Salt Sensitivity and Hypertension

“Role of Azilsartan”

1
 Rule of Halves
prevails in hypertension

2
 Rule of Half
Rule of Half
for
for Treatment
for BP
prevalence
forcontrol
Diagnosis

JAPI • VOL. 51 • FEBRUARY 2003 3

Mater Sociomed. 2016 Apr; 28(2): 95–98.
 But
one rule of half
that significantly contributes to hypertension
is least discussed

4
 Salt Salt Rule of Half
Non- Sensitive
Sensitive for Salt
Sensitivity

5
Endocr Pract. 2010;16:940-944
 HYPER
HYPER FLUID
FLUID
CALCIUR
CALCIUR CV
CV
IA RETENTI
RETENTI
IA DISEASE
DISEASE ON
ON KIDNEY
KIDNEY
STONES
STONES

SAL
CATARA

SAL
CATARA
CT
CT

Proteinuri
Proteinuri

LV
TT aa
LV STOMAC
Hypertroph
Hypertroph
STOMAC
HH
yy ASTHMA
ASTHMA
MENIERE'S
MENIERE'S
DISEASE
DISEASE
CANCER
CANCER

6
 The relationship between salt and
hypertension is well documented..
• Various models for blood pressure rise following salt load

• Pressure Natriuresis
Salt, plasma volume, and BP

• A Unifying Hypothesis
Endogenous Ouabain, a Key
Player

• Sympathetic nerve Activity

A Pressure
UnifyingNatriuresis
Hypothesis

7
Am J Physiol Heart Circ Physiol 302: H1031–H1049, 2012.
 Salt as CV risk
• In cohort studies, a 5 g per day higher salt
intake (2000 mg of sodium) is associated with
a 17% greater risk of total cardiovascular
disease, and crucially a 23% greater risk of
stroke.

8Kidney Int Suppl (2011). 2013 Dec; 3(4): 312–315

 Salt as CV risk
• In Japan, a government campaign to reduce
salt intake saw a fall from 13.5 to 12.1 g/day
(from 5400 to 4840 mg sodium) in a decade.
This was associated with a substantial
reduction in stroke mortality, despite increases
in the population's fat intake, cigarette
smoking, alcohol consumption, and body mass
index.

9
Kidney Int Suppl (2011). 2013 Dec; 3(4): 312–315
Though
Thoughrole
roleof
of
Salt
Saltin
in
SALT
SALT
hypertension
hypertension Sensitivity
Sensitivity
IsIswell
well still
still
Remains
Remainsaamystery
documented
documented mystery

10
 Salt sensitivity
is defined as a quantitative trait
in which increase in sodium (Na+) load
leads to an increase in blood
pressure

11
 The pressure natriuresis Curve
best defines Salt sensitive hypertension

The rise in plasma [Na] is, however,

similar in normotensive and
hypertensive, or salt resistant and salt-
sensitive, humans as well as in animals .
A long-held view is that in salt-
sensitive humans and animals, the
salt-dependent elevation of BP and
the consequent pressure natriuresis
rebalance salt intake and output and
thereby prevent a rise in plasma
[Na]Am and plasma
J Physiol Heart Circ volume .
Physiol 302: H1031–H1049, 2012.

12
 The pressure natriuresis Curve
best defines Salt sensitive hypertension
According the model, the initial
BP elevation in response to a high-
salt diet and/or defect in salt
excretion is due to plasma volume
expansion and an increase in CO,
where BP=CO*TPR. Then, to
compensate for tissue over
perfusion, there is a slow shift
from high CO to high TPR (whole
body autoregulation of the
vasculature) to sustain the elevated
BP.
Am J Physiol Heart Circ Physiol 302: H1031–H1049, 2012.

