Open Journal of Endocrine and Metabolic Diseases, 2013, 3, 252-258 Published Online September 2013 (
Amelioration of Albuminuria in Japanese Type 2 Diabetic
Patients by Maximal Dose of Candesartan*
Yoichi Oikawa1,2, Akira Shimada1, Mizumi Kyo2
1Department of Internal Medicine, Tokyo Saiseikai Central Hospital, Tokyo, Japan
2Department of Internal Medicine, Eiju General Hospital, Tokyo, Japan
Received August 12, 2013; revised August 31, 2013; accepted September 10, 2013
Copyright © 2013 Yoichi Oikawa et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Introduction: It was recently reported that candesartan, an angiotensin II receptor blocker, had a protective effect
against cardiovascular events, comparable to that of calcium channel antagonists. Moreover, a renoprotective effect and
anti-diabetic action of candesartan had also been demonstrated. However, whether the renoprotective effect of cande-
sartan, especially in diabetes, was dose-dependent or not remain to be fully elucidated. The present study attempted to
clarify the dose effect of renoprotection by candesartan in Japanese type 2 diabetic patients. Subjects and Method: In
this case series study, we recruited 26 type 2 diabetic patients with albuminuria whose blood pressure did not reach the
target BP level (<130/80 mmHg) despite administration of 4 or 8 mg/day of candesartan. Subsequently, these lower
doses of candesartan were increased to the maximal dose in Japan, 12 mg/day. Clinical parameters were examined be-
fore, at 6 and 12 months after the increase in dose. Results: An ameliorating effect of the increased dose of candesartan
on albuminuria and hypertension was distinctly observed. No severe adverse effect was observed. Conclusion: It was
highly possible that the maximal dose of candesartan provided more effective renoprotection in hypertensive type 2 dia-
betic patients initially treated with lower doses of candesartan.
Keywords: Albuminuria; Angiotensin II Receptor Blocker (ARB); Candesartan; Hypertension; Type 2 Diabetes
1. Introduction
Diabetes is a chronic disease that occurs either when the
pancreas does not produce enough insulin or when the
body cannot effectively use the insulin it produces. Dia-
betes without proper treatment can cause many complica-
tions, such as diabetic retinopathy, nephropathy and neu-
ropathy. Diabetes, as well as hypertension, dyslipidemia
and obesity, is believed to be a strong risk factor for
cardiovascular disease [1]. Especially, the existence of
albuminuria, a characteristic of diabetic early nephro-
pathy, is considered to be an important risk factor for
increased cardiovascular events in diabetic patients [2].
Recently, the number of new cases of dialysis due to
diabetic nephropathy has been increasing in a linear fa-
shion in Japan [3], implying that prevention of the de-
velopment of diabetic nephropathy is absolutely impera-
tive. It is generally considered that the prevention of dia-
betic nephropathy requires strict blood pressure (BP)
control as well as good control of the blood glucose level
and an appropriate protein-restricted diet. At present, the
Japanese Society of Hypertension Guidelines for the Ma-
nagement of Hypertension (JSH 2009) recommend that
the target systolic and diastolic BP in diabetic patients
are set at <130 mmHg and <80 mmHg, respectively [4],
and <125 mmHg and <75 mmHg in patients with more
than 1 g/day of proteinuria, respectively. However, the
rate of achievement of the target BP seems to be low and
is not be satisfactory in clinical settings.
The renin-angiotensin system (RAS) plays a critical
role in the pathogenesis of chronic kidney disease (CKD)
as well as hypertension and cardiovascular events [5],
and inhibition of RAS by angiotensin II receptor blockers
(ARB) is known to confer a protective action not only on
renal function, but also on cardiovascular organs in dia-
betic [6] as well as non-diabetic [7] hypertensive patients
with CKD. On the other hand, it is unknown whether the
renoprotective effect of ARBs, especially in diabetics, is
dose-dependent or not. Regarding this point, the incipient
to overt, angiotensin II blocker, telmisartan, investiga-
tion on type 2 diabetic nephropathy (INNOVATION)
*Disclosure Statement: The Authors declare that there is no conflict
of interest.
opyright © 2013 SciRes. OJEMD
study demonstrated a higher remission rate of microal-
buminuria in Japanese type 2 diabetic patients with al-
buminuria administered telmisartan as compared to pla-
cebo [8]. However, when the telmisartan-treated subjects
were divided into high-dose and low-dose groups, no
significant difference in the remission rate of microalbu-
minuria was observed between the two.
