CLINICAL THERAPEUTICS / VOL. 25, NO.

12, 2003

Review Article
Losartan and Other Angiotensin II Antagonists
for Nephropathy in Type 2 Diabetes Mellitus:
A Review of the Clinical Trial Evidence

Luis M. Ruilope, MD, and Julian Segura, MD

Hypertension Unit, Hospital 12 de Octubre, Madrid, Spain

ABSTRACT

Background: End-stage renal disease (ESRD) in patients with type 2 diabetes

mellitus (DM) is associated with a bleak prognosis. The life span of patients with
DM who have undergone renal transplantation or who are undergoing dialysis is
up to 30% shorter than that of individuals in the general population. Preventing
or delaying the progression of renal disease from microalbuminuria to nephropa-
thy and, ultimately, to ESRD is thus a crucial goal of DM management.
Objective: This article reviews the growing worldwide problem of type 2 DM
and ESRD, the renoprotective benefits of angiotensin II (AII) antagonists (AIIAs)
such as losartan in patients with or without type 1 or 2 DM, potential mecha-
nisms of renoprotection of AIIAs beyond blood pressure (BP) control, and the
clinical-practice implications of available megatrials.
Methods: Articles included in this review were identified using a MEDLINE
search for English-language studies published between 1990 and 2003 and in-
cluded the search terms diabetic nephropathy, type 2 diabetes mellitus, microalbu-
minuria, proteinuria, angiotensin II antagonists, angiotensin-converting enzyme in-
hibitors, and cardiovascular disease. Articles describing major clinical trials, new
data, or new mechanisms pertinent to the management of type 2 DM were se-
lected for review.
Results: Currently, AIIAs such as losartan represent the only evidence-based
treatment strategy for patients with type 2 DM and proteinuria. The Irbesartan in

Accepted for publication October 9, 2003.

Printed in the USA. Reproduction in whole or part is not permitted. 0149-2918/03/$19.00

3044 Copyright 2003 Excerpta Medica, Inc.

 L.M. Ruilope and J. Segura

Patients with Type 2 Diabetes and Microalbuminuria (IRMA-2) study, the Reduc-
tion of End Points in NonInsulin-Dependent Diabetes Mellitus with the An-
giotensin II Antagonist Losartan (RENAAL) study, and the Irbesartan Type 2 Dia-
betic Nephropathy Trial (IDNT) indicate that AIIAs postpone the progression of
type 2 diabetic renal disease at all stages, ranging from microproteinuria to overt
nephropathy and ESRD. RENAAL showed that losartan improves renal outcomes
in patients with type 2 DM and nephropathy over and above that attributable to
BP control alone. The renoprotective effect of losartan corresponded to an aver-
age delay of 2 years in the need for dialysis or kidney transplantation.
Conclusions: AIIAs such as losartan should perhaps be considered mandatory
therapy in patients with diabetic nephropathy and should complement existing
management strategies, such as reduced dietary protein intake, strict blood glu-
cose control, and standard antihypertensive therapy. Collectively, these measures
should improve survival and quality of life and reduce the health care burden of
managing patients with diabetic nephropathy. (Clin Ther. 2003;25:30443064)
Copyright 2003 Excerpta Medica, Inc.
Key words: nephropathy, type 2 diabetes mellitus, microalbuminuria, proteinuria,
angiotensin II antagonists, angiotensin receptor blockade, cardiovascular disease.

INTRODUCTION
Type 2 diabetes mellitus (DM) is reaching epidemic proportions in many coun-
tries throughout the world; it represents the most common cause of end-stage re-
nal disease (ESRD).13 The prognosis of patients with type 2 DM and ESRD is
bleak. The life span of patients with DM who have undergone renal transplanta-
tion or who are undergoing dialysis is up to 30% shorter than that of individu-
als in the general population.4 Early identification of renal impairment associated
with DM and initiation of renoprotective therapy are imperative to prevent or
delay progression to ESRD.
In addition to antihyperglycemic therapy for tight control of blood glucose
(BG), antihypertensive drug therapy that provides renoprotection represents a
cornerstone of the recommended treatment strategy for any diabetic patient with
any stage of hypertension.57 A variety of antihypertensive therapies produce bene-
ficial effects in reducing proteinuria (urinary albumin excretion [UAE] 0.5 g/d),
a hallmark of progressive renal function decline.8 However, not all antihyperten-
sive agents are the same in terms of delaying the progression of renal disease in
patients with type 2 DM.
Although angiotensin-converting enzyme (ACE) inhibitors have proved benefi-
cial in treating renal disease in patients with type 1 DM or nondiabetic renal dis-
ease, evidence of renoprotection in patients with type 2 DM is lacking.9,10 Cur-