13
 Once salt sensitivity was believed to be associated
With African population only

SAL
SAL
But Analysis of 92 trials by Niels Graudal et al.
Suggested
SALT SENSITIVITY IS UNIVERSAL ACROSS THE
WORLD

T
T
SENSITIVIT
SENSITIVIT
YY

14 Front. Physiol.6:157. doi: 10.3389/fphys.2015.00157

Diabetes enhances the
hypertensive effect of salt
Hypertension in people with
diabetes is characterized by
increased salt sensitivity and
volume expansion. There is also
some recent evidence which
suggests that, under current
environmental conditions, high
salt intake may be a triggering
factor for type 2 diabetes
Progress in Cardiovascular Diseases, Vol.
49, No. 2 (September/October), 2006: pp
59-75
Salt Sensitivity: Relationship to
Insulin Resistance and the
Cardiometabolic Syndrome
Salt sensitivity (an exaggerated
response of blood pressure to
changes in sodium balance) has
been documented in more than 50%
of patients with hypertension, and
the frequency of occurrence varies
by age, ethnic background,
potassium balance, and other
factors
Endocr Pract. 2010;16:940-944

15
study done in an urban south 26% of normotensive population was salt
Indian population makes three sensitive & 50% of Hypertensive population
important points: was salt sensitive
(i) consumption of dietary salt is
higher than the currently
recommended by HO (ii) both
systolic and diastolic BP are
influenced by higher intake of
dietary salt among hypertensive
and normotensive subjects (iii)
Increased salt intake is
associated with increased
prevalence of hypertension and
this association is independent of
age, sex, body mass index, total Hypertension. 2001;37[part 2]:429-432.
energy and dietary fat intake. 16
JAPI • VOL. 55 • JUNE 2007
 Salt
Saltnot
notonly
only
Elevates
Elevatesof
ofblood
bloodpressure
pressure

but it creates
Double Whammy…

By
ByWeakening
Weakeningblood
blood
pressure
pressurereducing
reducingefficacy
efficacyof
of
key
keyanti
antihypertensive
hypertensive
molecules
molecules
17
Four-week study performed in
Four-week study performed in
24 patients with essential
24 patients with essential
hypertension who were given
hypertension who were given
a regular sodium diet (12-15 g
a regular sodium diet (12-15 g
of NaCI/d) in the first and
of NaCI/d) in the first and
third weeks and a sodium-
third weeks and a sodium- • 60 mg/d of nicardipine (Caantagonist)
restricted diet (1-3 g/d) in the
restricted diet (1-3 g/d) in the • 120 mg/d of propranolol (ß-blocker)
second and fourth weeks
second and fourth weeks
• 150 mg/d of Captopril (converting-enzyme
inhibitor)

18 Am J Hypertens 1988;1:372-379
Am J Hypertens 1988;1:372-37919
 Am J Hypertens 1988;1:372-37

CCBs
CCBs

HIGH
SALT

Without
Medication
With
Medication

Low
SALT

SLOPE OF THE CURVE IS

LEAST AFFECTED
20
 Beta
Beta RAAS
RAAS
CCBs
CCBs Blockers
Blockers Blockers
Blockers

Least affected
Moderately Significantly
by
affected by High affected by High
High salt
salt ingestion salt ingestion
ingestion

Open symbols and broken lines represent results obtained 21

before the administration of the drugs, Am J Hypertens 1988;1:372-379
Conclusion:
• The hypotensive effect of nicardipine and propranolol
did not differ with the change in sodium intake,
whereas that of Captopril was greater under sodium
restriction than under the regular sodium diet. Urinary
sodium excretion was plotted on the ordinate as a function of arterial pressure
before and after administration of the antihypertensive drugs. The pressure-
natriuresis curve was shifted left, without a change in the
slope, by nicardipine and propranolol and also left, but with a
decrease in the slope, by Captopril..The decrease in the
slope might be due mainly to the inhibition of the renin-
angiotensin system.

22
 The
Theeffect
effectofofaa4-day
4-day
oral
oral salt
salt load
load (150
mmol
(150 The antiproteinuric and
mmol NaCl
NaCl extra
extra per
per
day)
day) on
on blood
blood blood pressure lowering
pressure,
pressure, six
six males
with
males
primary
effect of ACE inhibition
with primary
hypertension,
hypertension, who who is blunted by or even lost
had attained
had
normotension
attained
on
during a high sodium
normotension on
chronic
chronic enalapril
enalapril intake
treatment
treatmentfor
for44years
years

