Nephrol Dial Transplant (2011) 26: 35733577

doi: 10.1093/ndt/gfr102
Advance Access publication 8 March 2011

Irbesartan treatment does not influence plasma levels of the advanced

glycation end products N e(1-carboxymethyl)lysine and
N e(1-carboxyethyl)lysine in patients with type 2 diabetes and
microalbuminuria. A randomized controlled trial
Lian Engelen1,2, Frederik Persson3, Isabel Ferreira1,2,4, Peter Rossing3, Peter Hovind3,5, Tom Teerlink6,
Coen D. Stehouwer1,2, Hans-Henrik Parving7,8 and Casper G. Schalkwijk1,2
1

Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, The Netherlands,
Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, The Netherlands, 3Steno Diabetes Center,
Gentofte, Denmark, 4Department of Clinical Epidemiology and Medical Technology Assessment (KEMTA), Maastricht University
Medical Centre, Maastricht, The Netherlands, 5Department of Clinical Physiology and Nuclear Medicine, Glostrup Hospital, Glostrup,
Denmark, 6Department of Clinical Chemistry, VU University Medical Centre (VUMC), Amsterdam, The Netherlands, 7Department of
Medical Endocrinology, University Hospital of Copenhagen, Copenhagen, Denmark and 8Faculty of Health Science, University of
Aarhus, Aarhus, Denmark
2

Abstract
Background. In vitro and animal experiments have shown
inhibiting effects of angiotensin receptor blockers (ARBs)
on the formation of advanced glycation end products
(AGEs), which are known to be involved in the development of cardiovascular complications in diabetes. However, sufficient human data to confirm such beneficial
effects of ARBs on AGEs are lacking. Therefore, we investigated the effects of irbesartan treatment on plasma
levels of the AGEs N(1-carboxymethyl)lysine (CML)
and N(1-carboxyethyl)lysine (CEL) in hypertensive patients with type 2 diabetes and microalbuminuria.
Methods. We analysed data from a multicentre, doubleblind, parallel, randomized controlled trial in patients with
type 2 diabetes and microalbuminuria, the primary goal of
which was to examine the renoprotective effects of irbesartan treatment (150 or 300 mg daily). Secondary end points
included plasma CML and CEL in the treatment arm receiving 300 mg irbesartan (n 139) and in the placebo
group (n 125). Effects of treatment at 1- and 2-year
follow-up were analysed by means of generalized estimating equations according to an intention-to-treat principle.
Results. Levels of CML and CEL did not differ between
groups at baseline. No significant changes were observed in
CML and CEL over time in either group and there was no
effect of treatment on CML and CEL at any time-point.
Mean differences for the irbesartan versus placebo group
over time were 0.96 lmol/mol lysine (95% confidence
interval: 3.43 to 1.51) for CML and 0.10 lmol/mol
lysine (0.76 to 0.56) for CEL.
Conclusions. Long-term irbesartan treatment does not
influence plasma levels of the AGE CML and CEL in
patients with type 2 diabetes and microalbuminuria.

Keywords: advanced glycation end products; albuminuria; angiotensin II

type I receptor blockers; hypertension; irbesartan; type 2 diabetes

Introduction
Increased formation of advanced glycation end products
(AGEs) constitutes a potential mechanism by which hyperglycaemia and its immediate biochemical sequelae induce
micro- and macrovascular complications in diabetes [1].
Although the exact mechanisms through which AGEs are
involved in vascular complications are still under debate,
direct modification of extracellular matrix proteins, resulting
in collagen cross-links and increased vascular stiffness, is
likely involved [1]. In addition, binding of AGEs to a variety
of cell-surface receptors, such as the receptor for advanced
glycation end products (RAGE) could trigger signal transduction pathways and the production of reactive oxygen species, resulting in proinflammatory cellular responses [2].
Several potential AGE inhibitors have thus been developed,
although the clinical value remains to be established [3].
The reninangiotensinaldosterone system (RAAS),
which is upregulated in diabetes, also plays an important
role in the development of renal and cardiovascular diseases [46]. Blockade of the RAAS with the use of angiotensin receptor blockers (ARBs) reduces the progression of
nephropathy and other cardiovascular outcomes in patients
with type 2 diabetes [7, 8]. Interestingly, it has been shown
that several ARBs attenuate the in vitro production of
AGEs and dicarbonyl compounds, which are reactive intermediates in the formation of AGEs [9]. In addition, several animal experiments have also shown a reduction in
AGE accumulation in the kidneys [1014] and eyes [15]
after treatment with ARBs. These observations led to the

