See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/10746141

Perindopril and candesartan comparative efficacy and safety in type II diabetic

hypertensive patients

Article in Journal of Human Hypertension · July 2003

DOI: 10.1038/sj.jhh.1001572 · Source: PubMed

CITATIONS READS

6 701

5 authors, including:

Arrigo Francesco Giuseppe Cicero Amedeo Mugellini

University of Bologna University of Pavia
853 PUBLICATIONS 21,506 CITATIONS 236 PUBLICATIONS 4,974 CITATIONS

SEE PROFILE SEE PROFILE

Roberto Fogari
University of Pavia
465 PUBLICATIONS 12,840 CITATIONS

SEE PROFILE

All content following this page was uploaded by Amedeo Mugellini on 24 April 2015.

The user has requested enhancement of the downloaded file.


RESEARCH LETTER
Perindopril and candesartan comparative
efficacy and safety in type II diabetic
hypertensive patients
Journal of Human Hypertension (2003) 17, 433–435.
doi:10.1038/sj.jhh.1001572
Dear Sir,
Cardiovascular and cerebrovascular disease risks are
almost doubled when the hypertensive patient is
also affected by diabetes mellitus. Lowering of blood
pressure markedly decreases the rate of cardiovas-
cular events and renal deterioration in these
patients.1 Recent comparative studies in diabetes
suggest that, for the prevention of cardiovascular
events, angiotensin converting (ACE) inhibitors may
be superior to alternative antihypertensive agents,
independently of their antihypertensive effect.2
Compared to ACE inhibitors, angiotensin receptor
blockers (ARBs) offer more complete and pharma-
cologically desirable blockade of the renin–angio-
tensin system, and they are free from the adverse
effect of cough observed with the administration of
ACE inhibitors.3 Metabolic abnormalities as insulin
resistance, impairment lipid profile, and decreased
fibrinolytic activity can be improved by ACE
inhibitors.2 ARBs have been shown to retard the
progression of albuminuria and the development
and progression of nephropathy,4 but there are few
data of the ARBs action on metabolic parameters,
especially in comparison with ACE inhibitors, in
diabetic subjects.
The aim of our study was to compare glucose
homeostasis, serum lipid profile, fibrinolytic activ-
ity, albumin excretion rate (AER), and homocysteine
(Hct) in patients with mild hypertension and type II
diabetes, during therapy with perindopril (a long-
acting ACE inhibitor) and candesartan (a long-acting
ARB).
A total of 96 patients (M : F ¼ 47 : 49) with type II
diabetes according to the American Diabetes Asso-
ciation criteria,5 who had been diagnosed within the
last 6 months and with mild essential hypertension
according to the World Health Organization criteria
(DBP490 and o105 mmHg) on repeated measure-
ments in the absence of any antihypertensive
treatment, were recruited for the study. They were
all in adequate glycaemic control (glycosylated
haemoglobin (HbA1c) o7.5%) with diet or oral
Received 17 September 2002; revised 14 December 2002; accepted
4 February 2003
Journal of Human Hypertension (2003) 17, 433–435
& 2003 Nature Publishing Group All rights reserved 0950-9240/03 $25.00
www.nature.com/jhh
hypoglycaemic agents (second-generation sulphanil-
ureas), were not taking antihypocholesterolaemic
drugs, and did not have evidence of macroangio-
pathy (by electrocardiogram and Doppler examina-
tion), or nephropathy (by microalbuminuria,
defined as AER o30 mg/24 h), or neuropathy (by
vibration perception threshold).5
The study had a randomized, double-blind design
for parallel groups: after an initial 4-week wash-out
placebo period, patients were randomly given
perindopril, 4 mg once daily, or candesartan, 16 mg
once daily for 12 months.
At the end of the placebo and active treatment
periods, body mass index (BMI), fasting plasma
glucose (FPG), HbA1c, fasting plasma insulin (FPI),
homeostasis model assessment (HOMA index), SBP,
DBP, lipid profile with lipoprotein (Lp(a)), plasma
plasminogen activator inhibitor 1 (PAI-1), Hct levels,
and AER were evaluated. All variables (except for
HbA1c at 1 month) were evaluated at the end of the
placebo period (baseline), and 1, 6, and 12 months
later, and after a wash-out period of 1 month.
Blood pressure was monitored at each clinical
visit (every month) in the seated position (right
arm), by using a standard mercury sphygmoman-
ometer with a cuff of appropriate size. Measure-
ments were always taken by the same investigator in
the morning before daily drug intake (ie B24 h after
dosing) and after the subject had rested 10 min in a
quiet room. Three successive blood pressure read-
ings were obtained at 1 min intervals and averaged.
All plasma parameters were determined after a
12-h overnight fast with the standardized method as
described in Fogari et al.6 The estimate of insulin
resistance was calculated by HOMA index with the
formula: FPI (mU/ml)  FPG (mmol/l)/22.5. HOMA
index is an inexpensive alternative to more sophis-
ticated techniques and has a good correlation with
glucose-clamp technique, the gold standard in the
assessment of insulin sensitivity.7
One-way analysis of variance (ANOVA) followed
by t-test was carried out to assess eventual differ-
ence from baseline values and between the two
treatment groups. A value of Po0.05 has been
considered as significant for each test.
After 4 weeks of placebo treatment, patients were
entered into treatment period and randomly allo-
cated to take either perindopril (N ¼ 49; mean
 Research Letter

