TITLE: Functional Vascular Study in Hypertensive Subjects with Type 2
Diabetes Using Losartan or Amlodipine

  ABSTRACT.BACKGROUND:
Antihypertensive drugs are used to control blood pressure (BP) and reduce
macro- and microvascular complications in hypertensive patients with
diabetes.

ABSTRACT.OBJECTIVES:
The present study aimed to compare the functional vascular changes in
hypertensive patients with type 2 diabetes mellitus after 6 weeks of
treatment with amlodipine or losartan.

ABSTRACT.METHODS:
Patients with a previous diagnosis of hypertension and type 2 diabetes
mellitus were randomly divided into 2 groups and evaluated after 6 weeks of
treatment with amlodipine (5 mg/day) or losartan (100 mg/day). Patient
evaluation included BP measurement, ambulatory BP monitoring, and assessment
of vascular parameters using applanation tonometry, pulse wave velocity
(PWV), and flow-mediated dilation (FMD) of the brachial artery.

ABSTRACT.RESULTS:
A total of 42 patients were evaluated (21 in each group), with a predominance
of women (71%) in both groups. The mean age of the patients in both groups
was similar (amlodipine group: 54.9 ± 4.5 years; losartan group: 54.0 ± 6.9
years), with no significant difference in the mean BP [amlodipine group: 145
± 14 mmHg (systolic) and 84 ± 8 mmHg (diastolic); losartan group: 153 ± 19
mmHg (systolic) and 90 ± 9 mmHg (diastolic)]. The augmentation index (30% ±
9% and 36% ± 8%, p = 0.025) and augmentation pressure (16 ± 6 mmHg and 20 ±
8 mmHg, p = 0.045) were lower in the amlodipine group when compared with the
losartan group. PWV and FMD were similar in both groups.

ABSTRACT.CONCLUSIONS:
Hypertensive patients with type 2 diabetes mellitus treated with amlodipine
exhibited an improved pattern of pulse wave reflection in comparison with
those treated with losartan. However, the use of losartan may be associated
with independent vascular reactivity to the pressor effect.

BODY.INTRODUCTION:
Systemic arterial hypertension (SAH) and type 2 diabetes mellitus (T2DM) are often
associated1. SAH induces
vascular damage by promoting endothelial dysfunction and atherosclerosis. Early
treatment of hypertension is particularly important in patients with diabetes to
prevent cardiovascular disease (CVD) and to minimize the progression of kidney
disease and diabetic retinopathy2.  Arterial stiffness has been recognized as a cardiovascular risk marker3. Patients with both SAH and T2DM
exhibit increased arterial stiffness compared with those with either diabetes or
hypertension4. Increased
arterial stiffness is an important and independent risk factor associated with early
mortality and assumes greater importance in clinical prognosis when compared with
other known cardiovascular risk factors such as age, gender, smoking history, and
dyslipidemia5. The gold
standard for assessment of arterial stiffness is pulse wave velocity (PWV)6. An important parameter used to
estimate arterial compliance is the augmentation index (AIx), which can be obtained
using applanation tonometry7.  SAH, when associated with atherosclerosis and endothelial dysfunction, constitutes a
risk factor that significantly increases cardiovascular morbidity and
mortality8. Flow-mediated
dilatation (FMD) of the brachial artery is a noninvasive method used to assess
endothelial function. Using FMD, previous studies have indicated improved
endothelial function in patients with hypertension, coronary artery disease, and
heart failure who were treated with angiotensin-converting enzyme inhibitors
(ACEIs)9,10 and in patients with diabetes treated with
losartan11. The effects of
amlodipine on endothelial function were evaluated in subjects with risk factors for
coronary artery disease. Although, the subjects showed improvement in the parameters
evaluated with FMD, this improvement was not significant when compared with the
placebo group12.  The present study aimed to compare the functional vascular changes in hypertensive
patients with T2DM after 6 weeks of use of a calcium channel antagonist (CCA;
amlodipine) or an angiotensin receptor blocker (ARB; losartan).