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3574

L. Engelen et al.

hypothesis that AGE-inhibiting effects may contribute, at

least in part, to the beneficial effects of ARBs on diabetic
micro- and macrovascular complications [12, 15]. However, sufficient clinical evidence from human studies to
sustain this contention is still lacking. Indeed, decreases
in circulating [1618] or urinary [18] AGEs in patients with
type 2 diabetes after treatment with ARBs have been observed in very small clinical studies lacking control groups,
but no such effects on circulating AGEs were confirmed in
a larger subsample of a placebo-controlled trial [19] neither
by our previous observations on AGE peptides [20], which,
however, do not represent AGEs appropriately as it has
been shown that AGE peptide measurements only reflect
total low-molecular weight fluorophores, which are not
only due to AGEs or even AGE peptides and could show
non-AGE-related effects [21].
In view of these considerations, we have now investigated the long-term effects of irbesartan treatment as compared with placebo on plasma levels of the AGEs N e(1carboxymethyl)lysine (CML) and N e(1-carboxyethyl)lysine (CEL), as determined by the gold standard technique
for measuring plasma AGEs [i.e. high-performance liquid
chromatography (HPLC)-tandem MS] in a randomized
controlled trial in patients with type 2 diabetes and microalbuminuria, the primary goal of which was to examine the
renoprotective effects of irbesartan treatment [8].

3 body mass 3 (0.85 if female)]/(72 3 serum creatinine in mg/dL)}.

These variables were evaluated at the time of randomization, 2 and 4
weeks after randomization and at 3, 6, 12, 18 and 2224 months [20].
CML and CEL residues in plasma proteins were measured using
HPLC-Tandem Mass Spectrometry [25] with interassay coefficients of
variation being 5.2% for CML and 3.6% for CEL. Laboratory technicians were blinded to the allocated treatment and clinical status of the
patients.

Methods

Baseline characteristics are shown in Table 1. Plasma levels of CML and CEL, as well as all other patient characteristics, did not differ between groups. A more detailed
description of patient characteristics, such as ongoing use
of non-study medication and adverse events during the
trial, has been presented elsewhere [8].

The IRMA 2 study was a 2-year multicentre, double-blind, parallel

randomized controlled trial in patients with type 2 diabetes and microalbuminuria in which the main goal was to compare the effects of irbesartan (150 or 300 mg once daily) versus placebo, in addition to
conventional antihypertensive treatment, on the development of overt
nephropathy [8]. Briefly, we enrolled patients with type 2 diabetes (diagnosed according to the World Health Organization criteria [22]) and hypertension (defined as mean systolic blood pressure >135 mmHg and/or
mean diastolic blood pressure >85 mmHg in two of three consecutive
measurements 1 week apart) and persistent microalbuminuria (defined as
an albumin excretion rate of 20200 lg/min in two of three consecutive overnight urine samples) and a serum creatinine concentration of
1.5 mg/dL for men and 1.1 mg/dL for women. A total of 590 (186
women) patients, aged 3070 years, were included and randomly assigned
to receive 150 mg irbesartan once daily (n 195), 300 mg irbesartan once
daily (n 194) or matching placebo (n 201).
The study protocol was in accordance with the Declaration of Helsinki and
approved by the institutional review board at each centre. All patients gave
written informed consent.
Results regarding the primary end point [8], and other secondary end
points such as markers of inflammation and endothelial dysfunction [20],
have been reported previously. The aim of the present study was to evaluate the effect of irbesartan treatment on plasma levels of the AGEs CML
and CEL. Samples for their assessment at baseline and at 1- and 2-year
follow-up were available from 139 patients in the treatment arm receiving
300 mg irbesartan and from 125 patients receiving placebo because, unfortunately, all samples from the 150-mg irbesartan group were discarded
by error. However, in the initial analyses of this study, no significant
effects of 150 mg irbesartan treatment versus placebo were found on the
development of nephropathy, creatinine clearance or blood pressure [8].

