Newer ARBs

1. AZILSARTAN
NOVEL ANGIOTENSIN RECEPTOR
BLOCKER
1

2. BURDEN OF HYPERTENSION IN INDIA
 About 33% urban and 25% rural
Indians are hypertensive
 Only 25% rural and 38% of urban
Indians are being treated for
hypertension
 Only one-tenth of rural and one-fifth of
urban Indian hypertensive population
have their BP under control
2
 J Hypertens. 2014 Jun;32(6):1170-7

3. ARBS ARE THE FIRST CHOICE IN HYPERTENSION
Population Goal BP
mm Hg
Initial drug treatment
options
General ≥ 60 y <150/90 ARB, ACEI, Thiazide type
diuretics or CCB
Diabetes
(All ages)
<140/90 ARB, ACEI, Thiazide type
diuretics or CCB
CKD (All ages) <140/90 ARB, ACEI
3
JNC 8 Recommendations

4. GUIDELINE RECOMMENDATIONS :
ARBS ARE PREFERRED AS FIRST CHOICE
CHEP: Canada Guidelines. Prevention & Treatment Hypertension
NICE: The National Institute for Health and Care Excellence
KIDGO: KIDNEY DISEASE | IMPROVING GLOBAL OUTCOMES

5. ESH GUIDELINE IDENTIFIED
Sub optimal control of BP with monotherapy
 Monotherapy can effectively reduce BP in only in a
limited no. of individuals
5
 2013 ESH/ESC Guidelines for the management of arterial hypertension

6. LIMITATION : CURRENT TREATMENT OPTIONS
CCB:
 In clinical studies frequency of peripheral edema (5% to 70%)
have been reported 1
ACEI:
 The angiotensin II inhibition escape in 39 % patients with type 2
diabetes and diabetic nephropathy have been reported 2
 5-35 % incidence of dry cough have been reported 3
 0.1 to 0.7 % induce angioedema have been reported 4
 With this limitation especially for ACEi, treatment with an ARB
can be the initial choice of treatment
6
1. J Clin Hypertens. 2003;5:291–294, 297.
2. Ter Arkh. 2008;80(1):49-52
3. Chest. 2006; 129(1 Suppl):169S-173S
4. http://www.uptodate.com/contents/ace-inhibitor-induced-angioedema

7. LIMITATION : CURRENT TREATMENT OPTIONS
Olmesartan:
 Occurrence of few cases of enteropathy is reported 1
Telmisartan
 Impaired Hepatic Function: Majority of telmisartan is
eliminated by biliary excretion, patients with biliary
obstructive disorders or hepatic insufficiency can be
expected to have reduced clearance and dose adjustment
is required 2
7
1. Ann Gastroenterol. 2017; 30(1): 131–133.
2. Micardis . Prescribing information By Boehringer

8. REGULATORY STATUS
 Approved By:
 Brand name: Edarbi (Takeda Pharmaceuticals)
 Also marketed in Canada, Japanm Mexico, UA
8

9. PHARMACOKINETICS
 t-max: 1.5 to 3 hours
 Food effect: NO
 Bioavailability: Approx. 60 % which is superior compared to
olmesartnan and telmisartan
 Plasma protein binding: >99
 Half-life : 11 hrs
9

10. AZILSARTAN HAS HIGHEST
SELECTIVITY TO AT1 RECEPTORS
 Hypertens Res. 2013 February ; 36(2): 134–139.
 Micardis . Prescribing information By Boehringer Ingelheim
 Losartan Prescribing information by Apotex
 BENICAR Prescribing Information By Daiichi Sankyo 10
Drug Name AT1 receptor selectivity
Azilsartan 39,000 times
Telmisartan >3000 times
Olmesartan >12,500 times
Losartan about 1000 times
Valsartan
30000 times

11. AZILSARTAN HAS SLOW DISSOCIATION FROM AT1
RECEPTOR
 Vascular Health and Risk Management 2012:8 ;133-143
11

12. AZILSARTAN REDUCE NHE3 PROTEIN FUNCTION
 Therefore , Azilsartan appears to an effective treatment option
for salt sensitive hypertensive patients
12
 Receptors & Clinical Investigation 2016; 3: e1352.
 NHE3 : Sodium–hydrogen antiporter 3

