ORIGINAL PAPER
Fixed-Combination Olmesartan/Amlodipine Was Superior to
Perindopril + Amlodipine in Reducing Central Systolic Blood Pressure in
Hypertensive Patients With Diabetes
Luis M. Ruilope, MD1,2 on behalf of the SEVITENSION Study Investigators
From the Institute of Research & Hypertension Unit, Hospital 12 de Octubre;1 and Department of Public Health and Preventive Medicine, Universidad
Autonomy, Madrid, Spain2
This post hoc analysis from the Sevikar Compared to the
Combination of Perindopril Plus Amlodipine on Central
Arterial Blood Pressure in Patients With Moderate-to-Severe
Hypertension (SEVITENSION) study assessed the efficacy
and tolerability of olmesartan (OLM) and amlodipine (AML) in
reducing central systolic blood pressure (CSBP) compared
with perindopril (PER) plus AML in hypertensive patients with
type 2 diabetes. Patients were randomized to OLM/AML 40/
10 mg or PER/AML 8/10 mg for 24 weeks. The primary
efficacy endpoint was the absolute change in CSBP from
baseline to week 24, which was greater with OLM/AML
Recently, a number of studies have demonstrated that
central systolic blood pressure (CSBP) measurements
could provide a better estimate of cardiovascular (CV)
risk compared with the traditional method of measuring
brachial blood pressure (BP). Indeed, CSBP provides
valuable insights into arterial stiffness and organ dam-
age.1–4 Studies comparing different treatment regimens
have found that patients in parallel treatment groups
may display comparable levels of brachial BP measure-
ments while at the same time showing major differences
in CSBP, which may relate to differences seen in organ
damage and CV outcomes.2
This phenomenon was highlighted by the Conduit
Artery Function Evaluation (CAFE) study, a substudy of
the Anglo-Scandinavian Cardiac Outcomes Trial-Blood
Pressure Lowering Arm (ASCOT-BPLA).5 ASCOT-
BPLA was an outcomes study which found that patients
treated with a combination of the calcium channel
blocker (CCB) amlodipine (AML) plus the angiotensin-
converting enzyme (ACE) inhibitor perindopril (PER)
showed lower rates of CV outcomes, such as stroke and
death, compared with patients treated with the
b-blocker atenolol plus the diuretic bendroflumethi-
azide. The substudy CAFE found that patients treated
with AML/PER showed significantly greater reductions
in CSBP compared with patients treated with atenolol
plus bendroflumethiazide, despite similar reductions in
brachial BP. These findings raise the possibility that the
Address for correspondence: Luis M. Ruilope, MD, Institute of Research
& Hypertension Unit, Hospital 12 de Octubre, Madrid, Spain
E-mail: ruilope@ad-hocbox.com
Manuscript received: April 28, 2015; revised: July 7, 2015; accepted:
July 19, 2015
DOI: 10.1111/jch.12673
( 13.721.14 mm Hg) compared with PER/AML
( 10.211.11 mm Hg). The between-group difference was
3.511.60 mm Hg (95% confidence interval, 6.66 to
0.36 mm Hg) and was within the noninferiority margin
(2 mm Hg) as well as the superiority margin (0 mm Hg). In
addition, OLM/AML was associated with a higher proportion
of patients achieving blood pressure normalization. In
hypertensive patients with diabetes, the fixed-dose combi-
nation of OLM/AML was superior to PER/AML in reducing
CSBP, as well as other secondary endpoints. J Clin Hyper-
tens (Greenwich). 2015:1–8. ª 2015 Wiley Periodicals, Inc.
lower rates of CV outcomes seen in patients treated with
AML/PER in ASCOT-BPLA may be the result of larger
reductions in CSBP.
The ONgoing Telmisartan Alone and in Combination
With Ramipril Global Endpoint Trial (ONTARGET)6
showed that compared with ACE inhibitors, angiotensin
II receptor blockers (ARBs) are as effective at lowering
BP and reducing CV risk and show improved tolerabil-
ity. The results from ONTARGET suggested that it
would be possible to use an ARB to provide the renin-
angiotensin system (RAS) blockade component and to
combine this with AML to deliver effective lowering of
CSBP free from the tolerability issues associated with
the use of ACE inhibitors.
The results from the SEVIkar Compared to the
Combination of Perindopril Plus Amlodipine on Central
Arterial Blood Pressure in Patients With Moderate-to-
Severe HyperTENSION (SEVITENSION) study7 con-
firmed that a combination of the ARB olmesartan
(OLM) plus AML was not only noninferior to PER/
AML in reducing CSBP, but was also superior for this
endpoint, as well as a range of other hemodynamic
variables that included measurements of office and
ambulatory BP. The SEVITENSION study included
patients with a range of factors that put them at
increased risk of CV disease, including a substantial
proportion of patients with diabetes.
Hypertension and diabetes commonly occur together.
It is estimated that between 40% and 80% of diabetic
patients may also be hypertensive.8–10 Patients who
have both diabetes and hypertension are at a higher risk
for CV events than patients with hypertension or
diabetes alone.11–13 Indeed, diabetic patients with
hypertension are at approximately a two-fold risk for
CV-related events compared with those with normal
The Journal of Clinical Hypertension 1
OLM/AML in Diabetic Hypertensive Patients | Ruilope
BP.9 Furthermore, between 60% and 80% of patients
with type 2 diabetes mellitus (T2DM) die as a result of
CV complications, and high BP is associated with
