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OR I GI NA L R E S E A R CH
open access to scientic and medical research
Open Access Full Text Article
http://dx.doi.org/10.2147/DDDT.S53253
Difference in the effects of switching from
Candesartan to Olmesartan or Telmisartan to
Olmesartan in hypertensive patients with type 2
diabetes: the COTO study
Hiroyuki Daikuhara
Kensaku Fukunaga
Tomie Ohshima
Department of Internal Medicine,
Sakaide City Hospital, Kagawa, Japan
Correspondence: Hiroyuki Daikuhara
Department of Internal Medicine,
Sakaide City Hospital, 1-6-43 Bunkyo-
cho, Sakaide, Kagawa 762-0031, Japan
Tel +81 877 465 131
Fax +81 877 462 377
Email [email protected]
Purpose: This open-label controlled study compared the therapeutic efficacy of three
representative angiotensin II receptor blockers (ARBs) in hypertensive patients with type 2
diabetes attending a hospital outpatient clinic. The primary measure in this study was morning
home blood pressure (BP).
Patients and methods: Two studies were done concurrently to investigate the effects of switch-
ing from two different ARBs to olmesartan. Patients prescribed candesartan (8 mg once daily
in the morning) or telmisartan (40 mg once daily in the morning) for 16 weeks were switched
to olmesartan (20 mg once daily in the morning) for 16 weeks. Then, they were switched back
to candesartan (CO group) or telmisartan (TO group) for another 16 weeks.
Results: Data from all patients in the CO group (n=165) and the TO group (n=152) were ana-
lyzed. Clinic and morning home BP and urinary albumin levels showed a signicant decrease
from baseline at 16 weeks after switching to olmesartan in both the CO and the TO group
(clinic BP, morning home diastolic BP, and urinary albumin, P,0.05; morning home systolic
BP, P,0.01). In contrast, clinic BP, morning home BP, and urinary albumin were signicantly
increased again 16 weeks after switching back to candesartan or telmisartan (clinic BP, morning
home diastolic BP, and urinary albumin, P,0.05; morning home systolic BP, P,0.01). No
subjects experienced an adverse reaction that required withdrawal from the study. No adverse
reactions attributable to the study drugs were observed.
Conclusion: Olmesartan is a promising ARB for BP control in hypertensive type 2
diabetics.
Keywords: type 2 diabetes, morning home blood pressure, albuminuria, olmesartan
Introduction
The Japanese Society of Hypertension (JSH) Guideline for the Management of
Hypertension (JSH 2009) mentions the necessity for tight blood pressure (BP) con-
trol in patients with type 2 diabetes.
1
JSH 2009 recommends that the target BP for
hypertensive type 2 diabetics should be 130/80 mmHg as the clinic BP, and 125/75
mmHg as the home BP. Despite this recommendation of the JSH 2009, the target BP
is achieved in only 30%40% of patients.
2
Based on evidence for the improvement of
glucose metabolism and cardiorenal protection, the JSH 2009 recommends angiotensin
II receptor blockers (ARBs) as rst-line antihypertensive drugs for hypertensive patients
with type 2 diabetes.
1
However, hypertensive type 2 diabetics are commonly treated
with various combinations of drugs, because these patients do not respond well to
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Daikuhara et al
antihypertensive therapy. Therefore, it would be desirable to
include at least one drug that shows efcacy for hypertensive
diabetics in the case of combined therapy.
Among ARBs, olmesartan has been reported to show the
highest level of binding with the angiotensin II type 1 receptor
and, thus, has a strong hypotensive effect.
35
Recently, it was
reported that olmesartan effectively controlled both the clinic
BP and the morning home BP after 16 weeks of treatment,
indicating that its antihypertensive effect is stable over the
medium term.
6
As for candesartan, basic studies have shown
that it can improve insulin sensitivity, but only limited clinical
data that support this action of the drug have been published.
7