23
Am J Hypertens 1988;1:372-379
 Losartan monotherapy
Losartan monotherapy
reduced proteinuria by
reduced proteinuria by
30%, and the addition
30%, and the addition
of a low-sodium diet
of a low-sodium diet
led to a total reduction
led to a total reduction
by 55%
by 55%

24
J AM Soc Nephro 2008 May; 19(5):999-1007
 Telmisartan displayed
Telmisartan displayed
differential reduction in blood
differential reduction in blood
pressure in Low and high
pressure in Low and high
Dietary salt groups
Dietary salt groups

Diabetes Care 32:1398–1403, 2009

25
 When Low Dietary Sodium
When Low Dietary Sodium
group
group
Was subjected to High
Was subjected to High
Sodium diet,
Sodium diet,
Sodium not only negated
Sodium not only negated
blood pressure reducing
blood pressure reducing
efficacy but protective effects
efficacy but protective effects
also
also

26
Diabetes Care 32:1398–1403, 2009
 • The effects of a high-salt diet
are related to the function of
the renin-angiotensin system,
which is normally suppressed
by a high-salt diet

•  The high-salt diet caused a

reduction in both plasma
angiotensin II and aldosterone
levels
Kidney Blood Press Res. 2011 Jan; 34(1): 1–
11.

In presence of high salt,

elevated blood pressure may be precipitated by pressure natriuresis
mechanism 27
Azilsartan
28
“In today’s world the attitude
within drug classes
is they are all created
equal..”

Prof.
George Bakri
http://www.cardiometabolichealth.org/arb-azilsartan-shows-greater-efficacy-in- 29
lowering-blood-pressure-among-patients-with-prediabetes-and-type-2-diabetes.html
“Unfortunately, this is not true, at least within the
ARB class, as azilsartan is clearly superior for
blood pressure lowering when compared to other
well-known agents in the class. Thus, at least for
ARBs, they are not all created equal.”

Prof.
George Bakri
http://www.cardiometabolichealth.org/arb-azilsartan-shows-greater-efficacy-in- 30
lowering-blood-pressure-among-patients-with-prediabetes-and-type-2-diabetes.html
 • Losartan
• Candesarta
n
• Valsartan Azilsartan
Azilsartan
• Irbesartan
• Telmisartan The88
The
th
thARB
ARB
• Olmysartan
• Eprosartan
 Azilsartan
Medoxomil
Structural Modification
of
CANDESART
AN
5-oxo-1,2, 4-oxadiazole
ring in place of the
Journal of The Association of Physicians of India Vol. 64
March 2016
32
 Azilsartan- “Different” ARB
POWERFU
POWERFU
LL

RAA
RAA INVERSE
INVERSE SALT
AGONISM
AGONISM SENSITIVE
SENSITIVE
SS HYPERTENSION
HYPERTENSION

BLOCKADE
BLOCKADE
33
 Azilsartan- “Different” ARB
Improved Binding Behavior of Azilsartan
Compared With Candesartan

Highest
Highest
affinity
affinityfor
for
AT1
AT1receptor
receptor

Hypertens Res. 2013 February ; 36(2): 134–139. 34

 Azilsartan- “Different” ARB
Improved Binding Behavior of Azilsartan
Compared With Candesartan

1.Gln257 binds to the oxadiazole ring by hydrogen

Highest
Highest bonding, with a bond distance of 2.6 Å.

affinity
affinityfor
for 2.Tyr113 binds to the biphenyl group of azilsartan 3.4
Å. While the same for Candesartan is 4 Å
AT1
AT1receptor
receptor 3.Lys199 was a candidate for binding to the carboxyl
group of azilsartan, and the bond distances were 2.6
and 3.2 Å.

SHORTER BOND LENGTH MEANS STRONG BONDING

Hypertens Res. 2013 February ; 36(2): 134–139. 35

 Azilsartan- “Different” ARB
Dissociation Rate
One of the most Different feature of azilsartan
reported is its ability to remain tightly bound to AT1
receptors for very long period of time after drug
washout
Slowest
Slowest
Dissociation
Dissociation
rate
rate

Slowest Dissociation means “POWERFUL RAAS

BLOCKADE”