Variables with skewed distribution (i.e. creatinine clearance) were log

transformed prior to further analyses.
The effects of treatment with irbesartan on plasma levels of AGEs over
time were examined according to the intention-to-treat principle and with
the use of generalized estimating equations (GEE). This is a regression
model for analyses of repeated measurements that adjusts for the correlation between repeated observations within individuals. We analysed the
mean differences in plasma CML and CEL between the irbesartan treatment and the placebo groups using a first model only including group (i.e.
irbesartan or placebo) and time (treated as a categorical variable) as determinants of plasma CML or CEL. We then added interaction terms between
group and time to the initial model, in order to assess the exact differences
in CML and CEL between groups at each time-point. In all GEE analyses,
an exchangeable correlation structure was used which was deemed the
most appropriate after examination of the inter-period correlation matrices
of the dependent variables.
All analyses were performed with the use of STATA 9.0 (Stata Corp.,
College Station, TX).

Results

Effects of irbesartan treatment on plasma levels of

CML and CEL
Plasma levels of CML and CEL did not change significantly over time in either group and did not differ between
groups (Figure 1). Specifically, overall differences between
irbesartan versus placebo throughout the course of followup were 0.96 lmol/mol lysine (95% confidence interval:
3.43 to 1.51) for CML and 0.10 lmol/mol lysine
(0.76 to 0.56) for CEL, and also these effects did not
differ at any time-point (P-values for interaction between
group and time were all
0.674, Table 2).
Additional analyses
Additional adjustments for age, sex and duration of diabetes (time-independent covariates) and HbA1c, creatinine
clearance and BMI (time-dependent covariates) did not
materially change our results (data not shown).

Biochemical measurements

Discussion

HbA1c was measured by ion-exchange HPLC [23]. Serum creatinine concentration was measured by the Jaffe reaction with the use of a HoffmannLaRoche kit [24] and creatinine clearance (in mL/min/1.73m2 body surface area) was estimated with the Cockcroft-Gault equation {[(140  age)

The present multicentre, double-blind, randomized controlled trial in patients with type 2 diabetes and microalbuminuria comparing the effects of treatment with irbesartan

Downloaded from http://ndt.oxfordjournals.org/ by guest on August 9, 2015

Study design and participants

Statistics

Irbesartan treatment and plasma AGEs

3575
a

Table 1. Clinical characteristics of the study participants at baseline

Men/women, n
Age (years)
Known duration of diabetes (years)
HbA1c (%)
Body mass index (kg/m2)
Total cholesterol (mmol/L)
Current smoking [n (%)]
Systolic blood pressure (mmHg)
Diastolic blood pressure (mmHg)
Pulse pressure (mmHg)
Creatinine clearance (mL/min/1.73m2 body
surface area)
Urinary albumin excretion rate (mg/24 h)
Ne(1-carboxymethyl) lysine (CML in lmol/mol lysine)
Ne(1-carboxyethyl) lysine (CEL in lmol/mol lysine)

300 mg irbesartan
(n 139)

Placebo
(n 125)

98/41
57.3 6 7.9
7 (412)
6.9 6 1.7
29.8 6 4.3
5.7 6 1.1
22 (15.8)
154 6 13
92 6 10
62 6 12
106 (91123)

83/42
58.2 6 9.1
8 (415)
7.1 6 1.7
30.5 6 4.3
5.8 6 1.1
25 (20.0)
154 6 15
90 6 8
64 6 14
107 (86127)

52 (3583)
49.0 6 14.9
13.2 6 4.8

50 (3180)
49.9 6 11.9
13.2 6 3.2

Data are expressed as mean 6 SD, median (interquartile range) or percentages. Data are stratified according to treatment group: 300 mg irbesartan or
placebo.