BODY.METHODS.STUDY SAMPLE:
Patients with SAH and T2DM were selected for this study during clinical follow-up
at the Pedro Ernesto University Hospital [Hospital Universitário Pedro Ernesto
(HUPE)], State University of Rio de Janeiro. Patients of both sexes aged between
40 and 70 years who were diagnosed with SAH and T2DM, without changes in dietary
treatment or oral medication usage in the last 4 weeks, were included in the
study. The main exclusion criteria were signs of secondary hypertension,
decompensated diabetes mellitus [fasting glucose levels of > 300 mg/dL or
glycated hemoglobin (HbA1c) levels of > 7%], need for insulin therapy, and
chronic renal disease with an estimated glomerular filtration rate (GFR) of <
30 mL/min. The study was approved by the Research Ethics Committee of HUPE
(protocol No. 20406/2012), and all participants read and signed the informed
consent form.  After initial clinical and laboratory evaluation, the patients were randomized
into 2 groups for treatment with either amlodipine (5 mg/day) or losartan (100
mg/day). After 6 weeks, a cross-sectional study involving analysis of clinical
and laboratory data and performance of vascular tests was conducted.

BODY.METHODS.CLINICAL EVALUATION:
To determine blood pressure (BP), the patients remained seated for 30 min and
refrained from using tobacco or caffeine. BP was evaluated using a
semi-automatic calibrated device, model HEM-705CP (Omron Healthcare Inc.,
Illinois, USA), with the cuff adjusted for arm circumference. Three measurements
were obtained in each upper limb, and the respective mean value was calculated.
The highest mean value was used in data analysis.  With regard to anthropometric measurements, a precision scale (Filizola) with a
maximum capacity of 180 kg was used to determine weight, and a stadiometer was
used to measure height. The body mass index (BMI) was calculated by dividing the
weight (in kilograms) by the squared height (in meters). Waist circumference was
measured at the midpoint between the last rib and the iliac crest, and hip
circumference was measured at the point of largest circumference in the gluteal
region. The waist-hip ratio (WHR) was determined by dividing the values obtained
for the respective circumferences.

BODY.METHODS.LABORATORY TESTS:
For performance of biochemical tests and quantification of HbA1c levels using
turbidimetry (BioSystems), venous blood samples were collected after fasting
period of 10-12 h. GFR was estimated using the Modification of Diet in Renal
Disease (MDRD) formula: GFRMDRD = 186 (serum
creatinine)1.154 × (age)0.203 × [0.742 (if female) or
1.212 (if black)]13.  Serum lipids were analyzed using a colorimetric method (Bioclin). When the
triglyceride level was 400 mg/dL, low-density lipoprotein (LDL) cholesterol was
calculated using the Friedewald formula: LDL cholesterol = [total cholesterol −
high-density lipoprotein (HDL) cholesterol] − (triglycerides/5). For
quantitation of C-reactive protein (CRP), turbidimetry (BioSystems) was used,
and the possibility of evaluating patients with acute infectious or inflammatory
processes developed in recent weeks was excluded.  For evaluation of microalbuminuria, the urine albumin-to-creatinine ratio (UACR)
was obtained from urine samples collected in the morning. Urine creatinine was
quantitated using a colorimetric method, and albuminuria was determined using a
nephelometric method.

BODY.METHODS.AMBULATORY BLOOD PRESSURE MONITORING (ABPM) :
ABPM was performed using the SpaceLabs 90207 device (SpaceLabs Inc., Redmond, WA,
USA) scheduled to start between 8 and 9 am, with a minimum duration of 24 h. BP
was measured every 20 min during the waking period (6 am-11 pm) and every 30 min
during the sleeping period (11 pm-6 am). The test was considered satisfactory
when at least 70% of the BP readings were valid, with a minimum of 16 readings
during the waking period, 8 readings in the sleeping period, and a period < 2
h without BP measurements.

BODY.METHODS.VASCULAR TESTS.DETERMINATION OF THE CENTRAL AORTIC PRESSURE:
Pulse waves of the radial artery were obtained using an applanation tonometer
(model SPC-301-Millar Instruments, Houston, Texas, USA), calibrated
according to the brachial artery pressure. Pulse wave analysis was performed
to obtain central arterial pressures and other hemodynamic parameters using
the SphygmoCor system (Atcor, United States)14. Aortic pressure waves were subjected to
several analyses to identify the time between the beginning and the first
and second peaks of the arterial pulse wave during systole. The pressure
difference between the first component and the maximum pressure at systole
[pressure increase (PI)] was identified as the reflected pressure wave
during systole. AIx was defined as the ratio between PI and central pulse
pressure (PP); it was expressed as a percentage [AIx = (PI/PP) × 100] and
was subsequently adjusted for a heart rate of 75 bpm (AIx@75).