Similarly, telmisartan has been shown to selectively bind with
peroxisome proliferator-activated receptor gamma (PPAR)
in preclinical studies, and it has been suggested that this
action may improve insulin sensitivity.
8
However, the clinical
data are insufcient to support this action of telmisartan.
In Japan, seven ARBs are currently marketed. However,
there have been few reports regarding differences among
these drugs in terms of achieving BP control in hypertensive
patients with type 2 diabetes. Therefore, the purpose of this
study was to compare the effects of three representative
ARBs on morning home BP, urinary albumin excretion, and
parameters of glucose metabolism in hypertensive patients
with type 2 diabetes mellitus.
Patients and methods
Patients
Treated hypertensive patients with type 2 diabetes mellitus
who were attending the outpatient clinic for diabetes mellitus
at Sakaide City Hospital (Sakaide, Japan) were invited to
participate in this single-center, open-label, controlled study.
The study protocol was approved by the Institutional Ethical
Committee at Sakaide City Hospital. All the patients were
given an explanation of the study, and written consent to
participate and for the use of their data was obtained before
enrolment. We also explained to the patients that no personal
information would be disclosed during the publication of
the results.
Patients meeting the following criteria were eligible for
inclusion: hypertension in the presence of type 2 diabetes
mellitus; systolic BP or diastolic BP at medical examination
of $130 mmHg or $80 mmHg, respectively; and no planned
changes in antidiabetic therapy.
Patients meeting any of the following criteria were
excluded: secondary hypertension or grade 3 hypertension;
contraindication for any of the test drugs; uncontrolled
diabetes mellitus; diabetic nephropathy (urinary albumin
excretion $300 mg/g of creatinine [Cr]) before the late
stage of overt nephropathy (because blood insulin clearance
may decrease after the late stage of overt nephropathy and
may mask glucose metabolic status); history of acute coro-
nary syndrome or cerebrovascular disorders within 1 year
of enrolment; severe infection before or after surgery, or
serious trauma; history of hypersensitivity to the study drugs;
pregnant women or women with the possibility of being
pregnant; other reasons for ineligibility, as determined by
the investigator.
Study design and treatment
The COTO study was, in effect, comprised of two studies
done concurrently to investigate the effects of switching
from candesartan to olmesartan, and from telmisartan to
olmesartan (Figure 1).
Study 1
CO group
Candesartan
8 mg
Candesartan
8 mg
Telmisartan
40 mg
Telmisartan
40 mg
Study 2
TO group
16 weeks
Clinic-measured blood pressure and heart rate
Home-measured blood pressure and heart rate
Blood tests (glucose metabolism, lipid metabolism, etc)
Urinalysis (urinary albumin, etc)
16 weeks 32 weeks Baseline
Olmesartan
20 mg
Olmesartan
20 mg
Figure 1 Study design.
Abbreviations: CO, candesartanolmesartan; TO, telmisartanolmesartan.
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Difference in the effects between ARBs
In study 1, hypertensive patients with type 2 diabetes
were treated with 8 mg of candesartan once daily in the
morning for 16 weeks; these individuals were part of the
CO group. Candesartan was switched to olmesartan, which
was administered at 20 mg once daily in the morning for
16 weeks. Olmesartan was then switched back to candesar-
tan, which was administered at 8 mg once daily for another
16 weeks.
In study 2, hypertensive patients with type 2 diabetes
were treated with 40 mg of telmisartan once daily in the
morning for 16 weeks; these individuals were part of the
TO group. Telmisartan was switched to olmesartan, which
was administered at 20 mg once daily in the morning for
16 weeks. Then, olmesartan was switched back to telmisar-
tan, which was administered at 40 mg once daily for another
16 weeks.
The hypotensive effect of ARBs is inuenced by the sea-
son when therapy is instituted, so the subjects were enrolled
in this study evenly across the four seasons to avoid any
seasonal bias on treatment effects.
The primary measure in this study was morning home BP.
The secondary measures were clinic BP, glucose metabolism
parameters, and urinary albumin.
In both groups, BP and heart rate were measured in the
outpatient clinic and at home at baseline, 16 weeks, and
32 weeks. Fasting blood glucose, hemoglobin A
1c
(HbA
1c
)
(US National Glycohemoglobin Standardization Program
[NGSP]), and urinary albumin levels were measured at
baseline, 16 weeks, and 32 weeks. During the treatment
period, the type and dosage of concomitant antihyper-
tensive drugs and antidiabetic treatments were not to be
changed.
BP was measured in the clinic multiple times at 1- or
2-minute intervals, with the patient resting in a seated
position. The mean value of two measurements that provide
a stable value (difference in the values ,5 mmHg) was
recorded. BP was also measured at home after waking in
the morning, using a pressure measurement device for the
upper arm. The patient was instructed to measure BP while
in the sitting position, with a 1- to 2-minute rest, after uri-
nation, but before the administration of hypotensive drugs,
as recommended by the JSH 2009.
1
Additional parameters
were determined using blood and urine samples. Changes in
BP and heart rate measured in the early morning at home,
urinary albumin, HbA
1c
(NGSP), and fasting blood glucose
between the start of therapy and after 16 weeks and 32 weeks
of therapy were dened as endpoints in this study. HbA
1c

