1818 Diabetes Care Volume 39, October 2016

Intensive Glycemic Therapy Tetsuro Tsujimoto,1 Takehiro Sugiyama,2,3

Mitsuhiko Noda,4 and Hiroshi Kajio1

in Patients With Type 2 Diabetes

on b-Blockers
Diabetes Care 2016;39:18181826 | DOI: 10.2337/dc16-0721

OBJECTIVE
Recent studies have suggested that b-blockers may decrease the adverse inu-
ence of hypoglycemia and reduce hypoglycemia-associated cardiac arrhythmias
and death. We evaluated whether intensive glycemic therapy in patients with
diabetes receiving treatment with b-blockers showed benecial effects for the
prevention of cardiovascular events without increased mortality compared with a
standard glycemic therapy.

RESEARCH DESIGN AND METHODS

We used Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial data to
assess the risks of cardiovascular events, all-cause death, and cardiovascular
death in patients with diabetes receiving treatment with b-blockers (n = 3,079)
and not receiving treatment with b-blockers (n = 7,145) using Cox proportional
hazard models.

RESULTS
In patients receiving treatment with b-blockers, the cumulative event rates for
cardiovascular events were signicantly lower in the intensive therapy group
CARDIOVASCULAR AND METABOLIC RISK

compared with the standard therapy group (hazard ratio [HR] 0.81; 95% CI
0.670.97; P = 0.02), whereas those rates in patients not receiving treatment with
b-blockers were not signicantly different (HR 0.92; 95% CI 0.781.09; P = 0.36). 1
Department of Diabetes, Endocrinology, and
Conversely, the cumulative event rates for all-cause and cardiovascular deaths in Metabolism, Center Hospital, National Center
patients receiving treatment with b-blockers were not signicantly different be- for Global Health and Medicine, Tokyo, Japan
2
tween the standard therapy and intensive therapy groups (all-cause death: HR Department of Clinical Study and Informatics,
Center for Clinical Sciences, National Center for
1.08; 95% CI 0.831.42; P = 0.54; cardiovascular death: HR 1.05; 95% CI 0.721.51; Global Health and Medicine, Tokyo, Japan
P = 0.79), whereas in patients not receiving treatment with b-blockers, the event 3
Department of Public Health/Health Policy, The
rates were signicantly higher in the intensive therapy group compared with the University of Tokyo, Tokyo, Japan
4
standard therapy group (all-cause death: HR 1.25; 95% CI 1.021.52; P = 0.02; Department of Endocrinology and Diabetes,
Saitama Medical University, Saitama, Japan
cardiovascular death: HR 1.43; 95% CI 1.031.98; P = 0.03).
Corresponding author: Tetsuro Tsujimoto,
CONCLUSIONS ttsujimoto@hosp.ncgm.go.jp.
Received 2 April 2016 and accepted 4 July 2016.
Intensive glycemic therapy may be effective in patients with type 2 diabetes re-
This article contains Supplementary Data online
ceiving treatment with b-blockers.
at http://care.diabetesjournals.org/lookup/
suppl/doi:10.2337/dc16-0721/-/DC1.
Glycemic control in patients with diabetes is necessary to prevent diabetes-related 2016 by the American Diabetes Association.
complications. Intensive glycemic control for patients with type 2 diabetes can Readers may use this article as long as the work
is properly cited, the use is educational and not
decrease the risks for microvascular diseases, such as diabetic retinopathy and nephrop-
for prot, and the work is not altered. More infor-
athy (1), but the prevention of macrovascular diseases remains difcult. Recent large- mation is available at http://www.diabetesjournals
scale randomized control trials (24) did not show the efcacy of intensive glycemic .org/content/license.
care.diabetesjournals.org
therapy for the prevention of cardiovas-
cular events. In addition, the Action to
Control Cardiovascular Risk in Diabetes
(ACCORD) trial revealed that intensive
glycemic therapy can increase all-cause
and cardiovascular mortalities (2). A
possible explanation for these results is
the fact that glucose-lowering therapy
may increase the frequency of hypogly-
cemic episodes, which in turn is associ-
ated with increased risks for vascular
events and mortality (5,6). In fact, pa-
tients with diabetes with severe hypo-
glycemia face many critical problems
such as severe hypertension, hypokale-
mia, and QT prolongation, which could
lead to cardiovascular disease, fatal ar-
rhythmia, and death (7,8).
