intensive glucose lowering to explore the relationship between
severe hypoglycemia and adverse clinical outcomes.
Methods
We examined the associations between severe hypoglycemia and the risks of mac-
rovascular or microvascular events and death among 11,140 patients with type 2 dia-
betes, using Cox proportional-hazards models with adjustment for covariates mea-
sured at baseline and after randomization.
Results
During a median follow-up period of 5 years, 231 patients (2.1%) had at least one severe
hypoglycemic episode; 150 had been assigned to intensive glucose control (2.7% of
the 5571 patients in that group), and 81 had been assigned to standard glucose
control (1.5% of the 5569 patients in that group). The median times from the onset
of severe hypoglycemia to the first major macrovascular event, the first major mi-
crovascular event, and death were 1.56 years (interquartile range, 0.84 to 2.41), 0.99
years (interquartile range, 0.40 to 2.17), and 1.05 years (interquartile range, 0.34 to
2.41), respectively. During follow-up, severe hypoglycemia was associated with a sig-
nificant increase in the adjusted risks of major macrovascular events (hazard ratio,
2.88; 95% confidence interval [CI], 2.01 to 4.12), major microvascular events (hazard
ratio, 1.81; 95% CI, 1.19 to 2.74), death from a cardiovascular cause (hazard ratio,
2.68; 95% CI, 1.72 to 4.19), and death from any cause (hazard ratio, 2.69; 95% CI,
1.97 to 3.67) (P<0.001 for all comparisons). Similar associations were apparent for
a range of nonvascular outcomes, including respiratory, digestive, and skin conditions
(P<0.01 for all comparisons). No relationship was found between repeated episodes
of severe hypoglycemia and vascular outcomes or death.
Conclusions
Severe hypoglycemia was strongly associated with increased risks of a range of ad-
verse clinical outcomes. It is possible that severe hypoglycemia contributes to adverse
outcomes, but these analyses indicate that hypoglycemia is just as likely to be a
marker of vulnerability to such events. (Funded by Servier and the National Health
and Medical Research Council of Australia; ClinicalTrials.gov number, NCT00145925.)
The New England Journal of Medicine
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Sever e Hypoglycemia and R isk s of Vascul ar Event s a nd Death
n engl j med 363;15 nejm.org october 7, 2010
1411
I
n patients with diabetes treated with
insulin or insulin secretagogues, severe hypo-
glycemia is more common when glucose con-
trol is intensified.
1-4
Although most episodes of
severe hypoglycemia resolve without apparent per-
manent injury, there are anecdotal reports of acute
coronary syndromes coinciding with hypoglyce-
mia in people with type 2 diabetes.
5,6
In addition,
observational studies have suggested that hypo-
glycemia and reduced levels of glycated hemo-
globin are associated with an increased risk of
death in patients with diabetes or hyperglyce-
mia who have been hospitalized for myocardial
infarction.
7-11
Recently completed trials investigating the ef-
fect of intensive glucose control on macrovascular
outcomes in patients with long-standing type 2
diabetes have individually failed to demonstrate
clear reductions in cardiovascular events or mor-
tality.
1-3
A meta-analysis showed that intensive
glucose control reduced the risk of myocardial
infarction by 15%, with no adverse effect on the
risk of death, but that it simultaneously increased
the risk of severe hypoglycemia.
12
Nonetheless,
the excess mortality observed with intensive glu-
cose control in the Action to Control Cardiovas-
cular Risk in Diabetes (ACCORD) study has fueled
speculation about the adverse effects of such regi-
mens in patients with type 2 diabetes.
13
Post hoc
analyses of ACCORD study data suggest that the
excess mortality in the intensively treated group
was not directly explained by the high rate of hy-
poglycemia.
14
We examined the relationship between severe
hypoglycemia and the subsequent risks of vascu-
lar complications and death among 11,140 pa-
tients with type 2 diabetes who participated in the
Action in Diabetes and Vascular Disease: Preterax
and Diamicron Modified Release Controlled Eval-
uation (ADVANCE) study (ClinicalTrials.gov num-
ber, NCT00145925).
M e t hod s
Study Design and Oversight
ADVANCE was a factorial trial with two random-
ized comparisons: a double-blind assessment of
the efficacy of perindopril–indapamide in lower-
ing blood pressure, as compared with placebo, and
an open-label assessment of the effects of inten-
sive glucose lowering with the use of a modified-
release formulation of gliclazide as compared with
standard, guideline-based glucose lowering on the
risks of vascular outcomes and death among pa-
tients with type 2 diabetes. Approval for the trial
was obtained from the ethics committee of each
study center, and all participants provided written
informed consent.
3,15
The main results for each
comparison have been reported previously.
3,15
Study Popul ation
A total of 11,140 patients who were at least 55 years
of age were recruited for the study from 215 cen-
ters in 20 countries between June 2001 and March
2003. Eligible patients had received a diagnosis of
type 2 diabetes after the age of 30 years and had
a history of major macrovascular or microvascu-
lar disease or at least one other cardiovascular
risk factor.
