Vol.29 (2006) No.9
Olmesartan Reducing Incidence of Endstage
Renal Disease in Diabetic Nephropathy Trial
(ORIENT): Rationale and Study Design
Enyu IMAI1), Sadayoshi ITO2), Masakazu HANEDA3), Juliana C. N. CHAN4),
and Hirofumi MAKINO5), for the ORIENT Investigators
Diabetic nephropathy (DN) is a leading cause of endstage renal disease (ESRD) in Japan and Hong Kong.
Asian patients are known to be more predisposed to DN and ESRD than Caucasians. Strict blood glucose
and blood pressure control are key factors in prevention and treatment of DN. In the last decade, inhibition
of the renin-angiotensin-aldosterone (RAA) system has been confirmed to reduce the incidence of cardio-
vascular complications in Caucasian patients with diabetes. Although the RENAAL study has demonstrated
the beneficial effects of inhibition of the RAA system on prevention of ESRD and death in type 2 diabetic
patients with overt proteinuria, only 17% of patients in this multicenter study were of Asian ethnicity. Given
the predilection of Asian diabetic patients for renal complications and the rising burden of ESRD, there is
a need to confirm these findings in a homogenous group of Asian patients. The ORIENT (Olmesartan Reduc-
ing Incidence of Endstage Renal Disease in Diabetic Nephropathy Trial) is a randomized, double-blind, pla-
cebo-controlled study in Japan and Hong Kong to evaluate the renal protective benefits of olmesartan
medoxomil in type 2 diabetic patients with overt proteinuria (urinary albumin to creatinine ratio ≥300 mg/g
creatinine) and renal insufficiency (serum creatinine: 1.0–2.5 mg/dl). The study has a targeted enrollment of
400 Japanese and Hong Kong Chinese patients. The primary outcome is the composite endpoint of time to
the first occurrence of doubling of serum creatinine, ESRD (serum creatinine more than 5.0 mg/dl, the need
for chronic dialysis, or renal transplantation) or death. The average follow-up period is 4 years and the study
ends in 2009. (Hypertens Res 2006; 29: 703–709)
Key Words: angiotensin II receptor blocker, diabetic nephropathy, endstage renal disease, type 2 diabetes,
The population of diabetic patients is growing significantly
worldwide, and its high prevalence in Asia, including in
Japan and Hong Kong, is a matter of great concern in light of
the increasing number of patients with severe diabetic com-
plications such as blindness, leg amputation and renal death,
and the associated medical expenditures.
Diabetic nephropathy (DN), one of the major complications
of diabetes mellitus, is a progressive renal microangiopathy
characterized by mesangial expansion and nodular sclerosis
From the 1)Department of Nephrology, Osaka University Graduate School of Medicine, Suita, Japan; 2)Division of Nephrology, Endocrinology and Vas-
cular Medicine, Department of Clinical Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan; 3)Department of Medicine, Asa-
hikawa University of Medical Science, Asahikawa, Japan; 4)Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese
University of Hong Kong, Shatin, Hong Kong; and 5)Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine,
Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Address for Reprints: Enyu Imai, M.D., Ph.D., Department of Nephrology, Osaka University Graduate School of Medicine, 2–15, Yamadaoka, Suita
565–0871, Japan. E-mail: email@example.com
Received April 21, 2006; Accepted in revised form June 16, 2006.
Hypertens Res Vol. 29, No. 9 (2006)
due to chronic hyperglycemia. It develops with clinical man-
ifestations such as proteinuria, hypertension and edema, and
culminates in renal failure.
As the prevalence of diabetes increases, the number of new
renal dialysis patients is expected to continue to rise in Asia,
including in Japan and Hong Kong (1–3). Along with the
growing concerns about escalating medical costs and the
increased risk of cardiovascular disease caused by chronic
kidney disease (4, 5), interruption of the development of DN
and slowing the progression of endstage renal disease
(ESRD) have become urgent issues.
