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TELMISARTAN EFFECT VERSUS
VALSARTAN EFFECT UPON THE
REDUCTION OF MICROALBUMINURIA AT
THE PATIENTS WITH METABOLIC
SYNDROME
MELINDA KOLCSÀR1*, GRIGORE DOGARU2, CAMIL E. VARI1,
BIANCA TĂTAR1, MARIA T. DOGARU1
1
Pharmacology Department, Faculty of Pharmacy
Nefrology Department, IVth Medical Clinic
University of Medicine and Pharmacy, Târgu-Mureş, 38, Gh. Marinescu
street, 540139, Romania
*corresponding author: kolcsarm@rdslink.ro
2
Abstract
Microalbuminuria (MIA), considered nowadays an important marker of insulin
resistance syndrome can be influenced by a variety of antiangiotensinic drugs. We
compared in 31 patients the antiproteinuric efficacy of two antiangiotensinic drugs:
valsartan (80mg/day) and telmisartan (40mg/day). The duration of the study was 3 month,
during which the metabolic, hemodynamic parameters and MIA were measured. Both
valsartan and telmisartan reduced statistically significant the blood pressure and MIA, but
there was no difference regarding the metabolic effects of the drugs. An important
difference between the studied drugs was noticed in the high percentage of patients with
normalbuminuria after telmisartan administration (40% versus 12.5%). Based on this data
we concluded that the angiotensin-receptor-blocking agent with PPAR-gamma (peroxisome
proliferator- activated receptor) agonist activity (telmisartan) has a beneficial effect in
nephroprotection compared to a classical one (valsartan).
Rezumat
Microalbuminuria (MIA), considerată la ora actuală ca fiind un marker important
al sindromului rezistenţei la insulină, poate fi influenţată de mai multe tipuri de
medicamente antiangiotensinice. Studiul de faţă a comparat eficacitatea antiproteinurică a 2
medicamente antiangiotensinice: valsartan (80 mg/zi) şi telmisartan (40 mg/zi). Durata
tratamentului a fost de 3 luni, perioadă în care s-au înregistrat parametrii metabolici,
hemodinamici şi microalbuminuria. Atât valsartanul cât şi telmisartanul au redus
semnificativ statistic presiunea arterială şi MIA, între cele 2 medicaţii nefiind o diferenţă
semnificativă în acest caz. O diferenţă importantă între medicamentele studiate a fost în
procentul înalt al pacienţilor cu normalbuminurie după administrarea de telmisartan (40%
vs. 12,5%). Pe baza acestor rezultate se poate afirma că blocanţii receptorilor angiotensinei
II cu acţiune agonistă la nivelul receptorilor PPAR-gamma (telmisartan) prezintă avantaje
privind efectul nefroprotector faţă de compuşii clasici (valsartan).


Microalbuminuria
metabolic syndrome


insulin resistance
normalbuminuria
FARMACIA, 2008, Vol.LVI, 6
709
INTRODUCTION
Insulin resistance, which is in part due to hypersympaticotony and
thus to an excess of type II angiotensin, is involved in the pathogenesis of
type two diabetes, metabolic syndrome (MS) and even polycystic ovary
syndrome [1, 2, 3].
The microalbuminuria (MIA), which is nowadays considered an
important marker of the syndrome of insulin resistance which can be thus
influenced by the antiangiotensinic medication, useful not only for patients
with diabetes, but possibly also in other forms of insulin resistance.
Valsartan and telmisartan are blockers of the angiotensinic
receptors (BRA) with marked tissular afinity, telmisartan having special
metabolic properties through the agonistic action on PPAR-gamma
(peroxisome proliferator-activated receptor) [4]. In this regard, telmisartan
seems to have an effect on insulin sensitivity and the literature emphasize
other sartans do not possess this biological action [5, 6].
In the present research, we aimed to compare MIA reduction effect
of valsartan and telmisartan in patients with metabolic syndrome.
MATERIAL AND METHODS
31 patients have been included in the study, consulted in the
ambulatory of the Endocrinology Clinic, Tg. Mures and at the Marmed
Polyclinic, Tg. Mures, in the period of July the 1st 2005-March the 31st 2006.