approximately 75% of these deaths.14,15
RAS inhibitors have been found to be effective in
preventing CV complications in diabetic patients.16–18
Because of the increased risk of CV events in hyperten-
sive patients with diabetes, it is important to assess the
effects of dual RAS-calcium channel blockade on
arterial stiffness in these patients. The aim of the
present post hoc analysis was to assess the effects of
OLM/AML compared with PER/AML in reducing
CSBP and other hemodynamic variables in patients
with diabetes who took part in the SEVITENSION
study.
METHODS
Patients
The CAFE substudy has provided important insights
into the effects of dual-combination therapy with RAS
and calcium channel blockade on central BP; therefore,
the SEVITENSION study set out to recruit patients with
similar characteristics to aid the comparison of results.
As such, SEVITENSION enrolled male and female
Caucasian patients aged 40 to 80 years from 16 centers
across Spain, who were hypertensive and had three or
more additional risk factors. Additional risk factors
included age older than 55 years in men and older than
65 years in women, smoking, dyslipidemia, abnormal
glucose tolerance test, abdominal obesity, family history
of premature cardiovascular disease, left ventricular
hypertrophy, cerebrovascular disease, heart disease,
advanced retinopathy, atherosclerosis, and renal dis-
ease. The diabetic subgroup consisted of all patients
from SEVITENSION who had T2DM.
For the diabetic subgroup, inadequate BP control was
defined as having an systolic BP (SBP) >130 mm Hg or
diastolic BP (DBP) >80 mm Hg according to 2007
European Society of Hypertension/European Society of
Cardiology (ESH/ESC) guidelines for the management
of arterial hypertension, as these were the active
guidelines at the start of the study.19
Design
The full trial design and rationale of the SEVITENSION
study have previously been described (clinicaltrials.gov
identifier NCT01101009).20 A subgroup analysis of the
SEVITENSION study is presented here.
SEVITENSION involved a 2- to 4-week open-label,
run-in period that depended on patients’ existing treat-
ment at study entry. At weeks 4 to 2, patients not
currently receiving AML as part of their antihyperten-
sive treatment received AML 5 mg in addition to their
current therapy, except for patients receiving other
CCBs, which were discontinued. During weeks 2 to 0,
all patients received AML 10 mg monotherapy as their
only hypertensive medications and had all other anti-
hypertensive medications discontinued. Patients receiv-
2 The Journal of Clinical Hypertension
ing AML 10 mg monotherapy prior to the study entered
the randomization period directly. Except for patients
who were receiving AML 10 mg monotherapy prior to
the study, this resulted in all other patients being treated
with AML 5 mg for at least 2 weeks (together with any
former medication except for CCBs) and then receiving
AML 10 mg without other antihypertensive medication
for another 2 weeks prior to randomization. After
randomization to double-blind treatment, patients were
followed for 24 weeks.
Interventions
Patients were randomized into one of two treatment
groups: active treatment or matching placebo. In the
OLM arm, patients received a single-pill fixed-dose
combination of OLM 40 mg and AML 10 mg plus
PER/AML placebo. In the PER arm, patients received a
combination of PER 8 mg plus AML 10 mg and OLM/
AML placebo. For patients whose BP was not at target
at weeks 4, 8, 12, and 18, hydrochlorothiazide (HCTZ)
12.5 mg was added to their regimen; patients already
receiving 12.5 mg HCTZ were uptitrated to HCTZ
25 mg. If BP remained >180/110 mm Hg after the
addition of HCTZ 25 mg, they were removed from the
study.
Endpoints
The primary efficacy endpoint was the absolute change
in CSBP from baseline (week 0) to final examination
(week 24) with OLM/AML vs PER/AML using the last-
observation-carried-forward (LOCF) approach in the
per-protocol set (PPS). CSBP was measured by tonom-
etry with the SphygmoCor Vx Pulse Wave Velocity
System.
The secondary endpoints included absolute change in
seated SBP; mean 24-hour, daytime, and nighttime
ambulatory SBP; and the proportion of patients achiev-
ing normalized BP according to 2007 ESH/ESC guide-
lines for the management of arterial hypertension19 and
2009 ESH guidelines reappraisal.21 All secondary end-
points were measured in the full analysis set (FAS).
Brachial BP was measured using calibrated tensiometers
(OMRON). 24-hour ambulatory BP was measured
using standard measurement devices (Spacelabs) to
record 24-hour BP profiles. Daytime measurements
were taken at 15-minute intervals between 6 AM and
9:59 PM and nighttime measurements were taken at 30-
minute intervals between 10 PM and 5:59 AM.
Statistical Analysis
The primary efficacy endpoint was analyzed using a
parametric analysis of covariance (ANCOVA) using
treatment as a main effect and baseline CSBP as a
covariate. The primary objective was one-sided nonin-
feriority (a=0.025) of OLM/AML compared with PER/
AML in the change in CSBP from week 0 to week 24.
The primary endpoint was analyzed in the PPS, which
included all members of the FAS who had no major
protocol violations. The FAS was used to analyze all
 OLM/AML in Diabetic Hypertensive Patients | Ruilope