13. 13
•Apart from AT1 receptor blocking, Azilsartan enhances ACE2–ANG-(1–7)–Mas axis for
decreasing cardiovascular diseases & Hypertrophic action
• ANG-(1–7), which stimulates Mas receptors. to release nitric oxide (NO) from endothelial cells
and thereby counteracts the effects of ANG II & lessen vascular dysfunction
Azilsartan: Parallel RAAS for Counter Regulatory Action
Hypertension 2014;;63;e53-e59

14. AZILSARTAN VS TELMISARTAN
Parameters Azilsartan Telmisartan
AT1 receptor selectivity 39,000 times >3000 times
IC 50 value before washout (nM) 2.6 5.1
IC 50 value after washout (nM) 7.4 191.6
Bioavailability (%) Approx. 60 42
14 Hypertens Res. 2013 February ; 36(2): 134–139.
 Micardis . Prescribing information By Boehringer Ingelheim
 Azilsartan exhibits 13 time more At1 selectivity compared to
telmisartan
 Approx. 2 to 26 time more potent than telmisartan
 Azilsartan exhibits superior bioavailability compared to telmisartan
40 mg
 Azilsartan’s greater AT1 receptor affinity and tighter binding may
contribute towards more BP lowering effects than Telmisartan.
 Azilsartan has a significantly stronger hypotensive effect than
other ARBs including telmisartan in hemodialysis patients

15. AZILSARTAN VS OLMESARTAN
 Hypertens Res. 2013 February ; 36(2): 134–139.
 Losartan Prescribing information by Apotex
 Vascular Health and Risk Management 2012:8 ;133-143
15
Parameters Azilsartan Olmesartan
AT1 receptor selectivity 39,000 times > 12,500 times
IC 50 value before washout (nM) 2.6 6.7
IC 50 value after washout (nM) 7.4 242.5
Bioavailability (%) Approx. 60 26
 Azilsartan exhibits 3 time more At1 selectivity compared to
telmisartan
 Approx. 3 to 33 time more potent than telmisartan
 More potent in improving insulin sensitivity and reducing
proteinuria than olmesartan
 Azilsartan exhibits superior bioavailability compared to 40 mg
olmesartan
 Azilsartan is superior, in terms of BP reduction, with respect to
olmesartan
 Azilsartan is more potent in improving insulin sensitivity and

16. AZILSARTAN VS ACEI
 1153 patients with newly diagnosed hypertension
 789 were prescribed Azilsartan and 364 were prescribed an ACEI
 Follow up: 12 months
16
Azilsarta
n
ACEI p-
value
Percentage of the
patient achieving target
BP (<140/90 mm Hg)
64.8 56.3 p<0.01
Azilsartan provides superior blood pressure
reduction and better target blood pressure
achievement
J Clin Hypertens (Greenwich). 2015 Dec;17(12):947-53.
ACEI: Ramipril was most commanly used in studies

17. AZILSARTAN VS ACEI
180
-29.9 -25.2
120
-14.8 -12.1
-50
0
50
100
150
200
Baseline Azilsartan ACEI
Reduction in Mean BP
Mean SBP Mean DBP
17
 J Clin Hypertens (Greenwich). 2015 Dec;17(12):947-53.
 ACEI: Ramipril was most commanly used in studies
Azilsartan provides superior SBP and DBP
reduction compared to ACEI
SBP :
p<0.0001
DBP: p<0.001

18. 18
Conclusion: In conclusion, the ability of Azilsartan to Reduce BP may
be superior to that of prior ARBs (including Telmisartan & Losartan)
with equivalent safety in hypertensive patients with CAD.
Depressor & Anti-Inflammatory Effects of Azilsartan
on Hypertensive Patients with CAD (DIAMOND STUDY)
78% Patients achieved Target BP goal (<130/80) in
Azilsartan Grp as compared to 45% in Olmesartan
Reduces Inflammatory
(hs- CRP) Bio-Markers on
0 & 12 Wks

19. AZILSARTAN VS OLMESARTAN, VALSARTAN
Azilsartan offers:
 45 % greater SBP reduction compared to valsartan
 24 % greater SBP reduction compared to olmesartan
19
 Hypertension. 2011;57:413-420.
 ( p<0.001 against valsrtan and p <0.009 against olmesartan)
Randomized, double-blind, placebo-controlled study
1291 patients
Clinical assessments, were performed at baseline and at 2, 4, and 6 weeks
post randomization.