was measured by column chromatography at our institute.
Urinary albumin levels were measured by a turbidimetric
immunoassay at Shikoku Chuken, Inc. (Takamatsu, Japan)
Values are expressed in all patients as means standard
deviation, except for the urinary albumin level values, which
are expressed as means standard error.
Unpaired t-tests and paired t-tests were used to determine
the signicance of the differences between the two groups
and within each group, respectively. The number of patients
who achieved their target BP was compared using the
2
-test.
The level of signicance was set at 5%. Intention-to-treat
analytical procedures were applied.
Results
Between January 2011 and January 2012, hypertensive
patients with type 2 diabetes were enrolled. After enroll-
ment, 165 patients received candesartan (CO group) and
152 patients received telmisartan (TO group) for 16 weeks.
The baseline characteristics of these two groups are listed
in Table 1. The baseline values are measurements that are
performed before treatment with olmesartan, but after the
patients had received candesartan or telmisartan. Both groups
were comparable with respect to their patients baseline
characteristics.
Data from all patients in the CO group and TO group were
analyzed. Changes in the clinic BP, morning home BP, as well
as parameters of glucose metabolism and urinary albumin
obtained during the study are shown in Tables 2 and 3.
In study 1 (Table 2), in the CO groups clinic BP showed
a signicant decrease after 16 weeks of treatment with olm-
esartan in comparison with the baseline clinic BP measured
at the end of the initial candesartan treatment during the
16-week run-in period. After switching back to the cande-
sartan treatment for another 16 weeks, the patients clinic
BP was signicantly elevated again. Morning home BP
was also signicantly decreased by 16 weeks of treatment
with olmesartan in comparison with the baseline morning
home BP at the end of the run-in period. At 16 weeks after
switching back to candesartan treatment, the morning home
BP was also signicantly elevated again.
Glucose metabolism was assessed from the fasting
blood glucose and HbA
1c
values. There were no signicant
changes at any of the times of assessment, including at the
time of switching to olmesartan, after 16 weeks of olmesartan
treatment, and after switching back to candesartan for another
16 weeks (week 32).
In study 2 (Table 3), in the TO group, the clinic BP
was signicantly decreased as a result of treatment with
olmesartan for 16 weeks when compared with the baseline
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Daikuhara et al
clinic BP measured at the end of the initial telmisartan
treatment time during the 16-week run-in period. After
switching back to telmisartan for another 16 weeks
(week 32), the clinic BP was signicantly elevated again.
Morning home BP was also signicantly decreased after
16 weeks of treatment with olmesartan in comparison with
the baseline morning home BP at the end of the run-in
period. After switching back to telmisartan treatment for
another 16 weeks, the morning home BP was also signi-
cantly elevated again.
Glucose metabolism (fasting blood glucose and HbA
1c
)
showed no signicant changes at any of the times of assess-
ment, including at the time of switching to olmesartan, after
16 weeks of olmesartan treatment, and after switching back
to telmisartan for 16 weeks (week 32).
Therefore, treatment with olmesartan achieved similar
outcomes in both the CO group and the TO group in terms of
clinic BP, morning home BP, and the parameters of glucose
metabolism.
In the CO group, treatment with olmesartan resulted in
a decrease in the urinary albumin level by 20.66.1 mg/g
Cr from baseline, whereas it increased by 15.45.6 mg/g
Cr after switching back to treatment with candesartan
for another 16 weeks. There was a signicant difference
between olmesartan and candesartan with regard to the
change in urinary albumin excretion (P,0.001). In the TO
group, treatment with olmesartan resulted in a decrease
in urinary albumin by 18.25.5 mg/g Cr from baseline,
whereas it increased by 13.45.3 mg/g Cr after switching
back to treatment with telmisartan for another 16 weeks.
There was a signicant difference between olmesartan and
telmisartan in terms of the change in urinary albumin excre-
tion (P,0.001).
In the CO group, the achievement rate for the target clinic
BP (,130/80 mmHg) was 63.6% at week 0 after the initial
candesartan treatment (during the run-in period), and 64.8%
at week 32 (upon completion of another 16-week treatment