secondary endpoints and included all patients who were
randomized to treatment, received one or more dose of
medication, and had CSBP measured at baseline with at
least one follow-up measurement.
The secondary endpoints were analyzed from baseline
to final examination using the same ANCOVA analysis
as the primary endpoint with the corresponding baseline
values as covariates.
The noninferiority of OLM/AML compared with
PER/AML was shown if the upper limit of the 95%
confidence interval (CI) was below 2 mm Hg. In
addition, if the 95% CI lies above 0 mm Hg, then there
is evidence of superiority at the 5% level and superiority
can be tested. This is in accordance with the Committee
for Proprietary Medicinal Products, which states that it
is acceptable to calculate the P value associated with a
test of superiority in such situations.22
The proportion of patients with normalized BP at
week 24 was analyzed by a chi-square test using the
LOCF approach.
RESULTS
Patients
A total of 600 patients were enrolled into the
SEVITENSION study and 486 patients were random-
ized to treatment.7 Of these, 233 patients had diabetes
mellitus (Figure 1) and were randomized into the safety
analysis set (SAF II), with a total of 111 patients
randomized to OLM/AML and 122 to PER/AML. From
the SAF II, 22 patients did not provide efficacy
measurements and were excluded from the FAS, which
contained 211 patients (OLM/AML, n=101; PER/AML,
n=110). A further 24 patients had major protocol
violations and were not included in the PPS (OLM/
AML, n=91; PER/AML, n=96). Major protocol viola-
tions were defined as non-Caucasian patients, patients
with no baseline or postbaseline CSBP measurement,
compliance not within range (80%–120%), participa-
tion in another clinical trial at the time of the study or
≤1 month prior to study start, premature discontinua-
tion, and the use of prohibited concomitant medication.
The baseline patient characteristics and demographics
for the 233 patients in the SAF II are shown in Table I.
Mean age was 61.79.0 years, 72.5% were men, and
mean BMI was 31.84.31 kg/m2. There were no
significant differences in patient characteristics or
demographics between the two treatment groups. In
addition, compared with the total study population, the
diabetic subgroup had no significant differences in
patient characteristics.
At final examination, in the SAF II, 15.9% of patients
were receiving add-on HCTZ 12.5 mg (OLM/AML,
15.3%; PER/AML, 16.4%) and 54.9% were receiving
HCTZ 25 mg (OLM/AML, 49.5%; PER/AML,
59.8%).