BODY.METHODS.VASCULAR TESTS.PULSE WAVE VELOCITY :
Pulse waves were obtained via the transcutaneous route using a COMPLIOR SP
device (Artech Medical), with transducers placed in the regions of the right
carotid artery, right radial artery (peripheral PWV), and right femoral
artery (central PWV)15.
Two measurements were made during the same consultation, and when
differences were > 10%, a third measurement was made. The mean of the 2
measurements was used for analysis. The measure was corrected for the mean
arterial pressure (MAP) by using the formula PWV-N = (PWV/MAP) × 100.

BODY.METHODS.VASCULAR TESTS.FLOW-MEDIATED DILATION OF THE BRACHIAL ARTERY:
This technique was performed using a 2-dimensional ultrasound device with
color and spectral Doppler (Vivid-3, GE, United States) and a linear
transducer with a frequency of 10 MHz. The patients were placed in supine
position with the right arm slightly stretched. After the brachial artery
was located, the transducer was placed on the anteromedial side of the right
upper limb, perpendicular to the arm axis and 5-10 cm above the antecubital
fold in the region of the brachial artery. The basal brachial artery
diameter (BBAD) and post-occlusion brachial artery diameter (POBAD) were
measured manually between the lumen-intima interfaces at end-diastole. After
BBAD measurement, the site of contact of the probe on the skin was marked to
allow POBAD measurement at the same site. Flow occlusion was maintained for
5 min using an arm cuff, allowing the recording of a BP of 60 mmHg above the
systolic arterial pressure. POBAD was measured at 30, 60, and 90 s after
blood flow release16. The
tests were performed by the same examiner who was unaware of the data
recorded. FMD was calculated as the percentage increase in POBAD compared
with baseline values using the following formula: FMD (%) = (POBAD −
BBAD/BBAD) × 100.

BODY.METHODS.STATISTICAL ANALYSIS:
To calculate the sample size, the Sample Power module of the SPSS® software
version 18.0 was used. By adopting a significance criterion (alpha) of 0.05, a
minimum sample size of 16 patients was proposed for each group. After analyzing
the changes in FMD of the brachial artery and based on the results of other
clinical studies, the statistical significance power was determined as 80.7% and
the accuracy was ± 1.44 points, using a 95% confidence interval11,12.  Statistical analyses were performed using SPSS® software version 18.0. The
results were expressed as the mean ± standard deviation or as absolute and
percentage values. The continuous variables of each group were compared using
unpaired Student's t test between groups with a 95% confidence interval. A
p-value of < 0.05 was considered significant.