In order to interrupt the development of DN, it is critical to
manage blood glucose, hypertension and proteinuria aggres-
sively (6–9). In recent years, large-scale clinical trials con-
ducted in type 2 diabetic patients with nephropathy, such as
the RENAAL study of losartan (10), the IDNT study of irbe-
sartan (11), and the IRMA-2 study (12), have shown that
angiotensin II (AII) receptor blockers (ARB) can slow the
progression of DN (10–15). Treatment with an ARB signifi-
cantly reduces the risk of doubling of the serum creatinine
level, dialysis, renal transplantation, and death in addition to
protecting against the development of microalbuminuria into
There have been studies suggesting that Asian patients with
diabetes are more predisposed to develop nephropathy than
their Caucasian counterparts (16, 17). In a subgroup analysis
of the RENAAL study, ARB therapy was found to be more
effective in Asian than Caucasian patients in delaying the pro-
gression of DN (18). In order to examine more closely the
effects of ARB treatment in Asian patients on the inhibition
of progression of DN, we are conducting a large-scale clinical
trial named ORIENT (Olmesartan Reducing Incidence of
Endstage Renal Disease in Diabetic Nephropathy Trial). This
is a randomized, double-blind, placebo-controlled, multina-
tional study to evaluate the renal protective benefits of olme-
sartan medoxomil using the composite clinical endpoint of
time to the first occurrence of doubling of serum creatinine,
ESRD, or death.
The ORIENT is a multinational, multi-center study currently
underway in Japan and Hong Kong. A total of 400 Japanese
and Hong Kong Chinese patients with type 2 DN met the
inclusion and exclusion criteria shown in Table 1 and have
been enrolled. In this clinical trial, DN patients are defined as
those who meet at least one of the following entry criteria: 1)
patients who have been diagnosed with DN by renal biopsy;
2) patients with diabetic retinopathy or diabetic neuropathy;
and 3) patients with duration of type 2 diabetes of more than
5 years. The trial is being conducted under the Helsinki Dec-
laration, and was approved by the Institutional Review Board
at each trial site. All participants have been fully informed by
the investigators and gave their informed consent.
This clinical trial is a randomized, double-blind, placebo-con-
trolled study (Fig. 1).
During the 6-week screening period (already completed)
patients were assessed for inclusion and exclusion criteria for
eligibility for entry to this trial.
Active Treatment Period
To achieve an average follow-up period of 4 years, the active
treatment period is 240 weeks (5 years), taking into account
the likely enrollment period of 2 years.
According to the Japanese Society of Hypertension guide-
lines (JSH 2000) for the management of hypertension (19),
the target blood-pressure should be <130 mmHg systolic
blood pressure and <85 mmHg diastolic blood pressure
(seated blood pressure) in both diabetic patients and hyperten-
sive patients with renal disease. In ORIENT, this blood pres-
Table 1. Eligibility Criteria
1) Patients with diabetic nephropathy (DN) associated with
type 2 diabetes
2) Patients aged 30 to 70 years
4) Urinary albumin to creatinine ratio: ≥300 mg/g creati-
nine in the first morning urine sample
5) Serum creatinine level: 1.0–2.5 mg/dl in women and
1.2–2.5 mg/dl in men
1) Type 1 diabetes or non-DN
2) History of myocardial infarction (MI) or coronary artery
bypass grafting (CABG) within 3 months prior to con-
3) History of percutaneous coronary intervention (PCI),
carotid artery or peripheral artery revascularization
within 6 months prior to consent acquisition
4) Stroke or transient ischemic attack (TIA) within the last
5) Unstable angina pectoris
6) Heart failure of New York Heart Association (NYHA)
functional class III or IV
7) Rapid progression of renal disease within 3 months prior
to consent acquisition
8) Severe orthostatic hypotension
9) Serum potassium level: ≤3.5 mEq (mmol)/l or ≥5.5
Imai et al: ORIENT: Rationale and Study Design
sure is used as a target level.