The Candesartan Antihypertensive Survival Evalua-
tion in Japan (CASE-J) trial recently revealed a protect-
tive effect of candesartan against cardiovascular events
comparable to that of amlodipine and an anti-diabetic
effect [9]. In addition, sub-analysis of the CASE-J trial
also showed a renoprotective effect of candesartan in
hypertensive patients with CKD [10]. However, the dose
effect of renoprotection by candesartan in diabetics re-
mains to be elucidated. To investigate whether the reno-
protective effect of candesartan in diabetes is dose-de-
pendent or not, we increased the prescribed amount of
candesartan from lower doses to the maximal dose in
Japanese type 2 diabetic patients with hypertension and
albuminuria, and evaluated the time course of a variety
of clinical parameters including urine albumin excretion
(UAE) level.
2. Subjects and Method
2.1. Study Design
This study was an uncontrolled longitudinal observa-
tional study; i.e. a case series study.
Fifty-six Japanese type 2 diabetic patients with hyper-
tension, whose BP did not reach the target systolic/dia-
stolic BP (<130/80 mmHg) despite administration of 4 or
8 mg/day of candesartan for more than 6 months, were
recruited at Eiju General Hospital. Of these patients, 26
were shown to have albuminuria without overt proteinu-
ria, and their baseline UAE level in a single spot-urine
collection ranged from 31.2 to 620.0 mg/gCr (creatinine).
After the need for an increase in dose to reach the target
BP level was approved by the 26 patients, the dose of
candesartan (4 mg/day or 8 mg/day) was increased to the
maximal dose in Japan, i.e. 12mg/day. Venous blood
samples were obtained from the patients regardless of
fasting or non-fasting state and a variety of clinical pa-
rameters were investigated before, at 6 months and 12
months after the increase in dose. Exclusion criteria were
as follows; type 1 diabetes, patients with stage I (UAE
level <30 mg/gCr), IIIb (urine protein level 1 g/day or
estimated glomerular filtration rate (eGFR) <60 mL/
min/1.73 m2), IV (increased serum creatinine level above
normal range) or V (receiving dialysis) diabetic neph-
ropathy, serum potassium level >5.5 mEq/L, unconsent-
ing patients, overt bacteriuria, severe autonomic neu-
ropathy including orthostatic hypotension, seated systolic
BP/diastolic BP 180/100 mmHg, severe liver dysfunc-
tion and definable chronic kidney disease other than dia-
betic nephropathy.
Hemoglobin A1c (HbA1c) was expressed as a NGSP
(National Glycohemoglobin Standardization Program)
equivalent value in this study; i.e., HbA1c (NGSP equi-
valent value) (%) = HbA1c (Japan Diabetes Society
value) (%) + 0.4%.
2.2. Statistical Analysis
Data are expressed as mean S.D. Continuous variables
were compared using paired t-test. A P value less than
0.05 was considered to be statistically significant.
3. Results
3.1. Patients’ Baseline Characteristics
The mean age of the 26 patients (21 male, 5 female) with
albuminuria was 60.3 years, their mean BMI was 25.9
kg/m2 and their mean systolic/diastolic BP was 145.3/
85.6 mmHg at enrollment (Table 1). Of the 26 patients,
4 mg/day and 8 mg/day of candesartan had been initially
prescribed to 15 patients and 11 patients, respectively. Ca
channel antagonists were administered in 57.7% (15/26)
of the patients, whereas one patient was treated with an
-blocker and no patient was treated with a
-blocker or
diuretic. Approximately 70% (18/26) of patients were
treated with a sulfonylurea, 46.2% (12/26) with an
glucosidase inhibitor, 38.5% (10/26) with a biguanide,
and 26.9% (7/26) with a thiazolidine against type 2 dia-
betes. Insulin treatment was given in 15.4% (4/26) of
patients. During this study, the dose of sulfonylurea was
increased in one patient, and the dose of thiazolidine was
increased in another one. However, there was no change
in the formulation of any drugs other than candesartan or
that of insulin therapy during the observation period.