Recent studies have suggested that
b-blockers may prevent or decrease
the adverse inuence of severe hypo-
glycemia, such as severe hypertension
and hypokalemia, and may reduce se-
vere hypoglycemia-associated cardiac
arrhythmias and death (9,10). There-
fore, the use of b-blockers may help to
achieve maximum effects of glycemic
control, particularly in intensive glyce-
mic therapy, due to a decrease in the
adverse inuence of severe hypoglyce-
mia. Although b-blockers theoretically
pose a potential risk for the occurrence
and prolongation of severe hypogly-
cemia (11), there is little evidence to
support the assertion that b-blockers
should be routinely contraindicated
in patients with diabetes (1218). In
the current study, we assessed whether
intensive glycemic therapy in patients
with diabetes receiving treatment with
b-blockers showed benecial effects
for the prevention of cardiovascular
events without increased mortality,
compared with a standard glycemic
therapy.
RESEARCH DESIGN AND METHODS
Study Design
We used ACCORD data to evaluate
the associations between the use of
b-blockers and cardiovascular events,
and all-cause and cardiovascular mor-
talities in patients with type 2 diabetes.
The detailed design and description of
glycemia interventions of the ACCORD
trial have been reported previously
(2,1921). Briey, the ACCORD trial
was sponsored by the National Heart,
Lung, and Blood Institute (NHLBI) and
was conducted in 77 clinical centers
across the U.S. and Canada. In total,
10,251 men and women between
40 and 79 years of age with type 2
diabetes, a glycated hemoglobin level
of $7.5%, and who either were be-
tween 40 and 79 years of age and had
cardiovascular disease or were be-
tween 55 and 79 years of age and had
albuminuria, anatomical evidence of
signicant atherosclerosis, left ven-
tricular hypertrophy, or at least two
additional risk factors for cardiovascu-
lar disease (current smoker, obesity,
hypertension, or dyslipidemia) were
included in the trial (2,19). Exclu-
sion criteria included a BMI (weight
in kilograms per square meters) of
.45 kg/m 2, an unwillingness to per-
form home glucose monitoring or to
inject insulin, frequent or recent seri-
ous hypoglycemia, a serum creatinine
level of .1.5 mg/dL, or any other se-
rious illness. All 10,251 patients were
randomly allocated into one of the
two groups: one group of patients re-
ceived comprehensive intensive glyce-
mic therapy that targeted a glycated
hemoglobin level of ,6.0%; and the
other group of patients received stan-
dard glycemic therapy that targeted a
level of 7.07.9%. The medications
used to achieve these targets were
the same in the two groups and in-
cluded metformin, short-acting and
long-acting insulins, sulfonylureas,
acarbose, meglitinides, thiazolidine-
diones, and incretins. Patients were fol-
lowed up at least every 4 months to
ensure that therapeutic goals were
met and maintained, and to monitor
study outcomes and adverse effects.
The study protocol was approved by
the ethics committee of each study
center, and approved and monitored
by an independent data safety and
monitoring board. All participants pro-
vided written informed consent. Be-
cause of the increase in all-cause and
cardiovascular mortalities, intensive
glycemic therapy was discontinued on
6 February 2008 (2). Participants were
switched to the standard regimen and
were followed up until 31 December
2010. The occurrence of outcomes in
this study was maximally followed up
for 7 years. This study was approved
by the institutional review board of
the National Center for Global Health
and Medicine, and NHLBI has approved
our use of the ACCORD data.
Tsujimoto and Associates 1819
Outcome Measurements
The primary outcome in this study was
the rst occurrence of a cardiovascular
event, which included nonfatal myocar-
dial infarction, unstable angina, nonfatal
stroke, and cardiovascular death. Sec-
ondary outcomes were all-cause death,
cardiovascular death, and severe hypo-
glycemia. Cardiovascular death was de-
ned as presumed cardiovascular death;
unexpected death; and death from a
myocardial infarction, arrhythmia, con-
gestive heart failure, stroke, and other
cardiovascular diseases, including ab-
dominal aortic aneurysm rupture and
pulmonary emboli (19). Severe hypogly-
cemia was dened as hypoglycemic
events with conrmed blood glucose
levels of ,50 mg/dL and requiring
medical assistance.