In the active treatment period, patients will be assigned ran-
domly to commence treatment with either 10 mg olmesartan
medoxomil (or placebo) in addition to their existing antihy-
pertensive therapy. If the target blood pressure of less than
130/85 mmHg is not achieved after the first 4 weeks of ther-
apy or at any time thereafter, the dose of olmesartan medox-
omil (or placebo) will be increased to 20 mg daily (or
placebo), with further titration to a dose of olmesartan medox-
omil 40 mg daily (or placebo), if necessary.
Every reasonable attempt will be made to up-titrate the test
drug to the maximum dose, even if the target blood pressure
levels are achieved. However, if the target blood pressure lev-
els are not achieved in a patient with a maximal dosage of
olmesartan medoxomil, additional antihypertensive agents
may be used. Except for the use of potassium-sparing diuret-
ics, other ARBs or angiotensin-converting enzyme inhibitors
(ACE-Is) not given at baseline, additional antihypertensive
agents may include diuretics, β-blockers, calcium channel
blockers, and α-blockers. Any patient taking an ACE-I prior
to entering the study must continue with the same dose of
ACE-I throughout the study. New prescription of an ACE-I
after commencement of the study is not allowed.
Use of concomitant immunosuppressants, adrenocortico-
tropic hormones (ACTH), carbonaceous adsorbents, and any
investigational drugs under development is prohibited.
Chronic use of systemically administered steroids and/or non-
steroidal anti-inflammatory drugs (NSAIDs), or aspirin >330
mg/day is also prohibited.
All patients will visit the clinic at 2, 4, 8, and 12 weeks, and
then return every 12 weeks throughout the study duration. At
each visit, blood pressure will be measured and clinical sam-
ples collected for measurement of the urinary protein to crea-
tinine ratio, and the levels of serum creatinine and serum
potassium. All randomized patients including those discon-
tinued from the study for any reason other than death will be
followed up to collect information on primary and secondary
endpoints until termination of study.
Fig. 1. Overview of the Design of the ORIENT. *Neither an increase in dose nor administration of an additional antihyperten-
sive drug is allowed during the screening period and the first 12 weeks of the active treatment period.
Table 2. Primary and Secondary Outcomes
1) Efficacy: Composite endpoint of the first occurrence of
any of the following events: Doubling of serum creati-
nine level, ESRD (serum creatinine ≥5.0 mg/dl, trans-
plantation, dialysis), Death
1) Composite endpoint of the first occurrence of any of the
following events: Cardiovascular death, Non-fatal stroke
except for transient ischemic attacks (TIAs), Non-fatal
myocardial infarction, Hospitalization for unstable
angina, Hospitalization for heart failure, Coronary/
carotid/peripheral revascularization, Lower extremity
2) Change in proteinuria
3) Reciprocal of serum creatinine
ESRD, endstage renal disease.
Hypertens Res Vol. 29, No. 9 (2006)
The primary and secondary outcomes are shown in Table 2.
The primary efficacy endpoint of ORIENT is a composite
endpoint of the time to first occurrence of doubling of serum
creatinine, ESRD, or death. ESRD is defined as serum creati-
nine more than 5.0 mg/dl, the need for chronic dialysis, or
renal transplantation. Throughout the trial, the safety and tol-
erability of olmesartan medoxomil will be assessed.
Secondary efficacy endpoints of ORIENT are as follows: 1)
A composite endpoint of the time to first occurrence of a cere-
bro/cardiovascular event or cardiovascular death, non-fatal
stroke except for transient ischemic attacks (TIAs), non-fatal
myocardial infarction, hospitalization for unstable angina,
hospitalization for heart failure, coronary/carotid/peripheral
revascularization, and lower extremity amputation. 2) Change
in proteinuria. 3) Reciprocal of serum creatinine.