Vascular Health and Risk Management 2012:8 133–143 36

 Azilsartan- “Different” ARB
Dissociation Rate
One of the most Different feature of azilsartan
reported is its ability to remain tightly bound to AT1
receptors for very long period of time after drug
washout
Slowest
Slowest
Dissociation
Dissociation
rate
rate

Slowest Dissociation means “POWERFUL RAAS

BLOCKADE”

Vascular Health and Risk Management 2012:8 133–143 37

Highest
Highest Azilsartan Slowest
Slowest
Affinity
Azilsartan Dissociation
Dissociation
Affinityfor
for isis Different
AT Different from
fromAT
AT11
AT11receptor
receptor

38
Inverse Agonist Activity with
Azilsartan

Azilsartan binds to the AT1 receptor as an agonist but

induces a pharmacological response opposite to that
Ang. II 39
AZILSARTAN
BLOOD PRESSURE REDUCTION

40
 Azilsartan “Different” ARB

POWERFUL 24 HOUR REDUCES

EARLY MORNING
BLOOD PRESSURE BLOOD PRESSURE

REDUCTION CONTROL SURGE

IMPROVES EQUIPOTENT
CONTROLS RESPONSE IN
BLOOD PRESSURE DIPPING SALT SENSITIVE
VARIABILITY PATTERNS HYPERTENSION

41
 Azilsartan was found better than
Candesartan in

24 hr Mean BP
Day time BP
Night time BP
Early morning BP
Before awakening BP
Pre awakening surge

42
Blood Press Monit 19:164–169
 Azilsartan Reduces
Early morning surge

43
Blood Press Monit 19:164–169
 Randomized, double-blind study of azilsartan (20 – 40 mg once
daily) and candesartan (8 – 12 mg once daily) in Japanese
patients with essential hypertension, an exploratory analysis was
performed using ambulatory BP
monitoring (ABPM) at baseline and Week 14

44
Blood Pressure Monitoring 2014, 19:164–169
Blood Pressure, 2013; 22 (Suppl 1): 22–28 45
Blood Pressure Monitoring 2014, 19:164–169
Azilsartan improves
Nocturnal dipping pattern

46
Blood Pressure, 2013; 22 (Suppl 1): 22–28
 Azilsartan
Azilsartan
Powerful
PowerfulBP
BPReduction
Reduction
inincomparative
comparative
trials
trials

Vascular Health and Risk Management 2012:8 133–143 47

 Changes in clinic systolic and diastolic BPs from baseline in Japanese
patients with grade I–II essential hypertension after treatment for 16
weeks with azilsartan or candesartan cilexetil as reported by Rakugi et

Azilsartan
Azilsartan
Powerful
PowerfulBP
BPReduction
Reduction
inincomparative
comparative
trials
trials

Vascular Health and Risk Management 2012:8 133–143 48

AZL-M is well tolerated & more efficacious
at its maximal dose than the highest dose of
OLM-M

49
J Clin Hypertens (Greenwich). 2011;13:81–88.
 Forty-four hypertensive patients who had coronary artery
disease (CAD) were enrolled. We randomly assigned
patients to changeover from their prior angiotensin II
receptor blockers (ARBs) to either azilsartan or olmesartan,
and followed the patients for 12 weeks.

50
 % patients
achieving BP
targets
Before Therapy

After Therapy

51
J Clin Med Res. 2016;8(10):743-748
Though Azilsartan provided
Powerful BP reduction
Morning surge improvement
Reduction in BP variability

But most important was

Improvement in Circadian rhythm
(Dipping pattern)

52
 Azilsartan “Different” ARB
Improvement in nocturnal dipping Improved
after Azilsartan Therapy

53
 • there seems to be a strong concordance between
sodium sensitivity and nondipping in hypertensive
Nocturnal dipping
subjects. We suggest that there are different limits to
sodium excretory capacity between individuals, which
closely related to
are revealed when sodium intake increases. SS
Salt Sensitivity
individuals respond to sodium loading as if their
daytime capacity is insufficient to maintain sodium
balance so that they must excrete a greater proportion
of sodium at night to maintain overall sodium balance.

Hypertension. 2006;48:527-533 54
 • A strong concordance between sodium sensitivity and
nondipping in hypertensive subjects.
• There are different limits to sodium excretory capacity
between individuals, which are revealed when sodium intake
increases. SALT SENSITIVE individuals respond to
sodium loading as if their daytime capacity is
insufficient to maintain sodium balance so that they
must excrete a greater proportion of sodium at night
to maintain overall sodium balance.