Statistical Analysis
Demographic data were presented as
numbers with proportions (percentage)
or means with SDs. Continuous vari-
ables were compared using Student
t tests, and categorical variables were
compared using x2 tests or Fisher ex-
act tests, as appropriate. The study par-
ticipants were rst divided into two
groups according to their use or non-
use of b-blockers. With the exception
of severe hypoglycemia, the number
of events occurring within 1 year was
small, and there were concerns regard-
ing subject identication. Therefore,
before we analyzed the data, follow-up
times for all early events were trimmed
to 1 year by the NHLBI. For cardiovascu-
lar events and all-cause and cardiovas-
cular deaths within 1 year, we compared
the incidences of these events by inten-
sive glycemic therapy with standard gly-
cemic therapy in each patient receiving
treatment with and not receiving treat-
ment with b-blockers. We analyzed haz-
ard ratios (HRs) with 95% CIs in patients
receiving intensive glycemic therapy
compared with those receiving standard
glycemic therapy by Cox proportional
hazard models, again for each patient
receiving treatment with and not receiv-
ing treatment with b-blockers. Analyses
of events before the treatment transi-
tion were also performed. Kaplan-Meier
survival curves were constructed for the
cardiovascular events and all-cause and
cardiovascular mortalities.
All statistical analyses were con-
ducted using Stata software (version
1820 b-Blockers in Patients With Diabetes
14.1; StataCorp). P , 0.05 was consid-
ered statistically signicant for all tests.
RESULTS
Study Participants
The characteristics of patients with
type 2 diabetes receiving treatment
with and not receiving treatment with
b-blockers are presented in Table 1.
Among the study patients, 3,079 were
receiving treatment with b-blockers
(standard glycemic therapy, n = 1,580;
intensive glycemic therapy, n = 1,499)
and 7,145 were not receiving treatment
with b-blockers (standard glycemic
therapy, n = 3,526; intensive glycemic
therapy, n = 3,619). In patients receiving
treatment with and not receiving treat-
ment with b-blockers, the characteris-
tics were not signicantly different
between those receiving standard glyce-
mic therapy and those receiving inten-
sive glycemic therapy. Characteristics,
including age, sex, duration of diabetes,
history of cardiovascular disease, smok-
ing status, BMI, cholesterol and triglyc-
eride levels, and estimated glomerular
ltration rate, were signicantly differ-
ent between patients receiving treat-
ment with and not receiving treatment
with b-blockers. The rate of b-blocker use
in patients with a history of coronary
heart disease and heart failure was 66%,
and that in patients without such a history
was 21% (Supplementary Table 1), which
indicated guideline-compliant b-blocker
use for patients with a history of coronary
heart disease and/or heart failure.
Cardiovascular Events and All-Cause
and Cardiovascular Mortalities
The incidences of cardiovascular events
and all-cause and cardiovascular deaths
within 1 year in all patients receiv-
ing intensive and standard glycemic
therapies and in those receiving treat-
ment with and not receiving treat-
ment with b-blockers are presented
in Fig. 1. In patients receiving treat-
ment with and not receiving treat-
ment with b-blockers, the incidences of
cardiovascular events, all-cause death,
and cardiovascular death were not sig-
nicantly different between patients
receiving standard and intensive glyce-
mic therapies in the rst year. Kaplan-
Meier survival curves and the event
rates for the following periods are
shown in Fig. 2 and Table 2, respec-
tively. The mean follow-up periods
(6SD) were 4.6 6 1.5 years in pa-
tients not receiving treatment with
b-blockers and 4.3 6 1.5 years in those
receiving treatment with b-blockers.
Consistent with previous studies on
the ACCORD trials (2,21), the cumu-
lative event rates for cardiovascular
events were lower, and those for all-
cause and cardiovascular deaths were
higher, in the intensive therapy group
compared with the standard therapy
group (Fig. 2A, C, and E). In patients re-
ceiving treatment with b-blockers, the
cumulative event rates for cardiovascu-
lar events were signicantly lower in the
intensive therapy group compared with
the standard therapy group (HR 0.81;
95% CI 0.670.97; P = 0.02), whereas
those in patients not receiving treat-
ment with b-blockers were not signif-
icantly different (HR 0.92; 95% CI
0.781.09; P = 0.36) (Fig. 2B). Con-
versely, the cumulative event rates for
all-cause and cardiovascular deaths in
patients receiving treatment with
b-blockers were not signicantly differ-
ent between the standard and intensive
therapy groups (all-cause death: HR
1.08; 95% CI 0.831.42; P = 0.54; cardio-
vascular death: HR 1.05; 95% CI 0.72
1.51; P = 0.79), whereas in patients not
receiving treatment with b-blockers,
the event rates were signicantly higher
in the intensive therapy group com-
pared with the standard therapy group
(all-cause death: HR 1.25; 95% CI 1.02
1.52; P = 0.02; cardiovascular death: HR
1.43; 95% CI 1.031.98; P = 0.03) (Fig.
