diabetes research and clinical practice 79 (2008) 8690

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A renoprotective effect of low dose losartan in patients

with type 2 diabetes

Hideaki Sawaki *, Jungo Terasaki, Atsushi Fujita , Seiko Nakagawa,

Norio Kanatsuna, Katsuhiko Sadahiro, Haruhiko Isotani,
Akihisa Imagawa, Toshiaki Hanafusa
First Department of Internal Medicine, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan

article info abstract

Article history: It has been reported that angiotensin II receptor blocker (ARB) improves proteinuria in
Received 24 July 2007 diabetic patients. However, whether this is a direct effect of ARB or through lowering blood
Accepted 14 August 2007 pressure is still controversial. The aim of this study is to determine the direct effect of ARB
Published on line 24 September 2007 on diabetic nephropathy. Thirty-four type 2 diabetic patients with early kidney damage were
divided into two groups: losartan group (n = 17) and control group (n = 17). In losartan group,
Keywords: low dose (25 mg) of losartan was administered once daily for a year. Blood pressure at home,
Blood pressure at home blood pressure at office and urinary albumin/creatinine ratio (UACR) were measured before
Low dose ARB and during the treatment. After a 1-year observation, the increment of UACR was signifi-
Losartan cantly smaller in losartan group than that in control group [ 23.8  13.7 mg/g Cr vs.
Renoprotective effect 15.9  13.2 mg/g Cr, mean  S.E.M., P = 0.0114]. Mean blood pressure levels did not change
before and during the observation period both in losartan group and control group, though
only systolic blood pressure at home decreased slightly but significantly. There were no
significant differences in the levels of HbA1c, fasting plasma glucose, total cholesterol,
triglyceride and body mass index between the two groups. The observed decrease in UACR
in the losartan-treated group might be attributed to a direct renoprotective action in
addition to a subtle decrease in systolic blood pressure at home.
# 2007 Elsevier Ireland Ltd. All rights reserved.

1. Introduction diabetes. However, the subjects of these studies suffered from

Diabetic nephropathy is the leading cause of end-stage renal
disease (ESRD) in patients starting renal replacement therapy
[1] and is associated with increased cardiovascular mortality
[2]. Accumulating evidences suggest that the risk for devel-
oping diabetic nephropathy [36] and cardiovascular disease
[7,8] starts when urinary albumin excretion rate are still within
the normoalbuminuric range. Both the RENAAL study [9] and
the Irbesartan Diabetic Nephropathy Trial [10] have confirmed
the renoprotective effects of ARB in patients with type 2
established nephropathy with continuous proteinuria at
baseline, and the direct renoprotective effect of ARB to the
patients without established nephropathy remains to be
clarified.
On the other hand, it is necessary to accurately evaluate the
blood pressure of the patients taking antihypertensive drugs
to prevent the development of diabetic vascular complications
and to avoid side effects such as hypotension. Recently a
discrepancy between screening blood pressure and ambula-
tory blood pressure has been noted [11]. Self-measurement of

* Corresponding author. Tel.: +81 72 683 1221; fax: +81 72 683 1801.
E-mail address: h-sawaki@poh.osaka-med.ac.jp (H. Sawaki).

Deceased on 13 November 2003.
0168-8227/$ see front matter # 2007 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.diabres.2007.08.004
 diabetes research and clinical practice 79 (2008) 8690 87

blood pressure at home (HBP), a technique that makes it

Fig. 1 Flow of patients through the study.
possible to obtain multiple measurements under well-con-
trolled conditions, is more reliable than measurement of blood
pressure at office (OBP), since it avoids observer bias and
eliminates the white-coat effect that could lead to over-
treatment of hypertension. It has also been shown that HBP
measurement is the best method for evaluating the blood
pressure lowering effect of antihypertensive agents in clinical
trials [12] and for detecting morning hypertension which
relates to diabetic microvasucular and macrovascular compli-
cations [13]. The current gold standard for evaluating blood
pressure is ambulatory blood pressure monitoring (ABPM) over
24 h. However, ABPM is expensive and requires considerable
investment in hardware, software and training of operators [14],
and therefore difficult to offer to patients with type 2 diabetes in
the clinic. Compared with ABPM, HBP measurement is less
expensive, less cumbersome and has the potential of improving
the patients compliance to treatment [15].
To clarify the hypothesis that ARB has a direct renopro-
tective effect even in the early stage of diabetic nephropathy,