period) with candesartan after switching back from olmesar-
tan, whereas this level showed a signicant increase to 74.5%
at week 16 of olmesartan treatment. In the TO group, the
achievement rate for the target clinic BP was 65.1% at week 0
after the initial telmisartan treatment during the run-in period,
and 65.8% at week 32 upon completion of another 16-week
treatment period with telmisartan after switching back from
olmesartan; conversely, there was a signicant increase to
77.0% at week 16 of olmesartan treatment.
Figure 2 shows the achievement rates for the target
morning home BP (,125/75 mmHg). Regarding the home
BP, the target achievement rate of the home BP in the CO
group was 44.2% at week 0 after the initial candesartan
treatment during the run-in period, and 45.5% at week 32
upon completion of another 16-week period of candesartan
treatment. There was a signicant increase in the rate to
60.6% at week 16 of olmesartan treatment. In the TO group,
the achievement rate for the target home BP was 46.1% at
week 0 after the initial telmisartan treatment during the
run-in period, and 47.4% at week 32 upon completion of
another 16-week period of telmisartan treatment; conversely,
it increased signicantly to 61.2% at week 16 of olmesartan
treatment. Overall, the achievement rate for the target home
BP was lower than that for the clinic BP.
Table 1 Patient characteristics
a
Group CO
(n=165)
TO
(n=152)
ARB monotherapy/ARB + other
concomitant medicine (n)
44/121 35/117
Age (years) 61.510.3 62.010.8
Sex (n, male/female) 89/76 82/70
Body mass index (kg/m
2
) 24.04.4 24.24.6
Duration of diabetes mellitus (years) 9.64.6 9.14.8
Clinic-measured
SBP (mmHg) 126.910.7 126.011.0
DBP (mmHg) 78.28.2 77.88.3
Heart rate (beats/min) 72.99.8 71.69.9
Morning home-measured
SBP (mmHg) 125.910.7 125.110.9
DBP (mmHg) 77.18.0 76.37.9
Heart rate (beats/minute) 71.89.8 71.69.9
Serum Cr (mg/dL) 0.90.2 0.90.2
Blood urea nitrogen (mg/dL) 14.23.8 14.53.8
Uric acid (mg/dL) 6.01.6 5.91.6
Serum sodium (mEq/L) 141.03.9 141.13.8
Serum potassium (mEq/L) 4.30.4 4.30.4
Serum chloride (mEq/L) 104.64.2 104.84.1
Fasting blood glucose (mg/dL) 128.010.8 127.110.4
HbA
1c
(NGSP) (%) 7.50.8 7.50.8
LDL-C (mg/dL) 117.227.1 118.127.0
HDL-C (mg/dL) 61.112.9 61.312.7
Triglycerides (mg/dL) 146.142.0 147.345.0
Urinary albumin: Cr ratio (mg/g Cr), 189.15.9 177.25.7
eGFR (mL/minute/1.73 m
2
) 73.018.5 73.219.0
Concomitant antihypertensive drugs
Calcium channel blockers, n (%) 121 (73.3) 117 (77.0)
Diuretics, n (%) 0 (0) 0 (0)
-blockers, n (%) 0 (0) 0 (0)
Note:
a
Mean standard deviation, unless otherwise stated, except for the urinary
albumin: Cr ratio, which is expressed as the mean standard error.
Abbreviations: CO, candesartanolmesartan; n, number; TO, telmisartan
olmesartan; ARB, angiotensin II receptor blockers; SBP, systolic blood pressure;
DBP, diastolic blood pressure; Cr, creatinine; HbA
1c
, hemoglobin A
1c
; NGSP,
National Glycohemoglobin Standardization Program; LDL-C, low-density
lipoproteincholesterol; HDL-C, high-density lipoproteincholesterol; eGFR,
estimated glomerular fltration rate.
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Difference in the effects between ARBs
In both groups, none of the subjects experienced any
symptoms or adverse reactions that required withdrawal
during the study. Similarly, we noted no adverse reactions
caused by administration of the study drugs.
Discussion
This study compared three ARBs in terms of their ability
to achieve the target BP level recommended by JSH 2009
for patients with type 2 diabetes, because this antihyper-
tensive drug class is most widely used for the treatment of
hypertensive patients with type 2 diabetes. Briey, treatment
with olmesartan for 16 weeks after switching from cande-
sartan or telmisartan achieved a signicant reduction in the
clinic BP, morning home BP, and urinary albumin excretion
from baseline levels. In the present study of hypertensive
type 2 diabetics, the target achievement rates for both clinic
BP and morning home BP were signicantly higher after
the completion of 16 weeks of olmesartan therapy than after
the completion of 16 weeks of treatment with candesartan or
telmisartan. This result suggests that the hypotensive effect
Table 2 Change in parameters of the candesartan-olmesartan group
a
Baseline
(n=165)
16 weeks
(n=165)
32 weeks
(n=165)
P-value (baseline
versus 16 weeks)
P-value (16 weeks
versus 32 weeks)
Clinic-measured SBP (mmHg) 126.910.7 123.010.1 126.310.5 ,0.05 ,0.05
Clinic-measured DBP (mmHg) 78.28.2 76.47.9 77.97.9 ,0.05 ,0.05