2D and F, respectively). In patients re-
ceiving treatment with and not receiv-
ing treatment with b-blockers, the
cumulative event rates for nonfatal
myocardial infarction and nonfatal stroke
were nonsignicantly lower in the inten-
sive therapy group compared with the
standard therapy group (Table 2). The cu-
mulative event rates for fatal or hospital-
ized congestive heart failure in patients
receiving treatment with b-blockers
were not signicantly different between
the standard and intensive therapy
groups (HR 0.96; 95% CI 0.711.30; P =
0.80), whereas in patients not receiving
treatment with b-blockers, the event
rates were higher in the intensive ther-
apy group compared with the standard
therapy group (HR 1.23; 95% CI 0.92
1.64; P = 0.15).
Kaplan-Meier survival curves for car-
diovascular events and all-cause and
Diabetes Care Volume 39, October 2016
cardiovascular deaths in intensive and
standard glycemic therapies before treat-
ment transition in all patients and those
receiving treatment with and not re-
ceiving treatment with b-blockers are
shown in Fig. 3. Similarly, we found that
the cardiovascular event rate in patients
with diabetes receiving treatment with
b-blockers was lower in the intensive
therapy group than in the standard ther-
apy group (HR 0.81; 95% CI 0.661.01;
P = 0.06). In addition, the cumulative
event rates for all-cause and cardiovascu-
lar deaths in patients receiving treatment
with b-blockers were not significantly
different between the standard and inten-
sive therapy groups (all-cause death: HR
1.00; 95% CI 0.731.38; P = 0.96; cardiovas-
cular death: HR 0.85; 95% CI 0.551.31; P =
0.48), whereas in patients not receiving
treatment with b-blockers, the event
rates were signicantly higher in the in-
tensive therapy group compared with the
standard therapy group (all-cause death:
HR 1.27; 95% CI 1.011.59; P = 0.03; car-
diovascular death: HR 1.52; 95% CI 1.06
2.18; P = 0.02).
Severe Hypoglycemia
The HRs for severe hypoglycemia are
presented in Supplementary Table 2.
Although the event rates per year were
higher in patients receiving treatment
with b-blockers compared with those
not receiving treatment with b-blockers,
HRs for severe hypoglycemia in the in-
tensive therapy group compared with
the standard therapy group differed
only slightly between those receiving
treatment with b-blockers (HR 2.98;
95% CI 2.194.06; P , 0.001) and not
receiving treatment with b-blockers
(HR 2.87; 95% CI 2.273.62; P , 0.001).
In the model that included the interac-
tion term between the use of b-blockers
and the type of therapy (intensive/stan-
dard glycemic therapy), we found that
the association between intensive glyce-
mic therapy and the incidence of severe
hypoglycemia was not interacted by the
use of b-blockers (P for interaction
term = 0.86, data not shown).