Table 1 Baseline characteristics and measures of patients with type 2 diabetes

Characteristics and measures Control Losartan P

n 15 14
Age (years) 54  9 54  7 NS
Gender (men/women) 8/7 6/8 NS
BMI (kg/m2) 24.5  3.9 24.3  2.8 NS
Duration of diabetes (years) 77 76 NS
Serum creatinine (mg/dl) 0.6  0.1 0.6  0.2 NS
Total cholesterol (mg/dl) 203  29 199  24 NS
HDL cholesterol (mg/dl) 57  13 57  12 NS
Triglyceride (mg/dl) 117  47 121  48 NS
HbA1c (%) 6.9  0.6 6.9  0.7 NS
Uric acid (mg/dl) 5.0  1.0 4.3  1.1 NS
Estimated GFR 133.5  7.5 136.5  7.7 NS
Albumin excretion (mg/g Cr) 19.3  31.2 61.7  79.9 NS
Normoalbuminuria/microalbuminuria 12/3 8/6 NS

Blood pressure at office by mercury sphygmomanometer

Systolic blood pressure (mmHg) 128  15 130  11 NS
Diastolic blood pressure (mmHg) 77  9 79  7 NS
Mean blood pressure (mmHg) 94  10 96  8 NS

Blood pressure at office by automatic device

Systolic blood pressure (mmHg) 131  15 134  14 NS
Diastolic blood pressure (mmHg) 82  12 78  14 NS
Mean blood pressure (mmHg) 98  12 97  11 NS

Averaged blood pressure at home by automatic device

Systolic blood pressure (mmHg) 122  9 128  6 0.0243
Diastolic blood pressure (mmHg) 73  7 78  5 0.0321
Mean blood pressure (mmHg) 89  7 95  5 0.0305

Morning blood pressure at home by automatic device

Systolic blood pressure (mmHg) 121  12 130  5 0.0217
Diastolic blood pressure (mmHg) 75  8 80  6 0.0358
Mean blood pressure (mmHg) 90  9 97  5 0.0469

Bedtime blood pressure at home by automatic device

Systolic blood pressure (mmHg) 122  8 128  7 0.0399
Diastolic blood pressure (mmHg) 71  7 75  6 0.0421
Mean blood pressure (mmHg) 88  6 93  5 NS

Data are means  S.D. P values were calculated by x2-test for sex and normoalbuminuria/microalbuminuria and by MannWhitney U-test for
others.
88 diabetes research and clinical practice 79 (2008) 8690

we investigated the effect of low dose ARB for 1 year in patients
with type 2 diabetes with special attention to urinary albumin/
creatinine ratio (UACR) and HBP.
2. Research design and methods
We screened consecutive 50 patients with type 2 diabetes in
our outpatients clinic who fulfilled the following criteria: age
<65-year old, HbA1c <8%, serum creatinine <2 mg/dl, urinary
protein dipsticks ( ) to (+), and without the history of taking
antihypertensive or antiplatelet agents. After obtaining their
informed consent, we provided them with the devices (Omron
HEM762fussy, Omron, Tokyo, Japan) for HBP measurement.
HBP in the morning (morning HBP) and bedtime (bedtime HBP)
were followed for a month (Fig. 1). This device is an arm-cuff
device based on the cuff-oscillometric method that has been
validated officially. The HBP was measured at the left upper
arm. The HBP was monitored under the following conditions.
Morning HBP measurements were taken within 1 h after
waking, after micturition, in a sitting position after 12 min of
rest, before drug ingestion and before breakfast. Bedtime HBP
measurements were taken just before going to bed and in a
sitting position after 12 min of rest. HBP was measured at
least once in the morning and once in the evening. All HBP
measurements were documented without selection, together
with the date, time, and pulse rate. According to the Japanese
Society of Hypertension (JSH) guideline for HBP, normoten-
sion is defined as less than 125/80 mmHg and definite
normotension as less than 125/75 mmHg [16].
Next, we selected 34 patients according to the second
screening criteria of several measurements of systolic HBP
125 mmHg to reduce the influence of white coat effect.
Sixteen patients were ineligible: 10 normotension, 4 hyperten-
sion (stage 2 hypertension and over) [17], 2 rejection. The
remaining 34 patients were selected as the study subjects and
divided at random and continuously into two groups for the
open-label trial. Written informed consent was given from all
patients. Patients in the losartan group were administered
25 mg of losartan once daily for a year. We measured biological
parameters and calculated the estimated GFR at the baseline
and after 1-year observation. We calculated the GFR by using
the recommended equation by the National Kidney Founda-
tion: GFR (ml min 1 1.73 m 2) = 186  [serum creatinine (mg/
dl) 1.154  age (years) 0.203  (0.742 if female)]. This equa-
tion predicts GFR as measured by using an accepted method
(urinary clearance of 125I-iothalamate) [18].
2.1. Statistical analysis
Baseline characteristics between the groups were compared
using a MannWhitney U-test. The changes of 1-year observa-
tion (D) between the groups were calculated by (12 months
levelbaseline level), and compared using a MannWhitney