3.2. UAE Level Was Improved by Increase in
Candesartan to Maximal Dose
UAE level was investigated before (at baseline), at 6
months and 12 months after an increase in dose of can-
desartan from 4 or 8 mg/day to 12 mg/day. As shown in
Table 1 and Figure 1, UAE level slightly decreased be-
tween baseline and 6 months, but there was no signifi-
cant difference in UAE level between the two time points.
Ultimately, UAE level was significantly decreased at 12
months as compared to baseline and 6 months.
3.3. BP Was Significantly Decreased by Increase
in Candesartan to Maximal Dose
The increase in dose of candesartan to 12 mg/day re-
sulted in significant decreases in systolic and diastolic
BP both at 6 and 12 months as compared to the baseline
systolic and diastolic BP, though there was no significant
Copyright © 2013 SciRes. OJEMD
Copyright © 2013 SciRes. OJEMD
Table 1. Patients’ clinical characteristics.
Baseline (0 M) 6 months (6 M) 12 months (12 M)
Number 26 - -
Sex (male/female) 21/5 - -
Age (years) 60.3 ± 11.5 - -
Duration of diabetes (years) 8.9 ± 3.9 - -
Initial dose of candesartan before increase to 12 mg/day (4 mg/8 mg) 15/11 - -
Current smoking (yes/no)
Ca antagonist (yes/no) 15/11 - -
-blocker (yes/no) 1/25 - -
Sulfonylurea (yes/no) 18/8 - -
Glinide (yes/no) 1/25 - -
Biguanide (yes/no) 10/16 - -
Thiazolidine (yes/no) 7/19 - -
-glucosidase inhibitor (yes/no) 12/14 - -
Insulin therapy (yes/no) 4/22 - -
Statin (yes/no) 7/19 - -
Fibrate (yes/no) 3/23 - -
Clinical parameters
Body mass index (kg/m2) 25.9 ± 4.4 25.7 ± 4.3 25.8 ± 4.3
Systolic BP (mmHg) 145.3 ± 8.7 134.4 ± 12.3* 137.3 ± 9.5*
Diastolic BP (mmHg) 85.6 ± 7.9 78.4 ± 8.3* 80.0 ± 6.6*
Serum Cr (mg/dl) 0.86 ± 0.29 0.83 ± 0.27 0.88 ± 0.27##
HbA1c (NGSP) (%) 7.52 ± 0.96 7.51 ± 0.97 7.36 ± 0.96
Serum potassium (mEq/L) 4.24 ± 0.41 4.37 ± 0.32** 4.34 ± 0.40
Total cholesterol (mg/dL) 197.9 ± 33.7 196.5 ± 39.5 193.7 ± 33.8
HDL-C (mg/dL) 56.8 ± 14.5 55.3 ± 15.0 55.0 ± 14.5
Triglyceride (mg/dL) 168.5 ± 90.8 164.5 ± 98.2 146.8 ± 74.3
Non-HDL-C (mg/dL) 141.1 ± 37.1 141.2 ± 40.4 138.6 ± 34.2
UAE (mg/gCr) 147.8 ± 155.0 124.5 ± 155.3 91.9 ± 100.3*#
*; P < 0.01 vs. 0M by paired t-test, **; P < 0.05 vs. 0M by paired t-test, #; P < 0.05 vs. 6M by paired t-test, ##: P < 0.01 vs. 6M by paired t-test. BP: blood pres-
sure, Ca: calcium, Cr: creatinine, HDL-C: high-density lipoprotein-cholesterol, NGSP: National Glycohemoglobin Standardization Program, UAE: urine albu-
min excretion.
difference in both systolic and diastolic BP between 6
and 12 months (Table 1 and Figures 2(a) and (b)).
3.4. Maximal Dose of Candesartan Did Not
Affect HbA1c Level
The CASE-J trial revealed that candesartan has the capa-
bility to protect against new onset of type 2 diabetes [9],
suggesting an anti-diabetic effect of candesartan. To
clarify the effect of candesartan on glucose tolerance, we
investigated the time course of HbA1c level. As shown
in Ta ble 1 and Figure 3, HbA1c level tended to decrease
with time, although there was no significant difference in
0 6 12
UAE (mg/gCr)
Months after increase in candesartan dose
Figure 1. Time course of UAE level by 12 mg/day of can-
desartan. Changes in UAE level of the patients are shown
(n = 26). *; P < 0.01 and **; P < 0.05 by paired t-test. Re-
sults are mean S.D. UAE: urine alb umin excre tion.