CONCLUSIONS
In the current study, cardiovascular event
rates in patients receiving treatment
with b-blockers were signicantly lower
in the intensive therapy group com-
pared with those in the standard ther-
apy group. In addition, all-cause and
1821

Table 1Baseline characteristics of patients with type 2 diabetes who are receiving treatment with and not receiving treatment with b-blockers
Tsujimoto and Associates

b (2) b (+)
All Standard Intensive All Standard Intensive b (2) vs. b (+)
Characteristics (N = 7,145) (n = 3,526) (n = 3,619) P value (N = 3,079) (n = 1,580) (n = 1,499) P value P value
Age (years) 62.6 (6.4) 62.6 (6.4) 62.6 (6.5) 0.80 63.1 (7.1) 63.1 (7.2) 63.2 (7.0) 0.62 ,0.001
Female sex (%) 40.2 40.1 40.3 0.89 34.8 34.7 34.8 0.93 ,0.001
Duration of diabetes (years) 10.5 (7.4) 10.7 (7.4) 10.4 (7.4) 0.10 11.4 (8.0) 11.3 (8.0) 11.6 (8.0) 0.23 ,0.001
History of coronary heart disease (%)* 14.0 13.4 14.6 0.14 43.7 43.3 44.1 0.65 ,0.001
History of heart failure (%) 2.7 2.6 2.9 0.40 9.7 9.7 9.6 0.95 ,0.001
History of stroke (%) 5.2 5.4 5.0 0.49 8.3 8.5 8.1 0.73 ,0.001
Race and ethnicity (%)
White 61.5 61.0 62.0 0.37 64.3 65.7 62.9 0.10 0.007
Black 19.2 18.9 19.5 0.54 18.7 18.0 19.4 0.32 0.58
Hispanic 7.2 7.5 7.0 0.36 7.1 7.2 7.1 0.93 0.82
Others 12.1 12.6 11.5 0.17 9.9 9.1 10.6 0.16 0.001
Educational attainment (%)
Less than high school 14.5 14.1 14.9 0.28 15.6 13.9 17.5 0.006 0.13
High school 25.9 25.6 26.1 0.64 27.7 29.1 26.2 0.07 0.05
Some college 32.9 33.0 32.8 0.85 32.4 32.5 32.3 0.88 0.64
College degree or higher 26.7 27.3 26.2 0.26 24.2 24.5 24.0 0.72 0.008
Current smoking (%) 12.6 12.4 12.9 0.56 11.1 10.6 11.5 0.42 0.02
BMI (kg/m2) 32.0 (5.5) 32.0 (5.4) 32.0 (5.5) 0.80 32.7 (5.3) 32.7 (5.3) 32.6 (5.2) 0.47 ,0.001
Medications (%)
Insulin 33.1 34.2 32.1 0.06 39.9 40.0 39.8 0.92 ,0.001
Sulfonylurea 53.0 52.5 53.4 0.41 54.6 53.9 55.4 0.42 0.12
Metformin 63.9 64.1 63.8 0.74 64.3 64.6 63.9 0.68 0.74
ARB/ACE-I 67.2 67.5 66.9 0.62 74.7 74.4 75.1 0.69 ,0.001
CCB 10.7 10.8 10.6 0.81 13.9 13.9 13.9 0.99 ,0.001
Thiazide 25.8 25.5 26.2 0.48 32.0 32.6 31.3 0.43 ,0.001
Statin 58.2 58.7 57.7 0.38 76.4 75.6 77.1 0.33 ,0.001
Aspirin 50.2 49.9 50.4 0.70 65.1 64.3 66.0 0.33 ,0.001
Systolic blood pressure (mmHg) 136.0 (15.9) 136.1 (15.9) 135.9 (15.9) 0.61 136.5 (17.9) 136.6 (17.7) 136.3 (18.0) 0.73 0.21
Glycated hemoglobin (%) 8.3 (1.0) 8.3 (1.0) 8.3 (1.0) 0.36 8.3 (1.0) 8.3 (0.9) 8.3 (1.0) 0.75 0.69
Cholesterol (mg/dL)
LDL 107.4 (33.1) 107.4 (33.3) 107.4 (32.9) 0.94 98.1 (31.9) 98.2 (31.3) 97.9 (32.6) 0.74 ,0.001
HDL 42.9 (11.4) 42.9 (11.2) 42.8 (11.5) 0.53 39.4 (10.4) 39.6 (10.4) 39.2 (10.3) 0.36 ,0.001
Triglyceride (mg/dL) 194.8 (122.2) 192.1 (113.1) 181.5 (114.8) 0.58 195.8 (121.1) 195.0 (120.5) 196.6 (121.7) 0.71 ,0.001
care.diabetesjournals.org

Estimated GFR (mL/min/1.73m2) 91.5 (22.5) 91.8 (22.2) 91.1 (22.8) 0.16 87.1 (22.5) 87.3 (22.3) 87.0 (22.7) 0.72 ,0.001
Data are presented as the mean (SD), unless otherwise indicated. Among the 10,251 study patients, 27 did not have the information on their use of b-blockers. Glycated hemoglobin: 8.3% = 67 mmoL/moL.