Table 2 The change in measures after 1-year observation

Measures Control Losartan P
2
DBMI (kg/m ) 0.3  0.7 0.4  1.0 NS
DSerum creatinine (mg/dl) 0.0  0.1 0.0  0.1 NS
DTotal cholesterol (mg/dl) 1  23 2  34 NS
DTriglyceride (mg/dl) 8  46 4  55 NS
DHbAlc (%) 0.2  0.5 0.3  0.7 NS
DUric acid (mg/dl) 0.1  0.7 0.1  0.6 NS
DEstimated GFR 0.6  21.8 2.0  13.1 NS
DAlbumin excretion (mg/g Cr) 15.9  45.8 23.8  56.6 0.0114

Blood pressure at office by mercury sphygmomanometer

DSystolic blood pressure (mmHg) 0.3  13.5 2.1  16.1 NS
DDiastolic blood pressure (mmHg) 2.7  11.0 3.2  10.0 NS
DMean blood pressure (mmHg) 2.2  2.7 2.9  2.8 NS

Blood pressure at office by automatic device

DSystolic blood pressure (mmHg) 1.7  12.2 3.4  17.4 NS
DDiastolic blood pressure (mmHg) 1.1  9.9 4.6  16.2 NS
DMean blood pressure (mmHg) 1.7  3.4 4.2  3.5 NS

Averaged blood pressure at home by automatic device

DSystolic blood pressure (mmHg) 3.3  7.8 2.7  7.2 0.0229
DDiastolic blood pressure (mmHg) 0.6  5.7 0.7  4.0 NS
DMean blood pressure (mmHg) 1.5  1.4 1.4  1.4 NS

Morning blood pressure at home by automatic device

DSystolic blood pressure (mmHg) 4.5  8.9 2.4  7.8 0.0301
DDiastolic blood pressure (mmHg) 0.4  6.1 0.5  5.2 NS
DMean blood pressure (mmHg) 1.8  6.1 1.4  5.7 NS

Bedtime blood pressure at home by automatic device

DSystolic blood pressure (mmHg) 1.9  7.7 3.4  7.6 0.0272
DDiastolic blood pressure (mmHg) 0.1  6.1 1.1  4.9 NS
DMean blood pressure (mmHg) 0.6  6.1 1.8  5.3 NS

Data are means  S.D. P values are calculated by MannWhitney U-test.