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CLINICAL THERAPEUTICS

rently, angiotensin II (AII) antagonists (AIIAs) are the only class of antihyperten-
sive agents to show favorable mortality and morbidity outcomes in end-point tri-
als in patients with type 2 DM, as evidenced by findings of the following studies:
the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria (IRMA-2)
study,11 the Reduction of End Points in NonInsulin-Dependent Diabetes Melli-
tus with the Angiotensin II Antagonist Losartan (RENAAL) study,12 the Irbesar-
tan Type 2 Diabetic Nephropathy Trial (IDNT),13 and the Losartan Intervention
For Endpoint Reduction in Hypertension (LIFE) study.14 The LIFE study14 also
provides convincing evidence that the AIIA losartan can be considered for car-
diovascular protection in hypertensive patients with type 2 DM and left ventric-
ular hypertrophy (LVH).
This article reviews the growing worldwide problem of type 2 DM and ESRD,
the renoprotective benefits of AIIAs in patients with or without type 2 DM,
potential mechanisms of renoprotection of AIIAs beyond blood pressure (BP)
control, and the clinical-practice implications of megatrials such as IRMA-2,11
RENAAL,12 IDNT,13 and LIFE.14

METHODS
This review is based on articles identified using a MEDLINE search for English-
language studies published between 1990 and 2003 and using the search terms
diabetic nephropathy, type 2 diabetes mellitus, microalbuminuria, proteinuria, an-
giotensin II antagonists, angiotensin-converting enzyme inhibitors, and cardiovascular
disease. Articles describing major clinical trials, new data, or new mechanisms
pertinent to the management of type 2 DM were selected for review.

THE WORLDWIDE BURDEN OF TYPE 2 DM AND RENAL DISEASE

The worldwide incidence of DM is high.15 Estimates indicate that ~124 million
people worldwide have DM; the vast majority (97%) have type 2 DM.2 By the
year 2010, the prevalence of type 2 DM is expected to reach 221 million indi-
viduals worldwide.2 This epidemic is largely a result of longer life spans, obesity,
reduced exercise, and other factors.2
Data14 indicate that DM is the single largest cause of ESRD requiring chronic
dialysis or kidney transplantation in the United States, accounting for >50% of
new cases of renal failure each year. As mentioned earlier, once ESRD develops
in patients with DM, the prognosis is bleak. Compared with the general popula-
tion, dialysis patients have an estimated life span that is 20% to 25% shorter, and
transplant patients have a life span that is 20% to 30% shorter.4
A large proportion of the cost of DM treatment results from the management
of long-term complications, especially renal disease. In 2000, the Medicare ESRD
program incurred >$12 billion in costs, consuming almost 6% of the entire
Medicare budget.4 Development of ESRD can increase DM treatment costs by

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 L.M. Ruilope and J. Segura

770%.16 Thus, preventing or delaying the progression of renal disease from mi-
croalbuminuria to diabetic nephropathy (persistent proteinuria in overnight spec-
imens [UAE >200 g/min and >30% higher than baseline levels]) and, ultimately,
to ESRD, is an important goal of management.

PROGRESSION OF DIABETIC RENAL DISEASE:

MICROALBUMINURIA TO ESRD
Renal disease associated with type 2 DM progresses through several key stages,
collectively spanning a 20- to 30-year period.3 From 1.5 to 5 years after the on-
set of type 2 DM, early renal involvement is evident, characterized by glomerular
membrane thickening, mesangial expansion, hypertension (BP >140/>90 mm Hg),
and increased glomerular filtration rate (GFR, >150 mL/min).3
From 5 to 15 years after DM onset, a phase of incipient renal disease occurs,
characterized by hypertension and microalbuminuria (defined as a median UAE
of 3 nonconsecutive overnight urine collections in the range of 20200 g/min).
Small amounts of urinary protein, undetectable by conventional urine test strips,
mark the beginning of progressive renal disease, which is characterized by a re-
lentless decline in kidney function. Microalbuminuria with DM is a strong pre-
dictor of cardiovascular morbidity and mortality.1719
From 10 to 20 years after DM onset, overt renal disease develops, character-
ized by macroalbuminuria (defined as a urinary albumintourinary creatinine
ratio of >300 or UAE >0.5 g/d), decreased GFR (<125 mL/min), and hyperten-
sion.3 Approximately 20 to 30 years after the onset of DM, overt renal disease
progresses to ESRD, necessitating dialysis or kidney transplantation.3,5
The mechanisms involved in the renal changes in patients with DM are be-
coming elucidated and appear to involve a complex interaction between meta-
bolic and hemodynamic factors.20,21 Researchers have hypothesized that chronic
hyperglycemia associated with DM leads to the formation of renal polyols and ac-
cumulation of advanced glycation end products.22 These products, in turn, may
trigger intracellular signaling molecules (such as protein kinase C beta, nuclear
factor kappa beta, and mitogen-activated protein kinase) and induce the forma-
tion of various growth factors and cytokines. These metabolic pathways most
likely act both in concert with and independently of several hemodynamic fac-
tors, such as elevated systemic and intraglomerular pressure and the formation of
AII, to produce the structural and functional changes observed in diabetic
nephropathy.20,21

CRUCIAL ROLE OF ANTIHYPERTENSIVE THERAPY FOR

TYPE 2 DIABETIC RENAL DISEASE
Patients with type 2 DM have a high incidence of hypertension; up to 80% have
elevated BP or abnormal circadian BP rhythms.23 Hypertension typically precedes

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CLINICAL THERAPEUTICS

the onset of type 2 DM by years or even decades and is a part of the overall meta-
bolic syndrome of type 2 DM (insulin resistance, obesity, dyslipidemia, and hy-
pertension).23 The coexistence of type 2 DM and hypertension increases the risk
for a variety of complications, including cardiovascular disease, peripheral vas-
cular disease, diabetic nephropathy, and ESRD.5,7
Several management options, including antihypertensive drug therapy and tight
BG control, can slow the progression of renal disease, lessen the economic impact
of cardiovascular and renal disease complications, attenuate complications of ure-
mia, and prepare patients for the possibility of dialysis.24 Effective lowering of BP
is a key consideration in addition to BG control in preventing the cardiovascular
and renal sequelae of DM.25,26 As mentioned earlier, antihypertensive drug therapy
is thus recommended for any diabetic patient with any stage of hypertension.57
BP reduction dramatically slows the decrease in GFR and the progressive loss
of renal function associated with diabetic nephropathy and type 2 DM.1 Long-
term BP control in patients with DM has numerous potential benefits, decreasing
overall mortality; deaths from cerebrovascular accidents (CVAs), cardiovascular
events, and myocardial infarction (MI); proteinuria; and progression of renal
disease.7 The Seventh Report of the Joint National Committee on Prevention,
Detection, Evaluation, and Treatment of High Blood Pressure (JNC 727) and
the 2003 European Society of Hypertension-European Society of Cardiology
(ESH/ESC) guidelines28 both recommend a BP target of 130/80 mm Hg for pa-
tients with hypertension and DM.

ANTIHYPERTENSIVE AGENTS THAT DELAY

RENAL DISEASE IN TYPE 2 DM
In hypertensive patients with type 1 DM and hypertensive nondiabetic patients
with overt nephropathy, ACE inhibitors effectively delay the progression of renal
disease. ACE inhibitors are preferred to calcium channel blockers (CCBs), beta-
blockers, and diuretics.1,6,7,9,10,27 However, in hypertensive patients with type 2
DM, ACE inhibitors have yielded conflicting results in improving proteinuria and
renal function and have not shown better efficacy than nonACE-inhibitor treat-
ments in limiting the progression to ESRD.26,2936
The therapeutic utility of ACE inhibitors in patients with DM in general also
may be limited by several factors.37 First, ACE inhibitors incompletely inhibit the
renin-angiotensin system (RAS), allowing unimpeded formation of AII by non-
ACE pathways, such as cardiac chymase and chymostatin-sensitive AIIgenerating
enzyme. Second, ACE inhibitors alter the metabolism of other endogenous pep-
tides (eg, bradykinin). These alterations are believed to be responsible for several
common adverse reactions (eg, cough) to ACE inhibitors.37,38
The AIIAs may obviate these problems by blocking the RAS at the level of the
angiotensin I (AT1) receptor, the main receptor responsible for mediating the car-

