Vol.30 (2007) No.4
Effects of Monotherapy of Temocapril or
Candesartan with Dose Increments or
Combination Therapy with Both Drugs on the
Suppression of Diabetic Nephropathy
Susumu OGAWA1), Kazuhisa TAKEUCHI1), Takefumi MORI1), Kazuhiro NAKO1),
Yoshitaka TSUBONO2),3), and Sadayoshi ITO1)
We examined the effects of increasing the recommended initial doses of angiotensin-converting enzyme
inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), or of switching to combination therapy with both
drugs, on diabetic nephropathy. Hypertensive type 2 diabetic patients with urinary albumin excretion (ACR)
between 100 and 300 mg/g creatinine (Cre) were assigned to the following five groups in which an antihy-
pertensive drug was administered at a recommended initial dose for 48 weeks, and then either the dose was
doubled or an additional drugs was added to regimen for the following 48 weeks: N, nifedipine-CR (N) 20
mg/day (initial dose); T, ACEI temocapril (T) 2 mg/day; C, ARB candesartan (C) 4 mg/day; T+C, T first and
then addition of C; C+T, C first and then addition of C. ACR decreased in the T (n=34), C (n=40), T+C
(n=37) and C+T (n=35) groups, but not in the N group (n=18). However, the anti-proteinuric effect was less
in the T than in the C, T+C or C+T groups, while no differences existed among the latter three. In each
group, there were significant linear relationships between attained BP and ACR; however, the regression
lines were shifted toward lower ACR level in the renin-angiotensin system–inhibition groups compared with
the N group. These results indicate that an ACEI and/or ARB is superior to a CCB in retarding diabetic
nephropathy, while the combination of low doses of ACEI and ARB has effects similar to those of high-dose
ARB. Even among patients treated with an ACEI and/or ARB, lowering BP is important. (Hypertens Res 2007;
Key Words: microalbuminuria, diabetic nephropathy, hypertension, angiotensin-converting enzyme inhibi-
tors, angiotensin receptor blockers
The renin-angiotensin system (RAS) plays an important role
in the pathophysiology of diabetic nephropathy. Numerous
studies have shown that inhibition of the RAS delays the pro-
gression of diabetic nephropathy (1–4). At present, two types
of RAS inhibitors with different mechanisms of action are
commonly used: angiotensin-converting enzyme inhibitor
(ACEI), and angiotensin type 1 receptor blocker (ARB). It
has been shown that both ACEIs and ARBs confer renal pro-
tection by reducing blood pressure (BP) and also by certain
other mechanisms independent of their BP-lowering action.
It has also been reported that low-dose combination
therapy with ACEI temocapril and ARB losartan reduced
proteinuria in normotensive patients with immunoglobulin
From the 1)Division of Nephrology, Endocrinology and Vascular Medicine and 3)Division of Clinical Epidemiology, Tohoku University School of Med-
icine, Sendai, Japan; and 2)Division of Health Policy, School of Public Policy, Tohoku University, Sendai, Japan.
Address for Reprints: Susumu Ogawa, M.D., Ph.D., Division of Nephrology, Endocrinology, and Hypertension, Tohoku University Hospital, Seiryo-
machi 1–1, Aoba-ku, Sendai 980–8574, Japan. E-mail: email@example.com
Received August 8, 2006; Accepted in revised form December 12, 2006.
Hypertens Res Vol. 30, No. 4 (2007)
A nephropathy (5).
The Irbesartan in Patients with Type 2 Diabetes and
Microalbuminuria Study (IRMA 2) has shown that the effects
of ARB in reducing proteinuria and suppressing the progres-
sion to overt nephropathy are dose-dependent (6). It has also
been reported that very high doses of ARB exert better anti-
albuminuric effects than the more commonly used doses (7).
Moreover, recent studies indicate that dual blockade of the
RAS with an ACEI and an ARB is superior to either drug
alone in reducing proteinuria in diabetic patients (8–11).