20. MORE % OF PATIENTS ACHIEVED BP GOAL IN
AZILSARTAN COMPARED TO OLMESARTAN, VALSARTAN
49 49
58
44
46
48
50
52
54
56
58
60
Valsartan 320mg Olmesartan 40mg Azilsartan 80mg
Reduction of SBP to <140 mm Hg and/or
a reduction of ≥20 mm Hg
20 Hypertension. 2011;57:413-420

21. 24-HOUR MEAN SBP
-12.2
-13.5
-13.4
-14.6
-14.5
-12.6
-12
-10.2
-16
-14
-12
-10
-8
-6
-4
-2
0
Azil 20
Azil 40
Azil 80
Olme 40
Val 320
RCT 1 RCT 2
 Edarbi SPC

22. AZILSARTAN VS OMLESARTAN, VALSARTAN
IN DIABETIC HYPERTENSION
 A pooled analysis of 3821 patients
 Pool A (Olmesartan comparisons with Azilsartan)
 Pool B (Valsartan comparison with Azilsartan)
 Changes in ambulatory and clinic blood pressure (BP)
among patients with hypertension and prediabetes or T2DM
was performed
22
 J Hypertens. 2016 Apr; 34(4): 788–797.

23. AZILSARTAN VS OMLESARTAN, VALSARTAN
IN DIABETIC HYPERTENSION
23
Azilsartan offers:
• 23 % greater SBP reduction compared to olmesartan
• 17% greater SBP reduction compared to valsartan
FIGURE 1 Changes from baseline in 24-h SBP by treatment group and glycemic subgroup. (a) Pool A. (b) Pool B.
Azilsartan 40 mg, Valsartan 40 mg , olmesartan 40 mg

24. 24
Effects of azilsartan compared to other ARBs in
hemodialysis patients
Ther Apher Dial. 2014 Oct;18(5):398-403.
17 hypertensive patients, who had been administered
angiotensin receptor blockers, except for azilsartan, for more
than 6 months were enrolled and switched to azilsartan
Baseline After Azilsartan
treatment
Change in BP aft. 6
months (mm Hg)
150.9 131.3 (p=0.008)
Awakening time systolic
blood pressure (mm Hg )
152.1 131.2 (p=0.01)
Sleep-time systolic blood
pressure (mm Hg )
148.1 130.0 (p=0.001)

25. EFFECTS OF AZILSARTAN COMPARED TO OTHER ARBS
IN HEMODIALYSIS PATIENTS
 Azilsartan has a significantly stronger hypotensive
effect than other ARBs.
 Thus, the switch to azilsartan appears to improve
prognosis of hemodialysis patients.
25
 Ther Apher Dial. 2014 Oct;18(5):398-403.
 Elevated levels of noradrenaline cause cardiac cell hypertrophy
 left ventricular mass index : use to determine thickening of the heart muscle
Baseline After Azilsartan
treatment
Noradrenaline (pg/mL) 550.1 351.7
Left ventricular mass
index (g/m2)
117.1 111.3

26. AZILSARTAN, BUT NOT CANDESARTAN IMPROVES LEFT VENTRICULAR
DIASTOLIC FUNCTION IN PATIENTS WITH HTN AND HF
 Patients with HF, the patients who received azilsartan or
candesartan were retrospectively screened.
26
 International Journal of Gerontology 9 (2015) 201e205
 LV E/e : LV filling velocity/early diastolic velocity (E/e) ratio
9.5
10
10.5
11
11.5
12
12.5
13
13.5
Azilsartan candesartan
Change in LV/Ee ratio
Baseline after treatment
p = 0.03 p = 0.58

27. AZILSARTAN, BUT NOT CANDESARTAN IMPROVES LEFT VENTRICULAR
DIASTOLIC FUNCTION IN PATIENTS WITH HTN AND HF
Discussion:
 Compared to candesartan, azilsartan has a higher affinity for angiotensin II
receptors and a higher affinity for vasculature
 The effects on the arterial vasculature may affect the LV relaxation rate and
increases the capacitance of the aorta and delays the onset of ejection, and
thus increases the LV relaxation rate.
Conclusion:
 Azilsartan improves diastolic function in HF patients with
hypertension, and it may be the preferred option over other
angiotensin II receptor blockers in patients with HFpEF
27
 HFpEF: heart failure with a preserved ejection fraction
Continue…

28. 28
A Randomized Trial of Intensive versus Standard Blood-
Pressure Control : The SPRINT Research Group
Background:
To assess the most appropriate targets for systolic blood pressure to
reduce cardiovascular morbidity and mortality among persons without
diabetes
Method:
• Randomly assigned 9361 persons; SBP 130mm Hg and Above
• Intensive Treatment Arm: SBP target of less than 120 mm Hg
• standard treatment Arm: SBP target of less than 140 mm Hg
Results:
Figure 2. Systolic Blood Pressure in the Two Treatment Groups over the Course of the Trial.