The inclusion criteria were: the presence of the metabolic
syndrome and values of MIA between 30-300 mg/24 hours. The diagnostic
of metabolic syndrome was established according to the new criteria,
accepted in 2005 by the International Diabetes Federation (IDF) [5], with
the mention that arterial hypertension (HT) was a compulsory criterion for
the patients to be able to benefit from treatment with valsartan or
telmisartan. The exclusion criteria were: urinary infection, pyelonephritis,
manifest heart insufficiency, arterial hypertension with values above
180/100 mmHg, coronary event in the last 6 weeks, autoimmune diseases,
intense physical effort, hyper-proteic diet and allergy known to BRA.
The study was conducted according to principles of Declaration of
Helsinki (1964) and its amendments (Tokyo 1975, Venice 1983, Hongkong 1989).
The microalbuminuria was determined in the laboratory of the
Medical Clinic IV, Tg. Mures, on urine collected in 24 hours, using the
immunoturbidimetric method, (kits of Turbox® Microalbuminuria Orion
Diagnostica).
For patients included into study, the following parameters were
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FARMACIA, 2008, Vol.LVI, 6
determined: the abdominal circumference, the high density lipoproteins
HDL-cholesterol, the serum triglycerides, glycemy and glycosylated
hemoglobine (HgbA1C), creatinine, blood pressure values, then the patients
have been randomized in two lots. Lot A (n=15) followed the treatment with
telmisartan 40mg/day (Pritor®) and lot B (n=16) followed the treatment
with valsartan 80 mg/day (Diovan®), in a single morning dose.
The duration of the study was of 3 months, period in which the
patients were monitored monthly regarding systolic blood pressure (SBP)
and dyastolic blood pressure (DBP), seric creatinine, and at the end of the
study a complete reevaluation was done, with the determination of the same
parameters from the inclusion in the study.
The data obtained were processed through descriptive and
comparative statistical analysis, using the SPSS programme for Windows,
variant 12.0.
RESULTS AND DISCUSSION
The clinical values of the parameters registered for the patients
taken into study (before and after 3 months treatment either with telmisartan
or valsartan) are presented in table I.
Table I
The values of initial and post-therapeutical parameters
after the treatment with telmisartan and valsartan
Average
values±ES
Lot I
At the inclusion
(n=15)
After
telmisartan
(n=15)
Lot II
At the inclusion
(n=16)
After
valsartan
(n=16)
Age (years)
53.6±2.15
-
52.81±1.86
-
MIA (mg/24h)
92.57±13.35
60.74±10.09*
95.51±18.61
66.11±10.13*
Abdominal
93.19±1.64
circumference (cm)
92.39±1.67
91.35±2.1
90.36±2.06
SBP (mmHg)
154.39±2.65
136.18±1.97*
148.18±2.75
134.25±1.87*
DBP (mmHg)
90.90±1.7
82.94±1.90*
92.06±1.69
83.43±1.77*
HDL-cholesterol 39.80±1.60
(mg/dl)
39.92±1.75
40.12±2.03
40.17±1.93
Triglycerides
(mg/dl)
202.75±15.8
205.18±12.66
204.16±13.7
94.56±2.65
94.25±2.23
93.9±2.17
210.45±16.10
Glycemy (mg/dl) 95.34±2.54
HgbA1C (%)
5.54±0.24
5.32±0.23
5.18±0.13
5.06±0.29
Legend: ES – standard error, * - statistically significant decrease, with p<0.05
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It can be noticed that following the treatment with the two BRAs
over a period of 3 months, MIA, SBP and DBP decreased significantly.
Regarding the other parameters, as well as abdominal circumference, HDLcholesterol, creatinine, seric triglycerides, glycemy and HgbA1C, neither
after the treatment with valsartan, nor after the treatment with telmisartan
did we notice statistically significant modifications.
Comparing the degree of MIA decrease in the two groups of
patients, we didn't find a statistically significant difference in the MIA
reduction effect of valsartan and telmisartan (fig. 1).
valsartan
80 mg
valsartan
telmisartan
40 mg
telmisartan
80
34.35%
0,00%
5,00%
10,00%
15,00%
20,00%
25,00%
30,00%
35,00%
40,00%
mg
30.78%
160mg
p-0.49
Figure 1
Comparative analysis of the MIA reduction degree after valsartan and telmisartan.