434

Data are means 7 s.d.; *Po0.05 compared to values between treatments; **Po0.05 compared to values before treatments; ***Po0.02 compared to values before treatments; ****Po0.01 compared
age ¼ 53 7 10 years) or candesartan (N ¼ 47; mean

7.0 7 2.0*****
3.0 7 0.5*****

0.01 7 0.0001
age ¼ 55 7 9 years). There was no significant differ-

0.03 7 0.002

0.04 7 0.002***** 0.04 7 0.003

0.1 7 0.05
0.56 7 0.28
7.64 7 3.47* *****2.08 7 0.69
0.51 7 0.1*,***** 0.15 7 0.04
0.03 7 0.02***** 0.05 7 0.03
ence between clinical characteristics (age, sex dis-

2.0 7 1.1
1.1 7 0.6
5 7 2.4
C
tribution, BMI), haemodynamic parameters (BP,

1 month wash-out
heart rate) and laboratory data before perindopril
and candesartan administration.
No subject experienced adverse effects serious

5.0 7 1.5*****
4.0 7 1.0*****

1.0 7 0.7*****
enough to warrant discontinuing either drug, but

Table 1 Perindropil 4 mg (P) vs candesartan 16 mg (C): blood pressure and metabolic parameters before, after the treatments, and during the wash-out period

,
some side effects were manifested: dry cough,

0.03 7 0.002
0.06 7 0.023
0.1 7 0.05
0.39 7 0.17

0.9 7 0.1
8 7 3.6****** 8 7 4.1****** 6 7 2.6
abnormal taste, or epigastric discomfort in five

P
patients of the perindopril group and headache,
dizziness, or nausea in three patients of the
candesartan group. Creatinine values were not
altered and remained within the normal range

8.0 7 3.5** 8.0 7 3.6**11.0 7 4.1*** 10 7 3.9***13.0 7 4.5**** 12.0 7 4.1****
5.0 7 1.8** 3.0 7 0.8** 6.0 7 2.20*** 5.0 7 1.7***11.0 7 3.6*,**** 8.0 7 2.9****
during all phases of the trial.