BODY.RESULTS:
Initially, 120 hypertensive patients with diabetes who met the inclusion criteria
were selected. Among these, 73 (61%) met the exclusion criteria and were withdrawn
from the study. Accordingly, 47 subjects were included in the study and were
randomly divided into the losartan or amlodipine group. Because of 5 follow-up
interruptions during the evaluation period, only 42 patients completed the study (21
in each group) (Figure 1).  Figure 1Patient selection flowchart. ANL: amlodipine; T2DM: type 2 diabetes mellitus;
PMH: past medical history; CRF: chronic renal failure; LOS: losartan; DBP:
diastolic blood pressure; SBP: systolic blood pressure.  The groups were evaluated and compared according to their clinical and
epidemiological profiles, presence of cardiovascular risk factors, and prior use of
medications. All patients were sedentary. A comparison between the 2 groups
indicated no significant difference between the variables analyzed (Table 1).   Table 1 Profile of each group evaluated and comparison between the variables
analyzed Variables Losartan group (n = 21) Amlodipine group (n = 21) p-value Age (years) 54.0 ± 6.9 54.9 ± 4.5 0.619 Female, n (%) 15 (71.4) 15 (71.4) 1.000 Black, n (%) 4 (19.0) 3 (14.3) 0.679 BMI, kg/m 2 30.4 ± 3.5 29.8 ± 4.0 0.636 Smoking, n (%) 5 (23.8) 6 (28.6) 0.939 Dyslipidemia, n (%) 13 (61.9) 12 (57.1) 0.753 Statin use, n (%) 8 (38.1) 6 (28.6) 0.513 ASA use, n (%) 7 (33.3) 7 (33.3) 1.000 Metformin use, n (%) 18 (85.7) 18 (85.7) 1.000 Sulfonylurea use, n (%) 5 (23.8) 6 (28.6) 0.726 Data are expressed as mean ± standard deviation or as percentages, as
indicated. ASA: acetylsalicylic acid; BMI: body mass index. The p-values
were calculated using Student's t test for continuous variables and the
chi-square test for categorical variables.   The initial BP values were calculated in each group for the determination of systolic
blood pressure (SBP) and diastolic blood pressure (DBP). Mean SBP and DBP were 147 ±
11 mmHg and 85 ± 9 mmHg, respectively, in the losartan group and 147 ± 21 mmHg and
84 ± 8 mmHg, respectively, in the amlodipine group.  Table 2 shows the laboratory profiles,
estimated GFRs using MDRD, and UACR. Mean microalbuminuria was lower in the
amlodipine group when compared with the losartan group; however, the difference was
not significant. In the losartan group, 33% of patients presented with
microalbuminuria, with a mean value of 81.3 mg/g creatinine; in the amlodipine
group, 24% of patients presented with microalbuminuria, with a mean value of 57.3
mg/g creatinine.  Table 2 Laboratory profile of the study population Variables Losartan group (n = 21) Amlodipine group (n = 21) p-value Creatinine, mg/dL 0.7 ± 0.2 0.7 ± 0.2 0.577 Potassium, mEq/L 4.3 ± 0.4 4.3 ± 0.5 0.684 Blood glucose, mg/dL 111.7 ± 43.0 122.0 ± 47.8 0.467 HbA1c, % total Hb 6.2 ± 0.5 6.4 ± 0.5 0.270 Total cholesterol, mg/dL 196.4 ± 35.6 191.9 ± 30.0 0.662 HDL cholesterol, mg/dL 55.1 ± 19.5 55.0 ± 12.1 0.985 LDL cholesterol, mg/dL 115.9 ± 40.1 111.6 ± 27.1 0.585 Triglycerides, mg/dL 127.3 ± 48.0 127.0 ± 56.4 0.984 CRP, mg/dL 0.3 ± 0.3 0.5 ± 0.5 0.393 GRF MDRD , mL/min/1, 73 m 2 91.9 ± 21.4 100.0 ± 34.6 0.368 UACR, mg/g creatinine 34.6 ± 40.1 24.8 ± 25.9 0.352 Data are expressed as mean ± standard deviation. Hb: hemoglobin; HbA1c:
glycated hemoglobin; HDL: high-density lipoprotein; LDL: low-density
lipoprotein; CRP: C-reactive protein; MDRD: Modification of Diet in
Renal Disease; UACR: urinary albumin-to-creatinine ratio; GFR:
glomerular filtration rate. The p-values were calculated using Student's
t test.   After 6 weeks of treatment, the losartan and amlodipine groups no significant
differences in SBP (153 ± 19 mmHg and 145 ± 14 mmHg, respectively, p = 0.127), and
DBP (90 ± 9 mmHg and 84 ± 8 mmHg, respectively, p = 0.063), although the values were
slightly lower in the amlodipine group. The data obtained with ABPM after treatment
with losartan or amlodipine revealed no significant differences between the 2
groups, and similar results were obtained during the waking and sleeping periods
(Table 3).  Table 3 Data obtained with ambulatory blood pressure monitoring Variables Losartan group (n = 21) Amlodipine group (n = 21) p-value SBP in 24 h, mmHg 136 ± 14 137 ± 14 0.947 DBP in 24 h, mmHg 81 ± 11 82 ± 9 0.892 MAP in 24 h, mmHg 100 ± 12 101 ± 10 0.888 SBP during the waking period, mmHg 139 ± 15 139 ± 14 0.888 DBP during the waking period, mmHg 84 ± 12 85 ± 10 0.787 MAP during the waking period, mmHg 103 ± 12 104 ± 10 0.836 SBP during the sleeping period, mmHg 132 ± 15 131 ± 16 0.846 DBP during the sleeping period, mmHg 75 ± 12 75 ± 9 0.942 MAP during the sleeping period, mmHg 95 ± 13 94 ± 10 0.893 Data are expressed as mean ± standard deviation. DBP: diastolic blood
pressure; SBP: systolic blood pressure; MAP: mean arterial pressure. The
p-values were calculated using Student's t test.   The PWV results revealed no significant differences between the 2 treatment groups.
In contrast, applanation tonometry data indicated that the mean augmentation
pressure was significantly higher in the losartan group in comparison with the
amlodipine group (20 ± 8 mmHg and 16 ± 6 mmHg, respectively, p = 0.045). Similarly,
a significantly higher mean AIx was observed in the losartan group when compared
with the amlodipine group (36% ± 8% and 30% ± 9%, respectively, p = 0.025, Table 4). Increased endothelial function was
observed in the losartan group using FMD (8.4% ± 4.6% and 7.5% ± 3.0%, respectively
p = 0.431); however, the difference was not significant between the 2 groups (Figure 2).  Table 4 Values obtained with pulse wave velocity and applanation tonometry Variables Losartan group (n = 21) Amlodipine group (n = 21) p-value CR-PWV, m/s 9.9 ± 1.1 9.5 ± 1.4 0.347 CF-PWV, m/s 10.4 ± 2.2 10.6 ± 2.7 0.880 NCF-PWV, m/s 9.5 ± 1.8 9.8 ± 2.5 0.595 ASBP, mmHg 144 ± 19 136 ± 12 0.108 ADBP, mmHg 90 ± 10 84 ± 10 0.100 PI, mmHg 20 ± 8 16 ± 6 0.045 AIx, % 36 ± 8 30 ± 9 0.025 APP, mmHg 53 ± 16 49 ± 11 0.386 AIx@75, % 32 ± 7 28 ± 7 0.050 Data are expressed as mean ± standard deviation. AIx: augmentation index;
AP: augmentation pressure; AIx@75: augmentation index corrected for a
heart rate of 75 bpm; ADBP: aortic diastolic blood pressure; ASBP:
aortic systolic blood pressure; APP: aortic pulse pressure; CF-PWV:
carotid-femoral pulse wave velocity; NCF-PWV: normalized carotid-femoral
pulse wave velocity; CR-PWV: carotid-radial pulse wave velocity. The
p-values were calculated using Student's t test.   Figure 2Distribution of values of flow-mediated dilation (FMD) of the brachial artery
in the amlodipine (ANL) and losartan (LOS) group; p = 0.431 using Student's
t test.