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 L.M. Ruilope and J. Segura

diovascular effects of AII.37,39 In contrast to ACE inhibitors, which do not pro-

duce complete inhibition of AII formation by all synthetic pathways, AIIAs block
the action of AII formed by both ACE and non-ACE routes. In addition, AIIAs
do not alter the metabolism of other endogenous peptides such as bradykinin.37,38
The avoidance of adverse effects may be important because the only effective
antihypertensive treatment is one that a patient will use on a long-term basis.

ANTIPROTEINURIC EFFECTS OF THE AIIAs

Proteinuria is an important marker of glomerular damage and promotes the pro-
gression of renal lesions; it also represents a powerful predictor of the long-term
beneficial effect of antihypertensive therapy.4042 Numerous studies4351 have
shown that AIIAs consistently reduce urinary albumin concentration in patients
with type 2 DM, in patients with nondiabetic nephropathy, in renal transplant
recipients, and in experimental models.
Recently, Zandbergen et al52 demonstrated the antiproteinuric effects of losartan
in normotensive patients with type 2 DM and persistent microalbuminuria. Using
a randomized, double-blind, placebo-controlled study protocol, these investigators
showed that patients receiving 50 mg losartan over the initial 5 weeks of the study
demonstrated a 25% reduction in UAE (vs 6.8% in the placebo group). This value
increased to a 34% reduction (vs an increase of 1.3% in the placebo group) after
a dose of 100 mg over the subsequent 5 weeks. The adjusted mean difference in
UAE rate between losartan and placebo at 5 weeks was 16.9 g/min (P < 0.001).
A multivariate analysis showed that the alterations in UAE occurred independently
of BP, suggesting an independent renoprotective effect of losartan.
A compilation of data12,13,4345,48,5375 on the effect of losartan on urinary pro-
tein loss (Figure 1) in diabetic and nondiabetic patients shows that patients re-
ceiving losartan demonstrated a mean 44% reduction in urinary albumin (Figure
1A) and a mean 36% reduction in urinary protein/albumin (Figure 1B). These ef-
fects are generally consistent for patients with renal disease with or without DM.
With respect to patients with type 2 DM, 2 randomized, controlled trials,
IRMA-211 and the MicroAlbuminuria Reduction with VALsartan (MARVAL) trial,76
demonstrated that AIIAs reduce the progression from microalbuminuria to overt
nephropathy.

IRMA-2 Study
IRMA-211 was a multinational, randomized, double-blind study involving 590
patients (~70% male and 97% white) with type 2 DM and hypertension. It
showed that patients receiving irbesartan had a reduced rate of progression of mi-
croalbuminuria (UAE rate, 20200 g/min in 2 of 3 overnight urine collections)
to clinical proteinuria.11 IRMA-211 compared irbesartan (150 or 300 mg/d) with
placebo for the time to onset of diabetic nephropathy.

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CLINICAL THERAPEUTICS

A 350
348

Diabetic renal disease

300 Nondiabetic renal disease
UAE Rate (mg/24 h)
250
212
200 188
174

153
150
115 101
100 101 94
100 89 92
83
69 66
57 60 55
45 50
50 40 39
30 37
21 22 15
15
0
G ta al
co ein l

Ko re e l
ka l
so al

Es no l
jes al

-V er l

re l
l
ue al

ley l
uv al

sc al
La inst et a
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Ba et

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Lo y e

Sc o e
l
n

lle
ha

os t
or

at
C

ur
r

Pa
de

B 6 5.8
5.8

5
UAE Rate (g/24 h)

4 3.8
3.5 3.5

3 2.8
2.9 2.7
2.5

2 1.9
1.8
1.7 1.6
1.2 1.6
1.2 1.2
1 1 1.1
0.7 1 1 0.8
0.6
0.6 0.9
0.6 0.5
0.4
0.1
0
al
ad ill al