FIGURE 1. Patient flow. AML indicates amlodipine; FAS, full analysis set; OLM, olmesartan; PER, perindopril; PPS, per-protocol set; SAF II,
safety analysis set. Major protocol deviations were defined as non-Caucasian patients, patients with no baseline or postbaseline central
systolic blood pressure measurement, compliance not within range (80%–120%), participation in any other clinical trial currently or ≤1 month
prior to study start, premature discontinuation, and the use of prohibited concomitant medication.

The Journal of Clinical Hypertension 3

OLM/AML in Diabetic Hypertensive Patients | Ruilope

TABLE I. Baseline Demographics and Patient Characteristics of the Diabetic Subgroup

Characteristic OLM/AML 40/10 mg PER/AM 8/10 mg Total
Safety Analysis Set (n=111) (n=122) (N=233)

Mean age, y 60.9 (9.2) 62.4 (8.8) 61.7 (9.0)

Males 80 (72.1) 89 (73.0) 169 (72.5)
Caucasian 111 (100) 122 (100) 233 (100)
Bodyweight, kg 86.2 (13.90) 87.4 (14.93) 86.8 (14.43)
Height, cm 165.3 (9.29) 165.1 (9.18) 165.2 (9.22)
BMI, kg/m2 31.5 (4.05) 32.0 (4.54) 31.8 (4.31)
Men aged >55 y/women aged >65 y 69 (62.2) 88 (72.1) 157 (67.4)
Smoker 15 (13.5) 32 (26.2) (47 (20.2)
Dyslipidemia 102 (91.9) 109 (89.3) 211 (90.6)
Abnormal glucose tolerance test 6 (5.4) 11 (9.0) 17 (7.3)
Abdominal obesity 94 (84.7) 106 (86.9) 200 (85.8)
Family history of premature CV disease 9 (8.1) 10 (8.2) 19 (8.2)
Left ventricular hypertrophy 18 (16.2) 27 (22.1) 45 (19.3)
Cerebrovascular disease 8 (7.2) 7 (5.7) 15 (6.4)
Heart disease 5 (4.5) 7 (5.7) 12 (5.2)
Advanced retinopathy 2 (1.8) 6 (4.9) 8 (3.4)
Atherosclerosis 4 (3.6) 3 (2.5) 7 (3.0)
Renal disease 33 (29.7) 31 (25.4) 64 (27.5)

Per Protocol Set n=91 n=96 N=187

Central SBP, mm Hg 133.5 (11.90) 134.7 (11.16) 134.1 (11.51)