29. 29
SPRINT TRIAL
Conclusions:
• Achieving Target BP goal (<120 mmHg) significantly lower relative
risk of
fatal and nonfatal cardiovascular events and death by 25% as
compared
to standard BP goal of less than 140 mm Hg.
The intensive-treatment group (less than 120 mmHg) had lower rates
of
• Heart failure (38% lower relative risk),
• Death from cardiovascular causes (43% lower relative risk)
• Death from any cause (27% lower relative risk)
N Engl j med 373;22 nejm.org November 26, 2015

30. AZILSARTAN IN RENAL IMPAIRMENT
 Pharmacokinetics of Azilsartan 40 mg in 24 subjects with mild, moderate, or
severe renal impairment or end stage renal disease requiring hemodialysis
was studied
 Renal impairment had no clinically meaningful effect on the plasma protein
binding of Azilsartan.
 Single doses of Azilsartan 40 mg were well tolerated in all subject groups
 No dose adjustment of Azilsartan is required for subjects with any
degree of renal impairment, including end stage renal disease
30
 Clin Pharmacokinet. 2013 May;52(5):34758

31. AZILSARTAN OFFERS CARDIOPROTECTION*
 Plasminogen activator inhibitor-1 (PAI-1) is a protein
present in humans.
 Elevated PAI-1 is a risk factor for thrombosis and
atherosclerosis.
 Azilsartan reduce the expression of PAI-1 in aortic
wall, thereby offers cardioprotection
31
 Integrated Blood Pressure Control 2012:5
* Preclinical Data

32. IMPROVES METABOLIC PROFILE*
 Activates PPAR gamma
 More potent in improving insulin sensitivity and
reducing proteinuria than olmesartan
 Improves insulin sensitivity better than candesartan
32
 JAPI • july 2013 • VOL. 61
• Experimental studies, PPAR gamma: Peroxisome proliferator-activated
receptor gamma

33. DOSAGE – SPECIAL POPULATIONS
Type of patients Recommendation
Elderly patients No initial dose adjustment is
required
Mild to severe renal
disease, end stage
renal disease
No initial dose adjustment is
required
Mild to severe hepatic
dysfunction
No initial dose adjustment is
required
Severe hepatic
impairment
No data available
33

34. ADVERSE EFFECTS
 Azilsartan is well-tolerated with an overall incidence of
adverse reactions similar to placebo
 The most common adverse reaction in adults was diarrhea
 Small reversible increases in serum creatinine are seen in
patients receiving 80 mg Azilsartan
 Patients (>75 years of age) with moderate to severe renal
impairment are more likely to report abnormally high serum
creatinine values
34

35. SALIENT FEATURES
Azilsartan:
 Is superior than other sartans including telmisartan,
olmesartan, valsartan, and candesartan.
 has a significantly stronger hypotensive effect than other
ARBs including telmisartan, losartan, olmesartan in
hemodilysis patients
 Azilsartan can be Initial choice of ARB for intensive BP
lowering efficacy in all HTN including both young, elderly
with any degree of renal dysfunction
35

36. SALIENT FEATURES
 Dissociates from AT1 receptors more slowly than other ARBs
including olmesartan, telmisartan, and valsartan
 Has highest selectivity to AT1 receptors compared to other ARBs
 Offers greater reduction in 24 h BP as compared to other ARBs
 Approx. 2 to 26 time more potent than telmisartan
 Approx. 3 to 33 time more potent than telmisartan
 Exhibits superior bioavailability compared to telmisartan 40 mg
and omlesartan 40 mg
36

37. SALIENT FEATURES
 Azilsartan’s ability to bind tightly with At1 receptors for
extended period of time seems to offer BP protection in
patients who miss scheduled drug doses
 Appears to an effective treatment option for salt sensitive
hypertensive patients
 Superior to any ACE inhibitor in terms of BP goal
achievement
 Safety profile is comparable with other ARBs
37

38. 38
For the treatment of:
• Hypertension either alone or in combination with other antihypertensive
agents
• Hypertension associated with diabetes
• Hypertension associated with renal impairment
• Hypertension associated with CHF
Dosage:
• Recommended dose is 40 mg once daily
• Can be increased up to 80 mg
• When used with diuretic prefer 40 mg dose
Azilsartan medoxomil 40mg/80mg Tablets

39. THANK YOU
39