Clinic-measured heart rate (beats/minute) 72.99.8 72.99.6 73.210.0 NS NS
Morning home-measured SBP (mmHg) 125.910.7 120.110.0 125.310.3 ,0.01 ,0.01
eGFR $60 (mL/minute/1.73 m
2
) (n=133) 125.810.6 120.09.8 125.210.1 ,0.01 ,0.01
eGFR ,60 (mL/minute/1.73 m
2
) (n=32) 126.310.2 120.69.4 125.79.7 ,0.01 ,0.01
Morning home-measured DBP (mmHg) 77.18.0 74.87.7 76.87.7 ,0.05 ,0.05
Morning home-measured heart rate (beats/minute) 71.89.8 70.810.0 71.910.0 NS NS
Body mass index (kg/m
2
) 24.04.4 24.04.4 24.04.4 NS NS
Fasting blood glucose (mg/dL) 128.010.8 126.510.9 128.210.4 NS NS
HbA
1c
(NGSP) (%) 7.50.8 7.40.8 7.50.9 NS NS
Serum creatinine (mg/dL) 0.90.2 0.90.2 0.90.2 NS NS
eGFR (mL/minute/1.73 m
2
) 73.018.5 73.719.0 73.219.2 NS NS
Urinary albumin:Cr ratio (mg/g Cr) 189.15.9 168.55.7 183.95.9 ,0.05 ,0.05
Change in urinary albumin:Cr ratio (mg/g Cr) -20.66.1
b
15.45.6
c
,0.001
Note:
a
Mean standard deviation for all values, except the urinary albumin:Cr ratio, which is expressed as mean standard error.
b
Value at 16 weeks value at baseline.
c
Value at 32 weeks value at 16 weeks.
Abbreviations: n, number; SBP, systolic blood pressure; DBP, diastolic blood pressure; NS, not signifcant; eGFR, estimated glomerular fltration rate; HbA
1c
, hemoglobin A
1c
;
NGSP, National Glycohemoglobin Standardization Program; Cr, creatinine.
Table 3 Change in parameters of the telmisartan-olmesartan group
a
Baseline
(n=152)
16 weeks
(n=152)
32 weeks
(n=152)
P-value (baseline
versus 16 weeks)
P-value (16 weeks
versus 32 weeks)
Clinic-measured SBP (mmHg) 126.011.0 122.49.8 125.510.5 ,0.05 ,0.05
Clinic-measured DBP (mmHg) 77.88.3 76.27.9 77.68.0 ,0.05 ,0.05
Clinic-measured heart rate (beats/minute) 71.69.9 71.19.8 72.310.2 NS NS
Morning home-measured SBP (mmHg) 125.110.9 119.810.3 124.810.4 ,0.01 ,0.01
eGFR $60 (mL/minute/1.73 m
2
) (n=125) 125.010.9 119.710.0 124.710.3 ,0.01 ,0.01
eGFR ,60 (mL/minute/1.73 m
2
) (n=27) 125.410.5 120.19.8 125.19.9 ,0.01 ,0.01
Morning home-measured DBP (mmHg) 76.37.9 74.27.5 76.17.6 ,0.05 ,0.05
Morning home-measured heart rate (beats/minute) 71.69.9 70.510.1 71.89.9 NS NS
Fasting blood glucose (mg/dL) 127.110.4 126.010.7 126.910.7 NS NS
Body mass index (kg/m
2
) 24.24.6 24.24.6 24.24.6 NS NS
HbA
1c
(NGSP) (%) 7.50.8 7.40.9 7.50.9 NS NS
Serum Cr (mg/dL) 0.90.2 0.90.2 0.90.2 NS NS
eGFR (mL/minute/1.73 m
2
) 73.219.0 73.819.1 73.518.9 NS NS
Urinary albumin:Cr ratio (mg/g Cr) 177.25.7 159.05.3 172.45.6 ,0.05 ,0.05
Change in urinary albumin:Cr ratio (mg/g Cr) -18.25.5
b
13.45.3
c
,0.001
Note:
a
Mean standard deviation for all values, except the urinary albumin:Cr ratio, which is expressed as mean standard error.
b
Value at 16 weeks value at baseline.
c
Value at 32 weeks value at 16 weeks.
Abbreviations: n, number; SBP, systolic blood pressure; DBP, diastolic blood pressure; NS, not signifcant; eGFR, estimated glomerular fltration rate; HbA
1c
, hemoglobin A
1c
;
NGSP, National Glycohemoglobin Standardization Program; Cr, creatinine.
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Daikuhara et al
of olmesartan is stronger and more sustained than that of the
other two ARBs.
Regarding the strength and durability of the antihyper-
tensive effect of olmesartan in patients with essential hyper-
tension, Brunner et al
5
conducted a double-blind controlled
study that compared olmesartan and candesartan on the
basis of ambulatory BP, whereas Sezai et al
9
assessed the
antihypertensive effect of olmesartan on early morning BP,
and Furukawa et al
10
investigated the efcacy of olmesartan
therapy on ambulatory BP monitoring. These studies have
revealed the superiority of olmesartan over candesartan
with regard to the strength and duration of its antihyper-
tensive effects. Nakayama et al
11
compared olmesartan
and telmisartan in type 2 diabetics with hypertension and
reported that olmesartan achieved superior control of the
24-hour BP and nocturnal BP on the basis of ambulatory
BP monitoring; it also had a stronger inammatory effect
than telmisartan. It has also been reported that switching
from telmisartan to olmesartan resulted in a further reduc-
tion in BP and a decrease in urinary cystatin C, a marker
of renal function.
12
When olmesartan was administered
to hypertensive patients with chronic kidney disease, the
circadian rhythm of BP was altered from a nondipper pat-
tern to a dipper pattern by its natriuretic activity;
13
this
effect has not been reported for other ARBs. Similarly,
olmesartan has been found to improve circadian rhythm of
BP in patients with essential hypertension and diabetics.
14