H riel al
An gad t al
or rso t al

Br cia al
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am wis al
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a
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da

dr
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ar

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M

nd
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Fe

Figure 1. Effects of the angiotensin II antagonist losartan on microalbuminuria (A) and pro-
teinuria (B), as measured by urinary albumin excretion (UAE) rate, in studies of
diabetic and nondiabetic renal disease.12,13,4345,48,5375 Adapted with permission.75

3050
 L.M. Ruilope and J. Segura

Approximately 5.3% of patients receiving 300-mg irbesartan, 9.7% of patients

receiving 150-mg irbesartan, and 14.9% of placebo-treated patients reached the
primary end point. The primary end point was the time to onset of diabetic
nephropathy. By 2 years, restoration to normoalbuminuria (<20 g/min) occurred
in 34% of patients in the irbesartan 300-mg group (P < 0.006 vs placebo), 24%
in the irbesartan 150-mg group, and 21% in the placebo group. The effects of the
AIIA were independent of alterations in systemic BP.

MARVAL Trial
The MARVAL trial76 was a randomized study that assessed the effects of valsar-
tan or amlodipine on UAE in 322 patients with type 2 DM and microalbuminuria,
with or without hypertension.76 Subjects were predominantly male (80%) and
white (87%), with an age range of 35 to 75 years. A diuretic (bendrofluazide) or
alpha-blocker (doxazosin) was added to valsartan or amlodipine treatment as
needed to control BP (target, 135/85 mm Hg). A total of 291 patients completed
the study (valsartan, n = 146; amlodipine, n = 145). More patients receiving val-
sartan (29.9%) than amlodipine (14.5%) achieved normoalbuminuria at week 24
(between-treatment difference, 15.4%; P < 0.001) despite similar reductions in BP.
Mean UAE rates decreased from 58 to 32 mg/min in valsartan-treated patients and
from 55 to 51 mg/min in amlodipine-treated patients (P < 0.001).

IMPACT OF AIIAs ON RENAL AND CARDIOVASCULAR OUTCOMES

IN TYPE 2 DM WITH PROTEINURIA
Over the past decade, the advent of evidence-based medicine has generated de-
mand for outcomes data from large clinical trials, which are currently considered
the most valid measure of clinical efficacy. Hard end points such as mortality or
morbidity are needed not only to properly position new and old treatments in a
constantly changing therapeutic armamentarium, but also to help make decisions
about the cost-effectiveness of various interventions.
Two long-term end-point studies in patients with type 2 DM and nephropathy
have addressed whether the marked antiproteinuric effect of AIIAs translates into
improved renal outcomes. These studies are RENAAL12 and IDNT.13 Both trials in-
volved similar study populations: mainly hypertensive patients with type 2 DM
with mild to moderate renal failure (serum creatinine concentration [SCC],
~1.03.0 mg/dL) and frank proteinuria. The results of outcomes studies such as
RENAAL12 provide important evidence-based guidance for physicians and have re-
sulted in a marked change in the treatment paradigm of patients with type 2 DM.

RENAAL Study
The RENAAL study12 represents an important research initiative in the treat-
ment of patients with type 2 DM and nephropathy. The study assessed the po-

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CLINICAL THERAPEUTICS

tential renoprotective benefits of specific AII blockade with losartan in terms of