It is assumed that the primary endpoint in this study, defined
as the composite renal event rate, would be 0.583 events/
patient during an average 4-year follow-up period in the pla-
cebo group. The assumed event rate is calculated based on the
results for Japanese patients in the RENAAL study (18)
(event rate: 34/52=0.654 with 3.4 years average follow-up
period). We assume that a 30% risk reduction would be
achieved with baseline ACE-I treatment (20). Therefore, the
event rate of the placebo group with baseline ACE-I treatment
was assumed to be 0.583 with an average follow-up period of
4 years. On the other hand, the event rate of the olmesartan
group with ACE-I treatment was assumed to be 0.434, since
we hypothesized an additional 35% risk reduction in the olm-
esartan group compared to the placebo group. Based on these
assumptions, 172 patients are needed in each treatment group
to detect a statistically significant difference between treat-
ment groups using the log-rank test with α=0.05 (two-sided)
and 1 − β=0.80. Assuming that fewer than 15% of patients
will be lost to follow-up, the number of patients is determined
to be 200 per group.
The following statistical analysis plan will be applied inde-
pendently for two study populations, Japanese and Chinese
patients, and an integrated analysis plan for the two popula-
tions will be created including similar analysis.
All patients who have taken the study drug at least once will
be included in the safety analysis set.
The primary efficacy analysis set will be the full analysis
set (FAS). The FAS will include all patients satisfying the fol-
1) Fulfilled all entry criteria; 2) Took the study drug at least
once; 3) Were followed-up at least once after randomization.
The secondary efficacy analysis set will be the per protocol
set (PPS). The PPS will consist of patients included in the
FAS who had no major protocol violations.
The Cox regression model will be used to estimate the hazard
ratios with 95% confidence intervals in the renal composite
event rate, the cerebro/cardiovascular composite event rate,
and the event rate for each renal, cerebro- or cardiovascular
event separately. The covariates included in the model will be
determined based on the results of blind data review before
the study is unblinded. The candidate covariates are gender,
age, ACE-I treatment, baseline urinary albumin:creatinine
ratio and baseline serum creatinine level. The cumulative
event rate for each defined event will be estimated by the
Kaplan-Meier method for each treatment group.
The linear mixed effect model, including study drugs, mea-
surement times and other covariates selected after the blind
data review, will be used for comparing the trend in the per-
cent change in proteinuria, and the trend in the reciprocal of
the serum creatinine level between treatment groups. Similar
analyses for each endpoint will also be applied for the sub-
group of each prognostic factor.
Adverse events will be summarized for each treatment group.
The cumulative occurrence rate of all adverse events and
drug-related adverse events in each treatment group will be
estimated by the Kaplan-Meier method, and the log-rank test
will be used to compare two groups. The summary statistics,
such as the mean, median and standard deviation for the quan-
tified laboratory test values, will be calculated at each mea-
surement point, and scatter plots of each of the test values for
pre- and post-treatment will be presented. Contingency tables
showing the number of patients and the percentage of patients
within each category pre- and post-treatment will also be pre-
sented for the categorical test values.
Study Coordinating Committee
The Study Coordinating Committee advises the sponsor with
regard to the study design, protocol amendments, site selec-
tion, and ethical conduct of the study.
Endpoint Evaluation Committee
The Endpoint Evaluation Committee is responsible for the
adjudication and classification of the primary and secondary
endpoints under the blinded condition.
Independent Data Monitoring Committee
Since this trial requires follow-up of clinical events over a
long period of time, the Independent Data Monitoring Com-
mittee (IDMC) monitors the trial for appropriate and ethical
conduct of the study. The IDMC includes experts in the fields
of nephrology, diabetes, and statistics who are independent
Imai et al: ORIENT: Rationale and Study Design
from any of the study investigators and sponsor.