ACE-I, angiotensin-converting enzyme inhibitors; ARB, angiotensin II receptor blockers; b (2), patients not receiving treatment with b-blockers; b (+), patients receiving treatment with b-blockers; CCB,
calcium channel blockers; GFR, glomerular ltration rate; Intensive, intensive therapy group; Standard, standard therapy group. *Coronary heart disease was dened as myocardial infarction or angina
pectoris; P value was calculated by comparing variables in intensive therapy with those in standard therapy; The estimated GFR was calculated using the following Modication of Diet in Renal Disease (MDRD)
Study equation: estimated GFR (mL/min/1.73 m2) = 175 3 (serum creatinine in mg/dL)21.154 3 (age in years)20.203 3 (0.742 for female) 3 (1.212 for African American).
1822 b-Blockers in Patients With Diabetes
Figure 1Incidences of cardiovascular events and all-cause and cardiovascular deaths within
1 year in intensive and standard glycemic therapies in all patients and in those receiving treat-
ment with and not receiving treatment with b-blockers. Incidence of cardiovascular events (A),
all-cause death (B), and cardiovascular death (C). b (2), patients not receiving treatment with
b-blockers; b (+), patients receiving treatment with b-blockers; Intensive, intensive therapy;
Standard, standard therapy.
cardiovascular mortalities in patients
receiving treatment with b-blockers were
not signicantly different between the in-
tensive and standard therapy groups. In
contrast, in patients not receiving treat-
ment with b-blockers, the cardiovascu-
lar event rate did not differ signicantly
between intensive and standard glyce-
mic therapies, whereas all-cause and
cardiovascular mortalities were signicantly
higher in the intensive therapy group.
A recent study on the ACCORD trial
(21) reported that ischemic heart disease
was less frequent in the intensive ther-
apy group compared with the stan-
dard therapy group. Considering the
results in the current study, the bene-
cial effects of intensive glycemic
Diabetes Care Volume 39, October 2016
therapy might be due to the efcacy
in patients receiving treatment with
b-blockers. In addition, although a pre-
vious report on the ACCORD trial (2)
demonstrated that intensive glycemic
therapy was associated with an in-
creased risk of all-cause and cardiovas-
cular deaths, the current study found
that the adverse effects of intensive gly-
cemic therapy might be attributed to
the effects of not receiving treatment
with b-blockers. Some reports have in-
dicated that severe hypoglycemia, of
which intensive glycemic therapy was
associated with higher risks, was asso-
ciated with an increased risk of car-
diovascular disease and death (5,6).
One possible reason for the association
between severe hypoglycemia and
cardiovascular events is that severe
hypoglycemia can lead to activation of
the sympathoadrenal system and the re-
lease of counter-regulatory hormones,
resulting in signicant hemodynamic
changes, hypokalemia, and QT pro-
longation (7,22). Based on pathophys-
iological mechanisms, a prior use of
b-blockers may prevent the adverse
inuence of the hypersecretion of
catecholamines induced by severe hy-
poglycemia, and that may reduce the
number of vascular events, cardiac ar-
rhythmias, and deaths due to severe
hypoglycemia (7,10). Indeed, the anal-
yses of patients receiving treatment
with b-blockers showed that the cardio-
vascular event rate was signicantly
lower in the intensive therapy group
compared with the standard therapy
group. In addition, although data on
arrhythmogenic cardiac mortality was
not assessed, the number of all-cause
and cardiovascular mortalities did not
increase in the intensive therapy group
in patients receiving treatment with
b-blockers, which is different from the
results of those not receiving treatment
with b-blockers. The HRs for severe hy-
poglycemia in the intensive therapy
group compared with the standard ther-
apy group were not very different be-
tween patients receiving treatment
with and not receiving treatment with
b-blockers, and the association be-
tween intensive glycemic therapy and
the incidence of severe hypoglyce-
mia was not interacted by the use of
b-blockers. Therefore, the decreased
risk of cardiovascular events in patients
receiving treatment with b-blockers
care.diabetesjournals.org
Figure 2Kaplan-Meier survival curves for cardiovascular events and all-cause and cardiovas-
cular deaths in intensive and standard glycemic therapies in all patients and in those receiving
treatment with and not receiving treatment with b-blockers. Rates of freedom from cardiovas-
cular events (A and B), all-cause death (C and D), and cardiovascular death (E and F). b (2),
patients not receiving treatment with b-blockers; b (+), patients receiving treatment with
b-blockers; Intensive, intensive therapy; Standard, standard therapy.