ESRD or death. The RENAAL study12 was a multinational, double-blind, placebo-
controlled trial that investigated whether losartan, either alone or in combination
with conventional antihypertensive therapy, reduced the number of patients with
type 2 DM who experienced a doubling of SCC, ESRD, or death compared with
placebo-treated patients. In addition, the study assessed the effects of losartan (vs
placebo) on cardiovascular mortality, morbidity, and proteinuria as well as on
quality of life and health care resource utilization.
A total of 1513 patients with type 2 DM, either hypertensive or normotensive,
were randomly assigned to receive losartan (50100 mg/d) or placebo in addi-
tion to their existing antihypertensive therapy for 4 years. Patients had severe re-
nal disease with macroalbuminuria and an SCC of 1.3 to 3.0 mg/dL, and were all
likely to progress to dialysis. The study population comprised male (63%) and
female (37%) patients who were white (49%), black (15%), Asian (17%), His-
panic (18%), or another race (1%), and had a mean age of 60 years. Patients re-
ceived conventional antihypertensive treatment (ie, CCBs, diuretics, alpha-blockers,
beta-blockers, and centrally acting agents) as needed to control BP.
Patients with type 2 DM and nephropathy receiving losartan, along with con-
ventional antihypertensive treatment as needed, demonstrated renal protection
(vs placebo-treated patients) over a follow-up period of 3.4 years.12 Compared
with placebo-treated patients, patients receiving losartan demonstrated a 16% re-
duction (P = 0.02) in the primary composite end point (doubling of SCC, ESRD,
or death from any cause), a 25% risk reduction for doubling of SCC (P = 0.006),
a 28% reduction in the risk of ESRD (P = 0.002), and a 20% risk reduction in
the composite end point of ESRD and death (P = 0.01) (Figure 2). Patients re-
ceiving losartan also demonstrated a 35% decrease in the level of proteinuria, as
evidenced by a significant decrease in the urinary albumin/creatinine ratio (P <
0.001). No differences were observed for the composite end point of cardiovas-
cular morbidity or mortality, although losartan was associated with a 32% re-
duction in the risk of hospitalization for heart failure (P = 0.005).
The renoprotective benefits of losartan occurred over and above the effects on
BP control (the losartan and placebo groups had similar trough systolic and dia-
stolic BPs during the study) and the effects of other therapies including aspirin,
beta-blockers, and lipid-lowering agents. Losartan plus conventional antihyper-
tensive therapy demonstrated excellent tolerability similar to that in the placebo
group. Similar numbers of patients in the 2 study groups discontinued because
of adverse events.

IDNT
IDNT,13 a prospective, randomized, double-blind, placebo-controlled clinical
trial, assessed whether the AIIA irbesartan or the CCB amlodipine protects against

3052
 Losartan
Placebo
A Risk reduction, 16% C Risk reduction, 28%
50 50
P = 0.02 P = 0.002

40 40

30 30

20 20

% of Patients with
10 10

% of Patients with ESRD

Primary Composite End Point

0 0
0 12 24 36 48 0 12 24 36 48

B Risk reduction, 25%

D Risk reduction, 25%
50 50
P = 0.006 P = 0.006

40 40

30 30

20 ESRD or Death 20

Doubling of SCC
% of Patients with

% of Patients with
10 10

0 0
0 12 24 36 48 0 12 24 36 48
Follow-Up (mo) Follow-Up (mo)

Figure 2. Results of the Reduction of End Points in Non-Insulin-Dependent Diabetes Mellitus with the Angiotensin II Antagonist
Losartan (RENAAL) study12: Kaplan-Meier curves showing the effects of losartan or placebo on the cumulative propor-
tion of patients with the primary composite end point (doubling of baseline serum creatinine concentration [SCC], end-

3053
L.M. Ruilope and J. Segura

stage renal disease [ESRD], or death) (A), doubling of SCC (B) or ESRD (C), and death (D). Data represent a mean
follow-up of 3.4 years. Reproduced with permission.12
CLINICAL THERAPEUTICS

the progression of nephropathy in patients with type 2 DM.77 The study involved
1715 hypertensive patients with proteinuria (defined as UAE >900 mg/d) due to
type 2 DM and SCC between 1.0 and 3.0 mg/dL in women and between 1.2 and
3.0 mg/dL in men. The study population comprised men (66%) and women
(34%) who were predominantly white (72%), with a mean age of ~59 years. Pa-
tients received either irbesartan (300 mg/d) or amlodipine (10 mg/d) for a mean
duration of 2.6 years to achieve a target BP of 135/85 mm Hg. The primary end
point of the study was a composite of the time to a doubling of the baseline SCC,
development of ESRD, or death.
Irbesartan-treated patients generally demonstrated better renal outcomes than
those in the amlodipine group (Figure 3).12 These included a 20% lower risk
(P = 0.02) for the primary end point than in the placebo group (23% lower risk
vs the amlodipine group; P = 0.006), a 33% lower risk (P = 0.003) of doubling
of SCC than in the placebo group (37% lower risk vs the amlodipine group;
P < 0.001), and a 23% lower relative risk of ESRD than in either the placebo or
amlodipine groups (not significant for either comparison). The SCC increased
24% more slowly in the irbesartan group than in the placebo group (P = 0.008)
and 21% more slowly than in the amlodipine group (P = 0.02). However, no dif-
ferences were found between groups with respect to the secondary composite end
point of cardiovascular events, including cardiovascular death, MI, hospitalization
for heart failure, or CVA. Irbesartan provided overall benefits even though both
groups had comparable degrees of BP control.