Full Analysis Set n=101 n=110 N=211

Blood pressure, mm Hg
Seated SBP 147.5 (11.93) 148.6 (12.96) 148.1 (12.46)
24-h ambulatory SBP 135.4 (12.47) 134.1 (10.79) 134.7 (11.63)
Daytime ambulatory SBP 138.9 (12.91) 137.9 (11.53) 138.4 (12.20)
Nighttime ambulatory SBP 127.3 (13.71) 125.7 (11.72) 126.5 (12.71)
Central DBP 84.8 (8.81) 85.2 (9.03) 85.0 (8.91)
Seated DBP 84.1 (8.50) 83.7 (8.72) 83.9 (8.60)
24-h ambulatory DBP 78.5 (8.22) 77.7 (7.60) 78.0 (7.90)
Daytime ambulatory DBP 81.0 (8.94) 80.5 (7.71) 80.7 (8.31)
Nighttime ambulatory DBP 72.7 (7.88) 71.6 (8.56) 72.1 (8.23)
Abbreviations: AML, amlodipine; BMI, body mass index; CV, cardiovascular; DBP, diastolic blood pressure; DP4, dipeptidyl peptidase-4 inhibitor;
HbA1c, glycated hemoglobin; OLM, olmesartan; PER, perindopril; SBP, systolic blood pressure; SGLT-2, sodium-glucose linked transporter-2.
Continuous variables are mean (standard deviation) and categorical values are patient number (percentage).

The most common risk factors were dyslipidemia
(90.6%), abdominal obesity (85.5%), and age (67.4%).
The majority of patients had four risk factors (43.3%),
followed by five (26.6%) and three (15.5%) risk factors,
Primary Efficacy Variable
A greater absolute change in CSBP from baseline was
seen in the OLM/AML group compared with the PER/
AML group ( 13.721.14 vs 10.211.11 mm Hg;
P<.0001; Figure 2). The point estimate for the differ-
ence between the two treatment groups was 3.51
(standard error, 1.60) mm Hg (95% CI, 6.66 to
0.36 mm Hg) in the PPS. Because the upper limit of
the 95% CI was below the noninferiority margin
(2 mm Hg), the noninferiority of OLM/AML over
PER/AML was observed. In addition, the superiority
of OLM/AML was demonstrated, with the upper 95%
CI below 0 mm Hg. This was seen in the FAS (P=.0041)
and supported in the PPS (P=.0291) (Figure 3).
Secondary Efficacy Variables
Similar to the primary efficacy endpoint, all secondary
endpoints demonstrated the noninferiority of OLM/
AML compared with PER/AML. In addition, a number
of secondary variables demonstrated the superiority of
OLM/AML over PER/AML.
Hemodynamic Variables. OLM/AML was associated
with a greater decrease in mean 24-hour SBP/DBP
compared with PER/AML ( 11.29/ 6.01 mm Hg and
8.64/ 4.69 mm Hg, respectively). In addition, the
95% CI was below the noninferiority margin for both
24-hour SBP (Figure 4A) and DBP (Figure 4B) indicat-
ing the noninferiority of OLM/AML. Similar results