0 6 12
Months after increase in candesartan dose
Systolic BP (mmHg)
0 6 12
Months after increase in candesartan dose
Diastolic BP (mmHg)
Figure 2. Time course of blood pressure by 12 mg/day of
candesartan. (a, b) Changes in systolic (a) and diastolic (b)
blood pressure of the patients are shown (n = 26). *; P <
0.05 by paired t-test. Results are mean S.D. BP: blood
0 6 12
Months after increase in candesartan dose
HbA1c (%)
Figure 3. Time course of HbA1c level by 12 mg/day of can-
desartan. Changes in HbA1c level of the patients are shown
(n = 26). No significant difference in HbA1c level among
each time point was observed. Results are mean ± S.D.
HbA1c level among each time point. Similarly, body
mass index and lipid profile were not affected by the in-
crease in dose of candesartan (Table 1).
3.5. Adverse Effects of Maximal Dose of
With regard to adverse effects of the increase in dose of
candesartan, we measured serum Cr level and serum po-
tassium level. As a result, serum Cr level was increased
from 6 to 12 months, although its change seemed to be
clinically negligible (Table 1 and Figure 4(a)). On the
other hand, serum potassium level was slightly increased
at 6 months, and thereafter was restored to near the base-
line level at 12 months (Table 1 and Figure 4(b)). No
other adverse effect attributable to the increase in dose of
candesartan was observed.
4. Discussion
The present study demonstrated an ameliorating effect of
an increase in dose of candesartan from 4 or 8 mg/day to
12 mg/day on UAE level, suggesting that the maximal
dose of candesartan probably provides more effective
renoprotection in Japanese type 2 diabetic patients with
hypertension initially treated with lower doses of cande-
Growing evidence has suggested that RAS inhibitors
have protective effects against the development of pro-
teinuria and the loss of renal function, the mechanisms
for which are believed to be partially independent of the
BP-lowering effect [11]. In the present study, the maxi-
mal dose of candesartan provided a significant improve-
ment in both BP and UAE level at 12 months, indicating
a close correlation between BP lowering and renoprotec-
tion (Figures 1, 2(a) and (b)). On the other hand, con-
sidering that UAE level significantly decreased between
Copyright © 2013 SciRes. OJEMD
Serum Cr (mg/dl)
0 6 12
Months after increase in candesartan dose
Serum potassium (mEq/l)
0 6 12
Months after increase in candesartan dose
Figure 4. Time courses of serum Cr and potassium levels by
12 mg/day of candesartan. (a, b) Changes in serum Cr level
(a) and serum potassium level (b) of the patients are shown
(n = 26). *; P < 0.01 and **; P < 0.05 by paired t-test. Re-
sults are mean S.D. Cr: cre a tinine.
6 and 12 months despite a slight increase in mean BP
over the same period, the renoprotective action of can-
desartan may be partially provided by a class effect of
ARBs beyond their BP-lowering effect. The INNOVA-
TION study demonstrated a significant reduction in al-
buminuria in type 2 diabetes by both high and low doses
of telmisartan [8]. Although the renoprotective effect of a
high dose of telmisartan tended to be superior to that of a
low dose of telmisartan, no significant difference in the
effect was actually observed between the two doses;
these findings seem to conflict with our findings. Intri-
guingly, the degree of BP lowering in the high-dose
telmisartan group was comparable to that in the low-dose
group in the INNOVATION study at the final observa-
tion, whereas in our study, a significant decrease in BP
by an increase in the dose of candesartan was observed at
the final observation. Therefore, the difference in BP-
lowering effect of the two ARBs might have contributed
to the discrepancy in dose effect of the two ARBs on re-
noprotection between their and our reports, although fur-
ther investigation is required.
As for the association between the dose of candesartan
and renoprotection, Rossing et al. previously demon-
strated that the renoprotective effect of candesartan was
exerted in dose-dependent manner in type 2 diabetic pa-
tients with nephropathy [12]. In their study, the patients
were randomly assigned to receive candesartan at a dose
of 8, 16 or 32 mg/day. However, the doses of 16 mg/day
and 32 mg/day are beyond the recommended dose range
of candesartan applied in Japan. Moreover, the treatment
using each dose of candesartan was provided for only 2
months; i.e. a long-term renoprotective effect of cande-
sartan remained to be elucidated. Therefore, it would
appear that their findings can not be applied to the clini-
cal situation in Japan.