The rationale of ORIENT is that the use of olmesartan
medoxomil against the renin-angiotensin-aldosterone (RAA)
system in type 2 DN may attenuate the disease progression
and reduce the risk of the composite endpoint of doubling of
serum creatinine, ESRD and death in the Japanese and Chi-
nese populations. In their subgroup analysis of the RENAAL
study focusing on the Asian subgroup, Chan et al. (18) dem-
onstrated that losartan significantly reduced the risk of new
onset of the primary composite endpoint (risk reduction 35%,
p=0.02) in the Asian subgroup. These findings have contrib-
uted significantly to the overall positive results of the
RENAAL study. If the Asian population was removed from
the RENAAL study, the results would not have been signifi-
cant for losartan. In the current worldwide epidemic of diabe-
tes, Asians are expected to become the largest affected
population. Given the increased risk of Asian patients for
developing ESRD, results from ORIENT will confirm the
clinical utility of olmesartan medoxomil in Asian patients
with type 2 diabetes.
ACE-Is or ARBs are recommended as first-line drugs in the
treatment of hypertension according to the American Diabe-
tes Association (ADA) Position Statement and the Seventh
Report of the Joint National Committee on Prevention, Detec-
tion, Evaluation, and Treatment of High Blood Pressure (JNC
7). ARBs are recommended especially for DN in type 2 dia-
betes (21–23), based on the evidence of large-scale random-
ized controlled trials in DN. In a recent meta-analysis (24)
which assessed 43 published randomized controlled trials
including a total of 7,545 patients with diabetes, ACE-I treat-
ment was found to significantly reduce the risk of all-cause
mortality by about 20% and progression from microalbumin-
uria to overt proteinuria by about 55%. However, nine trials
comparing ACE-I with placebo showed only weak evidence
for reduction of risk for progression to ESRD. In addition,
most of the studies investigated the effects of these drugs in
patients with type 1 diabetes. In contrast, there is strong evi-
dence regarding the use of ARBs in DN, with approximately
22% reduction in risk of ESRD, 51% risk reduction for pro-
gression from microalbuminuria to overt proteinuria, and
42% increased chance in regression from microalbuminuria
to normoalbuminuria. The meta-analysis included both type 1
and type 2 diabetic patients. Overall, both classes of drugs
reduced the risks of onset of DN, increase in proteinuria and
progression to ESRD. The clinical trials that investigated the
impacts of ACE-I and ARB treatment on outcomes of patients
with type 2 diabetes are listed in Table 3.
Strict control of blood glucose and blood pressure is of par-
amount importance in the treatment of DN. When the proto-
col for ORIENT was designed in 2002, the recommended
target blood pressure according to the hypertension treatment
Table 3. Clinical Trials of ARB and ACE-I on Nephropathy in Type 2 Diabetes
Brenner 1,513 Losartan 100 mg
3.4 yearsLosartan is effective in protecting against the
progression of DN
1,715 Irbesartan 300 mg
Amlodipine 10 mg
2.6 yearsIrbesartan is effective in protecting against the
progression of DN
590 Irbesartan 300 mg
Irbesartan 150 mg
24 months Irbesartan reduced microalbuminuria
199 Lisinopril 20 mg
Candesartan 16 mg
MR −16.7/−10.7 monotherapy
MR −14.1/−10.424 weeks
Equivalent reduction of BP and microalbumin-
uria between lisinopril and candesartan mono-
Combination therapy further decreased microal-
buminuria with reduction of BP
Lisinopril 20 mg+
candesartan 16 mg
MR −25.3/−16.3 combination
332 Valsartan 80 mg
Amlodipine 5 mg
24 weeksSame degree of BP reduction
Valsartan significantly reduced albuminuria
250 Enalapril 20 mg
Telmisartan 80 mg
MR (SBP) −2.9
MR (SBP) −6.9
5 yearsEquivalent renal protection
ARB, angiotensin II receptor blocker; ACE-I, angiotensin-converting enzyme inhibitor; BP, blood pressure; SBP, systolic blood pres-
sure; MR, mean blood pressure reduction; DN, diabetic nephropathy.