BODY.DISCUSSION:
This cross-sectional study aimed to evaluate cardiovascular risk markers, including
arterial stiffness and endothelial dysfunction, in a group of hypertensive patients
with T2DM after 6 weeks of treatment with an ARB or a CCA, which are important
antihypertensive drugs currently used in the treatment of such patients. Diabetes
mellitus increases the risk of cardiovascular morbidity and mortality in patients
with hypertension by 2- to 3-fold, and a decline in BP can decrease the rate of
cardiovascular events and renal impairment in these patients17. However, it is unclear whether
all classes of antihypertensive drugs play a similar role in the treatment of
hypertensive patients with diabetes and can lead to alterations in cardiovascular
risk markers.  A comparison between the 2 groups at the beginning of the study indicated
similarities in their clinical and epidemiological profiles, presence of
cardiovascular risk factors, and previous use of medications. Furthermore, the
initial antihypertensive treatment performed was similar between the 2 groups,
eliminating the difference in treatment as a confounding factor in the
interpretation of the results.  Glucose and lipid metabolism, serum potassium levels, and microalbuminuria were also
evaluated, although assessment of these parameters was not the primary aim of this
study. In the study by Otero et al18, improved glycaemia and HbA1c levels were reported in patients
treated with manidipine when compared with those treated with enalapril. In
contrast, Derosa et al19 found no
difference in blood glucose levels between patients who received telmisartan or
nifedipine, whereas Nishida et al20 observed better HbA1c levels in patients who received ARBs when
compared with those who received CCAs. In another study, Giordano et al21 obtained similar results for blood
glucose and HbA1c levels in patients on captopril or nifedipine. In the present
study, the mean blood glucose levels were higher in the amlodipine group than in the
losartan group; however, the difference was not significant. In contrast, HbA1c
levels were similar between the 2 groups. Moreover, no difference was found between
the 2 groups regarding the use of hypoglycemic agents. In view of these findings,
little can be inferred about the influence of ARBs or CCAs on glycemic control.  In the present study, we found no significant difference in mean serum potassium
levels between the losartan and amlodipine groups. These results are in contrast
with those obtained by Nishida et al20, who reported higher levels in patients using ARBs than in
those using CCAs. With regard to lipid metabolism, the levels of total cholesterol,
LDL cholesterol, HDL cholesterol, and triglycerides were similar between the 2
groups. In the study conducted by Derosa et al19, lower values of total cholesterol and LDL cholesterol were
found in patients treated with telmisartan compared with those treated with
nifedipine. These results are similar to those obtained by Nishida et al20, who compared patients using ARBs
and those using CCAs, thereby suggesting that ARBs may have improved benefits on
lipid metabolism in comparison with CCAs.  Microalbuminuria was determined by calculating UACR. Mean microalbuminuria was lower
in the amlodipine group in comparison with the losartan group; however, the
difference was not significant. The profile of the evaluated study group indicated a
decreased risk of nephropathy. Because of its cross-sectional nature, the present
study did not evaluate the effects of each drug on the variables analyzed, including
microalbuminuria. In contrast, Yasuda et al22 conducted a prospective study comparing patients on
losartan or amlodipine and found lower microalbuminuria in the losartan group. The
authors of the IDNT study23
evaluated patients with SAH and nephropathy secondary to T2DM; as primary outcomes,
they observed a lower risk of renal function impairment in patients who received
irbesartan when compared with those who received amlodipine or placebo. However,
there was no significant difference in the risk of all-cause death, even in subjects
with renal function impairment. Moreover, the RENAAL study24 evaluated the effects of losartan on renal and
cardiovascular outcomes in patients with T2DM and nephropathy compared with the
placebo group and found a decrease in the progression of renal disease in the
losartan group. However, no decrease in nephropathy- and CVD-related mortality was
observed. In contrast, Yilmaz et al25 compared the use of valsartan, amlodipine, or a combination of
these drugs in patients with hypertension and T2DM and observed decreased
microalbuminuria in the 3 patient groups. These findings suggest that although CCAs
do not have the same effects as ARBs on kidney hemodynamics, CCAs may have an
important role in reducing microalbuminuria in patients with hypertension and
diabetes, which can be explained by their antihypertensive efficacy.  After 6 weeks of treatment with losartan or amlodipine, lower mean BP levels were
observed in the amlodipine group in comparison with the losartan group, although the
differences were not significant. The Valsartan Antihypertensive Long-term Use
Evaluation (VALUE) trial26
compared patients with hypertension who were treated with valsartan or amlodipine
and revealed an increased control of BP in patients treated with amlodipine. Two
years later, Zanchetti et al27
performed further analysis of the VALUE trial data according to subgroups and
indicated improved BP control in the group treated with amlodipine compared with the
group treated with valsartan; furthermore, this reduction was more pronounced in
women. Phillips et al28 compared
patients with hypertension who were treated with amlodipine or losartan and found a
decrease in BP in both groups; however, this decrease was greater in the group
receiving amlodipine.  Previous studies have evaluated patients with hypertension and diabetes treated using
CCAs and compared them with those using ARBs or ACEIs. Derosa et al19 compared the use of telmisartan or
amlodipine, revealing similarities between the 2 drugs in the ability to decrease
BP; no significant difference was found between the treatment groups. Yasuda et
al22 studied the effects