Microalbuminuria is considered to be a risk factor for
cardiovascular disease [2], and the amelioration of UAE
level by intervention with ARBs was reported to contrib-
ute to the risk reduction of future cardiovascular events
in clinical studies. For example, the Reduction in End-
points in Non-insulin dependent diabetes mellitus with
the angiotensin II Antagonist Losartan (RENAAL) study
showed that a decrease in albuminuria by losartan led to
a significant reduction in cardiovascular and heart failure
risks [13]. Similarly, the Losartan Intervention For End-
point reduction in hypertension (LIFE) study demon-
strated that albuminuria is a powerful predictor for sub-
sequent cardiovascular events, and a reduction in albu-
minuria during hypertension treatment can translate to a
reduction in cardiovascular events [14]. These findings
suggest that the reduction in albuminuria by using ARBs
contributes to the suppression of cardiovascular events.
Therefore, the maximal dose of candesartan also has the
potential to exert a greater protective effect against car-
diovascular events than lower doses, although the details
remain to be elucidated.
The CASE-J trial revealed that both candesartan and
amlodipine equally suppressed the incidence of cardio-
vascular events [9]. However, the protective effect of
candesartan against cardiovascular events seemed to be
strengthened “later” in the study period as compared to
that of amlodipine, which exerted an effect “earlier” in
the study period, suggesting that it may take some time
for candesartan to exert beneficial effects. In fact, the
present study also revealed that amelioration of UAE
level was observed at 12 months, i.e. “later” in the ob-
servation period (Figure 1). Thereby, to exert the reno-
protective effect of candesartan most effectively, it may
be worth trying to prescribe the maximal dose of cande-
sartan to hypertensive type 2 diabetic patients at least in
the early stage of diabetic nephropathy.
Anti-diabetic effects of ARBs have been demonstrated
in the CASE-J trial [9] and several other clinical studies
Copyright © 2013 SciRes. OJEMD
using losartan [15], irbesartan [16] and valsartan [17],
thus far. In general, angiotensin II, a potent vasocon-
strictor, has the capability to impair insulin action and
induce glucose intolerance [18,19]. Therefore, inhibition
of angiotensin II action is currently believed to contribute
to an improvement in insulin sensitivity or
-cell respon-
siveness to glucose. Although the present study failed to
reveal a lowering effect on HbA1c level of the maximal
dose of candesartan, the mean HbA1c level tended to
slightly decrease between baseline and 12 months (Fig-
ure 3). It would appear that the obscure anti-diabetic
effect may be attributable to the small sample size; a lar-
ger scale study would thereby help to demonstrate the
beneficial effect of candesartan on glucose tolerance.
Limitations of our data include not only the small
sample size and gender imbalance, but also the observa-
tional nature of the case series study; i.e. a control group
continuing initial lower doses of candesartan was not set
for comparison. In addition, albuminuria was character-
ized by determination of UAE level in a single spot-urine
collection at baseline and each time point of follow-up;
however, a previous study demonstrated a close correla-
tion between spot-urine UAE level and measurements of
albuminuria from overnight or 24-hour urine collection
[20]. Considering the variability in determination of UAE
level, only one measurement at each time point would
weaken the relationship between UAE level and outcome
measures. To solve this problem, a larger number sample
size would be required.
It should be noted that our patients had been initially
treated with lower doses (4 or 8 mg/day) of candesartan
without any adverse effects before the increase in dose,
possibly contributing to the minimal change in serum Cr
level and serum potassium level without any severe ad-
verse effects in the present study. Thus, we would like to
emphasize that the maximal dose of candesartan should
be prescribed to diabetic patients after evaluating the to-
lerability of candesartan beforehand by using lower doses
of candesartan.
5. Conclusion
In conclusion, an increase in amount of candesartan from
a lower dose to the maximal dose exerted an ameliorating
effect on albuminuria as well as BP in hypertensive type
2 diabetic patients in the early stage of diabetic neph-
ropathy. Using the maximal dose of candesartan at the
earliest possible time may help to prevent not only loss
of renal function, but also future cardiovascular events in
hypertensive type 2 diabetic patients at high cardiovas-
cular risk.
6. Acknowledgements
This research received no specific grant from any fund-
ing agency in the public, commercial, or not-for-profit
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