Limitations of RENAAL and IDNT

Although clearly demonstrating that AIIAs produce clinically meaningful re-
ductions in mortality and morbidity end points in patients with type 2 DM and
nephropathy, RENAAL12 and IDNT13 have not been without criticism.7880 It
would have been interesting if both RENAAL12 and IDNT13 had included an
active treatment arm containing an ACE inhibitor, given the effectiveness of
these agents in postponing nephropathy in type 1 DM and in nondiabetic renal
disease.
These studies have additional limitations. The proportion of black subjects
studied was lower than the proportion who actually developed ESRD in the
United States. Also, neither trial showed a benefit in terms of cardiovascular mor-
tality, even though patients with type 2 DM are more likely to die from cardio-
vascular disease than renal disease. Furthermore, neither trial assessed the effects
of beta-blockers, which also inhibit the RAS, on renal disease progression. Finally,
both RENAAL12 and IDNT13 studied a doubling of SCC, which may not be an
accurate surrogate end point of renal damage.79 The SCC can be influenced
acutely by factors unrelated to GFR, such as the ingestion of cooked meat or some
commonly used medications (eg, cimetidine or trimethoprim).8183

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 L.M. Ruilope and J. Segura

Irbesartan
A Amlodipine
Placebo
0.7
0.6
Primary End Point
% of Patients with

0.5
0.4
0.3
0.2
0.1
0.0
0 6 12 18 24 30 36 42 48 54

B 0.7
0.6
a Doubling of SCC
% of Patients with

0.5
0.4
0.3
0.2
0.1
0.0
0 6 12 18 24 30 36 42 48 54

C 0.7
0.6
% of Patients with ESRD

0.5
0.4
0.3
0.2

0.1
0.0
0 6 12 18 24 30 36 42 48 54

Follow-Up (mo)

Figure 3. Results of the Irbesartan Type 2 Diabetic Nephropathy Trial (IDNT)13: Effects
of irbesartan, amlodipine, or placebo on the cumulative proportion of patients
with the primary end point (a composite of the time to a doubling of the base-
line serum creatinine concentration [SCC], development of end-stage renal
disease [ESRD], or death) (A), doubling of SCC (B), and ESRD (C). Data rep-
resent a mean follow-up time of 2.6 years. Reproduced with permission.13

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CLINICAL THERAPEUTICS

LIFE Substudy
The results of the LIFE substudy,14 a cardiovascular morbidity and mortality
end-point trial in hypertensive patients with LVH, corroborated the findings of
RENAAL12 and IDNT.13 As part of the LIFE substudy, the effects of losartan and
atenolol on cardiovascular morbidity and mortality were compared in a total of
1195 patients with hypertension, LVH, and DM.14 Patients averaged 67 years of
age, had a mean BP of 177/96 mm Hg, and were predominantly white (86%) and
female (53%).
The LIFE substudy in patients with DM showed that losartan was more effec-
tive than atenolol in decreasing cardiovascular morbidity and mortality (cardio-
vascular death, CVA, or MI) as well as mortality from all causes, despite similar
decreases in mean BP. The primary end point was a composite of cardiovascular
mortality and morbidity. Compared with atenolol, losartan was associated with a
24.5% lower risk for the primary end point (P = 0.031), a significantly lower risk
for cardiovascular mortality (relative risk, 36.6%; P = 0.028), and lower all-cause
mortality (P = 0.002).