3
No threshold for level of blood glu-
cose or glycated hemoglobin was specified for in-
clusion in the study, although patients with a clear
indication for long-term insulin use at baseline
were ineligible. Patients assigned to the intensive
glucose-lowering intervention were given modi-
fied-release gliclazide (Diamicron MR, Servier) and
other glucose-lowering drugs as required, with a
target glycated hemoglobin level of 6.5% or less.
3
Weight, height, blood pressure, and levels of gly-
cated hemoglobin and serum creatinine were mea-
sured at baseline, at 4 months, and every 6 months
thereafter.
3
Definition of Hypoglycemia
Hypoglycemia was defined as a blood glucose level
of less than 2.8 mmol per liter (50 mg per decili-
ter) 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 them-
selves (requiring help from another person) were
considered to have severe hypoglycemia. Episodes
of severe hypoglycemia were reported at the time
of their occurrence during study follow-up, with
a full description of the event. Each report was
reviewed to confirm that the criteria were met.
Patients with transient dysfunction of the central
nervous system who were able to treat themselves
were considered to have minor hypoglycemia.
Episodes of minor hypoglycemia were reported at
follow-up visits.
Clinic al Outcomes
The primary clinical outcomes considered were
the first major macrovascular event (death from
a cardiovascular cause, nonfatal myocardial infarc-
tion, or nonfatal stroke) and the first major micro-
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T h e
n e w e n g l a n d j o u r n a l
o f
m e d i c i n e
n engl j med 363;15 nejm.org october 7, 2010
1412
vascular event (new or worsening nephropathy or
retinopathy). The secondary outcomes considered
were death from any cause and death from a car-
diovascular event. Primary and secondary out-
comes were validated by an independent adjudi-
cation committee whose members were unaware
of the treatment assignments.
3
Nonvascular clin-
ical outcomes were reported during follow-up as
serious adverse events and coded according to the
International Classification of Diseases, 9th Revision.
Statis tical Analysis
A full description of the statistical analysis is pro-
vided in the Supplementary Appendix, available
with the full text of this article at NEJM.org. In
brief, rates of severe and minor hypoglycemia dur-
ing follow-up were estimated for the entire cohort
and according to treatment assignments. Baseline
risk factors for severe hypoglycemia were exam-
ined with the use of univariate and multivariate-
adjusted Cox proportional regression models. In-
cidence rates of clinical outcomes according to
hypoglycemic status were examined in the entire
cohort. Crude, annualized mortality rates within
each glucose treatment group (intensive glucose
control and standard glucose control) for patients
who did and those who did not report severe hypo-
glycemia were determined by dividing the num-
ber of deaths by the cumulative time at risk.
Associations between severe hypoglycemia and
clinical outcomes were tested with the use of time-
dependent Cox proportional-hazards models of
the time from randomization to the first clinical
outcome. Models were adjusted for all baseline and
time-dependent covariates (variables measured
during follow-up) that were thought to be poten-
tial confounders, as listed in the Supplementary
Appendix. For each clinical outcome, the follow-
up time for every patient was divided into as many
intervals as there were distinct event times in the
whole cohort. Each interval included the latest
measured value for each time-dependent covariate
and a variable indicating whether the patient had
the clinical outcome of interest during that inter-
val.
16
Follow-up for each participant was consid-
ered separately for each major outcome and ended
on the date of the first clinical event, the date
of death, or the date of data censoring at study
completion.
The primary analysis assumed that patients
were exposed to hypoglycemia from the time of
the first severe hypoglycemic episode until the end
of follow-up or the occurrence of a clinical event.
Additional sensitivity analyses tested various expo-
sure times, use of logistic-regression models, and
additional adjustment for cardiovascular events
occurring after randomization, as described in the
Supplementary Appendix. Model predictive capac-
ity, with and without severe hypoglycemia, was
tested with the use of C statistics,
17
the integrated-
discrimination-improvement statistic,
18
and the
Hosmer–Lemeshow chi-square statistic.
19
Analy-
ses were performed with the use of SAS statisti-
cal software, version 9.1 (SAS Institute). All statis-
tical tests were two-sided, and a P value of less
than 0.05 was considered to indicate statistical
significance, but all results were interpreted in
light of the many comparisons made.
R e s u lt s
Rates of Hypoglycemia over Time
During a median follow-up period of 5 years, 231
of 11,140 study patients (2.1%) reported 299 se-
vere hypoglycemic events: 150 patients in the in-
tensive-intervention group (2.7%) reported 195
events, and 81 patients in the standard-interven-
tion group (1.5%) reported 104 events (Table 1).