might be due to the protective effects of
b-blockers after the occurrence of se-
vere hypoglycemia. Intensive glycemic
therapy may be a preferable strategy
to prevent cardiovascular events in
patients receiving treatment with
b-blockers, which were essential for
treating underlying diseases, such as
coronary heart disease and heart fail-
ure, compared with standard glyce-
mic therapy. The benecial effects of
b-blockers on cardiovascular events
may be observed in the high cardiovas-
cular risk in patients with type 2 diabe-
tes, partly because these patients may
be at a higher risk of severe hypoglycemia
and severe hypoglycemia-associated
adverse events, and b-blockers may al-
leviate the damage from hypoglycemia-
associated adverse events. It has been
known that the use of b-blockers can
be a risk factor for hypoglycemia and
hypoglycemia unawareness, presum-
ably because of diminished or absent
early warning signs (11). However, there
was little evidence to support the asser-
tion that b-blockers should be routinely
contraindicated in patients with diabe-
tes as they have minimal clinical ef-
fects on hypoglycemia unawareness
and recovery (1216). Further studies
are needed to evaluate whether the use
of b-blockers in patients with diabetes
shows benecial or adverse effects.
Tsujimoto and Associates 1823
This study has several limitations.
First, this was a post hoc analysis of
the ACCORD trial, and residual con-
founding might still be present. In addi-
tion, although the current study was
large scale and evidence based, and
had a robust subgroup representation,
our ndings may not be applicable to
other patients with diabetes. Second,
we were only able to analyze data that
early events had been trimmed to
1 year. The number of events prior to
1 year was very small, and there were
concerns regarding subject identica-
tion. Therefore, before we analyzed
the data, follow-up times for all early
events were trimmed to 1 year by the
NHLBI. Although the incidences of car-
diovascular events, all-cause death, and
cardiovascular death in patients receiv-
ing treatment with and not receiving
treatment with b-blockers were not sig-
nicantly different between patients
receiving standard and intensive glyce-
mic therapies in a rst year, another
study is needed to conrm these results.
However, we believe that the current
study provides extremely important
information regarding glycemic con-
trol and diabetes management. Third,
adherence to medication, including
b-blockers, might inuence the study
outcomes. Poor adherence to medication
regimens is common and contributes
to substantially worse cardiovascular
outcomes (23). However, the average
rate of adherence in clinical trials is usually
high, owing to the monitoring programs
and to the selection of the patients. Be-
cause follow-up visits in patients in the
ACCORD trial, including a blood pressure
trial, were conducted for at least 4 months,
the rate of adherence to medications
might be remarkably high. Fourth, we
could not assess whether the different
types of b-blockers, such as cardioselec-
tive and nonselective b-blockers, had sim-
ilar effects on cardiovascular events and
death. Although the b-blockers exert their
effects by competitively inhibiting cat-
echolamines from binding to b-receptors,
each b-blocker has different characteristics
with respect to the cardioselectivity, phar-
macokinetics, intrinsic sympathomimetic
activity, and a-adrenergic blocking activ-
ity. Thus, further studies are needed to
clarify which types of b-blockers are
more benecial.
In conclusion, this study showed
that the cardiovascular event rate in
 1824

Table 2Cardiovascular events and all-cause and cardiovascular death in patients with type 2 diabetes receiving treatment with and not receiving treatment with b-blockers
All b-blockers (2) b-blockers (+)
b-Blockers in Patients With Diabetes

Event Standard Intensive P value Standard Intensive P value Standard Intensive P value
Cardiovascular events
No. of patients/total no. 559/4,912 489/4,915 300/3,386 284/3,472 257/1,509 205/1,433
Event rate per year (%) 3.0 2.6 2.3 2.1 4.9 3.9
HR (95% CI) 1.00 (ref) 0.86 (0.760.97) 0.02 1.00 (ref) 0.92 (0.781.09) 0.36 1.00 (ref) 0.81 (0.670.97) 0.02