0.02 7 0.009
0.33 7 0.17 0.83 7 0.22*,*** 0.44 7 0.11
2.78 7 0.35 9.72 7 6.25* *** 4.86 7 2.78
0.8 7 0.2*,*** 0.25 7 0.08
0.07 7 0.03 0.36 7 0.19*,*** 0.10 7 0.05
0.05 7 0.01

0.04 7 0.03 0.18 7 0.07*,*** 0.07 7 0.02

Our main results have been summarized in Table 1

0.2 7 0.1

5.0 7 2.4****** 3.0 7 0.9

0.9 7 0.1
(expressed as means 7 s.d.). Both tested drugs

C
significantly reduced BP and this reduction was

12* month
already visible at first month.

to values before treatments; *****Po0.05 compared to values at 12th month; ******Po0.05 compared to values before treatments.
We previously observed that FPG and HbA1c
values did not differ after treatment between

,
perindopril and losartan.6 Although our patients

0.03 7 0.02 0.05 7 0.01

0.05 7 0.02 0.25 7 0.13

0.3 7 0.02
0.2 7 0.1
were in good glucose control with diet and oral

P
hypoglycaemic agents, we obtained a further reduc-
tion of FPG with perindopril at 12th month
compared to candesartan (9.7 and 5.0%, respec-
tively). As expected, candesartan therapy did not
Changes

0.12 7 0.06

0.13 7 0.05
modify glycaemic profile during the study.8

2.0 7 0.8
0.05 7 0.2
7.2 7 3.8
Several studies comparing the effects of ACE C
inhibitors and ARBs have been undertaken to
6* month

elucidate the mechanism of the beneficial effect of

ACE inhibitors on insulin sensitivity. In our study,
perindopril improved HOMA index compared to 0.1 7 0.05
8.60 7 0.83 8.88 7 0.72 0.28 7 0.06 0.22 7 0.11 0.44 7 0.22
70.84 7 40.2873.62 7 42.363.47 7 0.49 1.39 7 0.07 6.25 7 0.69

LDL-C (mmol/l) 3.11 7 0.47 3.24 7 0.39 0.08 7 0.04 0.05 7 0.02 0.16 7 0.08
HDL-C (mmol/l) 1.11 7 0.10 1.04 7 0.13 0.03 7 0.01 0.02 7 0.0030.04 7 0.01
1.81 7 0.20 1.68 7 0.11 0.11 7 0.09 0.08 7 0.05 0.18 7 0.13
1.04 7 0.43 1.07 7 0.36 0.04 7 0.01 0.02 7 0.01 0.11 7 0.04

0.2 7 0.01
0.3 7 0.09 0.08 7 0.01 0.5 7 0.1

4.0 7 1.9

6.8 7 2.6
candesartan (20.7 vs 6.2%), while Higashiura
P

et al9 found that candesartan significantly improves

insulin resistance with glucose-clamp technique in
patients with essential hypertension, through ACE
inhibition. Moreover, after 12 months of perindopril
1.6 7 0.7
0.1 7 0.01 0.3 7 0.1
5.1 7 2.1
therapy, we noted a statistically significant improve-
F
C

ment of plasma LDL-C (11.7%) and Lp(a) (17.2%)

1* month

compared to candesartan (3.2 and +6.7%, respec-

tively), but ACE inhibitors are already known to
improve plasma LDL-C and Lp(a) levels.10
2.0 7 1.2

4.5 7 1.9

With regard to plasma fibrinolytic parameters, in

F
P

our study, we observed a reduction of PAI-1 at 12th

month with perindopril (13.2%) compared to an
increase at the same month with candesartan
6.40 7 0.90 6.50 7 1.10

3.99 7 2.5

(7.7%). It confirms our previous report where we

39 7 13

18 7 11
148 7 6
93 7 5

10.9 7 6

demonstrated that perindopril decreased PAI-1

C

compared to losartan, in hypertensive, type II

Baseline

diabetic patients.6
Finally, as expected,4,6 AER was decreased at the
3.86 7 2.2

38 7 11

17 7 10

end of the study in both groups (47.1 and 44.5%,

147 7 6
94 7 4

11.5 7 5
P

respectively). Our patients started as normoalbumi-

nuric and remained normoalbuminuric for all the
phases of the study, probably because the glycaemic
AER (mg/24 h)

control was good and the antihypertensive therapy

Lp(a) (mmol/l)
FPG (mmol/l)