of losartan and amlodipine on BP in patients with hypertension and diabetes and
reported that both drugs were capable of reducing BP levels; no significant
difference was found between these 2 groups. Similarly, Miyashita et al29 compared the effects of olmesartan
and amlodipine on BP and found similar results between the 2 drugs.  In the present study, the mean BP values ​obtained with ABPM were similar in both
groups, consistent with the results reported by Yasuda et al22 when comparing the effects of
losartan and amlodipine on BP. Ishimitsu et al30 studied the effects of losartan in hypertensive patients
without diabetes in comparison with patients receiving amlodipine and reported that
both drugs were able to decrease BP over 24 h; however, the effects of amlodipine
were greater than those of losartan. Otero et al18 used ABPM to evaluate BP in patients with hypertension and
diabetes treated with manidipine or enalapril and found no differences between these
2 drug classes.  SAH is associated with the pathogenesis of arterial stiffness and is a manifestation
of decreased arterial compliance31. Decrease in mean BP levels, and consequently in the pressure
distension on blood vessels, is the greatest beneficial effect common to all classes
of antihypertensive drugs31. In
this context, growing evidence indicates the beneficial effects of CCAs and other
drugs that interfere with the renin-angiotensin-aldosterone system (RAAS) for the
management of important hemodynamic parameters31. After conducting a meta-analysis comparing ACEIs and ARBs
with CCAs, diuretics, and beta blockers, Boutouyrie et al32 reported the improved ability of ACEIs and ARBs in
decreasing PWV and AIx. Kim et al33 evaluated 98 patients with hypertension and T2DM after 12 weeks
of use of valsartan and found a decrease in aortic pulse pressure (APP), AIx, and
PWV. Similarly, Asmar et al34
studied a group of 28 patients with hypertension and T2DM who were treated with
telmisartan and found a decrease in PWV and AIx in these patients compared with the
placebo group.  Kita et al35 evaluated 29 patients
hypertension treated with benidipine for 1 year and found a decrease in PWV in these
patients. Previous studies have compared the effects of drugs that affect RAAS with
CCAs. Rajzer et al36 evaluated 180
patients with hypertension who were randomized into 3 groups according to the drug
administered [quinapril (20 mg/day), amlodipine (10 mg/day), and losartan (100
mg/day)] and reported that all 3 drugs were able to decrease BP. However, only the
quinapril group exhibited a significant decrease in PWV. Moreover, Ichihara et
al37 compared the effects
of amlodipine with those of valsartan on PWV. The study monitored 100 patients with
hypertension for 1 year and indicated a similar decrease in PWV in the 2 groups.  In the present study, applanation tonometry results revealed lower mean values of
systolic and diastolic central aortic pressure, AIx, PI, and APP in the amlodipine
group when compared with the losartan group. These findings suggest an improved
pattern of pulse wave reflection in the amlodipine group. The results​ obtained with
ABPM indicated no differences in the final BP in both groups, which corroborates
these important hemodynamic findings. The average BP values over 24 h indicate an
improved control of BP in hypertensive subjects. The lowest casual BP observed in
the amlodipine group appears to reflect a more pronounced acute effect of the CCA in
comparison with the ARB. With regard to PWV, the results were similar in both groups
and indicated no significant differences in arterial stiffness.  In the present, FMD was used to assess endothelial dysfunction. Some previous studies
have also reported the effect of antihypertensive drugs on FMD. Cheetham et
al11 compared the efficacy
of losartan (50 mg/day) for 4 weeks with that of placebo in 12 hypertensive patients
with T2DM. The results indicated a significant increase in FMD in the losartan
group. Clarkson et al12 compared
the efficacy of amlodipine (5 mg/day) with that of placebo in 91 patients with
hypertensive. A significant increase in FMD was observed in both groups. However, no
significant differences between the groups could indicate the superiority of one
intervention over the other. Another study conducted by Anderson et al38 evaluated the effects of 3 classes
of drugs on FMD in 80 patients who were randomized into 4 groups according to the
treatment received: enalapril (10 mg/day), quinapril (20 mg/day), losartan (50
mg/day), and amlodipine (5 mg/day). After 8 weeks, only quinapril resulted in a
significant increase in FMD. Yilmaz et al25 compared the effect of amlodipine (10 mg/day), valsartan
(160 mg/day), or a combination of these 2 drugs on FMD. They observed that all
treatment regimens effectively increased FMD, and the largest increase was observed
in the group treated with the drug combination. In the present study, the mean
percentage increase in FMD was higher in the losartan group compared with the
amlodipine group. However, this difference was not significant, thereby preventing
further conclusions in the evaluation of this method.

BODY.CONCLUSIONS:
In hypertensive patients with T2DM with no evidence of advanced nephropathy,
treatment with amlodipine at an average dose resulted in similar BP levels in a 24-h
period when compared with treatment with losartan at the maximum dose. Assessment of
functional vascular alterations revealed a more favorable pattern of pulse wave
reflection in the amlodipine group when compared with the losartan group. The
decreased casual BP levels in patients treated with amlodipine, although not
significant, may have clinical importance. However, the other functional vascular
parameters evaluated were similar in both groups, which may indicate the occurrence
of vascular effects associated with the use of losartan, regardless of its
antihypertensive effect.

Question: Compared to losartan (100 mg/day) what was the result of amlodipine (5 mg/day) on flow-mediated dilation (FMD)?
Evidence: with no significant difference in the mean BP [amlodipine group: 145
± 14 mmHg (systolic) and 84 ± 8 mmHg (diastolic); losartan group: 153 ± 19
mmHg (systolic) and 90 ± 9 mmHg (diastolic)]. 
Answer: no significant difference