4 The Journal of Clinical Hypertension


FIGURE 2. Absolute change in central systolic blood pressure
(CSBP) from baseline (week 0) to final examination (week 24) by
randomized treatment group (last observation carried forward in the
per-protocol set). AML indicates amlodipine; OLM, olmesartan;
PER, perindopril.
FIGURE 3. Forest plot of the differences in absolute change of
central systolic blood pressure (CSBP) between diabetic patients
treated with OLM/AML 40/10 mg and PER/AML 8/10 mg from
baseline (week 0) to final examination (week 24) for the primary
efficacy endpoint (per protocol set) and in the full analysis set. AML
indicates amlodipine; OLM, olmesartan; PER, perindopril.
were found for daytime SBP/DBP, nighttime SBP/DBP,
seated SBP/DBP, and central DBP (CDBP) (Figure 4A
and 4B). In addition, the 95% CI for nighttime SBP and
seated SBP (Figure 4A) and CDBP (Figure 4B) were
below 0 mm Hg, indicating the superiority of OLM/
AML compared with PER/AML for these endpoints.
BP Normalization. At week 24, a significantly higher
proportion of patients treated with OLM/AML had
normalized BP (<130/80 mm Hg according to the study
protocol) compared with PER/AML (37.6% vs 21.8%;
P=.0118). In addition, OLM/AML was associated with
a significantly higher proportion of patients with nor-
malized BP according to the 2009 ESH guidelines
reappraisal21 (<140/90 mm Hg) compared with PER/
AML (73.3% vs 59.1%; P=.0300; Figure 5).
OLM/AML in Diabetic Hypertensive Patients | Ruilope
FIGURE 4. Forest plot of the differences in 24-hour systolic blood
pressure (SBP), daytime SBP, nighttime SBP, and seated SBP (A)
and central diastolic blood pressure (DBP), 24-hour DBP, daytime
DBP, nighttime DBP, and seated DBP (B) between diabetic patients
treated with OLM/AML 40/10 mg and PER/AML 8/10 mg from
baseline (week 0) to final examination (week 24) in the full analysis
set. AML indicates amlodipine; CDBP, central diastolic blood
pressure; CSBP, central systolic blood pressure; FAS, full analysis
set; OLM, olmesartan; PER, perindopril.
Tolerability. Both OLM/AML and PER/AML were
well tolerated with a similar proportion of patients
with more than one drug-related treatment-emergent
adverse event (TEAE) (OLM/AML, 21.6%; PER/AML,
27.0%) (Table II). The most common TEAE in both
groups was peripheral edema, which affected 18.9% of
OLM/AML patients and 19.7% of PER/AML patients.
Cough was experienced by 2.7% of OLM/AML and
5.7% of PER/AML patients (Table II).
There were low rates of discontinuations caused by
drug-related TEAEs across both treatment groups
(OLM/AML, 5.4%; PER/AML, 9.85%) and no inci-
dence of mortality in either treatment group.
DISCUSSION
This study shows that for hypertensive patients with
diabetes, who have inadequately controlled BP on AML
monotherapy, the dual combination of OLM/AML was
The Journal of Clinical Hypertension 5
OLM/AML in Diabetic Hypertensive Patients | Ruilope
FIGURE 5. Proportion of diabetic patients with normalized blood pressure at week 24 across the treatment groups according to the 2007
European Society of Hypertension (ESH)/European Society of Cardiology guidelines (systolic blood pressure/diastolic blood pressure 130/
80 mm Hg) and the 2009 ESH guidelines reappraisal (systolic blood pressure/diastolic blood pressure 140/90 mm Hg) in the full analysis set.
AML indicates amlodipine; OLM, olmesartan; PER, perindopril.
noninferior and indeed superior to PER/AML in reduc-
ing CSBP. In addition, the noninferiority of OLM/AML
to PER/AML was observed in a number of hemody-
namic variables and in the proportion of patients with
normalized BP.
Available evidence suggests that CSBP measurements
provide a more accurate assessment of CV risk com-
pared with brachial BP measurements.3,23 The ASCOT
study, and the CAFE substudy, have provided some
important insights into the effects of antihypertensive
treatment on CSBP, notably with regard to the benefits
of dual RAS-calcium channel blockade. Thus, the study
design and inclusion criteria used in SEVITENSION
were based on ASCOT to facilitate comparison and
allow assessment of whether dual RAS-calcium channel
blockade using an ARB would have similar effects on
central BP. The maximum RAS blocker dose used in
ASCOT was PER 8 mg, which is also the highest dose
recommended for the treatment of hypertension.24 Since
the maximum recommended dose of OLM is 40 mg,
this was selected as the most suitable for providing the
RAS blocker component in SEVITENSION.
The significance of the present findings is the demon-
stration that dual RAS-calcium channel blockade is
highly effective in reducing CSBP in hypertensive patients
with diabetes. Studies have shown that both type 1 and 2
6 The Journal of Clinical Hypertension
diabetes are associated with increased arterial stiffness,
and this may help to explain the increase in CV risk in
these patients since the heart needs to work harder to
generate higher pressures to pump blood through stiffer
central arteries.25,26 Increased arterial stiffness also leads
to raised SBP through elevations in pulse wave velocity
(PWV) and pressure wave reflection. Hypertensive
patients with diabetes have been shown to have signif-
icantly higher PWV compared with those without
diabetes,27 and the proportion of individuals with an
increased PWV has been reported to be greater among
hypertensive patients with diabetes compared with non-
diabetic hypertensive patients.26 The mechanisms by
which abnormal glucose metabolism affect vascular
structure and function are uncertain, but deteriorating
glucose tolerance is associated with increased central and
peripheral arterial stiffness, and this may contribute to
the increased CV risk seen in patients with both impaired
glucose metabolism and diabetes.28 The increase in
arterial stiffness caused by deteriorating glucose toler-
ance may result in a negative feedback loop of arterial
stiffness and damage to microcirculation.29
Current treatment guidelines point out that the
beneficial effects of RAS blockers on renal function
make it reasonable to use an ACE inhibitor or an ARB
in the management of hypertensive patients with
 OLM/AML in Diabetic Hypertensive Patients | Ruilope