Hypertens Res Vol. 29, No. 9 (2006)
guidelines in Japan (JSH 2000) (19) was <130/85 mmHg.
Since then, most guidelines have readjusted the target blood
pressure for hypertensive DN patients from <130/85 mmHg
to <130/80 mmHg, suggesting stricter blood pressure control.
Although based on the UKPDS36 (25), the risk associations
between blood pressure level and clinical outcomes appeared
to be continuous: there were no randomized clinical trial data
to show that a target blood pressure <130/80 mmHg con-
ferred superior organ-protective effects compared to blood
pressure ≥130/85 mmHg. Besides, in most of the clinical tri-
als on DN, systolic blood pressure was around 140 mmHg at
the last visit (Table 3). Olmesartan medoxomil showed simi-
lar antihypertensive effects as amlodipine in two clinical trials
of essential hypertension. In comparison with other ARBs,
olmesartan medoxomil showed the largest decrease in blood
pressure. Olmesartan medoxomil also achieved the target
blood pressure level of 130/85 mmHg in the highest number
of patients in these two studies (26, 27).
In contrast to the RENAAL and IDNT studies, in which
none of the patients received ACE-I, patients in ORIENT will
be allowed to continue their previously prescribed ACE-I
therapy during the study period. Hence, the combination
effects of ACE-Is and ARBs can also be evaluated in this
Based on their modes of actions, ACE-Is are expected to
increase bradykinin levels, reduce AII levels and lower aldo-
sterone levels, while ARBs offer more complete suppression
of AII activity via the AII type 1 (AT1) receptor, since AII
can also be produced by other non-ACE dependent pathways,
such as chymase. There is now evidence showing that
increased AII activity following treatment with an ARB may
enhance the activation of the AII type 2 (AT2) receptors,
which are presumed to have vasodilatory, antiproliferative,
and antifibrotic activities (28). In addition, ARBs may
increase bradykinin levels through mechanisms dependent on
the stimulation of AT2 receptors (29, 30). Thus, the combina-
tion of an ACE-I and ARB may have the additive effects of
inhibiting the RAA system and upregulating the bradykinin
A combination therapy with an ACE-I and ARB has been
suggested to exert stronger anti-proteinuric effects than either
agent used alone (6, 31, 32). This combination effect of an
ACE-I and ARB on proteinuria has been examined in DN
patients (13, 33–35). However, thus far, all of the combina-
tion studies have only used albuminuria as a surrogate marker
rather than using clinical endpoints, such as ESRD. In non-
diabetic patients, Nakao et al. (36) have indicated that combi-
nation therapy of an ACE-I and ARB decreased proteinuria
and interrupted the progression of nephropathy.
In conclusion, ORIENT aims to investigate the efficacy of
olmesartan medoxomil in DN exclusively in Asian type 2 dia-
betic patients with nephropathy. Results from this study are
expected to provide further definitive evidence regarding the
optimal treatment strategy in these high-risk patients.
ORIENT Study Coordinating Committee: Hirofumi Makino
(chair), Sadayoshi Ito, Enyu Imai, Masakazu Haneda, Juliana C.
1.Wakai K, Nakai S, Kikuchi K, et al: Trends in incidence of
endstage renal disease in Japan, 1983−2000: age-adjusted
and age-specific rates by gender and cause. Nephrol Dial
Transplant 2004; 19: 2044–2052.
Japanese Society for Dialysis Therapy: Condition as of
December 31, 2004, in: An Overview of Regular Dialysis
Treatment in Japan. Japanese Society for Dialysis Therapy,
2004, pp 2–22 (in Japanese).
Lui SF, Ho YW, Chau KF, Leung CB, Choy BY: Hong
Kong Renal Registry 1995−1999. Hong Kong J Nephrol
1999; 1: 53–60.