In the Japan Morning SurgeTarget Organ Protection
(J-TOP) study of candesartan,
15
microalbuminuria was
more effectively decreased by bedtime dosing compared
with morning dosing. In that study, the dosage of cande-
sartan was increased on the basis of home BP, so there were
no signicant between-group differences in morning BP,
evening BP, or bedtime BP. However, there was a difference
in BP between the morning and evening, which suggests that
morning dosing and bedtime dosing of candesartan have
different effects on urinary albumin excretion. Also, the
intensied inhibitory effect on urinary albumin excretion
was suggested to be independent of the circadian variation
in BP. Nevertheless, in the recent study
16
of olmesartan that
similarly compared evening dosing with morning dosing,
olmesartan was suggested to show a well-sustained antihy-
pertensive effect independent of dosing time when given
once daily. That is, olmesartan signicantly reduced the
urinary albumin:Cr ratio when given in the morning or in
the evening, but there was no signicant difference in the
reduction of this ratio between the morning and evening
dosing groups. The inhibitory effect of olmesartan on
albuminuria was not affected by the dosing time, because
olmesartan exhibits a strong antihypertensive effect that is
sustained for 24 hours, irrespective of whether the drug is
administered in the morning or in the evening.
100
90
80
70
60
50
40
30
20
10
0
100
A B
90
P<0.01 P<0.01 P<0.01 P<0.01
80
70
60
50
40
30
20
10
A
c
h
i
e
v
e
m
e
n
t