Hypertension. 2006;48:527-533 55
 • Nocturnal sodium excretion is affected by adjusting
blood pressure upward to stimulate pressure–
natriuresis, resulting in non dipping. During sodium
restriction or after diuretic treatment, sodium
excretory requirements fall back with the range that
can be met by daytime excretion, eliminating the
need for high blood pressure at night and restoring a
dipping pattern

Hypertension. 2006;48:527-533 56
To
Tounderstand
understand
Effect
Effectof
of
Mechanistic
Mechanistic
Azilsartan
Azilsartan study
study was
was
on
onsalt
salt
sensitivity
performed
performed
sensitivity

57
 SALT INTAKE increases blood pressure

In
In
SALT
SALT
SENSITIVE
SENSITIVE
HYPERTENSIO
HYPERTENSIO
NN

because of Pressure Natriuresis

PLOS ONE | DOI:10.1371/journal.pone.0147786 January 25, 2016 58

 SALT INTAKE negates blood pressure
reducing efficacy of ARBs

In
In
SALT
SALT
SENSITIVE
SENSITIVE
HYPERTENSIO
HYPERTENSIO
NN

because of Pressure Natriuresis

PLOS ONE | DOI:10.1371/journal.pone.0147786 January 25, 2016 59

 But Azilsartan is In
In
SALT
SALT
SENSITIVE
SENSITIVE
HYPERTENSIO
HYPERTENSIO
NN

Azilsartan
Azilsartanwas
was
found
foundtotobe
beleast
least
affected
affectedwith
withsalt
salt
“Different” loading
loading

PLOS ONE | DOI:10.1371/journal.pone.0147786 January 25, 2016 60

 NHE3
NHE3levels
levels
were
werestudied
studied
with
withAzilsartan
Azilsartan

http://hmphysiology.blogspot.in/p/renal-physiology.html
Physiological Reviews Published 1 April 2006 Vol. 86 no. 2, 709-746 DOI: 10.1152/physrev.00016.2005 61
 • The dopamine-stimulated dopamine D3 receptor inhibits
Angiotensin 2 protects
USP48 function,
NHE3 which leads to the promotion of NHE3
degradation
degradation via a ubiquitin–proteasomal pathway.
Angiotensin
Angiotensin22
&&
• The D3 receptor is also antagonized by angiotensin II-
Sodium
Sodium retention
retention
stimulated AT1R.
Through
ThroughNHE3
NHE3
• Leading to increased expression of USP48 , leading to
increased de-ubiquitination & sustained activity of NHE3

al Investigation 2016; 3: e1352. doi: 10.14800/rci.1352; © 2016 by Jun-Ya Kaimori, et al.

62
 NHE3 is responsible for Sodium
• When inazilsartan
Reabsorption exchange ofblocks the AT1R signal, In
Hydrogen the D3
In
SALT
receptor starts the course toward inhibition of USP48
SALT
expression. NHE3 de-ubiquitination SENSITIVE
by USP48 is
SENSITIVE
blocked, so NHE3 proceeds toHYPERTENSIO proteasomal
HYPERTENSIO
degradation . NN

Azilsartan
Azilsartanisis
Azilsartan Modulates NHE3,
Sodium Hydrogen Exchanger 3, “Different”
“Different”
in Proximal tubule

Investigation 2016; 3: e1352. doi: 10.14800/rci.1352; © 2016 by Jun-Ya Kaimori, et al. 63

 T2DM confers approximately a two-
Diabetes
Diabetesand
and fold increase of cardio-vascular events
• Unlike other ARBs, azilsartan
Salt
Saltsensitivity
sensitivity in men and three-fold increase in
assures powerful BP reduction even
are women; with concurrent hypertension,
areclosely
closely in Diabetic Hypertensive patients
related.. there is an approximately four fold
related.. increase in cardiovascular risk.