POTENTIAL MECHANISMS OF RENOPROTECTION OF

AIIAs BEYOND BP CONTROL
The RAS is inappropriately activated in type 2 DM. The generation of AII has an
enormous impact on the progression of renal damage through local and systemic
hemodynamic effects and nonhemodynamic effects, such as stimulation of growth
factors and cytokines and modulation of extracellular matrix metabolism
(Table).84,85 Almost all of the renal and cardiovascular actions of AII are mediated
via the AT1 receptor subtype.37,39 Blockade of these receptor sites with AIIAs not

Table. Effects of angiotensin II in the progression of diabetic renal disease.*

Hemodynamic Effects
Systemic hypertension
Systemic and renal vasoconstriction
Increased glomerular capillary pressure and permeability
Mesangial cell contraction leading to reduction in filtration surface area
Nonhemodynamic Effects
Induction of renal hypertrophy and cell proliferation
Stimulation of extracellular matrix synthesis
Inhibition of extracellular matrix degradation
Stimulation of cytokine production
Stimulation of superoxide production

*Adapted with permission.81

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 L.M. Ruilope and J. Segura

only lowers BP but also attenuates many of the deleterious actions of AII in renal
tissues.
AII may cause glomerular hypertension by contracting mesangial cells and
glomerular arterioles and may increase the filtration properties of the glomerular
basement membrane, leading to proteinuria.85 AII may mediate the increase in
glomerular membrane pore radius in DM, an effect that can be ameliorated by an
AIIA.51 AII may induce glomerular sclerosis, a hallmark of diabetic renal disease,
through the stimulation of growth factors and cytokines (eg, transforming growth
factor-, endothelin, and vascular endothelium growth factor) and modulation of
the extracellular matrix.84,85

CONCLUSIONS AND IMPLICATIONS FOR TREATMENT

A major goal of managing patients with type 2 DM and hypertension is prevent-
ing or delaying the development of diabetic renal disease. Strong evidence from
the IRMA-2,11 RENAAL,12 and IDNT13 randomized clinical trials indicates that an
AIIA postpones the progression of type 2 diabetic renal disease at all stages, rang-
ing from microproteinuria to overt nephropathy and ESRD. RENAAL12 also
showed a significant reduction in the incidence of ESRD. The LIFE substudy14
also provides convincing evidence that the AIIA losartan can be considered for
cardiovascular protection in hypertensive patients with DM and LVH. Neverthe-
less, for patients with DM and associated clinical conditions such as MI, CVA,
heart failure, and peripheral vascular disease, ACE inhibitors should be consid-
ered the initial drugs of choice. This assertion is based on the results of several
outcomes studies demonstrating beneficial effects of ACE inhibitors on secondary
prevention of mortality, as reviewed previously.86 In patients with DM and both
renal and cardiovascular disease, the choice of drug is at the discretion of the pre-
scriber. Data from the LIFE substudy,14 however, indicate that a losartan-based
regimen would provide adequate renal and cardiovascular protection for these
patients.
In RENAAL,12 the renoprotective effect of losartan corresponded to an esti-
mated mean delay of 2 years in the need for dialysis or kidney transplantation.
Losartan significantly improved renal outcomes in patients with type 2 DM over
and above that attributable to BP control alone.12 Thus, simply lowering BP with
standard antihypertensives such as beta-blockers or CCBs is inadequate to achieve
the maximal renoprotective benefits. Treatment with AIIAs is the only evidence-
based strategy for patients with type 2 DM and proteinuria, and AIIAs therefore
should perhaps be considered mandatory therapy. This assertion is consistent
with the ESH/ESC guidelines,28 which state that AIIAs should be used first in pa-
tients whose high-normal BP can be controlled using monotherapy. The guide-
lines also note that renoprotection may benefit from the regular inclusion of an
AIIA in antihypertensive combination therapies.

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Collectively, therefore, the current evidence favors the use of an AIIA such as
losartan rather than other antihypertensive agents, including ACE inhibitors, for
renoprotection in type 2 DM with renal damage. AIIA therapy should comple-
ment existing therapeutic options, such as reduced dietary protein intake, strict
BG control, and standard antihypertensive therapy. Together these measures will
help improve survival and quality of life and reduce the health care burden in pa-
tients with DM and nephropathy.

ACKNOWLEDGMENTS
Partial financial support for this document was provided by an educational grant
from Merck & Co., Inc., Whitehouse Station, New Jersey. Writing assistance was
provided by Kala-Jyoti V. Aiyer, PhD.

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Address correspondence to: Luis M. Ruilope, MD, Unidad de Hipertensin,

Hospital 12 de Octubre, 28041 Madrid, Spain. E-mail: luis_m_ruilope@teleline.es

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