Sarnak MJ, Levey AS, Schoolwerth AC, et al: Kidney dis-
ease as a risk factor for development of cardiovascular dis-
ease: a statement from the American Heart Association
Councils on Kidney in Cardiovascular Disease, High Blood
Pressure Research, Clinical Cardiology, and Epidemiology
and Prevention. Circulation 2003; 108: 2154–2169.
Levey AS, Beto JA, Coronado BE, et al: Controlling the
epidemic of cardiovascular disease in chronic renal disease:
what do we know? What do we need to learn? Where do we
go from here? National Kidney Foundation Task Force on
Cardiovascular Disease. Am J Kidney Dis 1998; 32: 853–
Wilmer WA, Rovin BH, Hebert CJ, et al: Management of
glomerular proteinuria: a commentary. J Am Soc Nephrol
2003; 14: 3217–3232.
Campbell RC, Ruggenenti P, Remuzzi G: Halting the pro-
gression of chronic nephropathy. J Am Soc Nephrol 2002;
Keane WF: Proteinuria: its clinical importance and role in
progressive renal disease. Am J Kidney Dis 2000; 35 (Suppl
Ruggenenti P, Perna A, Mosconi L, et al: Proteinuria pre-
dicts endstage renal failure in non-diabetic chronic nephrop-
athies. The “Gruppo Italiano di Studi Epidemiologici in
Nefrologia” (GISEN). Kidney Int Suppl 1997; 63: S54–S57.
10. Brenner BM, Cooper ME, de Zeeuw D, et al: Effects of
losartan on renal and cardiovascular outcomes in patients
with type 2 diabetes and nephropathy. N Engl J Med 2001;
11. Lewis EJ, Hunsicker LG, Clarke WR, et al: Renoprotective
effect of the angiotensin-receptor antagonist irbesartan in
patients with nephropathy due to type 2 diabetes. N Engl J
Med 2001; 345: 851–860.
12. Parving HH, Lehnert H, Brochner-Mortensen J, et al: The
effect of irbesartan on the development of diabetic nephrop-
athy in patients with type 2 diabetes. N Engl J Med 2001;
13. Mogencen CE, Neldam S, Tikkanen I, et al: Randomised
controlled trial of dual blockade of renin-angiotensin sys-
tem in patients with hypertension, microalbuminuria, and
Imai et al: ORIENT: Rationale and Study Design Download full-text
non-insulin dependent diabetes: the candesartan and lisino-
pril microalbuminuria (CALM) study. BMJ 2000; 321:
14. Viberti G, Wheeldon NM, MicroAlbuminuria Reduction
with VALsartan (MARVAL) Study Investigators: Microal-
buminuria reduction with valsartan in patients with type 2
diabetes mellitus: a blood pressure-independent effect. Cir-
culation 2002; 106: 672–678.
15. Barnett AH, Bain SC, Bouter P, et al: Angiotensin-receptor
blockade versus converting-enzyme inhibition in type 2 dia-
betes and nephropathy. N Engl J Med 2004; 351: 1952–
16. Morrish NJ, Wang S, Stevens LK, Fuller JH, Keen H: Mor-
tality and causes of death in the WHO Multinational Survey
of Vascular Diseases in Diabetes. Diabetologia 2001; 44
(Suppl 2): S14–S21.
17. Karter AJ, Ferrara A, Liu JY, et al: Ethnic disparities in dia-
betic complications in an insured population. JAMA 2002;
18. Chan JC, Wat NM, So WY, et al: Renin angiotensin aldo-
sterone system blockade and renal disease in patients with
type 2 diabetes. An Asian perspective from the RENAAL
Study. Diabetes Care 2004; 27: 874–879.
19. Japanese Society of Hypertension Guidelines Subcommit-
tee for the Management of Hypertension: Guidelines for the
Management of Hypertension for General Practitioners.
Hypertens Res 2001; 24: 613–634.