Death from any cause
No. of patients/total no. 279/5,070 328/5,066 173/3,493 218/3,576 105/1,560 110/1,480
Event rate per year (%) 1.4 1.6 1.2 1.5 1.8 1.9
HR (95% CI) 1.00 (ref) 1.18 (1.011.39) 0.04 1.00 (ref) 1.25 (1.021.52) 0.02 1.00 (ref) 1.08 (0.831.42) 0.54
Death from cardiovascular causes
No. of patients/total no. 119/5,005 146/4,999 61/3,448 88/3,526 57/1,540 58/1,463
Event rate per year (%) 0.6 0.7 0.4 0.6 0.4 0.6
HR (95% CI) 1.00 (ref) 1.24 (0.971.52) 0.09 1.00 (ref) 1.43 (1.031.98) 0.03 1.00 (ref) 1.05 (0.721.51) 0.79
Nonfatal myocardial infarction
No. of patients/total no. 268/4,914 225/4,925 127/3,476 147/3,391 120/1,506 98/1,439
Event rate per year (%) 1.4 1.2 1.1 0.9 2.1 1.8
HR (95% CI) 1.00 (ref) 0.83 (0.700.99) 0.04 1.00 (ref) 0.84 (0.671.07) 0.18 1.00 (ref) 0.84 (0.641.09) 0.20
Nonfatal stroke
No. of patients/total no. 79/4,970 58/4,958 49/3,426 39/3,498 30/1,527 19/1,450
Event rate per year (%) 0.4 0.3 0.4 0.3 0.5 0.3
HR (95% CI) 1.00 (ref) 0.73 (0.521.03) 0.07 1.00 (ref) 0.78 (0.511.20) 0.27 1.00 (ref) 0.65 (0.361.16) 0.15
Fatal or hospitalized congestive heart failure
No. of patients/total no. 173/4,955 184/4,937 84/3,421 104/3,494 87/1,517 80/1,434
Event rate per year (%) 0.9 1.0 0.6 0.8 1.5 1.5
HR (95% CI) 1.00 (ref) 1.07 (0.871.32) 0.49 1.00 (ref) 1.23 (0.921.64) 0.15 1.00 (ref) 0.96 (0.711.30) 0.80
All, all patients; b-blockers (2), patients not receiving treatment with b-blockers; b-blockers (+), patients receiving treatment with b-blockers; Intensive, intensive therapy group; ref, reference value; Standard,
standard therapy group.
Diabetes Care Volume 39, October 2016
care.diabetesjournals.org
Figure 3Kaplan-Meier survival curves for cardiovascular events and all-cause and cardiovas-
cular deaths in intensive and standard glycemic therapies before treatment transition in all
patients and in those receiving treatment with and not receiving treatment with b-blockers.
Rates of freedom from cardiovascular events (A and B), all-cause death (C and D), and cardio-
vascular death (E and F ). b (2), patients not receiving treatment with b-blockers; b (+),
patients receiving treatment with b-blockers; Intensive, intensive therapy; Standard, stan-
dard therapy.
patients with diabetes receiving treat-
ment with b-blockers was signicantly
lower in the intensive therapy group
compared with the standard therapy
group. In addition, all-cause and car-
diovascular mortalities in those pa-
tients not receiving treatment with
b-blockers were signicantly higher
in the intensive therapy group. Inten-
sive glycemic therapy may be effec-
tive in patients with type 2 diabetes
who are receiving treatment with
b-blockers.
Acknowledgments. This article was prepared
using ACCORD Research Materials obtained
from the NHLBI Biologic Specimen and Data
Repository Information Coordinating Center
and does not necessarily reect the opinions
or views of the ACCORD Study or the NHLBI.
Funding. This research was supported by Grant-
in-Aid for Scientic Research (KAKENHI) from the
Japan Society for the Promotion of Science (no.
26860701).
Duality of Interest. M.N. has received speaker
honoraria from Sano, Mitsubishi Tanabe
Pharma, Daiichi Sankyo, Eli Lilly Japan, MSD,
Sanwa Kagaku Kenkyusho, Ono Pharmaceutical
Co. Ltd, Takeda Pharmaceutical Co. Ltd, Astellas,
Kowa Pharmaceutical Co. Ltd, Novo Nordisk
Pharma Ltd, AstraZeneca, and Johnson & Johnson
K.K. and research grants from Takeda Pharma-
ceutical Co. Ltd, Mitsubishi Tanabe Pharma,
and AstraZeneca. No other potential conicts
of interest relevant to this article were
reported.
Tsujimoto and Associates 1825
Author Contributions. T.T. contributed to
the study concept and design; data acquisition,
analysis, and interpretation; and statistical anal-
ysis and drafted the manuscript. T.S. contributed
to the data acquisition, analysis, and interpre-
tation and statistical analysis and drafted the
manuscript. M.N. and H.K. drafted the manu-
script. T.T. is the guarantor of this work and, as
such, had full access to all the data in the study
and takes responsibility for the integrity of the
data and the accuracy of the data analysis.
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