Journal of Hypertension 2016, 34:788–797 64

Azilsartan
&
Kidneys

65
 • Renal impairment/disease did not
cause clinically meaningful increases
in exposure to AZL. M-II exposure
was higher in all renally impaired
subjects and highest in those with
severe impairment (approx fivefold
Azilsartan higher vs. control). M-II is
Azilsartan pharmacologically inactive; increased
&&
exposure was not considered
Kidney
Kidneyfunction
function important in dose selection for AZL-
M in subjects with renal impairment.
Hemodialysis did not significantly
remove AZL or M-II. Renal
impairment had no clinically
meaningful effect on the plasma
protein binding of AZL or M-II.
Transplantation Proceedings, 46, 492e495 (2014)
66
Examination
Examinationof of Candesartan

the
theEffect
Effectofof • The subjects were 20 patients (18 males, 2
Changing toto
ChangingSystolic females; baseline serum creatinine 2.39
Azilsartan
1.33 mg/dL) responding poorly to
Azilsartan
AzilsartanFrom
From candesartan, who suffered albuminuria (>0.3
Candesartan
Candesartaninin
Diastolic
g/g creatinine) and hypertension (>140/90
Renal
RenalTransplant
Transplant
mm Hg) following renal transplantation.

Patients
Patients

Transplantation Proceedings, 46, 492e495 (2014)

67
 Patients-
Twenty-two hemodialysis patients
Azilsartan
AzilsartanisisMore
More switched form Olmesartan to Azilsartan
Effective as Compared
Effective as Compared
totoOlmesartan
Olmesartaninin
Hemodialysis
Hemodialysis BP Measurement:
Patients
Patientswith
with Morning & Evening
Uncontrolled
Uncontrolled
Hypertension
Hypertension
Blood pressure before switch:
171/71 mmHg

Ukimura et al., J Nephrol Ther 2015, 5:1 68

69
In
conclusion
switching from olmesartan to azilsartan
, significantly and safely decreased home-
measured blood pressure in hemodialysis
patients

70
71
 Patients-
Twelve hemodialysis patients
Effects
EffectsofofAzilsartan
Azilsartaninin
Ambulatory
AmbulatoryPatients
Patientson
Maintenance
on BP Measurement:
Maintenance Home BP measurement
Hemodialysis:
Hemodialysis:
Monitoring
MonitoringatatNight
Nightand
and
Morning & Evening
atatHome
Home
Blood pressure Azilsartan:
167/83 mmHg

Ukimura et al., J Nephrol Ther 2015, 5:1 72

Azilsartan reduces
Morning Blood pressure
Evening blood pressure
Central Systolic pressure

73
This
This small
small study
study examined
examined
the
the effect
effect ofof azilsartan,
azilsartan, aa
newly
newlydeveloped
developedARB,ARB,on onBP
BP
ininpatients
patientsreceiving
receivingHD.HD.The
The
change
change from
from other
other ARBs
ARBs to
to
azilsartan
azilsartan reduced
reduced SBP SBP
throughout
throughout24 24hours,
hours,before
before
and
and after
after HD
HD session,
session, atat
home
home BP,BP, and
and atat night
night BP
BP
during
duringsleep.
sleep.

74
Azilsartan
Azilsartan
Safety
Safety

75
Among the AEs related to conditions associated with hypertension treatment in
general and RAS blockade specifically (in addition to dizziness and headache
noted earlier), hypotension, cough, peripheral edema, increased blood
creatinine, and postural dizziness were all reported by 2 to 55% of all subjects.
Gout and hyperuricemia were reported as AEs in 0.7 and 1.2% of subjects,
respectively. Serious AEs reported by more than one subject included: chest pain
(n=3 subjects [0.4%]), coronary artery disease (n=2 [0.3%]), small intestinal
obstruction (n=2 [0.3%]), road traffic accident (n=2 [0.3%]), vasovagal syncope
(n=2 [0.3%]), asthma (n=2 [0.3%]), pulmonary embolism (n=2 [0.3%]), and
hypotension (n=2 [0.3%]).

76
Clin Exp Hypertens, 2016; 38(2): 180–188
 Azilsartan appears to DIFFERENT
ARB
more efficacious in blood pressure
reduction than the other ARBs with a
similar safety and tolerability profile

77
Journal of The Association of Physicians of India ■ Vol. 64 ■