AML was effective in reducing BP throughout a 24-hour

TABLE II. Safety Observations During the Double-
period in patients with hypertension and T2DM.31
Blind Treatment Period in the Safety Analysis Set
In the SEVITENSION study, OLM/AML was supe-
OLM/AML PER/AML Total rior to PER/AML for the absolute change in CSBP from
Characteristic 40/10 mg (n=111) 8/10 mg (n=122) (N=233) baseline to final examination in both the total popula-
≥1 TEAE 50 (45.0) 60 (49.2) 110 (47.2) tion and the diabetic subgroup. In addition, OLM/AML
≥1 drug-related 24 (21.6) 33 (27.0) 57 (24.5) was superior in reducing seated SBP and DBP, 24-hour
TEAE ambulatory SBP and DBP, and nighttime SBP in the
≥1 serious TEAE 2 (1.8) 3 (2.5) 5 (2.1) total population. In the diabetic subgroup, only night-
≥1 serious 0 (0.0) 0 (0.0) 0 (0.0) time SBP and seated SBP were superior. The frequency
drug-related of adverse events was similar in the two treatment
TEAE groups in the diabetic subanalysis, and these frequencies
Deaths 0 (0.0) 0 (0.0) 0 (0.0) were also similar to those seen in the total population.
Discontinued 7 (6.3) 13 (10.7) 20 (8.6) In the primary analysis of the SEVITENSION study, a
because of higher proportion of PER/AML recipients (7.5%) dis-
TEAE continued the study compared with patients treated
Discontinued 6 (5.4) 12 (9.8) 18 (7.7) with OLM/AML (5.7%). In this post hoc analysis, this
because of
effect was even more pronounced. The proportion of
drug-related
diabetic patients who discontinued in the SEVITEN-
TEAE
SION study was almost twice as large with PER/AML
Patients with ≥1 TEAE
(9.9%) compared with OLM/AML (5.4%).
Peripheral 21 (18.9) 29 (20.5) 46 (19.7)
edema
Treatment with OLM/AML was associated with a
Nasopharyngitis 6 (5.4) 7 (5.7) 13 (5.6)
greater number of patients achieving BP control com-
Cough 3 (2.7) 8 (6.6) 11 (4.7)
pared with PER/AML. Based on the 2009 ESH guidelines
Erectile 1 (0.9) 2 (1.6) 3 (1.3) update definition of normalized BP (<140/90 mm Hg),21
dysfunction a significantly higher proportion of patients treated with
Malaise 2 (1.8) 1 (0.8) 3 (1.3) OLM/AML had normalized BP compared with those
Erythema 0 (0.0) 2 (1.6) 2 (0.9) treated with PER/AML (73.3% vs 59.1%; P=.03). A
Flushing 2 (1.8) 0 (0.0) 2 (0.9) similar pattern was also seen with the study protocol
Abbreviations: AML, amlodipine; OLM, olmesartan; PER, perindopril; definition of normalized BP (ie, <130/80 mm Hg), based
TEAE, treatment-emergent adverse event. on the 2007 ESH/ESC guidelines for the management of
atrial hypertension, which were applicable at the time of
study design,19 although it resulted in lower proportions
diabetes. The guidelines also point out that CCBs have of OLM/AML and PER/AML recipients achieving nor-
been shown to be useful in these patients, especially malization (37.6% vs 21.8%; P=.0118). The lower BP
when combined with a RAS blocker.23 The implications goal for diabetic patients has since been modified in the
of the present findings are that dual RAS-calcium 2013 ESH/ESC guidelines for the management of atrial
channel blockade with an ARB/CCB combination has hypertension, which recommend a BP goal of <140/
an important role to play in lowering BP and reducing 85 mm Hg for diabetic patients.23 Based on this goal, it
CV risk in patients with diabetes. If supported by is likely that OLM/AML would still show improvements
further research, treatment guidelines may need to be over PER/AML.
modified to specify that an ARB/CCB combination is the
recommended treatment option for hypertensive STUDY LIMITATIONS
patients with diabetes whose BP cannot be adequately This study has some limitations. First, it may be difficult
controlled with a single agent. to extrapolate these findings to the general hypertensive
The results presented here are in accordance with population since only Spanish Caucasian patients were
those of previous studies involving OLM/AML. A long- enrolled and because the study design was based on that
term (52 weeks) subgroup analysis of the Combination of the CAFE substudy, with all patients having diabetes
of Olmesartan medoxomil and Amlodipine besylate in and at least two additional risk factors. Second, only
Controlling High blood pressure (COACH) study30 patients with T2DM were enrolled, and although there
assessed the efficacy of OLM/AML in a number of is no reason to suspect that the results would be any
subgroups including diabetic patients. In the diabetic different in patients with type 1 diabetes mellitus, this
subgroup, OLM/AML was effective in reducing seated cannot be confirmed without clinical evaluation.
BP, with similar reductions noted in patients with and Finally, the duration of the SEVITENSION study was
without diabetes. Similar to the results presented here, too short to assess change in the rate of CV events.
in COACH, 26.9% of diabetic patients achieved BP
normalization (<130/80 mm Hg). Furthermore, results CONCLUSIONS
from the APEX study, which also involved diabetic The results from this subgroup analysis found that
patients, found that a titration regimen involving OLM/ OLM/AML was noninferior to PER/AML in reducing