(300 mg once daily) versus placebo in addition to conventional antihypertensive treatment [8, 20] showed no treatment effects of irbesartan on plasma levels of the AGEs
CML and CEL.
Blockade of the RAAS system has been shown to reduce
progression of nephropathy and cardiovascular outcomes
in patients with type 2 diabetes [7, 8]. The observation in
several in vitro [9] and animal experimental [1015] studies
showing inhibiting effects of ARBs on AGEs and their
sequelae led to the hypothesis that such AGE inhibiting
effects could explain, at least in part, the beneficial effects
of ARBs on renal and cardiovascular outcomes in patients
with type 2 diabetes [12, 15]. Specifically, such beneficial
effects could be due to the radical scavenging [13, 26] and
metal-chelating properties [26] of ARBs, downregulation
of RAGE expression [12] and/or restoration of glyoxalase 1
function [27]. However, although several small clinical
studies investigating the AGE-inhibiting effects of ARBs
have also shown decreases in circulating [1618] or urinary
[18] AGEs in patients with type 2 diabetes, Busch et al.
[19] showed no differences in plasma CML and pentosidine after 2 years of treatment with irbesartan versus placebo in patients with type 2 diabetes. Although our
previously published results on AGE peptides [20] were
in line with these results, it is currently known that AGE
peptide measurements only reflect total low-molecular

weight fluorophores, which are not only due to AGEs or

even AGE peptides and could show non-AGE-related effects [21]. Our current results in a larger, long-lasting,
randomized controlled trial using the gold standard for
the measurement of plasma AGEs (i.e. HPLC-tandem
MS, as opposed to former studies that used ELISA techniques [1619] or AGE peptides [20]) are in line with the
study of Busch et al. Altogether, these findings suggest that
AGE-inhibiting effects of ARBs may be restricted to experimental models of diabetes. Therefore, the beneficial
effects of ARBs on the renal and cardiovascular system
in patients with type 2 diabetes could more likely be explained by mechanisms other than inhibition of advanced
glycation. However, we cannot fully discard the possibility
that the discrepancy between our current results and the
beneficial effects previously shown in in vitro and animal
experiments lies in the type of tissue examined. It remains
possible that the potential beneficial effects of ARBs, as
seen in the kidneys [1013] and eyes [15] in experimental
models of diabetes, may not translate to changes in plasma
levels of CML and CEL.
A possible limitation to the present study lies in the fact
that it was not specifically designed to assess the effects of
irbesartan on plasma AGEs. However, given its design, size
and precise measurement of plasma AGEs, it provides the
best evidence so far in this regard. To further clarify the exact

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Fig. 1. Means and standard errors of plasma levels of CML and CEL at baseline, 1-year and 2-year follow-up for the irbesartan treatment group (n 139)
and the placebo group (n 125).

3576

L. Engelen et al.

Table 2. Regression coefficients for the effects of irbesartan treatment on plasma levels of CML and CEL as estimated by GEE analysesa
b
CML

CEL

Intercept: 49.899
Group: irbesartan versus placebo
Time
1 year
2 year
Group 3 time interaction
1 year
2 year
Intercept: 13.188
Group: irbesartan versus placebo
Time
1 year
2 year
Group 3 time interaction
1 year
2 year

95% CI

P-value

0.895

4.117 to 2.328

0.586

0.364
0.393

2.061 to 1.333
1.356 to 2.141

0.674
0.660

0.298
0.520

2.429 to 3.026
3.415 to 2.375

0.830
0.725

0.010

0.980 to 0.960

0.983

0.104
0.083

0.450 to 0.707
0.436 to 0.602

0.736
0.753

0.214
0.058

1.211 to 0.783
1.070 to 0.954

0.674
0.910

clinical impact, if any, of ARBs on advanced glycation, future research including more and different measurements of
advanced glycation (e.g. free methylglyoxal, intracellular
AGE concentrations or tissue AGE accumulation), which
may better reflect the advanced glycation processes that
may be affected by treatment with ARBs, is needed.
In conclusion, long-term irbesartan treatment does
not influence plasma levels of the AGEs CML and CEL
in hypertensive patients with type 2 diabetes and
microalbuminuria.
Acknowledgements. The authors thank Rob Barto from the Department of
Clinical Chemistry, VU University Medical Center in Amsterdam, The
Netherlands, for expert technical assistance.
I.F. is supported by a research grant from the Netherlands Heart Foundation (NHS; grant # 2006T050).