r
a
t
e

f
o
r

t
a
r
g
e
t

B
P

(
%
)
A
c
h
i
e
v
e
m
e
n
t

r
a
t
e

f
o
r

t
a
r
g
e
t

B
P

(
%
)
0
Baseline
TE 40 mg
16 weeks
OL 20 mg
32 weeks
TE 40 mg
Baseline
CA 8 mg
16 weeks
OL 20 mg
32 weeks
CA 8 mg
Figure 2 Achievement rates for target home BP.
Notes: (A) Candesartanolmesartan group; (B) telmisartanolmesartan group.
Abbreviations: BP, blood pressure; CA, candesartan; OL, olmesartan; TE, telmisartan.
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Difference in the effects between ARBs
In the present study, the change in urinary albumin from
baseline showed a signicant difference between olmesartan
treatment and candesartan treatment or telmisartan treatment.
This difference in the change in urinary albumin excretion
is considered to reect the sustained antihypertensive effect
of olmesartan. Furthermore, we previously reported that
olmesartan plus azelnidipine was more effective at lowering
morning home BP and reducing urinary albumin than can-
desartan plus amlodipine in the combination of OLmesar tan
and a CAlcium channel blocker (OLCA) study.
17
We had
thought that the improvement in microalbuminuria seemed
to be partially attributed to the difference between calcium
channel blockers. However, we found in the present study
that reducing urinary albumin might be explained by the
difference between ARBs. Reducing urinary albumin may
be associated with lowering home morning BP. While it has
been reported that telmisartan activates PPAR and, thus,
can directly improve insulin sensitivity without involving
angiotensin II type 1 receptor signaling, olmesartan was
comparable to telmisartan in terms of its effect on the clinical
parameters of glucose metabolism in the present study. This
result also suggests that telmisartan does not have any action
on PPAR at the standard clinical dose used in the present
study, although such an action has been detected in non-
clinical studies using higher doses.
18
The recently published
2013 European Society of Hypertension/European Society
of Cardiology Guidelines state that the study ONTARGET
has disproved the hypothesis that the PPAR activity of
telmisartan may render this compound more effective in
preventing or delaying the onset of diabetes;
19
the incidence
of new diabetes was not signicantly different between the
telmisartan-alone and telmisartan-plus-ramipril groups in
ONTARGET.
20
Olmesartan was also similar to candesartan
in terms of its effect on glucose metabolism. Therefore, all
three ARBs were suggested to have a similar effect on HbA
1c
,
although some differences in the effect on glucose metabo-
lism may have been masked because of the strict glycemic
control maintained by the subjects in this study.
This was not a randomized study, so we could not directly
compare olmesartan with candesartan, or with telmisartan.
Nonetheless, this study is thought to be clinically useful,
because olmesartan and candesartan were assessed in the
same patient cohort by switching between the two drugs,
while olmesartan and telmisartan were similarly assessed, so
that intercohort variation was avoided. Therefore, the study
is important in view of the ndings that further highlight
that antihypertensive effects on morning home BP can be
expected by switching treatment to olmesartan from other
ARBs in hypertensive patients with type 2 diabetes.
Conclusion
In hypertensive patients with type 2 diabetes who had
already been treated with candesartan or telmisartan,
switching to olmesartan, which has the strongest BP-
lowering effect in the ARB class, led to a further reduc-
tion in BP and a decrease in urinary albumin excretion.
Therefore, olmesartan is suggested to be more effective
than other ARBs for morning BP control in type 2 diabetics
with hypertension.
Acknowledgments
Medical editorial assistance was provided by Nature Japan
K.K. (Macmillan Medical Communications, Tokyo, Japan)
and funded by Daiichi Sankyo Co, Ltd (Tokyo, Japan).
The sponsor had no control over the study design; the
collection, analysis, and interpretation of data; or the decision
to submit the paper for publication.
Disclosure
The authors report no conicts of interest in this work.
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