The Journal of Clinical Hypertension 7

OLM/AML in Diabetic Hypertensive Patients | Ruilope
CSBP in a subgroup of hypertensive patients with
diabetes. Moreover, OLM/AML was found to have
superior BP-lowering effects compared with PER/AML.
At the time of final examination, a higher proportion
of patients treated with OLM/AML had normalized BP
according to both the 2007 ESH/ESC guidelines for the
management of arterial hypertension and the 2009 ESH
guidelines reappraisal, compared with PER/AML.
Both treatments were well tolerated and diabetic
patients showed no signs of having an additional risk for
TEAE compared with the general population. Further-
more, OLM/AML was associated with a lower inci-
dence of cough compared with PER/AML and a
clinically relevant lower rate of discontinuations.
This analysis shows that a single-pill fixed-dose
combination of OLM/AML 40/10 mg was associated
with significant BP-lowering effects and demonstrates
the importance of this type of dual-combination therapy
in the treatment of higher-risk hypertensive patients
with diabetes.
Acknowledgments: This study was sponsored by Daiichi Sankyo Europe
GmbH, Munich, Germany. Prof Dr Luis Ruilope was the coordinating
investigator and acted as the medical expert for the study. Medical writing
assistance during the preparation of this manuscript was funded by Daiichi
Sankyo Europe GmbH and provided by Matthew Bexon of inScience
Communications, Springer Healthcare, Chester, UK.
The author wishes to express gratitude to the investigators, study nurses,
and coordinators who were involved in the SEVITENSION study. The
SEVITENSION study investigators were: Jose Abellan, Pedro Aranda, Cesar
Cerezo, Jose Antonio Divison, Luis Garcia Ortiz, Juan Garcia Puig, Pablo
Gomez, Jorge Gomez Cerezo, Nieves Martell, Anna Oliveras, Enrique Rodilla,
Jose Saban, Julian Segura, Carmen Suarez, and Luis Vigil.
Disclosures: Dr Ruilope has served as an advisor and speaker for Daiichi
Sankyo.
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