However, only a few studies have examined which of the two
dosing regimens—monotherapy featuring dose increments or
combination therapy—is more effective (12). In addition, the
order of combination therapies, namely, adding an ARB to an
ACEI (ACEI+ARB), or adding an ACEI to an ARB
(ARB+ACEI), may be an important factor that influences the
outcome in short term studies.
We therefore compared the albuminuria-reducing effects
between monotherapy with dose increments and combination
therapy of ACEI and ARB, and between ACEI+ARB therapy
and ARB+ACEI therapy in hypertensive type 2 diabetic
patients with microalbuminuria.
This is a single-blind randomized clinical study. Type 2 dia-
betic outpatients who met the following criteria were
enrolled: 1) previously untreated moderate hypertension
(130/80–200/110 mmHg); 2) microalbuminuria with a uri-
nary albumin-to-creatinine ratio (ACR) of 100–300 mg/g cre-
atinine (Cre) in all three measurements during the observation
period; 3) glycated hemoglobin A1c (HbAlc)<8.0%; 4) no
changes in medications or hospitalization during the past 3
years; 5) body mass index (BMI)<30 kg/m2; 6) serum
Cre<1.2 mg/dl; 7) no other renal diseases; 8) no severe cere-
bral or cardiovascular diseases or liver dysfunction; and 9) no
active retinopathy. All the procedures were approved by the
ethics committees of Tohoku University Hospital, and
informed consent was obtained from all patients.
The study protocol is shown in Fig. 1. After a 16-week
observation period, subjects were assigned to one of five
groups: 1) a calcium channel blocker (CCB) nifedipine-CR
(N) monotherapy group, in which 20 mg of N was adminis-
tered for 48 weeks, and then the dose was increased to 40 mg
for the following 48 weeks; 2) an ACEI temocapril (T) mono-
therapy group in which 2 mg of T was administered for 48
weeks, and then the dose was increased to 4 mg for the fol-
lowing 48 weeks; 3) an ARB candesartan (C) monotherapy
group, in which 4 mg of C was administered for 48 weeks,
and then the dose was increased to 8 mg for the following 48
weeks; 4) a T+C combination group in which 2 mg of T was
administered for 48 weeks, and then 4 mg of C was added for
the following 48 weeks; and 5) a C+T combination group in
which 4 mg of C was administered for 48 weeks, and then 2
mg of T was added for the following 48 weeks (Fig. 1).
Routine examinations such as body weight (BMI), BP,
Fig. 1. The protocol of this study.
Hypertens Res Vol. 30, No. 4 (2007)
nitric oxide and related vasoactive factors following long-
term treatment with angiotensin-converting enzyme inhibi-
tor in patients with essential hypertension. Metabolism
1999; 10: 1256–1259.
27. Rasoul S, Carretero OA, Peng H, et al: Antifibrotic effect of
Ac-SDKP and angiotensin-converting enzyme inhibition in
hypertension. J Hypertens 2004; 3: 593–603.
28. Rhaleb NE, Peng H, Harding P, et al: Effect of N-acetyl-
seryl-aspartyl-lysyl-proline on DNA and collagen synthesis
in rat cardiac fibroblasts. Hypertension 2001; 3: 827–832.
29. Ogawa S, Mori T, Nako K, et al: Angiotensin II type 1
receptor blockers reduce urinary oxidative stress markers in
hypertensive diabetic nephropathy. Hypertension 2006; 47:
30. Yagi S, Morita T, Katayama S, et al: Combined treatment
with an AT1 receptor blocker and angiotensin converting
enzyme inhibitor has an additive effect on inhibiting neoint-
ima formation via improvement of nitric oxide production
and suppression of oxidative stress. Hypertens Res 2004;
31. Gaede P, Tarnow L, Vedel P, et al: Remission to normoal-
buminuria during multifactorial treatment preserves kidney
function in patients with type 2 diabetes and microalbumin-
uria. Nephrol Dial Transplant 2004; 19: 2784–2788.
32. Rossing K, Christensen PK, Hovind P, et al: Remission of
nephrotic-range albuminuria reduces risk of end-stage renal
disease and improves survival in type 2 diabetic patients.
Diabetologia 2005; 11: 2241–2247.