 diabetes research and clinical practice 79 (2008) 8690
U-test. Wilcoxon t-test was used to compare between baseline
level and 12 months level within the group. Spearmans
correlation coefficients (r) were calculated to compare between
Dsystolic HBPs (in the morning, at bedtime and on the average)
and DUACR in the whole subjects for the purpose of correlation
analysis. P value of <0.05 was considered statistically signifi-
cant.
3. Result
We calculated an arithmetic mean of seven successive values
in each HBP. Average HBP was calculated as an arithmetic
mean of both morning and bedtime HBP. As shown in Table 1,
control and losartan groups were matched for age, gender, BMI
and duration of diabetes at baseline. There were no significant
differences between the two groups in levels of creatinine,
estimated GFR, total cholesterol, triglyceride, HbA1c, uric acid,
OBP and ambulatory urinary albumin/creatinine ratio (UACR).
Losartan group had significantly higher mean arterial blood
pressure of HBP than control group.
After 1 years follow-up, the increment of UACR was
significantly smaller in losartan group than in control group
[ 23.8  56.6 vs. 15.9  15.9, mean  S.E.M., P = 0.0114] (Table 2,
Fig. 2). UACR was 6.7  3.2 at baseline and significantly
increased to 15.1  11.9 one year after (mean  S.E.M.,
P = 0.008) in control subjects with normoalbuminuria at base-
line. UACR was 130.3  81.5 at baseline and significantly
decreased to 72.1  53.3 one year after (mean  S.E.M.,
P = 0.031) in losartan group with microalbuminuria. During
Fig. 2 Change in urinary albumin excretion (DUalb) after 1
years follow-up.
89
the 1-year follow-up period, UACR did not change in control
subjects with microalbuminuria at baseline, and also in
losartan group with normoalbuminuria at baseline. There were
no significant differences between the two groups in the change
of levels of serum creatinine, estimated GFR, total cholesterol,
triglyceride, HbA1c, uric acid, BMI, mean HBP and mean OBP
(Table 2). However, Dsystolic but not diastolic and mean blood
pressure in the morning, at bedtime and on the average had a
subtle decrease in the losartan group as compared with control.
There were no correlations between Dsystolic HBPs (in the
morning (r = 0.2315, P = 0.2269), at bedtime (r = 0.2693, P =
0.1577) and on the average (r = 0.2595, P = 0.1741)) and DUACR
in the whole subjects. Hypotension was not observed both in
losartan and control groups throughout the follow-up period.
4. Discussion
Our present study suggested that ARB has a direct renopro-
tective effect in type 2 diabetic patients with the early stage of
nephropathy. Our conclusion that ARB has a direct renopro-
tective effect is based on the following findings.
First, administered losartan did not affect the mean blood
pressure levels both at office and at home during the
treatment. In the previous studies, their subjects were
accompanied with mild to moderate hypertension, which
should be treated as not diabetic nephropathy but hyperten-
sion [9,10]. Therefore, the direct effect of ARB and/or other
antihypertensive agents on the diabetic nephropathy could
not be distinguished from their indirect effects through
lowering blood pressure. In contrast, our subjects have kept
borderline level of blood pressure before and during the study.
It enabled us to use minimum dose of ARB alone, which did not
affect the mean blood pressure both at office and at home of
the subjects, and therefore, a direct effect of ARB was
suggested; though we can not completely exclude the
possibility that very slight reduction of systolic home blood
pressure might have contributed to the decrease in the
increment of UACR. The fact that a decrease of Dsystolic
HBPs were not correlated with a decrease of DUACR in the
whole body also suggest a direct effect of ARB.
Second, we identified the effects of low dose ARB by using a
simple but a new method, HBPM. HBPM is reported to be the
most optimal method among OBPM, HBPM, and ABPM in terms
of the evaluation of the efficacy in taking antihypertensive
agents [19] and that of the reproducibility [20]. Also in this
study, we could precisely identify the subjects with mild
masked hypertension (normotension in OBPM and hyperten-
sion in HBPM) and sustained hypertension (hypertension in
both measurements), and exclude those with white-coat
hypertension (hypertension in OBPM and normotension in
HBPM). The number of our subjects was small but they could
be regarded uniform by using HBPM. In addition to the
appropriate selection of the subject at baseline, HBPM enabled
us to achieve the precise measurement of blood pressure level
in the follow-up period. Several mechanisms have been
proposed regarding direct renoprotective effect of ARB; e.g.
hemodynamic effect in the intraglomerular pressure, reduc-
tion of proteinuria, decrease of collagen formation [21],
although the precise mechanism needs further investigation.
90 diabetes research and clinical practice 79 (2008) 8690
The number of patients with ESRD with diabetes was
explosively increasing and therapeutic strategies should be
established as soon as possible. In addition to the strict control
of blood glucose and blood pressure, our present study
suggests the efficacy of low dose ARB in the early stage of
diabetic nephropathy while using HBPM.
Although a low dose losartan decreased systolic HBP in the
morning and at bedtime, a decrease was very small. The
observed decrease in UACR in the losartan-treated group
might be attributed to a direct renoprotective action in
addition to a subtle decrease in systolic HBP in conclusion.
Acknowledgements
The authors are indebted to Shinobu Mitsui for her excellent
secretarial help.
We highly acknowledged the expertise and outstanding
support of Prof. Yasuichiro Nishimura (Division of Preventive
& Social Medicine, Department of Mathematics, Osaka
Medical College, Japan) with regard to the statistical analysis.
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