PAI-1 (ng/ml)
HOMA index
DBP (mmHg)
SBP (mmHg)

FPI (pmol/l)

Tg (mmol/l)

Hct (mmol l)

stopped the possible progression to microalbumi-

HbA1c (%)

nuria.
In conclusion, to the best of our knowledge, this is
a first study comparing perindopril and candesartan

Journal of Human Hypertension


on hypertensive, type II diabetic patients. These
data suggest that potentiation of the kinin system by
ACE inhibition may play an important role in the
positive effects of ACE inhibitors on insulin sensi-
tivity, fibrinolytic balance, improvement of lipid
profile, and on Lp(a) reduction, beyond blood
pressure control. However, we do not exclude a
contribution of angiotensin II or involvement of
other angiotensin receptor subtypes in these effects.
Further studies are needed to verify these points.
References
1 Arauz-Pacheco C, Parrott MA, Raskin P. The treatment of
hypertension in adult patients with diabetes. Diabetes Care
2002; 25: 134–147.
2 Pahor M, Psaty BM, Furberg CD. Treatment of hypertensive
patients with diabetes. Lancet 1998; 351: 689–690.
3 Pylypchuk GB. ACE inhibitorFversus angiotensin II block-
erFinduced cough and angioedema. Ann Pharmacother 1998;
32: 1060–1066.
4 Gradman AH. AT(1)-receptor blockers: differences that matter.
J Hum Hypertens 2002; 16 (Suppl. 3): S9–S16.
5 The Expert Committeee on the diagnosis and classification of
diabetes mellitus. Report of the Expert Committeee on the
diagnosis and classification of diabetes mellitus. Diabetes Care
2003; 26 (Suppl. 1): 5–20.
6 Fogari R et al. Losartan and perindopril effects on plasma
plasminogen activator inhibitor-1 and fibrinogen in hyperten-
View publication stats
Research Letter
435
sive type 2 diabetic patients. Am J Hypertens 2002; 15:
316–320.
7 Bonora E et al. Homeostasis model assessment closely mirrors
the glucose clamp technique in the assessment of insulin
sensitivity. 2000; 23: 57–63.
8 Trenkwalder P, Lehtovirta M, Dahl K. Long-term treatment
with candesartan cilexetil does not affect glucose homeostasis
or serum lipid profile in mild hypertensives with type II
diabetes. J Hum Hypertens 1997; 11 (Suppl. 2): S81–S83.
9 Higashiura K, Ura N, Miyazaki Y, Shimamoto K. Effect of an
angiotensin II receptor antagonist, candesartan, on insulin
resistance and pressor mechanisms in essential hypertension.
J Hum Hypertens 1999; 13 (Suppl. 1): S71–S74.
10 Derosa G et al. Effects of fosinopril on blood pressure, lipid
profile, and lipoprotein (a) levels in normotensive patients
with type 2 diabetes and microalbuminuria: an open-label,
uncontrolled study. Curr Ther Res Clin Exp 2002; 63: 216–226.
G Derosa, AFG Cicero, A Mugellini, L Ciccarelli and
R Fogari
Department of Internal Medicine and Therapeutics
University of Pavia, Pavia, Italy
Department of Clinical Medicine and Applied
Biotechnolgy ‘D Campanacci’, University of
Bologna, Bologna Italy
Correspondence: G Derosa Dr G Derosa
Department of Internal Medicine and Therapeutics
University of Pavia, P le C Golgi, 2, 27100 Pavia Italy
E-mail: giuderosa@tin.it
Journal of Human Hypertension