Over time, the rate of severe hypoglycemia in-
creased in the group undergoing intensive glucose
control (P<0.001 for trend) but remained relatively
stable in the group receiving standard treatment
(P = 0.38 for trend) (Fig. 1A). A total of 4975 pa-
tients (44.7%) reported minor hypoglycemia dur-
ing follow-up; 2898 of these patients (52.0%) had
been assigned to intensive control and 2077 (37.3%)
to standard control (Table 1).
Risk Factors for Severe Hypoglycemia
Univariate and multivariate analyses showed that
the following variables were independent risk fac-
tors for severe hypoglycemia: older age, longer du-
ration of diabetes, higher creatinine levels, lower
body-mass index, lower cognitive function, use of
two or more oral glucose-lowering drugs, history
of smoking or microvascular disease, and assign-
ment to intensive glucose control (P<0.05 for all
comparisons; for details, see Table 1 in the Sup-
plementary Appendix). When these analyses were
stratified according to treatment group, the risk
factors for severe hypoglycemia were similar.
Association of Severe Hypoglycemia
with Vascular Outcomes and Death
During follow-up, 2125 patients had a major mac-
rovascular or microvascular event, 87 of whom re-
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Sever e Hypoglycemia and R isk s of Vascul ar Event s a nd Death
n engl j med 363;15 nejm.org october 7, 2010
1413
ported severe hypoglycemia (before the event in
40 patients and after the event in 47), and 1031
patients died, 45 of whom had reported severe hy-
poglycemia. The median times from the episode
of severe hypoglycemia to the subsequent first
major macrovascular or microvascular event were
1.56 years (interquartile range, 0.84 to 2.41) and
0.99 years (interquartile range, 0.40 to 2.17), re-
spectively. The median time from severe hypogly-
cemia to death was 1.05 years (interquartile range,
0.34 to 2.41) — 1.31 years (interquartile range,
0.80 to 2.41) for death from a cardiovascular event
and 0.74 years (interquartile range, 0.13 to 2.60) for
death from a noncardiovascular cause (Fig. 1B).
Among patients who reported severe hypogly-
cemia, 16.8% (35 of 208) had a subsequent major
macrovascular event, 11.5% (24 of 209) had a sub-
sequent major microvascular event, and 19.5% (45
of 231) died; the respective rates for those who
did not report severe hypoglycemia were 10.2%
(1112 of 10,932 patients), 10.1% (1107 of 10,931),
and 9.0% (986 of 10,909), respectively. The propor-
tions of patients who died from cardiovascular
causes and from noncardiovascular causes were
similar among patients reporting severe hypogly-
cemia (49% and 51%, respectively) and those not
reporting severe hypoglycemia (53% and 47%, re-
spectively; P = 0.09). For those reporting severe hy-
poglycemia, annual death rates were lower in the
group receiving intensive treatment than in the
group receiving standard treatment (3.6% vs. 5.1%).
In contrast, for those not reporting severe hypo-
glycemia, annual death rates were similar in the
two treatment groups (1.8% with the intensive
intervention and 1.9% with standard treatment)
(
Table 2
). There was no evidence of interaction
among severe hypoglycemia, the assigned glucose-
lowering treatment, and the risk of death (P = 0.30).
The unadjusted risks of a major macrovascular
event, a major microvascular event, death from any
cause, and death from a cardiovascular or non-
cardiovascular cause were significantly increased
among patients who had severe hypoglycemia as
compared with those who did not (
Table 3
). After
adjustment for a number of potential confound-
ing variables measured at baseline or during fol-
low-up, the associations were markedly attenuated
but remained significant (P<0.01 for all com-
parisons).
In analyses in which the period of follow-up
after a severe hypoglycemic episode was limited
to 3 months and to 6 months, the unadjusted and
adjusted associations with all major macrovascu-
lar outcomes and death (from any cause or from
a cardiovascular or noncardiovascular cause), re-
mained significant (
Table 3
). The adjusted asso-
ciations for major microvascular events were no
longer significant when the period was limited to
3 months, but the point estimates of association
were similar (
Table 3
). When the analyses were
Table 1. Episodes of Severe and Minor Hypoglycemia in All Study Participants and According to Treatment Group.
Variable
All Participants
(N = 11,140)
Intensive
Glucose
Control
(N = 5571)
Standard
Glucose
Control
(N = 5569)
Hazard Ratio
(95% CI)
Severe hypoglycemia 1.86 (1.40–2.40)
No. of patients (%) 231 (2.1) 150 (2.7) 81 (1.5 )
No. of episodes
One 184 120 64
Two 35 22 13
Three or more 12 8 4
Rate (per person per year) 0.006 0.007 0.004
Minor hypoglycemia 1.58 (1.49–1.68)
No. of patients (%) 4975 (44.7) 2898 (52.0) 2077 (37.3)
No. of episodes
One 2610 1529 1081
Two 671 397 274
Three or more 1694 972 722
Rate (per person per year) 1.1 1.2 0.9
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