Student paired t test
Unlike the efficacy identical in MIA reduction, regarding the reach
of normal albuminury (the values of proteinury below 30 mg/24 h), we
found differences between the two groups treated with the pharmakons in
cause (fig. 2,3).
We can notice that following the administration of telmisartan the
normalbuminuria (MIA below 30 mg/24 h) was reached in 40 % of cases,
and after valsartan only in 12.5 % of cases, the difference being statistically
different, with p <0.05.
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FARMACIA, 2008, Vol.LVI, 6
40%
telmisartan
2
12,50%
valsartan
1
0,00%
10,00%
20,00%
30,00%
40,00%
Figure 2
The frequency of reaching normalbuminury after 3 months of treatment with
telmisartan, valsartan respectively
Legend:
1 – frequency of patients with normalbuminuria after valsartan
2 – frequency of patients with normalbuminuria after telmisartan
MIA3telm
5
5
4
4
Frequency
Frequency
MIA3vals
3
2
2
1
1
Mean = 66,1125
Std. Dev. = 40,52125
N = 16
0
20,00
3
40,00
60,00
80,00
100,00
120,00
140,00
160,00
Mean = 58,0733
Std. Dev. = 40,83165
N = 15
0
0,00
30,00
MIA3vals
60,00
90,00
120,00
150,00
MIA3telm
Figure 3
Comparative hystogrammes of MIA values after treatment
Legend:
MIA3vals – MIA values after 3 months of valsartan,
MIA3telm-MIA values after 3 months of telmisartan
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FARMACIA, 2008, Vol.LVI, 6
The factors which determine the occurrence of MIA in individuals
with non-diabetic metabolic syndrome are not well known, thus neither its
treatment is yet crystallised. Recent research emphasized that abdominal
adiposity is responsible for the growth of urinary albumin excretion, both in
women and men [7]. The link between visceral adiposity and
insulinoresistance is well known, also the role of type II angiotensine in the
production of these [8].
BRA are efficient drugs not only in the control of high blood
pressure, but also in the treatment of different nephropathies. In 2004 it was
found out that telmisartan has special properties, which are due to agonistic
action upon PPARγ [9].
Telmisartan also differs from other points of view from the other
BRAs, including valsartan, through the superior affinity towards R-AT1
(angiotensin receptor 1), which confers it a long lasting action and a superior
organ-protective effect [10]. Meanwhile, telmisartan is the only one which
does not contain tetrasole in its structure (fig. 4), which confers it a marked
lypophilia and thus, a high tissular affinity.
CH3
N
CH3
N
CH2 CH3
CH2
N
N
CH2
O
OH
C
Figure 4
Telmisartan chemical structure
Because of the partial agonistic properties, selective towards
PPARγ, telmisartan has positive effects in insulin resistance syndromes (IR).
The metabolic syndrome is closely linked to IR and consists of a
constellation of factors, like obesity, high blood pressure, hyperlypidemia,
all increasing the risk of developing cardiovascular diseases and diabetes
[10]. In order to protect the target organs in the metabolic syndrome,
whether diabetes occurs or not, it is needed for a drug to have both
antihypertensive properties and positive metabolic effects. The studies of
mollecular modelling suggest that telmisartan influences the PPARγ through
interaction at the level of the region of the field of ligand linking, without
being related to the action of blocking the R-AT1 [11]. The PPARγ
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influences not only the expression of the genes implicated in the glucidic
and lipidic metabolism, but has also an antiinflamatory, antiproliferative and
antioxidant action, with benefic effects in the processes of atherogenesis
[12]. All these observations suggest that the dual action mechanism of
telmisartan confers it promising properties, being a sartan with
cardiometabolic action.
CONCLUSIONS



Valsartan and telmisartan are blockers of the angiotensinic receptors
(BRAs) that are efficient not only in the reduction of blood pressure,
but also in the improvement of the endothelial disfunction, in
metabolic syndrome significantly reducing microalbuminuria
Regarding the reduction of microalbuminuria after 3 months
treatment in submaximal doses, there were noticed differences
between valsartan (a classical BRA) and telmisartan (BRA with
PPAR-gamma agonistic action).
In reaching normalbuminuria, telmisartan is more efficient than
valsartan.
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