20. Giatras I, Lau J, Levey AS: Effect of angiotensin-convert-
ing enzyme inhibitors on the progression of nondiabetic
renal disease: a meta-analysis of randomized trials. Angio-
tensin-Converting-Enzyme Inhibition and Progressive
Renal Disease Study Group. Ann Intern Med 1997; 127:
21. American Diabetes Association: Standards of Medical Care
in Diabetes. Diabetes Care 2002; 25: 33S–49S.
22. American Diabetes Association: Diabetic nephropathy:
diagnosis, prevention, and treatment. Diabetes Care 2002;
23. Chobanian AV, Bakris GL, Black HR, et al: The Seventh
Report of the Joint National Committee on Prevention,
Detection, Evaluation, and Treatment of High Blood Pres-
sure: the JNC 7 report. JAMA 2003; 289: 2560–2572.
24. Strippoli GF, Craig M, Deeks JJ, et al: Effects of angio-
tensin converting enzyme inhibitors and angiotensin II
receptor antagonists on mortality and renal outcomes in dia-
betic nephropathy: systematic review. BMJ 2004; 329: 828.
25. Adler AI, Stratton IM, Neil HA, et al: Association of sys-
tolic blood pressure with macrovascular and microvascular
complications of type 2 diabetes (UKPDS 36): prospective
observational study. BMJ 2000; 321: 412–419.
26. Chrysant SG, Marbury TC, Robinson TD: Antihypertensive
efficacy and safety of olmesartan medoxomil compared
with amlodipine for mild-to-moderate hypertension. J Hum
Hypertens 2003; 17: 425–432.
27. Oparil S, Williams D, Chrysant SG, Marbury TC, Neutel J:
Comparative efficacy of olmesartan, losartan, valsartan, and
irbesartan in the control of essential hypertension. J Clin
Hypertens 2001; 318: 283–291.
28. Taal MW, Brenner BM: Renoprotective benefits of RAS
inhibition: from ACEI to angiotensin II antagonists. Kidney
Int 2000; 57: 1803–1817.
29. Noris M, Remuzzi G: ACE inhibitors and AT1 receptor
antagonists: is two better than one? Kidney Int 2002; 61:
30. Siragy HM, de Gasparo M, El-Kersh M, et al: Angiotensin-
converting enzyme inhibition potentiates angiotensin II type
1 receptor effects on renal bradykinin and cGMP. Hyperten-
sion 2001; 38: 183–186.
31. Wolf G, Ritz E: Combination therapy with ACE inhibitors
and angiotensin II receptor blockers to halt progression of
chronic renal disease: pathophysiology and indications.
Kidney Int 2005; 67: 799–812.
32. Kuriyama S, Tomonari H, Tokudome G, et al: Antipro-
teinuric effects of combined antihypertensive therapies in
patients with overt type 2 diabetic nephropathy. Hypertens
Res 2002; 25: 849–855.
33. Hebert LA, Falkenhain ME, Nahman NS Jr, et al: Combina-
tion ACE inhibitor and angiotensin II receptor antagonist
therapy in diabetic nephropathy. Am J Nephrol 1999; 19: 1–
34. Jacobsen P, Andersen S, Rossing K, et al: Dual blockade of
the renin-angiotensin system versus maximal recommended
dose of ACE inhibition in diabetic nephropathy. Kidney Int
2003; 63: 1874–1880.
35. Horita Y, Tadokoro M, Taura K, et al: Low-dose combina-
tion therapy with temocapril and losartan reduces pro-
teinuria in normotensive patients with immunoglobulin A
nephropathy. Hypertens Res 2004; 27: 963–970.
36. Nakao N, Yoshimura A, Morita H, et al: Combination treat-
ment of angiotensin-II receptor blocker and angiotensin-
converting−enzyme inhibitor in non-diabetic renal disease
(COOPERATE): a randomised controlled trial. Lancet
2003; 361: 117–124.