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19. Busch M, Franke S, Wolf G et al. Serum levels of the advanced glycation end products Nepsilon-carboxymethyllysine and

Downloaded from http://ndt.oxfordjournals.org/ by guest on August 9, 2015

The intercept represents the plasma AGE levels (in lmol/mol lysine) for the placebo group at baseline; the regression coefficient (b) for the group
variable represents the difference in AGE levels between irbesartan treatment versus placebo groups at baseline; the b for the time variable (i.e. 1-year and
2-year follow-up) represents the change over time for the placebo group (versus baseline); the b for the group 3 time interactions represents the difference
in AGE levels between the irbesartan treatment versus placebo groups at 1-year and 2-year follow-up versus baseline, respectively. On the basis of these
equations, the mean levels of CML at 1-year follow-up were 49.535 ( 49.899  0.364) lmol/mol lysine in the placebo group and 48.938 ( 49.899 
0.895  0.364 1 0.298) lmol/mol lysine in the irbesartan group. CI, confidence interval.

Irbesartan treatment and plasma AGEs

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biomarkers of inflammatory activity in patients with type 2 diabetes
and microalbuminuria: an IRMA 2 substudy. Diabetes 2006; 55:
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their relevance to diabetic complications? Diabetes Obes Metab 2007;
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Received for publication: 21.10.11; Accepted in revised form: 4.2.11

Nephrol Dial Transplant (2011) 26: 35773581

doi: 10.1093/ndt/gfr079
Advance Access publication 7 March 2011

Benjamin Terrier1,2, Hassan Izzedine3, Lucile Musset4, Pascale Ghillani4, Gilbert Deray3,
David Saadoun1,2 and Patrice Cacoub1,2
1

Department of Internal Medicine, Groupe Hospitalier Pitie-Salpetrie`re, Universite Pierre et Marie Curie, Paris, France, 2CNRS UMR
7211, Groupe Hospitalier Pitie-Salpetrie`re, Universite Pierre et Marie Curie, Paris, France, 3Department of Nephrology, Groupe
Hospitalier Pitie-Salpetrie`re, Universite Pierre et Marie Curie, Paris, France and 4Department of Immunology, Groupe Hospitalier
Pitie-Salpetrie`re, Universite Pierre et Marie Curie, Paris, France
Correspondence and offprint requests to: Patrice Cacoub; E-mail: patrice.cacoub@psl.aphp.fr

Abstract
Background. Cryofibrinogenaemia (CryoFg) is an underrecognized cryoprotein that can be life-threatening when
untreated. Symptoms are mainly thrombotic cutaneous
manifestations, but other thrombotic localizations may occur. In patients with end-stage renal disease, thromboses
are common. However, the implication of CryoFg was
never assessed. The aim of this study is to describe the
prevalence and the significance of CryoFg in patients with
renal disorders.
Methods. One hundred and one consecutive patients admitted in a nephrology department for the management of
renal disorders were tested for the presence of serum cryoprotein, i.e. cryoglobulinaemia and CryoFg. We analysed
clinical and biological factors associated with the presence
of CryoFg.
Results. Among the 101 patients, 11 patients had positive
CryoFg without detectable cryoglobulin (11%). Median
CryoFg level was 0.07 g/L (0.051.16). Main epidemiological features and causes of nephropathy, in particular
vascular nephropathies, were similar between CryoFg
and CryoFg1 patients. No biological difference (haematuria, proteinuria, creatinine level and glomerular filtration

rate using Modification of Diet in Renal Disease) was

found between CryoFg- and CryoFg1 patients. In contrast,
CryoFg1 compared to CryoFg patients had more frequent severe thrombotic events (36 versus 0%, P <
0.0001). Severe thrombotic events included renal artery
thrombosis in two patients, recurrent arteriovenous
fistula thrombosis in one and recurrent dialysis catheter
thrombosis with superior vena cava obstruction in one.
The presence of CryoFg was not associated with other
manifestations, in particular cutaneous manifestations.
Conclusion. Cryofibrinogenaemia is detected in up to 11%
of patients with renal disorders. In such patients, the presence of CryoFg is associated with thrombotic events.
Keywords: cryofibrinogenaemia; nephropathy; thrombosis

Introduction
Cryofibrinogenaemia involves a cryoprotein originally
characterized by Korst and Kratochvil [1] and is defined as
the presence of cold precipitable proteins in the plasma. The
cryoprecipitate is made of fibrinogen, fibrin, fibronectin,

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Prevalence and clinical significance of cryofibrinogenaemia in patients

with renal disorders